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Radberger P.,Karolinska Institutet | Radberger A.,Karolinska Institutet | Vladimir J.N.B.,Karolinska Institutet | Seregard S.,Ophthalmic Pathology and Oncology Service | Economou M.A.,Ophthalmic Pathology and Oncology Service
Investigative Ophthalmology and Visual Science | Year: 2012

Purpose. It has been suggested recently that stem cell marker expression of jumonji AT-rich interactive domain 1B (JARID1B) is required for continuous tumor growth and maintenance in human cutaneous melanoma cells. The aim of this study is to determine whether JARID1B is also expressed in uveal melanoma (UM) and whether JARID1B marks an expanded cancer stem cell pool in poor prognosis UM. Based on the available data, this is the first time JARID1B expression in UM has been studied. Methods. A total of 121 consecutive patients diagnosed with UM and who underwent enucleation were included in the study. Immunohistochemical staining with JARID1B antibodies was performed and immunoreactivity was assessed. Correlations of JARID1B expression with established clinicopathological parameters and overall survival (OS) were evaluated in univariate and multivariate analyses. Results. JARID1B positive expression, as defined by >0% staining, was present in 55% of UMs and invariably in ciliary body epithelium. The correlation between JARID1B negative expression and JARID1B expression >5% inside the tumor tissue and OS was borderline statistically significant based on LogRank test at 5% significance level (P = 0.06). There were significantly more JARID1B positive cells in tumors with extrascleral extension than in tumors with no or minimal intrascleral invasion (P < 0.01, Mann-Whitney test). Conclusions. This study demonstrates that JARID1B is expressed by UM cells. Despite that JARID1B was highly expressed in UM, a statistically significant association (P < 0.05) between JARID1B expression and OS could not be obtained. However, a P-value of 0.06 could suggest that high JARID1B expression is correlated with lower survival; thus, a follow up study with a greater patient sample is recommended. In addition, samples of tumors characterized by high invasiveness showed a higher JARID1B expression. Furthermore, this study substantiates the presence of progenitor cells in the ciliary body epithelium. © 2012 The Association for Research in Vision and Ophthalmology, Inc. Source

Mougiakakos D.,Karolinska University Hospital | Johansson C.C.,Karolinska University Hospital | Trocme E.,Karolinska University Hospital | All-Ericsson C.,Ophthalmic Pathology and Oncology Service | And 4 more authors.
Cancer | Year: 2010

BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E2 (PGE2) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P = .004) and Treg intratumoral localization (P = .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2-positive tumors. CONCLUSIONS: The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE2 induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX-2-positive UM, and these results put COX-2 inhibitors and Treg depletion into the spotlight of potential novel treatment modalities for patients with UM. © 2010 American Cancer Society. Source

Johansson C.C.,Karolinska Institutet | Mougiakakos D.,Karolinska Institutet | Trocme E.,Karolinska Institutet | All-Ericsson C.,Ophthalmic Pathology and Oncology Service | And 4 more authors.
International Journal of Cancer | Year: 2010

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin-embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease-specific survival (DSS) as assessed by Kaplan-Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan-Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor. © 2009 UICC. Source

Trocme E.,Karolinska Institutet | Mougiakakos D.,Karolinska Institutet | Johansson C.C.,Karolinska Institutet | All-Eriksson C.,Ophthalmic Pathology and Oncology Service | And 5 more authors.
International Journal of Cancer | Year: 2012

HER3 is a member of the epidermal growth factor receptor (EGFR) family and is expressed in several types of cancer. Both the cytoplasmic and nuclear appearances of the receptor have been reported. Here, we investigate the expression and subcellular distribution of HER3 in uveal melanoma (UM) cells and tissues and its potential impact on clinical outcome of patients. Paraffin-embedded samples from 128 consecutive UM patients, enucleated without alternative treatment on UM diagnosis, were evaluated for HER3 using immunohistochemistry. Immunoreactivity was scored for frequency, intensity of positive cells, and subcellular distribution. The results were correlated with the established clinicopathological parameters using univariate and multivariate statistical analyses. HER3 expression was shown in 70% of the cases (89/128). This contrasts with the other EGFR family receptors (EGFR, HER2 and HER4) that are infrequently expressed in UM. Surprisingly, HER3 was found to be localized solely in the cell nuclei in 56 cases. The remaining 33 HER3 positive cases showed diffuse distribution (cytoplasmic ± nuclear). Nuclear HER3 was independently correlated with a more favorable overall survival (p = 0.043 and hazard ratio = 0.618) compared to cases with diffuse and/or no HER3. Nuclear localization of HER3 was also confirmed in fresh UM material and in UM cell lines. In conclusion, HER3 is frequently localized solely in the cell nuclei in UM and as such it predicts a more favorable overall survival. Copyright © 2011 UICC. Source

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