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Alternatives to fine-needle aspiration biopsy include vitreous cutter aspiration biopsy, incisional biopsy, and excisional biopsy. Vitreous cutter aspiration biopsy is performed with a 25- or 27-gauge vitreous cutter using a three-port, sutureless vitrectomy kit, without vitrectomy, retinopexy, or tamponade. Incisional biopsy of choroidal or ciliary body melanomas can be performed with Essen forceps through a deep sclerotomy under a superficial lamellar scleral flap, using tissue glue to close the flap and seal the wound, thereby preventing seeding of tumor cells into surrounding tissues. Excisional biopsy involves removal of the entire tumor, using techniques described elsewhere. Biopsy can be performed to establish a diagnosis (e.g., to differentiate melanoma from nevus or metastasis), or to identify the likely source of a metastasis, when the primary tumor is unknown, or to estimate the survival probability of a patient with uveal melanoma, by performing genetic tumor typing. Close collaboration with the laboratory is essential.

The orbit can harbor mass lesions of various cellular origins. The symptoms vary considerably according to the nature, location, and extent of the disease and include common signs of proptosis, globe displacement, eyelid swelling, and restricted eye motility. Although radiological imaging tools are improving, with each imaging pattern having its own differential diagnosis, orbital mass lesions often pose a diagnostic challenge. To provide an accurate, specific, and sufficiently comprehensive diagnosis, to optimize clinical management and estimate prognosis, pathological examination of a tissue biopsy is essential. Diagnostic orbital tissue biopsy is obtained through a minimally invasive orbitotomy procedure or, in selected cases, fine needle aspiration. The outcome of successful biopsy, however, is centered on its representativeness, processing, and interpretation. Owing to the often small volume of the orbital biopsies, artifacts in the specimens should be limited by careful peroperative tissue handling, fixation, processing, and storage. Some orbital lesions can be characterized on the basis of cytomorphology alone, whereas others need ancillary molecular testing to render the most reliable diagnosis of therapeutic, prognostic, and predictive value. Herein, we review the diagnostic algorithm for orbital mass lesions, using clinical, radiological, and pathological recommendations, and discuss the methods and potential pitfalls in orbital tissue biopsy acquisition and analysis.

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

BACKGROUND/AIMS: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death. METHODS: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure. RESULTS: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance. CONCLUSIONS: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment.

PURPOSE Nestin, a member of the intermediate filament protein family, has been described as a putative cancer stem cell marker (CSC) in uveal melanoma and poor prognostic factor in a variety of tumours, including cutaneous melanoma. In this study, we examined the expression of nestin in primary (PUM) and metastatic uveal melanoma (MUM) samples, and correlated the findings with histological, clinical and survival data. METHODS Nestin expression was assessed by immunohistochemistry in 141 PUM and 26 MUM samples; 11 PUM cases were matched with their corresponding metastases. The percentage of tumour cells expressing nestin was scored by three independent observers. Statistical analysis of all data was performed with SPSS. RESULTS Nestin expression was identified in both the cytoplasm and membrane of UM cells. Increased expression of nestin in PUM samples was associated with known poor prognostic parameters, including epithelioid cell morphology (p

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.

Uveal melanoma is a highly aggressive cancer of the eye, in which nearly 50% of the patients die from metastasis. It is the most common type of primary eye cancer in adults. Chromosome and mutation status have been shown to correlate with the disease-free survival. Loss of chromosome 3 and inactivating mutations in BAP1, which is located on chromosome 3, are strongly associated with ‘high-risk’ tumors that metastasize early. Other genes often involved in uveal melanoma are SF3B1 and EIF1AX, which are found to be mutated in intermediate- and low-risk tumors, respectively. To obtain genetic information of all genes in one test, we developed a targeted sequencing method that can detect mutations in uveal melanoma genes and chromosomal anomalies in chromosome 1, 3, and 8. With as little as 10 ng DNA, we obtained enough coverage on all genes to detect mutations, such as substitutions, deletions, and insertions. These results were validated with Sanger sequencing in 28 samples. In >90% of the cases, the BAP1 mutation status corresponded to the BAP1 immunohistochemistry. The results obtained in the Ion Torrent single-nucleotide polymorphism assay were confirmed with several other techniques, such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and Illumina SNP array. By validating our assay in 27 formalin-fixed paraffin-embedded and 43 fresh uveal melanomas, we show that mutations and chromosome status can reliably be obtained using targeted next-generation sequencing. Implementing this technique as a diagnostic pathology application for uveal melanoma will allow prediction of the patients’ metastatic risk and potentially assess eligibility for new therapies.

Adult-onset xanthogranuloma (AOX) of the corneoscleral limbus is a rare inflammatory condition of unknown aetiology. Similar to limbal juvenile xanthogranuloma (JXG), it presents as a growing mass at the corneoscleral junction. Limbal AOX and JXG can lead to sight-threatening complications if not managed in a timely manner. This systematic review summarises the main clinical and histopathological features of limbal AOX/JXG and discusses the management of this uncommon disease. We performed a literature search in the MEDLINE database for all historical entries, using the search terms “limbus”, “limbal” and “xanthogranuloma”, and retrieved all articles reporting on limbal xanthogranuloma. After refining the search to articles relevant to limbal AOX, we were able to identify ten adult cases of limbal AOX and compare those with all reported cases of limbal JXG. Clinically, AOX usually presents as an isolated smooth, yellowish, dome-shaped nodule at the corneoscleral junction, similar to an ocular presentation of JXG, with which it also shares similar histopathological features. Limbal JXG and AOX may represent the same disease entity. Diagnosis relies on the clinical presentation, pathology and immunohistochemical profile. Spontaneous regression is unlikely, and thus prompt surgical intervention should be considered to prevent sight-threatening complications. Xanthogranuloma should be included in the differential diagnosis of corneoscleral limbal masses in patients of all age groups.

Hintergrund: Eine therapieresistente Uveitis, gerade mit unklarer Genese, stellt eine diagnostische Herausforderung für den Augenarzt dar. Eine Karzinommetastasierung in die Vorderkammer oder den Glaskörper als Ursache darf in diesem Zusammenhang als absolute Rarität angesehen werden.[zum vollständigen Text gelangen Sie über die oben angegebene URL], 178. Versammlung des Vereins Rheinisch-Westfälischer Augenärzte

The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

Purpose of the Study: To describe the clinicopathological features, mutational and chromosomal copy number analysis, and 8-year follow-up of a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with clear-cell carcinoma of the endometrium. Methods: Histological evaluation, multiplex ligation-dependent probe amplification (MLPA) analysis and GNAQ/11 mutational analysis were performed in a 67-year-old female patient with the diagnosis of BDUMP. Results: Histological evaluation revealed proliferation of bland spindle cells, diffusely replacing the uveal tract, which showed a proliferation index of less than 1%. There was absence of mutations involving the codon 209 and 183 of GNAQ, and of GNA11. MLPA analysis showed disomy 3 with polysomy 8q for both eyes. The patient died 8 years later of an unrelated condition. Conclusions: Although BDUMP is considered to be a benign proliferative disease, copy number alterations of unknown significance may occur in these lesions.

Conjunctival lymphomas constitute 25% of all ocular adnexal lymphomas. The majority are B-cell non-Hodgkin lymphomas (NHLs) (98%), whereas conjunctival T-cell NHLs are rare (2%). The most frequent subtype of conjunctival B-cell lymphoma is extranodal marginal zone lymphoma (EMZL; 81%), followed by follicular lymphoma (8%), diffuse large B-cell lymphoma (3%), and mantle cell lymphoma (3%). Extranodal marginal zone lymphoma occurs slightly more often in women and, along with follicular lymphoma, presents late in the seventh decade of life, whereas diffuse large B-cell lymphoma and especially mantle cell lymphoma have a predilection for the male gender and typically present in the eighth decade. Extranodal marginal zone lymphoma and follicular lymphoma present most frequently in the forniceal and bulbar conjunctiva. Conjunctival diffuse large B-cell lymphoma, mantle cell lymphoma and T-cell NHLs are characterized by a short duration of symptoms before the first ophthalmologic consultation. External beam radiotherapy is the treatment of choice for extranodal marginal zone lymphoma and follicular lymphoma, whereas diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell NHLs are mainly treated with chemotherapy. Conjunctival T-cell NHLs are associated with a particularly poor prognosis, with 50% of patients having progression or recurrence during a 1-year follow-up period.

Background/aim The study9s aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies with those results obtained from subsequent endoresection/enucleation of the same CM. Methods A retrospective cohort of 28 patients with CM seen between 2007 and 2014 at the Liverpool Ocular Oncology Centre was analysed. Prognostic genetic testing, for chromosome 3 status, was performed on all tumour specimens, either by MLPA or MSA, depending on DNA yield. In nine cases genetic testing was performed on a sample taken after radiotherapy; four of these had genetic information pre- and post-radiotherapy. Results Fourteen biopsy specimens were analysed by MLPA and 14 by MSA. Twenty-seven endoresection or enucleation specimens were analysed by MLPA, and a single enucleation specimen by MSA. Chromosome 3 data showed prognostic concordance for the patient-matched samples in all 28 cases including 4 cases where samples were taken pre pre- and post radiotherapy. Thirteen cases were classified as monosomy 3 and 12 as disomy 3. Two cases had a loss of chromosome arm 3q in both samples and a single case showed loss of 3p in the biopsy sample with complete monosomy 3 in the subsequent enucleation sample taken 5 months later. Conclusions Intraocular biopsy of CM yields similar prognostic information to larger surgical specimens. Initial evidence, that genetic testing can be successfully conducted post radiotherapy, is also provided. Trial registration number NITRO trial, ISRCTN35236442.

Vitreoretinal diffuse large B-cell lymphoma is a rare disorder, occurring as primary ocular disease or as secondary involvement by primary central nervous system lymphoma. It is usually diagnosed by cytologic, immunocytochemical, and molecular examination of vitreous aspirates. However, distinguishing vitreoretinal diffuse large B-cell lymphoma from uveitis remains difficult, and clonality analysis may be either unsuccessful or misleading. Diffuse large B-cell lymphoma arising in immune-privileged sites (eg, the central nervous system) shows a high frequency of MYD88 mutations. Therefore, we retrospectively assessed the frequency of MYD88 mutations in vitreoretinal lymphoma (VRL) and their diagnostic potential in 75 vitrectomy samples of 69 patients, and validated our results in a separate cohort (n = 21). MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma. MYD88 mutations, especially L265P, are very frequent in VRL and their detection significantly improves the diagnostic yield of vitrectomy specimens.

Primary vitreoretinal lymphoma (PVRL) is the most common intraocular lymphoma. It is a high grade malignant B‑cell lymphoma, which is thought to arise in the retina. It often infiltrates the central nervous system (CNS) and is therefore associated with a poor prognosis. The PVRL must be differentiated from other forms of intraocular lymphoma, such as the low-grade B‑cell lymphoma that rarely arises in the choroid. The choroidal lymphomas do not spread to the brain, they can be treated with low-dose external beam radiotherapy and the patients have a good prognosis. Since PVRL is a relatively rare tumor, there is little information with respect to its true incidence, to any geographical or ethnic variability and to the main risk factors apart from an association with immunosuppression, as a result of HIV or Epstein-Barr virus infections. The treatment of PVRL is very variable between oncology centres and is also dependent on the unilaterality or bilaterality of disease and whether there is any concomitant CNS involvement. Further studies and research projects in this field are necessary in order to diagnose PVRL at an early stage and to develop new targeted individualized treatment.

Melanoma is the most common type of primary cancer to affect the adult eye. Approximately 95% of ocular melanomas are intraocular and arise from the uvea (i.e. iris, ciliary body, and choroid), while the remaining 5% are located in the conjunctiva. Although both uveal and conjunctival melanomas are derived from melanocytes, uveal melanoma is clinically and biologically distinct from conjunctival melanoma, and indeed from its more common cutaneous counterpart. Intense efforts have been recently made to understand the molecular pathobiology involved in the development of ocular melanomas, and in their progression. Molecular advances, particularly for uveal melanoma, have enhanced prognostication and the identification of rational therapeutic targets for disseminated disease. In this review, recent advances in the molecular characterization of both uveal and conjunctival melanomas are discussed, and how these may be used to develop personalized therapeutic strategies.

Background: Lymphomas of the lacrimal sac are rare, accounting for less than 10% of lacrimal sac malignant tumours. They may present with symptoms typical of secondary acquired nasolacrimal duct obstruction and are thus often misdiagnosed. Methods: Case series and literature review. Results: Herein we describe 3 cases of chronic lymphocytic leukaemia (CLL)/small-cell lymphocytic lymphoma (SLL) of the lacrimal sac with immunohistochemical and in 1 case molecular confirmation. Conclusion: Lymphomas of the lacrimal sac should be suspected in patients with known CLL presenting with epiphora and dacryocystitis. During dacryocystorhinostomy, an incisional biopsy of the lacrimal sac is essential for confirming CLL/SLL involvement and may guide treatment.

Purpose Nestin, a member of the intermediate filament protein family, has been described as a putative cancer stem cell marker (CSC) in a variety of tumours. In particular, increased Nestin expression is associated with an aggressive and primitive tumour phenotype as well as a poor prognosis in cutaneous melanoma. In this study, we examined the expression of nestin in primary (PUM) and metastatic uveal melanoma (MUM) samples, and correlated the findings with histological, clinical and survival data. Methods Nestin expression was assessed by immunohistochemistry in 141 PUM and 26 MUM samples; 11 of the PUM cases were matched with their corresponding metastases. The percentage of tumour cells staining positively for nestin was scored by three independent observers. Statistical analysis of all data was performed with SPSS Results Increased levels of nestin in PUM samples were associated with known poor prognostic parameters, including epithelioid cells (p

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

A young man presented with rapid, predominantly right-sided visual loss with a background of multifocal skin lesions. Visual acuity was right hand movements, left 6/5 Snellen, deteriorating to 6/38. He showed panuveitis with bilateral multifocal retinal infiltrates and retinal vasculitis. Multifocal brain lesions were identified. Biopsy of both skin and vitreous showed atypical lymphocytes, and immunohistochemistry confirmed T-cell lymphoma of gamma-delta subtype. Management with the CODOX-M/IVAC polychemotherapy regimen achieved rapid response including resolution of intraocular changes and substantial improvement of visual acuity to right 6/7.5, left 6/6. However, he relapsed before planned stem cell transplantation. Salvage with the gemcitabine/dexamethasone/cisplatin regimen, although temporarily effective, was followed by further relapse including widespread brain involvement, and he succumbed 10 months after presentation.

Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell‐based models. The poor overall response of UM cells to FDA‐approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1‐dependent kinase subnetwork in JQ1‐exposed cells that contained multiple cell cycle‐regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome‐wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients.

To the editor: Primary vitreoretinal lymphoma (PVRL) is often associated with primary central nervous system lymphoma (PCNSL) and is a rare high-grade diffuse large-cell B-cell lymphoma occurring within the vitreous and/or retina.[1][1][⇓][2]-[3][3] Overlapping clinical signs observed in PVRL

Background. The polysaccharide fucoidan is widely investigated as an anti-cancer agent. Here, we tested the effect of fucoidan on uveal melanoma cell lines. Methods. The effect of 100 µM fucoidan was investigated on five cell lines (92.1, Mel270 OMM1, OMM2.3, OMM2.5) and of 1 µg/mL–1 mg/mL fucoidan in two cell lines (OMM1, OMM2.3). Cell proliferation and viability were investigated with a WST-1 assay, migration in a wound healing (scratch) assay. Vascular Endothelial Growth Factor (VEGF) was measured in ELISA. Angiogenesis was evaluated in co-cultures with endothelial cells. Cell toxicity was induced by hydrogen-peroxide. Protein expression (Akt, ERK1/2, Bcl-2, Bax) was investigated in Western blot. Results. Fucoidan increased proliferation in two and reduced it in one cell line. Migration was reduced in three cell lines. The effect of fucoidan on VEGF was cell type and concentration dependent. In endothelial co-culture with 92.1, fucoidan significantly increased tubular structures. Moreover, fucoidan significantly protected all tested uveal melanoma cell lines from hydrogen-peroxide induced cell death. Under oxidative stress, fucoidan did not alter the expression of Bcl-2, Bax or ERK1/2, while inducing Akt expression in 92.1 cells but not in any other cell line. Conclusion. Fucoidan did not show anti-tumorigenic effects but displayed protective and pro-angiogenic properties, rendering fucoidan unsuitable as a potential new drug for the treatment of uveal melanoma.

Primary vitreoretinal lymphoma (PVRL) is the most common intraocular lymphoma occurring in the eye. It is a high-grade typically B-cell malignancy, arising in the retina, and is often associated with central nervous system (CNS) disease and thereby a poor prognosis. It needs to be distinguished from choroidal low-grade B-cell lymphomas, which do not disseminate to the brain and have a good prognosis. Because of the rarity of PVRL, information is lacking regarding its true incidence, its geographical or ethnic variation, and underlying risk factors apart from immunosuppression associated with human immunodeficiency virus (HIV) and Epstein Barr virus. PVRL often presents masquerading as other intraocular diseases and is therefore often associated with diagnostic delays. This is compounded by the fragility of the neoplastic B cells, which hampers vitrectomy yields and pathological work-up. The latter includes cytomorphology and immunoprofiling, with adjunctive tests such as cytokine analysis, polymerase chain reaction for clonality, MYD88 mutational testing, and possibly bespoke next generation sequencing. Recent examinations of PVRL and CNS lymphoma (CNSL) using whole genome sequencing confirm that these tumors arise from activated postgerminal center cells, reflecting their aggressive course in most cases. The treatment of PVRL varies between centers and is dependent on presence or absence of concomitant CNS disease. The prognosis remains poor, and yet progress is steadily being made through international collaborative clinical trials.

BackgroundSevere anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology is lacking and needed to improve outcomes.MethodsHIV-infected adults with severe (haemoglobin ≤70g/l) or very severe anaemia (haemoglobin ≤50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes of severe anaemia of anaemia and associations with anaemia severity and mortality were explored.Results199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. Over two potential causes for anaemia were present in 94% of the patients; including iron deficiency (55.3%), underweight (BMI1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 16 days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2).ConclusionMortality among severely anaemic HIV-infected adults is strikingly high. Clinicians must be aware of the urgent need for a multifactorial approach, including starting or optimising HIV treatment; considering TB treatment, nutritional support and attention to potential renal impairment.

IMPORTANCE: Studies on uveal melanomas (UMs) have demonstrated the prognostic value of 8q gain and monosomy 3, but the prognosis of UMs with partial deletion of chromosome 3 remains to be defined. OBJECTIVE: To examine the association of partial chromosome 3 deletion in UMs with metastasis-free survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study of 1088 consecutive comparative genomic hybridization arrays performed from May 1, 2006, to July 31, 2015, assessed patients presenting with UMs with and without partial loss of chromosome 3 at a referral center. Data analysis was performed from September 1, 2017, to November 30, 2017. EXPOSURE: Uveal melanoma with or without partial loss of chromosome 3. MAIN OUTCOMES AND MEASURES: Metastasis-free survival and overall survival at 60 months. RESULTS: Of the 1088 consecutive comparative genomic hybridization arrays that were performed, 43 UMs (4.0%) in 43 patients (median age, 58 years [range, 12-79 years]; 22 [51%] female) carried partial deletions of chromosome 3. Median follow-up was 66 months (range, 1.2-126.2 months). Metastasis-free survival at 60 months was 33.6% (95% CI, 15.8%-71.4%) for UMs that carried a deletion of the BAP1 (BRCA1 associated protein 1) locus (BAP1del; 24 tumors) and 80.5% (95% CI, 64.8%-100%) for UMs without the loss of the BAP1 locus (BAP1 normal [BAP1nl]; 19 tumors) (log-rank P = .001). Overall survival at 60 months was 64.5% (95% CI, 43.5%-95.8%) in the BAP1del group vs 84.1% (95% CI, 69.0%-100%) in the BAP1nl group (log-rank P < .001). In these 43 cases, metastasis-free survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 70.0% (95% CI, 50.5%-96.9%) for UMs that carried 1 of these alterations, and 12.5% (95% CI, 2.1%-73.7%) for those that carried both (log-rank P < .001). Similarly, overall survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 80.8% (95% CI, 63.3%-100%) for UMs that carried 1 of these alterations, and 46.7% (95% CI, 23.3%-93.6%) for those that carried both (log-rank P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that partial deletion of chromosome 3 encompassing the BAP1 locus is associated with poor prognosis. A cytogenetic classification of UMs could be proposed based on the status of the BAP1 locus instead of the chromosome 3 locus, while also taking chromosome 8q into account.

Background: The absence of BRCA1-associated protein 1 (BAP1) expression in uveal melanoma (UM) is associated with metastatic progression and reduced survival. In this study, we examine nuclear BAP1 (nBAP1) protein expression in primary UMs (PUMs) that show both ‘typical' and ‘atypical' clinical courses according to their chromosome 3 status, and secondary hepatic metastatic UM (MUM), correlating the results with histological, clinical and survival data. Methods: Nuclear BAP1 expression was immunohistochemically assessed in tissue microarrays (TMAs) of: (a) 68 PUM patients, who had been treated surgically; and (b) 13 MUM patients, with 5 cases being paired with primary tumour tissue. All cases were fully annotated. The percentage of tumour cell nuclei staining positively for BAP1 was scored by independent observers. Results: Nuclear BAP1 protein expression was absent in 35 out of 68 (51%) PUM patients, correlating strongly with poor prognostic clinicopathological and genetic parameters and reduced survival (Log rank, P

There have been tremendous advances in our understanding of the molecular etiology of uveal melanomas (UMs) in recent years that have allowed clinicians to accurately stratify patients on the basis of their risk of developing metastasis. Risk stratification in UM is now a very advanced field and is incorporated into routine care for the majority of patients, for example, with screening strategies. Such stratification also affords patients and clinicians the opportunity to evaluate the potential benefits of entering into clinical trials. However, the ultimate utility of our improved knowledge must be the development of targeted therapies, which bring about tangible improvements in patient survival. To date this aim is yet to be realized. From the Department of Molecular and Clinical Cancer Medicine, Liverpool Ocular Oncology Research Group, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (S.L.L., H.K., S.E.C.); and Ocular Oncology Service, University of California, San Francisco, California (B.E.D.). Correspondence: Sarah L. Lake, B.Sc., Ph.D., Department of Molecular and Clinical Cancer Medicine, Liverpool Ocular Oncology Research Group, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (s.l.lake@liv.ac.uk).

The T-box transcription factor Brachyury is expressed in a number of tumour types and has been demonstrated to have cancer inducing properties. To date, it has been linked to cancer associated induction of epithelial to mesenchymal transition, tumour metastasis and expression of markers for cancer stem-like cells. Taken together, these findings indicate that Brachyury plays an important role in the progression of cancer, although the mechanism through which it functions is poorly understood. Here we show that Brachyury regulates the potential of Brachyury-positive colorectal cancer cells to proliferate and reduced levels of Brachyury result in inhibition of proliferation, with features consistent with the cells entering a quiescent-like state. This inhibition of proliferation is dependent upon p27Kip1 demonstrating that Brachyury acts to modulate cellular proliferative fate in colorectal cancer cells in a p27Kip1-dependent manner. Analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours.

B cell non-Hodgkin's lymphomas (B-NHLs) consist of a wide spectrum of entities and consequently have varied clinical courses. Like many other malignancies, each of the B-NHL depend on their microenvironment for growth and survival; therefore, understanding the factors involved in their tissue localisation is likely to have implications for therapies designed to treat B-NHL. This review summarises the chemokines, integrins and sphingosine-1 phosphate receptors involved in normal B cell location and distribution within the lymphoid tissues (lymph nodes, spleen and bone marrow). It also provides a precis of what is known about these factors in the disease state: i.e., in some subtypes of B-NHL.

Aim To report on trans-scleral local resection of choroidal melanoma for exudative retinal detachment and neovascular glaucoma (toxic tumour syndrome) after proton beam radiotherapy (PBR). Methods A non-randomised, prospective study of secondary trans-scleral local resection of choroidal melanoma for exudative retinal detachment with or without neovascular glaucoma after PBR. The patients were treated at the Liverpool Ocular Oncology Centre between February 2000 and April 2008. The trans-scleral local resection was performed with a lamellar-scleral flap, using systemic hypotension to reduce haemorrhage. Results 12 patients (six women, six men) with a mean age of 51 years (range 20–75) were included in this study. The tumour margins extended anterior to ora serrata in six patients. On ultrasonography, the largest basal tumour dimension averaged 12.4 mm (range 6.8–18.1) and the tumour height averaged 7.1 mm (range 4.2–10.7). The retinal detachment was total in seven patients. Neovascular glaucoma was present in four patients. The time between PBR and local resection had a mean of 17.4 months (range 1–84). The ophthalmic follow-up time after the local resection had a mean of 46.2 months (range 14–99). At the latest known status, the eye was conserved in 10 patients, with a flat retina in all these patients and visual acuity equal or better than 6/30 in four patients. The reasons for enucleation were: patient request for enucleation when rhegmatogenous retinal detachment complicated the resection (one patient) and phthisis (one patient). Conclusions Exudative retinal detachment, rubeosis and neovascular glaucoma after PBR of a choroidal melanoma can resolve after trans-scleral local resection of the tumour. Our findings suggest that these complications are caused by the persistence of the irradiated tumour within the eye (‘toxic tumour syndrome’).

Background/Aims A retrospective service evaluation to report on recurrence of iris melanoma after proton beam therapy (PBT). Methods The cohort comprised 150 consecutive eyes with iris melanoma treated with proton beam radiotherapy. Treatment consisted of 53.1 Gy of proton beam irradiation delivered in four fractions over four consecutive days. Main outcome measures were local tumour control and tumour-related mortality. Results A total of 150 patients were treated. The median follow-up time was 66 months (range, 12–108 months). The tumour ultrasound thickness ranged from 1.1 mm to 4.9 mm, with a median of 2.4 mm. The tumours in these patients had a median largest basal diameter of 6.7 mm (range, 2.9–8.4 mm), involving more than two clock hours of iris or angle in five patients. The ciliary body was involved in three patients. Eight patients (5.3%) presented with local recurrence, diagnosed after a median follow-up of 24 months (range, 12–84 months). The recurrence was focal in two patients and diffuse in six. Six eyes were enucleated whereas one eye underwent iridocyclectomy and one received a second course of PBT. Conclusions PBT provides excellent local tumour control and ocular preservation with good retention of vision. Most recurrences occur because the extent of the tumour is clinically underestimated but some tumours are radioresistant. Recurrence can occur several years after treatment. These findings indicate the need for wide safety margins and even radiotherapy of the entire anterior segment in patients with diffuse disease. Surveillance after treatment needs to be lifelong.

Background Uveal metastasis is the most common intraocular malignancy. Methods This was a retrospective study of all patients with uveal metastases referred to the Liverpool Ocular Oncology Centre between January 2007 and December 2012. Biopsy was performed as a primary investigation if the clinical examination suggested metastasis with no evidence of any extraocular metastases. Results Ninety-six patients (109 eyes) were included. Breast and lung carcinomas were the most common primary malignancies, affecting 41 and 27 patients, respectively. The median time interval between detection of primary cancer and uveal metastasis was 24 months (range 1–288 months). Thirty-nine patients underwent ocular biopsy, confirming the diagnosis in all patients. The biopsy indicated the site of origin in 24 out of the 27 without a known primary tumour. In 7 of these 27 cases, previous systemic investigations had failed to identify the primary tumour. Seventy-three patients received external beam irradiation; two patients received photodynamic therapy; and two patients had Ru-106 plaque radiotherapy. The visual acuity was stable or improved in 75.5% of the cases. Conclusions Immediate biopsy provides a quick diagnosis that may expedite treatment and improve any opportunities for conserving vision while facilitating the general oncologic management on these patients.

Purpose To refine the anatomic classification and staging of ciliary body and choroidal melanomas in the TNM classification. Patients and Methods Tumor largest basal diameter and thickness of 7,369 patients were analyzed based on registry data from five ocular oncology centers. T categories were derived empirically by dividing data into blocks representing 3- × 3-mm fractions. Blocks with similar survival were grouped together so that no T category comprised a large majority of tumors, and each was uniform in survival, using randomly drawn 60% building and 40% validation data sets. Presence of ciliary body involvement (CBI) and extraocular extension (EXE) was analyzed among 5,403 patients to define T subcategories. Stages were generated by iteratively combining subcategories with similar survival. Results Of the 7,369 tumors analyzed, 24% were classified as T1, 33% as T2, 31% as T3, and 12% as T4. Ten-year Kaplan-Meier survival estimates for the T categories were 89%, 77%, 58%, and 39%, respectively (P < .001). Survival of patients in four subcategories based on presence or absence of CBI and EXE differed significantly within each T category (P = .018 for T1; P < .001 for T2 to T4). EXE exceeding 5 mm in largest diameter carried a worse prognosis than smaller extensions (P < .001) and was assigned a separate subcategory. Ten-year Kaplan-Meier survival estimates for stages I, IIA to IIB, and IIIA to IIIC were 88%, 80%, 67%, 45%, 27%, 10%, respectively (P < .001). Conclusion This evidence-based anatomic classification provides a basis for staging ciliary body and choroidal melanomas in the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer.

The diagnosis and treatment of orbital and periorbital malig- nancies are challenging. These tumors can result in blindness, death, and significant cosmetic deformities. Herein, we present the most common ocular malignancies and a systematic approach to diagnosis. Further, we integrate the seventh edition American Joint Committee on Cancer staging system, biomarkers, and multidisciplinary approaches to treatment.