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      Cytokine Profile in Human Eyes: Contribution of a New Cytokine Combination for Differential Diagnosis between Intraocular Lymphoma or Uveitis

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          Abstract

          Primary intraocular lymphoma (PIOL), also called primary vitreoretinal lymphomas, often masquerades as uveitis. This misdiagnosis can result in subsequent brain involvement and oculocerebral lymphoma (OCL). In this study, we sought to characterize the helper T-cell type 1 (Th1)/Th2 cytokine profile in vitreous samples from patients with PIOL, OCL, uveitis and controls with non-inflammatory disease. Vitreous and aqueous humor samples from 87 patients with PIOL (n = 30), OCL (n = 12), uveitis (n = 34), and retinal detachment (RD) without hemorrhage (n = 11) were analyzed and their concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined by flow cytometric bead arrays (CBA). The IL-10 levels determined by CBA were compared with those by ELISA. IL-10 concentrations measured by CBA and ELISA were highly correlated. IL-2, IL-4, and TNFα were not detected in any sample. The only cytokine detected at a significant level in samples from RD vitreous was IL-6. The IL-10/IL-6 ratio, as previously reported, was slightly higher in PIOL than in uveitis samples, but not for all patients. Cytokine profiles from PIOL and OCL samples did not differ. The combination of the IL-10/IL-6 and IL-10/IFNγ ratios was highly informative for discriminating PIOL/OCL from uveitis samples and for therapeutic follow up of PIOL. This strategy might be very helpful as an initial screening to rule out PIOL in patients thought to have uveitis.

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          Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium.

          Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.
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            IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma.

            To determine the value of IL-10 measurement in aqueous humor (AH) for screening in primary intraocular lymphoma (PIOL). One hundred consecutive diagnostic or therapeutic vitrectomies were performed in patients with uveitis. During surgery, 100 microL of both AH and pure vitreous was taken. IL-10 levels were determined with a standard quantitative sandwich enzyme immunoassay technique. Patients were distributed in two groups: 51 patients with proven PIOL, 108 patients with uveitis divided into 74 with uveitis of proven etiology and 34 with idiopathic uveitis. Groups were compared by ANOVA and the Tukey-Kramer test or nonparametric Wilcoxon test. Distributions were compared by using the chi(2) test. Segmentation was derived from the ROC curves by choosing a tradeoff between sensitivity and specificity. In patients with PIOL, IL-10 mean values were 2205.5 pg/mL (median: 1467 pg/mL) in the vitreous and 543.4 pg/mL (median: 424 pg/mL) in AH. In patients with uveitis (idiopathic and diagnostic uveitis), mean values were 26.6 pg/mL (median: 8 pg/mL) in the vitreous, and 21.9 pg/mL (median: 8 pg/mL) in AH. IL-10 mean values were significantly different between patients with PIOL and patients with uveitis (P < 10(-3)). The areas under the curves were 0.989 and 0.962 for vitreous and AH, respectively. A cutoff of 50 pg/mL in the AH was associated with a sensitivity of 0.89 and a specificity of 0.93. In the vitreous, a cutoff value of 400 pg/mL yielded a specificity of 0.99 and a sensitivity of 0.8. Diagnosis of PIOL is often made months or years after the initial onset of ocular symptoms. Cytology remains the gold standard for diagnosis. However, measurement of IL-10 in the AH is a good screening test to reduce diagnostic delays.
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              Ocular and central nervous system lymphoma: clinical features and diagnosis.

              To evaluate the clinical, angiographic, and cytopathologic features of ocular and central nervous system (CNS) lymphoma. Retrospective study of 44 patients over a 10-year period. A total of 36 women and six men, mean age 54 years (range: 36-90 years), were included. The mean time interval between onset of ocular symptoms and diagnosis was 40 months (range: 1-144 months). Ocular involvement was bilateral in 84% of the cases. Laser flare photometry readings averaged 9.6 photons/ms (2.9-78.3 photons/ms). Vitritis was constant. Funduscopy revealed RPE abnormalities in 60.49% of the cases and punctuate retinal infiltrates in 33.5%. The most common findings with fluorescein angiography were window defects and hypofluorescent round lesions. Patients had CNS involvement in 66% of the cases. Cytologic examination of the vitreous samples showed high-grade B lymphoma in 86% of the cases. Interleukin-10 dosage, when performed, showed elevated levels averaging 2352 pg/ml in all vitreous samples. Molecular biology based on PCR confirmed the diagnosis in 12 patients. Treatment included systemic chemotherapy alone or associated with radiotherapy in various regimens. Fourteen patients died during follow-up. Only 12 patients were in complete remission. The prognosis of the disease remains poor. However, the new diagnostic tools and therapeutic strategies may improve the diagnostic delay and the survival outcome.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                6 February 2013
                : 8
                : 2
                : e52385
                Affiliations
                [1 ]Institut National de la Santé et de la Recherche Médicale, UMRS872, Centre de Recherche des Cordeliers, Paris, France
                [2 ]Université Pierre et Marie Curie-Paris 6, UMRS 872, Paris, France
                [3 ]Université Paris Descartes, UMRS 872, Paris, France
                [4 ]Généthon, Evry, France
                [5 ]Institut National de la Santé et de la Recherche Médicale, U951, Evry, France
                [6 ]Université d'Evry Val d'Essonne, UMRS 951, Evry, France
                [7 ]Service d'Ophtalmologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
                [8 ]Service d'Hématologie Biologique, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
                [9 ]Service d'Onco-ophtalmologie, Département d'Oncologie Chirurgicale, Institut Curie, Paris, France
                Massachusetts Eye & Ear Infirmary, Harvard Medical School, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Revised the article: WHF CSF NC HMB. Conceived and designed the experiments: SF. Performed the experiments: SF HO AM. Analyzed the data: SF HO. Contributed reagents/materials/analysis tools: VT SB RBA SD CG BB PLH MB MLGT NC HMB. Wrote the paper: SF HO RBA SD.

                Article
                PONE-D-12-22925
                10.1371/journal.pone.0052385
                3566156
                23405064
                36b032e2-2e74-4640-a209-4d0f1c866479
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 July 2012
                : 12 November 2012
                Page count
                Pages: 7
                Funding
                This work was supported by the Institut National du Cancer (Grants RC013-C06N631-2005 and C06N748-2006), the Association pour la Recherche contre le Cancer, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Pierre and Marie Curie, the Université Paris-Descartes, the pole de compétitivité Ile de France (ImmuCan project), the Tunisian Direction Générale de la Recherche Scientifique, and the French-Tunisian CMCU “(Egide-PHC Utique)” project. R.B.A. was a recipient of grants from the DGRS-INSERM and the CMCU. S.D. was recipient of a grant from the Institut National du Cancer. V.T. was a beneficiary of study grants from the Fédération des Aveugles de France and the Fondation de France (Fouassier). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Diagnostic Medicine
                Oncology
                Cancers and Neoplasms
                Head and Neck Tumors
                Lymphomas of the Head and Neck
                Neurological Tumors
                Primary CNS lymphoma
                Ophthalmologic Tumors
                Ocularlymphoma
                Ophthalmology
                Eye Infections
                Ocular Tumors

                Uncategorized
                Uncategorized

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