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Stereotactic radiosurgery (SRS) is a valuable treatment option for uveal melanoma, offering excellent tumour control rates and eye preservation. Its efficacy relies upon accurate localisation of the tumour, which is challenging in the mobile eye. Various methods of globe immobilisation have been used, including non-invasive devices, such as eye movement tracking and suction cups, but common practice is to use local anaesthetic block with or without transconjunctival suturing of the extraocular muscles. Some studies have suggested that the addition of muscle suturing to local anaesthetic block provides better immobilisation of the globe, when compared to anaesthetic block alone. Controversy exists regarding the clinical relevance of this observation and ocular oncologists differ in their choice of immobilisation technique. In order to establish if the addition of muscle suturing to local anaesthetic block improves clinical outcomes, we performed a retrospective review of all cases that underwent SRS for uveal melanoma over a 10-year period (May 2008 to May 2018). Based on surgeon preference, all patients received either local anaesthetic block plus muscle suturing (Group A) or local anaesthetic block alone (Group B) to induce globe akinesia. Outcomes assessed were primary treatment failure, tumour recurrence, secondary enucleation and death rate. In our cohort of 290 eyes; 118 patients were in group A and 172 patients were in group B. There were no cases of primary treatment failure in either group. With a minimum of 24 months follow-up, only 3 patients experienced tumour recurrence (1 in group A and 2 in group B). There was no significant difference in recurrence, enucleation and all-cause death rates between the two groups. Our retrospective review suggests that although extraocular muscle suturing may be considered by some units to provide superior globe immobilisation for SRS, it does not alter the clinical outcome. [ABSTRACT FROM AUTHOR]

Background/Aims A retrospective service evaluation identified seven patients who developed local conjunctival metastases (LCMs) of the conjunctiva after a primary diagnosis of conjunctival invasive melanoma. The study was conducted to identify the clinicopathological characteristics and implications of these LCMs. Methods Seven patients with primary conjunctival melanoma seen by the ocular oncology service were identified as having also developed LCMs. The clinical history, histopathology, tumour biology, prognostic and staging implications of LCMs were evaluated. Results A total of 15 primary conjunctival melanomas and 19 LCMs were identified. The LCM developed 8-102 months after the first primary melanoma and, in three patients, non-conjunctival metastases developed 8-37 months after the first LCM. The LCMs showed some distinct histopathological features: they were well defined, were separated from the overlying epithelium by a Grenz zone, and were often multiple and associated with vessels and sometimes lymphocytic aggregates. Some appeared within the confines of the vascular drainage territory of the primary melanoma; others did not confine themselves to this distribution. Conclusions LCMs are local metastases of primary conjunctival melanoma that probably develop by dissemination through the local vessels and then becoming extavascular. Their accurate histopathological recognition is important, as it indicates a higher disease stage-indicating 'N' status within the TNM classification and may be a proxy indicator of the presence of nonconjunctival metastases, thus necessitating highresolution radiological imaging modalities or sentinel node biopsy. LCMs may represent an under-recognised lesion and may have been mistaken for primary 'nodular' conjunctival melanomas in the past. [ABSTRACT FROM AUTHOR]

The article discusses a study on local environmental influences on uveal melanoma. Since local environment can contribute to cancer growth and development, it is probable that the aqueous and vitreous humors have a vital role in regulating uveal melanoma behavior. Key findings indicate that in situ uveal melanoma development is caused by an interaction between the tumor and the environment of the eye.

Uveal melanoma is the most frequent primary malignant intraocular tumor of adults. Among various non-modifiable risk factors, Caucasian race seems to be the most significant with light skin color, blond hair, and blue eyes being specific risk factors. The racial predisposition to uveal melanoma have been explained on the basis of susceptibility of Caucasian race to oncogenic effects of sunlight. Although there is ample evidence in support of this hypothesis in regard to skin melanoma, the evidence in regard to uveal melanoma is insufficient and contradictory. In the following review, we examine physiologic, epidemiological, and genetic data in order to determine the role of sunlight exposure in the pathogenesis of uveal melanoma. [Copyright &y& Elsevier]

A 75-year-old man presented with deterioration of right eye vision for 6 months. He had no relevant medical history. Fundus examination revealed subretinal fluid, fibrosis, and subretinal hemorrhages. Ocular coherence tomography of the right macula illustrated an underlying subretinal lesion with internal lamellae, resembling trabecular bone elsewhere in the body. Bruch's membrane was clearly intact beneath the lesion, indicating an extrachoroidal location. The lesion appeared highly reflective on B-scan ultrasonography, consistent with ossification. Although initially misdiagnosed as choroidal osteoma, this lesion represents in-vivo intraocular osseous metaplasia at the site of neovascular age-related macular degeneration. The authors believe that similar lesions may have been misdiagnosed as "atypical" osteoma caused by failure to identify their extrachoroidal location. [ABSTRACT FROM AUTHOR]

Introduction Mechanical thrombectomy (MT) can improve outcomes following ischaemic stroke. Patient selection for MT is predominantly based on physiological and imaging parameters. We assessed whether people living with pre-stroke frailty had differing outcomes following MT. Methods We included consecutive patients undergoing MT at a UK comprehensive stroke centre. We calculated a cumulative deficits frailty index to identify pre-stroke frailty in those patients presenting directly to the centre. Frailty was defined as an index score ≥ 0.24. We assessed univariable and multivariable association between pre-stroke frailty and stroke outcomes. Our primary outcomes were modified Rankin Scale (mRS) and mortality at 90 days. Results Of 175 patients who underwent MT (2014–2018), we identified frailty in 49 (28%). Frail and non-frail patients had similar rates of thrombolysis administration, successful recanalization and onset to recanalization times. Those with pre-stroke frailty had higher 24 hour National Institutes of Health Stroke Scale (12(IQR: 8–17) versus 3(IQR: 2–13); P  = 0.001); were less likely to be independent (mRS 0–2: 18% versus 61%; P  < 0.001) and more likely to die (47% versus 14%; P  < 0.001) within 90 days. Adjusting for age, baseline NIHSS and thrombolysis, frailty remained a strong, independent predictor of poor clinical outcome at 90 days (Death OR: 3.12 (95% CI: 1.32–7.4); dependency OR: 3.04 (95%CI: 1.10–8.44). Age was no longer a predictor of outcome when adjusted for frailty. Conclusion Pre-stroke frailty is prevalent in real-world patients eligible for MT and is an important predictor of poor outcomes. Routine assessment of pre-stroke frailty could help decision-making around patient selection for MT. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented, that discusses the case of a 47 year old man who presented with peritonitis resulting caused from perforation in the terminal ileum.

To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors. Observational case series. Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas. Hematoxylin–eosin and PAX8 immunohistochemical stains were performed on all specimens. In appropriate cases, bleached preparations and other immunohistochemical stains, including AE1/AE3 cytokeratin, Lin28A, and CD45, were performed. Distribution of PAX8 expression in normal and neoplastic tissue. Strong nuclear PAX8 expression was observed in the normal corneal epithelium, iris sphincter pupillae muscle, iris pigment epithelium and dilator muscle complex, nonpigmented and pigmented epithelia of the ciliary body, lens epithelium, and a subset of retinal neurons. The normal retinal pigment epithelium and uveal melanocytes did not stain for PAX8. The ciliary body epithelial and neuroepithelial tumors (adenoma, adenocarcinoma, and medulloepithelioma) showed uniform strong nuclear PAX8 immunoreactivity. All melanocytic tumors (iris melanoma, ciliary–choroidal melanoma, and melanocytoma) and retinal pigment epithelial neoplasms showed negative results for PAX8. A subset of tumor-associated lymphocytes, most prominent in uveal melanoma, showed positive results for PAX8. The uniformity of the PAX8 staining was superior to the variable cytokeratin staining in the ciliary epithelial neoplasms and the variable Lin28A staining in malignant medulloepithelioma. The veracity of PAX8 staining was equally as robust on cytologic analysis and open-flap biopsy specimens of ciliary epithelial and iris epithelial neoplasms, melanocytoma, and melanoma. PAX8 has proven to be a very useful diagnostic marker in a select group of adult intraocular tumors, and we highly recommend its inclusion in diagnostic antibody panels of morphologically challenging intraocular neoplasms. [ABSTRACT FROM AUTHOR]

Aim To demonstrate a novel surgical technique for the accurate diagnosis of iris lesions using a minimally invasive aspiration cannula. Method 12 consecutive patients underwent biopsy of iris lesions at the Ocular Oncology Service, Royal Hallamshire Hospital, Sheffield, UK. Samples were obtained using a novel technique called trans-corneal fine cannula aspiration. This comprised a 25-gauge, Rycroft cannula aspiration technique performed by a single surgeon and samples transferred into alcohol-based tissue fixative. A specialist ophthalmic histopathologist performed a histological analysis of the samples. Results On average, the size of the specimens obtained in theatre ranged from 1 mm to 1.5 mm (maximum dimensions). This sample size allowed an unequivocal histological diagnosis in all 12 cases. In this study, 10 patients were diagnosed as having iris melanoma, one patient with metastatic adenocarcinoma and one patient with pigmented adenoma. Conclusions This simple iris tumour biopsy technique provides sufficiently large sample sizes to obtain a firm histological diagnosis in 100% of cases performed so far. The sample sizes permitted not only morphological interpretation but also ancillary investigations such as immunohistochemistry. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 34-year old man with toxic optic neuropathy, colour saturation, and visual loss. It notes that the linezolid treatment was prescribed to him. The article discusses the side effects of the linezolid treatment, the dysfunction of the retinal ganglion cells, and the various mitochondrial and protein synthesis activities in humans.

Background: Mechanical thrombectomy has revolutionised the treatment of acute ischaemic stroke due to large vessel occlusion. It is well recognised that patients are more likely to benefit when reperfusion happens quickly, however, there is uncertainty as to how best to deliver this service. Objectives: To compare outcomes of patients in Northern -Ireland who underwent thrombectomy via direct admission to the single endovascular centre (mothership [MS]) with those transferred from primary stroke centres (drip-and-ship [DS]). Methods: Analysis was conducted on the records of all patients who underwent thrombectomy from January 2014 to December 2017 inclusive. The primary outcome measure was 3 months functional independence (modified Rankin Score [mRS] 0–2). Secondary outcome measures were full recovery (mRS 0) at 3 months, symptomatic intracranial haemorrhage (sICH) rates and mortality rates. Results: Two hundred fourteen patients underwent thrombectomy (MS 124, DS 90). Patients in the MS group were older (median 73 vs. 70 years, p = 0.026), but there was no significant difference in baseline National Institutes of Health Stroke Scale (median 15 MS vs. 16.5 DS, p = 0.162) or thrombolysis rates (41.9% MS vs. 54.4% DS, p = 0.070) between the groups. Time from stroke onset to arrival at thrombectomy centre was shorter in the MS group (median 71 vs. 218 min, p < 0.001) but door to groin puncture time was shorter in the DS group (median 30 vs. 60 min, p < 0.001). There was no significant difference in 3 months functional independence (51.6% MS vs. 62.2% DS, p = 0.123), or in the secondary outcome measures of full recovery (21.8% MS vs. 12.2% DS, p = 0.071), sICH (MS 0.8%, DS 4.4%, p = 0.082) and mortality (MS 24.2%, DS 20.0%, p = 0.468). Conclusions: Our analysis showed similar outcomes after thrombectomy in the MS and DS groups. For patients potentially eligible for thrombectomy, rapid access to the endovascular centre is essential to optimise both the number of patients treated and the outcomes achieved. [ABSTRACT FROM AUTHOR]

Purpose Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. Design Multicenter, retrospective case series. Participants Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. Methods Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53 , and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. Main Outcome Measures Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. Results In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11 . Furthermore, 13 of 30 BAP1 , 5 of 30 EIF1AX , and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT , and TP53 were detected in 6 iris melanomas and 4 iris nevi. Conclusions Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Delivering thrombectomy for acute stroke using cardiology services," by A. Apps, S. Firoozan, and T. Kabir in the 2015 issue.

Background/aims Ocular surface squamous neoplasia (OSSN) is a spectrum of disease, on which few large series have been published, none in particular, from the UK. The purpose of this study is to describe experience of this condition from a UK national ocular oncology centre, including statistical analysis to elucidate factors significant in recurrence. Methods Retrospective review of case notes, clinical photographs and histopathology reports. Results 78 cases were included, of which 10 (12.8%) recurred during the follow-up time (mean 37 months). The 1-year recurrence rate was 10.9%, and 5-year recurrence rate was 18.5% using Kaplan-Meier analysis, with a mean time to recurrence of 9.5 months. Significant factors in recurrence were tumour size and first treatment given. Grade of OSSN, including presence of invasive disease and positive biopsy margins were not found to be statistically significant in recurrence. Conclusions OSSN in an uncommon disease in the UK population. However, when managed appropriately in a specialist centre, it is associated with good outcomes, even in recurrence situations. [ABSTRACT FROM AUTHOR]

Objective Intraocular melanocytoma is a rare naevus variant that can be located at the optic disc or within the uvea, and belongs to the group of non-epithelial-associated melanocytic lesions. We wanted to gain an understanding of the role of GNAQ, GNA11 and BRAF V600E in the pathogenesis of uveal melanocytoma and in cases of transformation to uveal melanoma and also to perform a differential immunohistochemical study comparing melanocytoma with uveal melanoma. Methods and results Two patients were identified with melanocytoma, one of which had transformed to melanoma. In the latter case, the melanocytoma exhibited an immunophenotype that featured nuclear p27 and no HMB45 staining, with very low Cyclin D1 expression compared with the melanoma that featured little nuclear but more cytoplasmic p27 positivity, much higher Cyclin D1 expression and HMB45 positivity. The melanocytomas were negative for CD68 allowing distinction from melanophages. Both melanocytomas and the melanoma harboured mutations in GNAQ, with no mutations of GNA11 or BRAF V600E. Conclusions GNAQ mutations are present in uveal melanocytomas and in a case of transformation to melanoma, implicating GNAQ-dependent mitogen activation signals, in the pathogenesis of uveal melanocytoma. This assists in explaining why a proportion of uveal melanocytoma can transform to uveal melanoma, known to harbour high-frequency GNAQ mutations at exon 5, codon 209. [ABSTRACT FROM AUTHOR]

Purpose: To compare long-term cognitive outcomes of patients treated with surgical clipping or endovascular coiling after subarachnoid haemorrhage (SAH). Method: Retrospective matched cohort study assessed neuropsychological functioning at least 12 months after aneurysmal SAH treatment. Fourteen patients treated by endovascular coiling and nine patients treated by surgical clipping participated. After gaining written consent, a comprehensive neuropsychological battery was completed. Standardised tests were employed to assess pre-morbid and current intellectual functioning (IQ), attention, speed of information processing, memory and executive function as well as psychosocial functioning and affect. Results: Treatment groups were not significantly different in terms of age, pre-morbid IQ, time from injury to treatment or time since injury. A significant effect of treatment on full-scale IQ score (p = 0.025), performance IQ (p = 0.045) and verbal IQ score (p = 0.029), all favouring the coiled group was observed. A medium effect size between groups difference in immediate memory (p = 0.19, partial η2 = 0.08) was also observed. No significant between group differences on attention, executive functioning and speed of information processing measures or mood and psychosocial functioning were noted. Both groups reported increased anxiety and memory, attention and speed of information processing deficits relative to normative data. Conclusions: Study findings indicate fewer cognitive deficits following endovascular coiling. Cognitive deficits in the clipped group may be due in part to the invasive nature of neurosurgical clipping. Further prospective research with regard to long-term cognitive and emotional outcomes is warranted. [ABSTRACT FROM AUTHOR]

Purpose To investigate the epidemiology and clinicopathological management for ocular sebaceous carcinoma (OSC) in the UK. Methods Observational prospective cohort study of patients with newly-diagnosed OSC. The British Ophthalmological Surveillance Unit captured incident cases of OSC between 2008 and 2010. Incident and 6-month follow-up questionnaires from reporting ophthalmologists captured OSC demographic and clinical data. Results Data were available on 51 patients with unilateral OSC (response rate 85%). The UK estimated annual incidence was 0.41 cases per million population (95% CI 0.31 to 0.54). Median age was 70 years (SD 14, range 28-98) with 57% women. OSC location was upper lid (54%), lower lid (20%), multicentric (14%) and caruncle (12%). Most common misdiagnoses included chalazion (42%), basal cell carcinoma (30%) and blepharoconjunctivitis (16%), with median delay in diagnosis of 10 months (SD 9, range 0.5-36). Specialist ophthalmic pathologists performed diagnostics in 62%, with pagetoid/intraepithelial spread present in 39%. Misdiagnosis of chalazion (p=0.019) and pagetoid tumour spread ( p=0.016) was associated with a significant diagnostic delay (one-way ANOVA/R2). Primary surgical management involved excision with reconstruction (49%), primary exenteration (10%) and Mohs surgery (8%). There were three deaths (out of 51) during the study period; one patient died of OSC-related disease and the other two due to other causes. Conclusions This population-based prospective study confirms OSC as a rare cancer in the UK. Masquerade syndromes result in significant diagnostic delays and increase the risk of pagetoid tumour spread. There is considerable UK variation in pathological and surgical management, and ocular reconstruction and radical surgery is often required for OSC due to delayed presentation. [ABSTRACT FROM AUTHOR]

Background Even in experienced hands, the classification of some melanocytic lesions of the conjunctiva remains challenging. In skin pathology, the recent application of fluorescence in situ hybridisation (FISH) has been demonstrated to be of use for the analysis and diagnosis of ambiguous melanocytic neoplasms of the skin. This study set out to evaluate this method on seven prospective conjunctival cases that were histologically equivocal. Methods 18 unequivocal retrospective melanocytic controls were exposed to FISH. Commercially available probes assessing copy numbers of RREB1 (6p25), MYB (6q23) and CCND1 (11q13) genes compared with CEP6 (a chromosome six centromeric reference point) were used. After control verification, seven prospective, equivocal cases were identified and exposed to FISH. Results There was complete correlation between FISH result and the control section histopathology report. Control cases of melanoma cases were all positive for FISH and control benign lesions were negative. Of the seven equivocal cases, five were positive and classed as invasive melanoma or melanoma-in situ, one was negative and one tetraploid, classed as negative (these last two cases were classed as naevi with careful clinical observation). Conclusions FISH is very useful in classifying equivocal conjunctival melanocytic lesions, especially those with atypical junctional activity and naevoid melanocytic proliferations of the conjunctiva. [ABSTRACT FROM AUTHOR]

The article presents case study of a 65-year-old male having a visual disturbance in both eyes who was taken to the local ophthalmology department. The clinical notion was that of bilateral diffuse uveal melanocytic proliferation (BDUMP). The patient was examined for systematic malignancy and a hospital autopsy was performed.

Background: We present our experience in treating ocular melanoma at the National Centre for Stereotactic Radiosurgery in Sheffield, UK over the last 20 years. Method: We analysed 170 patients treated with Gamma Knife radiosurgery, recorded the evolution of visual acuity and complication rates, and compared their survival with 620 patients treated with eye enucleation. Different peripheral doses (using the 50% therapeutic isodose) were employed: 50-70 Gy for 24 patients, 45 Gy for 71 patients, 35 Gy for 62 patients. Findings: There was no significant difference in survival between the 35-Gy, 45-Gy and 50- to 70-Gy groups when compared between themselves ( p = 0.168) and with the enucleation group ( p = 0.454). The 5-year survival rates were: 64% for 35 Gy, 62.71% for 45 Gy, 63.6% for 50-70 Gy and 65.2% for enucleated patients. Clinical variables influencing survival for radiosurgery patients were tumour volume ( p = 0.014) and location (median 66.4 vs 37.36 months for juxtapapillary vs peripheral tumours, respectively; p = 0.001), while age and gender did not prove significant. Regarding complications, using 35 Gy led to more than a 50% decrease, when compared with the 45-Gy dose, in the incidence of cataract, glaucoma and retinal detachment. Retinopathy, optic neuropathy and vitreous haemorrhage were not significantly influenced. Blindness decreased dramatically from 83.7% for 45 Gy to 31.4% for 35 Gy ( p = 0.006), as well as post-radiosurgery enucleation: 23.9% for 45 Gy vs 6.45% for 35 Gy ( p = 0.018). Visual acuity, recorded up to 5 years post-radiosurgery, was significantly better preserved for 35 Gy than for 45 Gy ( p = 0.0003). Conclusions: Using 35 Gy led to a dramatic decrease in complications, vision loss and salvage enucleation, while not compromising patient survival. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the possible causes of tumour latency in uveal melanoma primarily through the analysis of micro metastases in tissue obtained from donors postmortem. Various explanations have been proposed but there is no clear answer from animal studies and few human data. The main hypotheses may be divided into several areasdimmunological control of metastatic cells, lack of angiogenesis within micro metastases and reduced cell turnover. Methods: 196 patients were recruited to the study between 2003 and 2007. Patients were invited to take part and their relatives agreed to postmortem examination of their liver and lungs in the event of their death, including tissue sampling to assess the presence of micro metastases and their biology. Metastatic cells were detected by immunohistochemistry using a pan-melanoma antibody reagent, and by quantitative reverse transcriptase (qRT)ePCR for three melanoma-associated genes (tyrosinase Melan-A, and gp100) and a housekeeping gene (HMBS/PBGD) in samples stored in RNAlater or as formalin-fixed paraffin-embedded tissue. Results: 22 deaths were investigated at autopsy as part of the study. Sixteen patients died with large deposits of metastatic melanoma, while six patients died of other causes. In addition, a liver resection for hepatic adenoma provided further tissue from a case without clinical evidence of metastasis. Metastatic melanoma cells were identified by immunohistochemistry of the liver samples in one case and by qRTePCR in two further cases without macrometastases. There was no evidence of multicellular micrometastases sufficiently large to require angiogenesis and no associated inflammation was observed. Conclusion: The most likely explanation for latency in this setting is the inability of uveal melanoma cells in metastatic sites to grow. [ABSTRACT FROM AUTHOR]

Aim: In an effort to identify patients with uveal melanoma at high risk of metastasis, the authors undertook correlation of gene expression profiles with histopathology data and tumour-related mortality. Methods: The RNA was isolated from 27 samples of uveal melanoma from patients who had consented to undergo enucleation, and transcripts profiled using a cDNA array comprised of sequence-verified cDNA clones representing approximately 4000 genes implicated in cancer development. Two multivariate data mining techniques-hierarchical cluster analysis and multidimensional scaling-were used to investigate the grouping structure in the gene expression data. Cluster analysis was performed with a subset of 10 000 randomly selected genes and the cumulative contribution of all the genes in making the correct grouping was recorded. Results: Hierarchical cluster analysis and multidimensional scaling revealed two distinct classes. When correlated with the data on metastasis, the two molecular classes corresponded very well to the survival data for the 27 patients. Thirty two discrete genes (corresponding to 44 probe sets) that correctly defined the molecular classes were selected. A single gene (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin) could classify the molecular types. The expression pattern was confirmed using real-time quantitative PCR. Conclusions: Gene expression profiling identifies two distinct prognostic classes of uveal melanoma. Underexpression of autotaxin in class 2 uveal melanoma with a poor prognosis needs to be explored further. [ABSTRACT FROM AUTHOR]

Abstract: Uveal melanomas are the commonest ocular tumour of adults and are characterized by reproducible alterations of chromosomes 1, 3, 6 and 8. These alterations are of prognostic relevance and have also be shown to correlate to high risk and low risk metastatic categories of uveal melanoma as defined by micro-array analysis. It is, however, possible that a catalogue of relevant genetic alterations, involving gene rearrangement rather than amplification, have as yet eluded identification. To address this point we examined 14 primary uveal melanomas, using 24 colour multiplex fluorescence in situ hybridization (M-FISH). All tumours were karyotyped following G-Banding, and M-FISH was performed to confirm and clarify the identity of abnormal chromosomes. M-FISH data were obtained from all tumours and was able to establish the nature of most abnormalities not fully characterized by cytogenetics. Abnormalities of chromosome 6 were far more frequent than previously indicated, in approximately 70% of cases, indicating they have been substantially underrepresented in past studies of uveal melanoma. Spindle melanomas were found to have novel rearrangements affecting in particular chromosomes 6, 15 and 18, suggesting that juxtaposition of genes through translocational events may play a role in the development of some uveal melanomas. In conclusion, this study is the largest of primary uveal melanoma analysed by M-FISH and indicates that alterations of chromosome 6 have previously been underestimated. Furthermore spindle melanomas are prone to rearrangements affecting chromosomes 6, 15 and 18, which may relate to early changes in uveal melanoma development or associate with those melanomas of a more differentiated status. [Copyright &y& Elsevier]

Purpose: To evaluate clinical features at presentation of small choroidal melanocytic lesions that were predictive of growth. Design: Retrospective observational case series. Participants: A cohort of 240 patients with a presumptive diagnosis of small choroidal melanocytic lesions who were observed to document growth before treatment. Methods: Data regarding size, location, diagnostic features, and growth were collected. To evaluate the diagnostic features at presentation, Barnard and Fisher exact tests were performed for categorical variables, and the Wilcoxon rank sum test was used for continuous factors. Main Outcome Measure: Documented growth. Results: Eleven patients with small choroidal melanocytic lesions (4.6%) demonstrated growth within 50 months of follow-up. Lesions that demonstrated growth were significantly thicker (≥2.0 mm; P<0.001) and closer to the foveola (<3.0 mm; P = 0.002). Significant increases in the risk of growth also were observed for gender (male), presence of symptoms, and orange pigment. Conclusions: Significant clinical features of small choroidal melanocytic lesions predictive of growth are greater thickness (≥2.0 mm), location closer to the foveola (<3.0 mm), and presence of symptoms and orange pigment. [Copyright &y& Elsevier]

Although variation in the level of macrophage infiltration has been reported in uveal melanoma, little is known about the expression of other leucocyte markers. An immunohistochemistry study of the levels of expression of macrophage and other leucocyte markers, in a series of 10 primary choroidal melanoma biopsies, was undertaken. Biopsies were either fixed immediately in formalin and embedded in paraffin wax or established as short-term cultures. Using single- and double-labelling immunohistochemistry, cultured cells and paraffin sections were analysed for a range of melanoma (HMB45, Melan A, S100 and tyrosinase) and immune cell (CD68, CD163, CD45 and CD1a) markers. All samples expressed at least two known melanoma markers. Infiltrating macrophages were present in the majority of sections. When cultured specimens were studied by double-labelling immunofluorescence, uveal melanoma cells were seen to express macrophage markers or have cross-reactivity with related proteins. Expression of the leucocyte antigen CD45 was observed in three tumours but was not present in any cultured cells, whilst the expression of the dendritic cell marker CD1a was absent from all samples. [ABSTRACT FROM AUTHOR]

Iris melanomas are less likely to metastasize than posterior compartment melanomas. The anterior chamber of the eye is an immunosuppressed microenvironment where a wide range of immunosuppressive factors in aqueous humor contribute to the immune privilege. One such factor is α-melanocyte-stimulating hormone, a potent anti-inflammatory neuropeptide that exhibits efficacy in many studies of acute and chronic inflammation. The aim of this study was to investigate whether the different metastatic behavior of iris melanomas versus posterior compartment melanomas might be explained by the differing immunosuppressive/anti-inflammatory environments of these tumors in vivo . To investigate this hypothesis, we studied the effect of human aqueous and vitreous fluids, of the proinflammatory cytokine tumor necrosis factor α, and of the anti-inflammatory peptides α-melanocyte-stimulating hormone and melanocyte-stimulating hormone 11–13 (KP-D-V) on the invasion of three human uveal melanoma cell lines through human fibronectin. Fresh aqueous humor samples significantly decreased the invasion in two out of three uveal melanoma cell lines. In contrast, vitreous humor did not reduce invasion. Tumor necrosis factor α significantly increased the invasiveness of uveal melanoma cell lines by approximately 50%–80% over 20 h. Full-length α-melanocyte-stimulating hormone, at concentrations present in the aqueous humor (10-9 M), as well as melanocyte-stimulating hormone 11–13 (KP-D-V) reduced the invasion of cells through human fibronectin by 45%–50% and also protected uveal melanoma cells from the pro-invasive actions of tumor necrosis factor α. These data are consistent with inflammation playing a major role in affecting the metastatic ability of uveal melanomas. Thus, ocular microenvironments that differ in their immunosuppressive/anti-inflammatory properties may influence the invasiveness of developing tumors. [ABSTRACT FROM AUTHOR]

α-Melanocyte-stimulating hormone is produced by several different cell types including neural cells, endothelial cells, monocytes, and keratinocytes. A biologic role in melanocyte pigmentation is widely recognized, but more recent studies describe a part in modulating inflammatory and immune responses. The aim of the this study was to investigate the mechanism by which α-melanocyte-stimulating hormone antagonizes proinflammatory cytokine action. We report that α-melanocyte-stimulating hormone (10–9 M) was effective in opposing a tumor necrosis factor-α stimulated increase in NF-κB DNA binding activity in: (i) normal ocular melanocytes; (ii) cells cultured from ocular melanoma tumors; and (iii) two cutaneous melanoma cell lines. NF-κB is activated by many inflammatory mediators and controls transcription of genes required for immune and inflammatory responses. The transcription factor complex was positively identified as the p50/p65 heterodimer, recognized to have transcriptional activating potential. Maximum reduction of NF-κB DNA binding activity with α-melanocyte-stimulating hormone was detected 2 h after cellular stimulation and varied from between 53% and 18% depending on cell type. Whereas the acute inhibitory effects could be mimicked by elevating cyclic adenosine monophosphate, α-melanocyte-stimulating hormone was not found to have any effect on the relative level of IκBα protein expression over 24 h. These data show that α-melanocyte-stimulating hormone has a pronounced effect on NF-κB activity in melanocytes and melanoma cells, identifying a specific dimeric complex, and suggest this to be a key pathway by which immunomodulation/anti-inflammation may operate. The results may also be considered in the broader context of general inflammatory pathologies concerning cells which express α-melanocyte-stimulating hormone receptors and utilize the NF-κB... [ABSTRACT FROM AUTHOR]

We describe a case of primary hypertensive iridocyclitis with biopsy-proven Cytomegaloviral retinitis. It is an observational case report of a 69-year-old diabetic gentleman on azathioprine for Crohn's disease who presented with recurrent episodes of hypertensive iridocyclitis. On the 4 th attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid-peripheral fundus and a chorioretinal and vitreous biopsy performed. Vitreous PCR was positive for Cytomegalovirus (CMV). Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles and immunohistochemistry demonstrated CMV protein. This case provides further evidence implicating CMV infection in the etiology of hypertensive iridocyclitis. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis. [ABSTRACT FROM AUTHOR]

A 67-year-old former gold miner with rheumatoid arthritis, treated with steroids and methotrexate, presented to eye casualty with a painful right eye. Examination revealed an anterior uveitis and despite an initial response to topical steroids, the intraocular inflammation worsened with anterior and posterior uveitis development. Re-examination showed a white mass in the peripheral nasal retina initially suspected of being active Toxoplasmosis infection and anti-toxoplasmosis treatment commenced. After improvement and tapering of this treatment, the intraocular inflammation reoccurred. Cytopathological examination of a pars plana vitrectomy obtained vitreous sample that showed a non-diagnostic non-infectious chronic vitritis. The vitreoretinal surgeons elected to do a direct biopsy of the white subretinal mass in the peripheral nasal area. This revealed, quite unexpectedly, an abscess containing pigmented phaeohyphomycosis fungi. This case report documents the multidisciplinary approach that assisted in clinching a final diagnosis and the role of sub-retinal biopsy in this unprecedented scenario. [ABSTRACT FROM AUTHOR]

The middle meningeal artery (MMA) is the most proximal and largest branch of the internal maxillary artery (IMA). It courses superiorly to the foramen spinosum making a sharp right angle bend entering the skull. The MMA has frontal, parietal and petrosal branches, the frontal branch being identified by its anterior convex curve along the greater wing of sphenoid. Trauma and a resultant extradural haematoma (EDH) demands urgent neurosurgical intervention to prevent imminent foramen magnum herniation and rapid demise. The seriousness of EDHs cannot be overstated and is a clear neurosurgical emergency requiring immediate definitive management. Historically craniotomy is the gold standard. But recent advances propose angiography and subsequent embolization as an alternative to craniotomy. We employed embolization to manage EDHs in two cases whose original clinical presentation did not demand urgent surgery. We discuss their subsequent management focusing on treatment choices and the potential role of endovascular techniques. We describe an alternative diagnostic protocol and embolic agents using Onyx and coils. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a case study of a 41-year-old women with a slow-growing iris lesion.

Uveal melanoma (UM) is the most common primary intraocular tumour in adults, with a mean survival of six months following metastasis. The survival rates have not improved in over 30 years. This study has shown that sister chromatid exchange (SCE) is low in UM which is likely due to a reduced expression of FANCD2. As FANCD2 can function to suppress non-homologous end joining (NHEJ), this study therefore investigated NHEJ in UM. The activation of the catalytic subunit of the NHEJ pathway protein DNA-dependent protein kinase (DNA-PK) was measured by analysing the foci formation and the ligation efficiency by NHEJ determined using a plasmid-based end-joining assay. Using small-interfering RNA (siRNA) knock-down, and chemical inhibitors of DNA-PK, the survival of primary UM cultures and two cell lines were determined. To assess the homologous recombination capacity in response to the inhibition of DNA-PK, a SCE analysis was performed. In addition, to support the findings, the messenger RNA (mRNA) expression of genes associated with NHEJ was analysed using the Cancer Genome Atlas (TCGA)-UM RNAseq data (n = 79). The NHEJ activity and DNA-PKcs activation was upregulated in UM and the inhibition of DNA-PK selectively induced apoptosis and sensitized to ionising radiation and inter-strand cross-linking agents. The inhibition of the NHEJ protein DNA-PK is lethal to UM, indicating a potentially effective therapeutic option, either alone or as a sensitizer for other treatments. [ABSTRACT FROM AUTHOR]

Summary Uveal melanoma is a rare malignancy with a poor prognosis despite current therapeutic intervention. The current investigation focuses on the immunogenicity of uveal melanoma cells genetically modified with recombinant adenovirus encoding CD80 (AdCD80) in contrast to their parental counterpart. We demonstrate that costimulation provided by uveal melanoma cells improved immune responses in vitro as determined by mixed lymphocyte tumour cell cultures and cytotoxic T-cell assays using lymphocytes from healthy donors and uveal melanoma patients. Flow cytometry revealed T-cell stimulation by activated CD4+ and CD8+ T cells. Additionally, autologous lymphocytes proliferated in response to CD80-expressing primary uveal melanomas, indicating that this patient group is suitable for immunotherapy. Moreover, this study utilized AdCD80 modified and parental apoptotic tumour cells, loaded onto immature dendritic cells, as a source of tumour antigen. The ability of live or apoptotic tumour cells to stimulate lymphocyte proliferation and activation was determined. Apoptotic uveal melanoma cells expressing CD80 were efficient at inducing an immune response and served as a potent immunogen. The use of apoptotic uveal melanoma cells in combination with expression of costimulatory molecules could prove a novel adjuvant therapy for the treatment of this disease. [ABSTRACT FROM AUTHOR]