Diagnostic and therapeutic considerations in patients with bilateral diffuse uveal melanocytic proliferation.

PURPOSE: This review aims to summarize the current knowledge concerning the clinical features, diagnostic work-up, and therapeutic approach of bilateral diffuse uveal melanocytic proliferation (BDUMP). METHODS: A meticulous literature search was performed in the PubMed database. A supplementary search was made in Google Scholar to complete the collected items. Our search strategy utilized the following keywords: "bilateral diffuse uveal melanocytic proliferation", "BDUMP", and "Paraneoplastic Syndrome". Articles were considered based on their relevance, with the search spanning publications up to 2023. Studies were excluded if they did not contribute pertinent information or lacked methodological rigor. A critical appraisal of included studies was conducted, assessing study design, sample size, methodology, and potential bias, ensuring a thorough and transparent review process. RESULTS: BDUMP is a rare and potentially sight-threatening condition characterized by the bilateral proliferation of melanocytes within the uvea. BDUMP is typically observed in middle-aged or elderly individuals and is often associated with an underlying malignancy, most commonly of gastrointestinal origin. BDUMP is frequently misdiagnosed as a benign nevus or choroidal metastasis, leading to delayed diagnosis and treatment. The ophthalmic symptoms and signs typically precede the diagnosis of a systemic malignancy, emphasizing the crucial role of ophthalmologists in the recognition of BDUMP. Several diagnostic modalities can aid in the diagnosis of BDUMP, including ophthalmic examination, imaging studies such as optical coherence tomography, fluorescein angiography, and indocyanine green angiography, and biopsy of the uveal tissue. Treatment of BDUMP is directed towards the underlying malignancy and may include chemotherapy, radiotherapy, or surgical resection. Additionally, strict monitoring with regular follow-ups may contribute to the detection of new lesions and the reduction in the size of existing ones. CONCLUSIONS: BDUMP can be considered a potential biomarker in the management of malignancies, especially when the primary underlying tumor has not been detected. Further research is needed to better understand the pathogenesis of BDUMP and its association with malignancy.

Multipurpose ultrasonographic characteristics of primary uveal MALT lymphoma.

PURPOSE: To investigate the ultrasonographic features in patients with primary uveal mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: Medical records of 12 patients (13 eyes) diagnosed with primary uveal MALT lymphoma between September 2014 and September 2021 were retrospectively reviewed. Ultrasonography, B-scan ultrasonography, color Doppler flow imaging, and ultrasound biomicroscopy findings were retrieved from the medical records. RESULTS: Mean age of the included patients was 59.4 ± 8.6 years. Typical ultrasonographic features of the choroidal infiltrates were flat, diffuse, and thickened, with low and homogenous internal reflectivity and with rich arterial blood flow from posterior ciliary arterioles. The mean thickness of the choroidal infiltrates was 1.34 ± 0.68 mm (n = 13). Most of the affected eyes had posterior episcleral extensions, with a mean thickness of 1.66 ± 1.21 mm (n = 12). Typical crescent-like posterior episcleral extensions were detected in nine eyes (69.2%). In six eyes, the blood flow from the choroidal infiltrates communicated with the episcleral extensions. In the ciliary body, the mean thickness of the infiltrates was 1.08 ± 0.43 mm (n = 9), and seven eyes (77.8%) had 360° ring-like infiltrations. The initial best-corrected visual acuity (BCVA) was significantly correlated with the final BCVA after treatment (p < 0.001). CONCLUSION: Multipurpose ultrasonographic imaging revealed the unique characteristics of the primary uveal MALT lymphoma and is helpful in the diagnosis of this rare disease.

Canine and feline uveal melanocytic tumours: Histologic and immunohistochemical characteristics of 32 cases.

OBJECTIVE: Gross, histopathological, and immunohistochemical characteristics of uveal melanocytic neoplasms in dogs and cats were investigated. SAMPLES: Thirty-two enucleated globes with uveal melanocytic neoplasms, 27 from dogs and 5 from cats, were examined. PROCEDURES: Morphological characteristics of uveal melanocytic neoplasms in dogs and cats were evaluated with anti-PNL2, anti-Melan-A, anti-Ki-67, anti-caspase-3, and anti-BAP1 immunomarkers. Statistical analysis was performed to compare canine melanocytomas and melanomas. RESULTS: The 32 uveal neoplasms were classified as melanocytomas (19/27 in dogs) or melanomas (8/27 in dogs, 5/5 in cats). Most tumours (84%) were located in the anterior uvea. Neoplastic cells were classified as epithelioid, spindle-shaped, mixed, or special type (balloon and signet ring cells). The percentage of cells with melanin, melanin concentration within cells, anisocytosis and anisokaryosis, mitotic count, lymphocytic inflammation, necrosis, vascular invasion, and glaucoma were also characterized. Anisocytosis, percentage of neoplastic cells with melanin, mitotic count, and indices (proliferation and apoptotic) varied significantly between canine uveal melanomas and melanocytomas; in general, melanomas had greater cell variability, were less pigmented, and had a higher mitotic count. The melanocytic origin of the neoplasms was confirmed by positive anti-PNL2 immunolabelling (29/32) and positive anti-Melan-A immunolabelling (3/32). In canine uveal melanomas, anisocytosis and anisokaryosis correlated with less pigmentation and minimal pigmentation correlated with a high percentage of immunolabelling for caspase-3. CONCLUSIONS: Uveal melanocytomas were more common in dogs, and uveal melanomas were more frequent in cats. Anisocytosis, percentage of neoplastic cells with melanin, and mitotic count are important histologic characteristics of malignancy to evaluate in uveal melanocytic neoplasms. The proliferation and apoptotic indices are relevant when comparing malignant tumours with benign tumours.

Myeloid Cells in the Mouse Retina and Uveal Tract Respond Differently to Systemic Inflammatory Stimuli.

Purpose: In spite of clear differences in tissue function and significance to ocular disease, little is known about how immune responses differ between the retina and uveal tract. To this end we compared the effects of acute systemic inflammation on myeloid cells within the mouse retina, iris-ciliary body, and choroid. Methods: Systemic inflammation was induced in Cx3cr1gfp/gfp and CD11c-eYFP Crb1wt/wtmice by intraperitoneal lipopolysaccharide (LPS). In vivo fundus imaging was performed at two, 24, and 48 hours after LPS, and ocular tissue wholemounts were immunostained and studied by confocal microscopy. Flow cytometry was used to investigate the expression of activation markers (MHC class II, CD80, CD86) on myeloid cell populations at 24 hours. For functional studies, retinal microglia were isolated from LPS-exposed mice and cocultured with naïve OT-II CD4+ T-cells and ovalbumin peptide. T-cell proliferation was measured by flow cytometry and cytokine assays. Results: Systemic LPS altered the density and morphology of retinal microglia; however, retinal microglia did not upregulate antigen presentation markers and failed to stimulate naïve CD4+ T-cell proliferation in vitro. In contrast, uveal tract myeloid cells displayed a phenotype consistent with late-activated antigen-presenting cells at 24 hours. Systemic LPS induced remodeling of myeloid populations within the uveal tract, particularly in the choroid, where dendritic cells were partially displaced by macrophages at 24 hours. Conclusions: The disparate myeloid cell responses in the retina and uveal tract after systemic LPS highlight differential regulation of innate immunity within these tissue environments, observations that underpin and advance our understanding of ocular immune privilege.

Bilateral diffuse uveal melanocytic proliferation with multifocal diffuse integumentary melanocytic proliferation paraneoplastic syndrome: A case report.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males and uro-gynaecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterised. Herein, we present a female in her 70s with diagnosis of stage IV vaginal clear-cell carcinoma and metastatic melanoma of unknown primary that developed progressive bilateral loss of visual acuity compatible with 'B-DUMP'. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP be termed 'diffuse integumentary melanocytic proliferation (DIMP)'.

Acute Bilateral Neuroretinitis and Panuveitis in A Patient with Coronavirus Disease 2019: A Case Report.

Purpose: Herein, we report a case of bilateral neuroretinitis and panuveitis in a patient recovered from coronavirus disease 2019 (COVID-19).Case presentation: A 37-year-old male patient with a history of recovered COVID-19, which was confirmed with nasopharyngeal reverse transcriptase polymerase chain reaction (RT-PCR) for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), about one-month ago was referred with one-week history of bilateral severe vision loss. Visual acuity was counting fingers, and bilateral retinitis and panuveitis were revealed in ocular examination. The result of the vitreous sample using RT-PCR was positive for SARS-CoV-2 and negative for Herpesviridae viruses and mycobacterium tuberculosis. The patient was successfully treated with corticosteroid.Conclusion: We report a case of bilateral neuroretinitis and panuveitisin a recovered COVID-19 patient and positive RT-PCR of the vitreous sample. It is suggested to apply intraocular sampling and evaluation for COVID-19 in patients with the new-onset of uveitis and/or retinitis during the pandemic.

Bilateral Acute Anterior Uveitis and Corneal Punctate Epitheliopathy in Children Diagnosed with Multisystem Inflammatory Syndrome Secondary to COVID-19.

Purpose: To report bilateral anterior uveitis and corneal punctate epitheliopathy in children with multisystem inflammatory syndrome (MIS-C) secondary to coronavirus disease (COVID-19).Participants and methods: Five patients who were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies and diagnosed with MIS-C were evaluated. Ophthalmologic examinations were performed in order to reveal ocular findings in MIS-C disease.Results: Slit lamp examinations showed bilateral non-granulomatous acute anterior uveitis in all patients and severe corneal punctuate epitheliopathy in three of the patients. These ocular findings mostly disappeared with treatment in about one week.Conclusion: Bilateral non-granulomatous acute anterior uveitis and dry eye can be detected in patients diagnosed with MIS-C secondary to COVID-19. Even if generally, COVID-19 is not a life threatening disease in children by itself, inflammatory ocular manifestations can be detected in MIS-C secondary to COVID-19.

Classification Criteria for Sarcoidosis-Associated Uveitis.

PURPOSE: The purpose of this study was to determine classification criteria for sarcoidosis-associated uveitis. DESIGN: Machine learning of cases with sarcoid uveitis and 15 other uveitides. METHODS: Cases of anterior, intermediate, and panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed including cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used in the training sets to determine a parsimonious set of criteria that minimized the misclassification rate among the uveitides. The resulting criteria were evaluated in the validation sets. RESULTS: A total of 1,083 cases of anterior uveitides, 589 cases of intermediate uveitides, and 1,012 cases of panuveitides, including 278 cases of sarcoidosis-associated uveitis, were evaluated by machine learning. Key criteria for sarcoidosis-associated uveitis included a compatible uveitic syndrome of any anatomic class and evidence of sarcoidosis, either 1) tissue biopsy results demonstrating non-caseating granulomata or 2) bilateral hilar adenopathy on chest imaging. The overall accuracy of the diagnosis of sarcoidosis-associated uveitis in the validation set was 99.7% (95% confidence interval: 98.8-99.9). The misclassification rates for sarcoidosis-associated uveitis in the training sets were 3.2% in anterior uveitis, 2.6% in intermediate uveitis, and 1.2% in panuveitis; in the validation sets, the misclassification rates were 0% in anterior uveitis, 0% in intermediate uveitis, and 0% in panuveitis. CONCLUSIONS: The criteria for sarcoidosis-associated uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Classification Criteria for Tubulointerstitial Nephritis With Uveitis Syndrome.

PURPOSE: To determine classification criteria for tubulointerstitial nephritis with uveitis (TINU). DESIGN: Machine learning of cases with TINU and 8 other anterior uveitides. METHODS: Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand eighty-three cases of anterior uveitides, including 94 cases of TINU, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for TINU included anterior chamber inflammation and evidence of tubulointerstitial nephritis with either (1) a positive renal biopsy or (2) evidence of nephritis (elevated serum creatinine and/or abnormal urine analysis) and an elevated urine ß-2 microglobulin. The misclassification rates for TINU were 1.2% in the training set and 0% in the validation set. CONCLUSIONS: The criteria for TINU had a low misclassification rate and seemed to perform well enough for use in clinical and translational research.

Posterior uveal melanoma incidence and survival by AJCC tumour size in a 70-year nationwide cohort.

PURPOSE: While early treatment of posterior uveal melanoma can save the eye, the effect of early treatment on survival remains unknown. Therefore, we aimed to determine whether the tumour size at diagnosis has changed over time, and if this has affected survival rates of patients with posterior uveal melanoma in Denmark. METHODS: Nationwide retrospective cohort study linking data from registry-based resources to data from clinical charts and pathology records. Including all Danish patients diagnosed with posterior uveal melanoma from 1943 to 2017. Incidence rates were estimated as annual percentage change (APC) overall and by American Joint Committee on Cancer (AJCC) tumour sizes. The age-period-cohort model was applied to estimate the relative risk of calendar period. The cox proportional hazards model, relative survival Kaplan-Meier curves and cumulative incidence curves were applied to estimate the effect of calendar period on survival. RESULTS: An overall increase in incidence rate of uveal melanoma was found (APC = 0.25%, 0.08-0.42; 95% CI). This was due to increasing incidence rate of AJCC T1 + T2 tumours (APC = 0.97%, 0.57-1.37; 95% CI), whereas no increase in incidence rates of AJCC T3 + T4 tumours was found (APC = -0.01%, -0.26 to 0.25; 95% CI). The disease-specific survival improved with calendar period for all tumour sizes (HR = 0.988; 0.984-0.993; 95% CI). CONCLUSION: Increasing incidence rate and improved survival rate for uveal melanoma was found concordantly with a decrease in tumour size during a 70-year period.

NECROSIS OF THE RETINA AND UVEAL TRACT SECONDARY TO EXPANDING GAS TAMPONADE.

PURPOSE: To present a case of retinal and uveal necrosis caused by expanding gas tamponade after pars plana vitrectomy. METHODS: Single case report. RESULTS: An otherwise healthy 66-year-old woman underwent pars plana vitrectomy with intended 20% sulfur hexafluoride (SF6) tamponade for macular hole repair of her pseudophakic left eye. She developed intractable nausea, emesis and increasing left eye pain in association with gas expanded to totally fill the left eye, just hours after surgery. Extremely elevated intraocular pressure was lowered with a successful paracentesis but recurred within a few hours. She then underwent vitrectomy evacuation of all vitreous cavity gas, reformation of the anterior chamber, and silicone oil placement, normalizing intraocular pressure. Three weeks later, the left eye had no light perception, and devitalization of the retina, choroid, and iris was evident. CONCLUSION: We present a case of blindness and intraocular tissue dissolution/disorganization after vitrectomy with intended 20% SF6. To our knowledge, this is the most detailed report of the under-recognized complication of expanding gas tamponade. Institutions hosting vitrectomy surgery should consider enacting a formal "Time Out" that requires all team members to witness accurate fractionation of potentially expansile gas. In the event of acute postoperative glaucoma in such eyes, a single small volume paracentesis cannot be relied upon to protect against continued gas expansion.

CD73+ Dendritic Cells in Cascading Th17 Responses of Experimental Autoimmune Uveitis-Induced Mice.

Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73+ BMDCs play a critical role in cascading Th17 responses, and CD73+ BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73-/- mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73+ DCs is critically involved in augmented Th17 responses. We conclude that CD73+ DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses.

Dracocephalum heterophyllum (DH) Exhibits Potent Anti-Proliferative Effects on Autoreactive CD4+ T Cells and Ameliorates the Development of Experimental Autoimmune Uveitis.

Experimental autoimmune uveitis (EAU) is a CD4+ T cell-mediated organ-specific autoimmune disease and has been considered as a model of human autoimmune uveitis. Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. DH suppressed the production of inflammatory cytokines through the recruitment of myeloid-derived suppressor cells (MDSCs) to the liver. However, it remains elusive whether DH can directly regulate CD4+ T cell biology and hence ameliorates the development of CD4+ T cell-mediated autoimmune disease. In the current study, we found that DH extract significantly suppressed the production of pro-inflammatory cytokines by CD4+ T cells. Further study showed that DH didn't affect the activation, differentiation, and apoptosis of CD4+ T cells. Instead, it significantly suppressed the proliferation of conventional CD4+ T cells both in vitro and in vivo. Mechanistic study showed that DH-treated CD4+ T cells were partially arrested at the G2/M phase of the cell cycle because of the enhanced inhibitory phosphorylation of Cdc2 (Tyr15). In addition, we demonstrated that treatment with DH significantly ameliorated EAU in mice through suppressing the proliferation of autoreactive antigen specific CD4+ T cells. Taken together, the current study indicates that DH-mediated suppression of CD4+ T cell proliferation may provide a promising therapeutic strategy for treating CD4+ T cell-mediated diseases.

Kallistatin Attenuates Experimental Autoimmune Uveitis by Inhibiting Activation of T Cells.

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis. EAU spontaneously resolves and is marked by ocular autoantigen-specific regulatory immunity in the spleen. Kallikrein binding protein (KBP) or kallistatin is a serine proteinase inhibitor that inhibits angiogenesis and inflammation, but its role in autoimmune uveitis has not been explored. We report that T cells activation is inhibited and EAU is attenuated in human KBP (HKBP) mice with no significant difference in the Treg population that we previously identified both before and after recovery from EAU. Moreover, following EAU immunization HKBP mice have potent ocular autoantigen specific regulatory immunity that is functionally suppressive.

Diagnosis of bilateral diffuse uveal melanocytic proliferation unveils primary gastric adenocarcinoma: a case report.

BACKGROUND: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare paraneoplastic syndrome, with most cases reported as secondary to female urogenital and male lung malignancies. We reported this case of BDUMP patient whose primary malignancy was gastric adenocarcinoma verified with gastroscopy and subsequent pathological test. CASE PRESENTATION: A patient complaining blurred vision was suspected of bilateral diffuse uveal melanocytic proliferation (BDUMP), due to bilateral round oval patches at the posterior pole and cardinal signs in retinal angiography. Malignancy screening was suggested, and pathological report from gastroscopy confirmed the primary lesion as gastric adenocarcinoma. The patient chose palliative care due to late stage and unresectable nature of the malignancy. CONCLUSIONS: Identifying BDUMP warrants further investigation of a primary malignancy. Our case provided evidence for the link between gastric adenocarcinoma and BDUMP.

A20 Inhibits Intraocular Inflammation in Mice by Regulating the Function of CD4+T Cells and RPE Cells.

A20 is a negative regulator of inflammation and immunity and plays a role in several autoimmune and inflammatory diseases. Here, we demonstrate that A20 overexpression significantly ameliorates severity of EAU by inhibiting the infiltration of Th1 and Th17 cells, and by protecting integrity of the blood retinal barrier. In vitro studies showed that A20 silencing could promote CD4+T cells toward a Th1 and Th17 phenotype. A decreased expression of A20 in CD4+T cells was noticed in active BD patients but not in VKH patients. Furthermore, silencing of A20 in hRPE cells induced the production of IL-6, IL-8, and MCP-1 and downregulated ZO-1 and occludin expression which is mediated by inhibition of MAPK and NF-κB pathways. This study reveals a mechanism by which A20 prevents autoimmune uveitis.

Large B-cell lymphoma of the uvea: Histopathologic variants and clinicopathologic correlation.

Twenty-eight patients were identified with large B-cell lymphoma of the uvea. Uveal involvement was iris (1 case), ciliary body (1 case), or choroidal in 14 cases. Panuveal involvement was observed in 12 cases. The clinical presentation could be categorized into uveitis (8), intraocular mass (9), neovascular glaucoma (4), and vascular disorders (4). The majority (21 cases, 77%) were diagnosed at autopsy (11) or after enucleation (10). Only 7 were diagnosed with conservative techniques. Histopathologically, 3 distinct subgroups of large B-cell lymphoma could be identified: 15 were characterized as diffuse large B-cell lymphoma, 11 as intravascular large B-cell lymphoma, and 2 as plasmablastic lymphoma. All cases had a poor prognosis, with a median survival of 14 months. Most cases (19, 67%) represented secondary uveal involvement with widespread systemic lymphoma at ophthalmic presentation. Six cases were treated with radiotherapy, most of these diagnosed before the 1990s (4). Subsequent cases (9) received systemic or local chemotherapy and adjunct radiotherapy, depending on the organs affected. Two cases were treated only with enucleation, and systemic treatment was not specified in 13 cases. Large B-cell lymphoma can rarely involve the uvea. The presenting features are nonspecific, often leading to enucleation. Effective therapy is not known. In all 3 variants, the aggressive nature and widespread involvement at ophthalmic presentation is associated with short survival.

Multi-center analysis of intraocular biopsy technique and outcomes for uveal melanoma: Ocular Oncology Study Consortium report 4.

PURPOSE: To investigate the relationship between surgical approach for intraocular tumor biopsy of uveal melanoma and tumor morphologic features such as size and intraocular location and the effect of these variables on diagnostic yield and biopsy outcome. METHODS: Consecutive patients from nine Ocular Oncology centers with uveal melanoma (UM) undergoing tumor biopsy immediately preceding I125 plaque brachytherapy with tissue sent for gene expression profiling (GEP) testing were reviewed retrospectively. RESULTS: Three hundred sixty patients were included (50% men, mean age 60.2 years). Overall biopsy yield was 99% and 83% for GEP and cytopathology, respectively. Surgeon choice of biopsy approach (trans-vitreal vs. trans-scleral) was found to associate with both tumor location and tumor thickness. A trans-scleral rather than trans-vitreal approach was used more commonly for anteriorly located tumors (92% vs. 38% of posterior tumors, p < 0.001) and thicker tumors (86% vs. 55% of thin tumors, p < 0.001). When performing trans-vitreal biopsies, ocular oncologists with previous vitreoretinal surgery fellowship training were more likely to use wide-field surgical viewing systems, compared with indirect ophthalmoscopy (82.6% vs. 20.6%, p < 0.001). Surgical complications were rare and occurred more frequently with trans-vitreal biopsies (3.6% vs. 0.46%, p = 0.046). CONCLUSIONS: In this multi-center analysis of UM tumor biopsy, surgical yield was high for obtaining tumor tissue for GEP and cytopathology analysis with both trans-scleral and trans-vitreal techniques. Fellowship-trained ocular oncologists' preferred intraocular biopsy techniques associated strongly with tumor location, tumor thickness, and fellowship training of the surgeon. Short-term complication rates were low.

Ultrastructural Organization of Uveal Melanoma Stromal Cells.

Typical blood capillaries and vessels in uveal melanoma were shown and different types of uveal melanoma stromal cells were determined by electron microscopy and immunohistochemical analysis. Macrophages, fibroblasts of varying degrees of differentiation and endothelial-like cells with numerous caveolae in the cytoplasm were found in the channels of the extracellular matrix surrounding accumulations of tumor cells. The presence local structures positively stained for markers of the blood and lymphatic vessels (CD31 and podoplanin) in channels of the extracellular matrix suggests that the described endothelial-like cells can be the structural basis for blood and lymphatic vessels of the tumor.

Beta-blockers exert potent anti-tumor effects in cutaneous and uveal melanoma.

BACKGROUND: Melanoma is a life-threatening group of cancers mainly affecting the skin (cutaneous melanoma, CM) and the eyes (uveal melanoma, UM). Nearly half of patients with UM develop liver metastases regardless of the primary treatment. For this reason, adjuvant therapy to prevent disease progression is essential to improve survival of patients with melanoma. Beta-adrenoceptors (ß-AR) have emerged as novel targets to inhibit tumor growth and dissemination in CM, but have not been investigated in UM. METHODS: The aim of this study was to comprehensively evaluate the effects of a non-selective ß-blocker in UM and CM. Propranolol was tested on four UM and two CM cell lines to determine the effects of this beta-blocker. The expression of ß-AR in UM was assessed in enucleated eyes of 36 patients. RESULTS: The results showed that propranolol exerts potent anti-proliferative effects, attenuates migration, reduces VEGF and induces cell cycle arrest and apoptosis in both UM and CM in a dose-dependent manner. Furthermore, levels of cell-free DNA released from the cells correlated to propranolol treatment and may be an indicator of treatment response. Finally, immunohistochemical analysis revealed the expression of ß1 and ß2 adrenoceptors in all UM patients, with higher expression seen in the more aggressive epithelioid versus less aggressive spindle cells. CONCLUSIONS: Collectively our data suggest that a nonselective beta-blocker may be effective against melanoma. For the first time, we show potent anti-tumor effects in UM cells following propranolol administration and expression of ß1 and ß2 adrenoceptors in patient tissue.