Publications by authors named "Kazuhiko Umazume"

26 Publications

  • Page 1 of 1

Clinico-epidemiological analysis of 1000 cases of orbital tumors.

Jpn J Ophthalmol 2021 Sep 27;65(5):704-723. Epub 2021 Jul 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To clarify the incidence, demography and clinical features of orbital tumors diagnosed in a single institute in Japan.

Study Design: Retrospective, observational case series.

Methods: Patients with primary orbital tumors including tumor-like lesions diagnosed clinically or histopathologically at Tokyo Medical University Hospital between 1995 and 2019 were analyzed. Incidence of all orbital tumors, demographic profile and clinical features of major benign and malignant tumors were reviewed retrospectively.

Results: Totally 1000 cases of primary orbital tumor were diagnosed clinically or histopathologically during the study period. Benign tumors accounted for 72% and malignant tumors 28%. 55% of benign tumors and 99% of malignant tumors were proven histopathologically. The most common benign orbital tumor was idiopathic orbital inflammation (27%), followed by IgG4-related ophthalmic disease (17%), cavernous venous malformation (13%) and pleomorphic adenoma (9%). The most common malignant tumor was lymphoma (70%), followed by adenoid cystic carcinoma (7%) and solitary fibrous tumor (5%).

Conclusions: Epidemiology of orbital tumors has changed by the improvement of imaging techniques, establishment of novel clinical and histopathological criteria, and changes in population age structure associated with the aging society. Currently, lymphoproliferative diseases including lymphoma and IgG4-related ophthalmic diseases form the major orbital tumors in Japan.
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http://dx.doi.org/10.1007/s10384-021-00857-1DOI Listing
September 2021

Clinicopathologic analysis of 32 ciliary body tumors.

Jpn J Ophthalmol 2021 Mar 19;65(2):237-249. Epub 2021 Feb 19.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To describe the demographic profile, clinical and histopathologic features, and treatment of ciliary body tumors.

Study Design: Retrospective, observational case series.

Methods: Thirty-two patients (32 eyes) with ciliary body tumors diagnosed histopathologically at Tokyo Medical University Hospital between 1994 and 2017 were retrospectively reviewed.

Results: The patients' mean age at diagnosis was 45.4 ± 17.0 (range, 14-87) years. Ten of the patients were male, and 22, female. Twenty-four cases (75%) were benign tumors, comprising 9 melanocytomas, 7 adenomas, 4 mesectodermal leiomyomas, 2 leiomyomas, and 2 other tumors; and 8 cases (25%) were malignant tumors, comprising 6 melanomas and 2 low-grade adenocarcinomas. Local resection of the tumor was performed in 20 patients, including 3 cases of melanoma and 2 cases of adenocarcinoma. Enucleation was initially performed in 3 cases of melanoma, 1 case of melanocytoma with iris melanoma, and 2 cases of benign tumors difficult to differentiate clinically from melanoma. In the 17 patients who underwent local resection and were followed for at least 3 years, the outcome was best-corrected visual acuity better than 0.1 logMAR in 8 patients (47%), but hand motions in 2 patients (12%).

Conclusions: Melanocytoma and adenoma of the ciliary epithelium were the major ciliary body tumors found in this study. Management of ciliary body tumors with accurate clinical diagnosis remains challenging because of the anatomic characteristics and clinical similarities to melanoma in the majority of the cases.
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http://dx.doi.org/10.1007/s10384-021-00814-yDOI Listing
March 2021

Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles.

Ophthalmology 2021 Aug 21;128(8):1197-1208. Epub 2021 Jan 21.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Purpose: Various immune mediators have crucial roles in the pathogenesis of intraocular diseases. Machine learning can be used to automatically select and weigh various predictors to develop models maximizing predictive power. However, these techniques have not yet been applied extensively in studies focused on intraocular diseases. We evaluated whether 5 machine learning algorithms applied to the data of immune-mediator levels in aqueous humor can predict the actual diagnoses of 17 selected intraocular diseases and identified which immune mediators drive the predictive power of a machine learning model.

Design: Cross-sectional study.

Participants: Five hundred twelve eyes with diagnoses from among 17 intraocular diseases.

Methods: Aqueous humor samples were collected, and the concentrations of 28 immune mediators were determined using a cytometric bead array. Each immune mediator was ranked according to its importance using 5 machine learning algorithms. Stratified k-fold cross-validation was used in evaluation of algorithms with the dataset divided into training and test datasets.

Main Outcome Measures: The algorithms were evaluated in terms of precision, recall, accuracy, F-score, area under the receiver operating characteristic curve, area under the precision-recall curve, and mean decrease in Gini index.

Results: Among the 5 machine learning models, random forest (RF) yielded the highest classification accuracy in multiclass differentiation of 17 intraocular diseases. The RF prediction models for vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma achieved the highest classification accuracy, precision, and recall. Random forest recognized vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma with the top 5 F-scores. The 3 highest-ranking relevant immune mediators were interleukin (IL)-10, interferon-γ-inducible protein (IP)-10, and angiogenin for prediction of vitreoretinal lymphoma; monokine induced by interferon γ, interferon γ, and IP-10 for acute retinal necrosis; and IL-6, granulocyte colony-stimulating factor, and IL-8 for endophthalmitis.

Conclusions: Random forest algorithms based on 28 immune mediators in aqueous humor successfully predicted the diagnosis of vitreoretinal lymphoma, acute retinal necrosis, and endophthalmitis. Overall, the findings of the present study contribute to increased knowledge on new biomarkers that potentially can facilitate diagnosis of intraocular diseases in the future.
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http://dx.doi.org/10.1016/j.ophtha.2021.01.019DOI Listing
August 2021

Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma.

Invest Ophthalmol Vis Sci 2021 01;62(1):15

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers.

Methods: We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromatography time-of-flight mass spectrometry. The altered metabolomic profiles were visualized by heat map and principal component analysis. Metabolic pathway analysis was performed by Metabo Analyst 4.0 using differentially expressed metabolites. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. Machine learning algorithms were implemented by random forest using the R environment. Finally, an independent set of 18 IgG4-ROD and 17 orbital MALT lymphoma specimens were used to validate the identified biomarkers.

Results: The principal component analysis showed a significant difference of both IgG4-ROD and orbital MALT lymphoma for biopsy specimens and controls. Interestingly, lesions in IgG4-ROD were uniquely enriched in arachidonic metabolism, whereas those in orbital MALT lymphoma were enriched in tricarboxylic acid cycle metabolism. We identified spermine as the best discriminator between IgG4-ROD and orbital MALT lymphoma, and the area under the receiver operating characteristic curve of the spermine to discriminate between the two diseases was 0.89 (95% confidence interval, 0.803-0.984). A random forest model incorporating a panel of five metabolites showed a high area under the receiver operating characteristic curve value of 0.983 (95% confidence interval, 0.981-0.984). The results of validation revealed that four tissue metabolites: N1,N12-diacetylspermine, spermine, malate, and glycolate, had statistically significant differences between IgG4-ROD and orbital MALT lymphoma with receiver operating characteristic values from 0.708 to 0.863.

Conclusions: These data revealed the characteristic differences in metabolomic profiles between IgG4-ROD and orbital MALT lymphoma, which may be useful for developing new diagnostic biomarkers and elucidating the pathogenic mechanisms of these common orbital lymphoproliferative disorders.
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http://dx.doi.org/10.1167/iovs.62.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814356PMC
January 2021

Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing.

J Clin Med 2020 Oct 27;9(11). Epub 2020 Oct 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls ( = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ≥ 2 and < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs.
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http://dx.doi.org/10.3390/jcm9113458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693346PMC
October 2020

Distinctive Tissue and Serum MicroRNA Profile of IgG4-Related Ophthalmic Disease and MALT Lymphoma.

J Clin Med 2020 Aug 5;9(8). Epub 2020 Aug 5.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since the work-up and treatment can vary greatly, is often challenging due to the lack of specific biomarkers. Although miRNAs play an important role in the regulation of carcinogenesis and inflammation, the relationship between miRNA and orbital lymphoproliferative diseases remains unknown. We performed a comprehensive analysis of 2565 miRNAs from biopsy and serum specimens of 17 cases with IgG4-ROD, where 21 cases with orbital MALT lymphoma were performed. We identified specific miRNA signatures and their miRNA target pathways, as well as the network analysis for IgG4-ROD and orbital MALT lymphoma. Machine-learning analysis identified miR-202-3p and miR-7112-3p as the best discriminators of IgG4-ROD and orbital MALT lymphoma, respectively. Enrichment analyses of biological pathways showed that the longevity-regulating pathway in IgG4-ROD and the mitogen-activated protein kinase (MAPK) signaling pathway in orbital MALT lymphoma was most enriched by target genes of downregulated miRNAs. This is the first evidence of miRNA profiles of biopsy and serum specimens of patients with IgG4-ROD and orbital MALT lymphoma. These data will be useful for developing diagnostic and therapeutic interventions, as well as elucidating the pathogenesis of these disorders.
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http://dx.doi.org/10.3390/jcm9082530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464164PMC
August 2020

Clinical features and prognosis of sebaceous carcinoma arising in the eyelid or conjunctiva.

Jpn J Ophthalmol 2020 Sep 8;64(5):549-554. Epub 2020 Jul 8.

Department of Plastic Surgery, Tokyo Medical University, Tokyo, Japan.

Purpose: The aim of this study was to clarify the demographics, clinical features, and outcomes of Japanese patients with sebaceous carcinoma of the eyelid or conjunctiva.

Study Design: Retrospective study.

Methods: One hundred twenty-five patients with sebaceous carcinoma of the eyelid or conjunctiva diagnosed at Tokyo Medical University Hospital between 1994 and 2017 were reviewed. The outcomes of the 116 patients who were treated and followed for at least 24 months at our hospital were investigated.

Results: The patients reviewed comprised 52 men and 74 women. The average age at diagnosis was 70.6 ± 13.8 (range 31-96) years. The main lesion was located in the upper eyelid in 51% of the patients; in the lower eyelid in 38% of the patients; and in other regions in 11% of the patients. Treatments included surgical resection with or without eyelid reconstruction in 108 cases (93%), orbital exenteration in 5 cases (4%), and radiation therapy in 3 cases (3%). Local recurrence was detected in 11 cases (9%). Metastasis to the regional lymph nodes was confirmed in 10 cases (9%). Four patients (3%) died because of direct intracranial invasion of the tumor. Risk of local recurrence and metastasis was significantly related to larger tumor size.

Conclusion: Proper diagnosis and treatment at the optimal timing is critical to improve the outcome of sebaceous carcinoma of the eyelid or conjunctiva. Long-term follow-up is required because local recurrence and metastasis may occur several years after treatment.
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http://dx.doi.org/10.1007/s10384-020-00756-xDOI Listing
September 2020

High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis.

J Clin Med 2020 Jun 12;9(6). Epub 2020 Jun 12.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Purpose: Vitreoretinal lymphoma (VRL) is a non-Hodgkin lymphoma of the diffuse large B cell type (DLBCL), which is an aggressive cancer causing central nervous system related mortality. The pathogenesis of VRL is largely unknown. The role of microRNAs (miRNAs) has recently acquired remarkable importance in the pathogenesis of many diseases including cancers. Furthermore, miRNAs have shown promise as diagnostic and prognostic markers of cancers. In this study, we aimed to identify differentially expressed miRNAs and pathways in the vitreous and serum of patients with VRL and to investigate the pathogenesis of the disease.

Materials And Methods: Vitreous and serum samples were obtained from 14 patients with VRL and from controls comprising 40 patients with uveitis, 12 with macular hole, 14 with epiretinal membrane, 12 healthy individuals. The expression levels of 2565 miRNAs in serum and vitreous samples were analyzed.

Results: Expression of the miRNAs correlated significantly with the extracellular matrix (ECM) ‒receptor interaction pathway in VRL. Analyses showed that miR-326 was a key driver of B-cell proliferation, and miR-6513-3p could discriminate VRL from uveitis. MiR-1236-3p correlated with vitreous interleukin (IL)-10 concentrations. Machine learning analysis identified miR-361-3p expression as a discriminator between VRL and uveitis.

Conclusions: Our findings demonstrate that aberrant microRNA expression in VRL may affect the expression of genes in a variety of cancer-related pathways. The altered serum miRNAs may discriminate VRL from uveitis, and serum miR-6513-3p has the potential to serve as an auxiliary tool for the diagnosis of VRL.
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http://dx.doi.org/10.3390/jcm9061844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356511PMC
June 2020

Successful Treatment of Necrotizing Retinitis with Epstein-Barr Virus-Positive Ocular Fluid by Intravitreal Methotrexate Injection.

Ocul Immunol Inflamm 2020 May 3;28(4):552-555. Epub 2019 Jul 3.

Department of Ophthalmology, Tokyo Medical University , Tokyo, Japan.

Purpose: To present a case of necrotizing retinitis with Epstein-Barr virus (EBV)-positive ocular fluid in a patient with sudden unilateral vision loss, which was successfully treated with intravitreal methotrexate (MTX) injections.

Methods: Retrospective case report.

Results: An 83-year-old female who had been on methylprednisolone for 20 years due to interstitial pneumonia developed vitreous opacity and extensive necrotizing retinitis with retinal hemorrhage sparing the posterior pole in the left eye. Multiplex polymerase chain reaction (PCR) for viral DNA using vitreous sample was positive for EBV but negative for herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Real-time PCR detected EBV-DNA in aqueous humor but not in peripheral blood sample. Serologic testing was negative for , syphilis, and HIV. The patient did not respond to systemic ganciclovir or acyclovir. Subsequent treatment with intravitreal MTX resulted in immediate clinical improvement correlating with a decrease in copy number of EBV-DNA.

Conclusion: Intravitreal MTX may be an effective treatment option for patients with necrotizing retinitis and EBV-positive ocular fluid not responding to conventional antiviral therapy.
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http://dx.doi.org/10.1080/09273948.2019.1609047DOI Listing
May 2020

Absence of Posterior Vitreous Detachment Is a Risk Factor of Severe Bleb-Related Endophthalmitis.

J Ophthalmol 2019 14;2019:1585830. Epub 2019 Jan 14.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: Bleb-related endophthalmitis (BRE) after glaucoma surgery is an infection caused by bacteria in the avascular bleb gaining access into the eye. We report the clinical features and outcome of 10 consecutive eyes with severe BRE treated at our hospital.

Methods: Ten patients (10 eyes) with stage IIIb BRE after trabeculectomy diagnosed and treated at the Department of Ophthalmology, Tokyo Medical University, between April 2013 and May 2015, were studied. Patient background, type of glaucoma, interval from the first trabeculectomy, pretreatment bleb findings, causative microorganisms, surgical methods, status of posterior vitreous detachment (PVD), and postoperative visual acuity were examined.

Results: The 10 patients comprised 8 males and 2 females, with mean age of 70.6 years at BRE onset. The types of glaucoma were open-angle glaucoma in 7 patients, neovascular glaucoma in 2, and secondary glaucoma in 1. All eyes underwent trabeculectomy combined with mitomycin C prior to the development of BRE. The interval from the first glaucoma surgery to onset of endophthalmitis was 8.5 ± 4.1 years. Examination of the bleb revealed leakage of aqueous humor from the avascular bleb in all eyes. Bacteria were isolated from intraocular samples of 8 eyes; namely, in 5 eyes, in 1, in 1, and coagulase-negative Staphylococci in 1. BRE was treated by vitrectomy in 9 eyes and enucleation in 1 eye. PVD was produced intentionally during vitrectomy in 6 eyes. Histopathological examination of the enucleated eye showed no PVD. Visual acuity improved by 3 lines or more in 6 patients, while decimal visual acuity remained lower than 0.1 in 4 patients.

Conclusion: BRE developed frequently in eyes with no PVD. The absence of PVD may be a risk factor of severe BRE.
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http://dx.doi.org/10.1155/2019/1585830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348893PMC
January 2019

Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Müller cells.

Exp Eye Res 2017 11 15;164:90-94. Epub 2017 Aug 15.

Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd., Louisville, KY 40202, USA. Electronic address:

Transdifferentiated Müller cells that adopt a fibroblastic/myofibroblastic phenotype have been identified in epiretinal membranes (ERMs) in several ocular disorders, and have been implicated to play a role in the formation and/or the contraction of ERMs. We have previously demonstrated that dasatinib, a dual inhibitor of Src-family kinases and Abl kinase, can prevent matrix contraction by transdifferentiated Müller cells. In this study, we examined molecules involved in matrix contraction downstream of primary dasatinib targets. Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAK and PYK2, and PF573228, which only inhibits FAK and not PYK2, significantly reduced matrix contraction by transdifferentiated Müller cells. Dasatinib and PF431396 significantly reduced phosphorylation of Hic-5, a protein implicated to play a role in focal adhesions and cell signaling. Our data shows that FAK family members are involved in matrix contraction by transdifferentiated Müller cells, and also implicates that Hic-5 is situated downstream of the FAK family within the signaling pathway.
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http://dx.doi.org/10.1016/j.exer.2017.08.010DOI Listing
November 2017

A Case of Choroidal Melanoma Resulted in Eyeball Enucleation 2 Years after Carbon Ion Radiotherapy Due to Local Recurrence.

Nippon Ganka Gakkai Zasshi 2017 May;121(5):419-24

Background: Recently, carbon ion radiotherapy (CIR) has become the standard therapy for choroidal melanoma to preserve the eyeballs in Japan. We report a case of choroidal melanoma resulting in eyeball enucleation 2 years after carbon ion radiotherapy due to local recurrence. Case: A 64-year-old man was referred to Tokyo Medical University hospital with a diagnosis of choroidal tumor. Intraocular tumor was located at the equator of temporal area in ocular fundus. After systemic work-up, clinical diagnosis of choroidal melanoma was made and CIR was applied. After CIR, the intraocular tumor was stable for 2 years. However, 2 years and 3 months after CIR, local recurrence of the tumor was detected. Eventually, the eyeball was enucleated. Histopathologically, the original lesion was composed of melanoma cells containing abundant melanin pigments, and these cells were positive for HMB-45, Melan-A and S-100 protein. In contrast, the recurrent lesion showed lack of melanin pigment and proved less positive for HMB-45, Melan-A and S-100 protein. Four months after enucleation, the patient developed liver metastasis and received the appropriate supportive care. Conclusions: Even after CIR with remission, choroidal melanoma can recur. Recurrent lesions of the tumor may reveal alternative histopathological findings compared to the original lesion.
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May 2017

Clinical Analysis of Uveal Melanoma.

Nippon Ganka Gakkai Zasshi 2017 May;121(5):413-8

Purpose: To clarify clinical features of patients with uveal melanoma. Method: We analyzed 125 eyes of 125 patients diagnosed as uveal melanoma from 1992 to 2014 retrospectively. Results: The mean age of the patients at the time of diagnosis was 58.1±14.4 years. Tumors were originated in the choroid (93%), ciliary body (4%) and iris (3%). The main reasons leading to diagnosis included decreased vision (27%), visual field loss (17%), and no significant symptoms (16%). Average tumor size of the choroidal melanoma was 10.4 mm in largest basal diameter and 7.2 mm in height. Treatment included enucleation of eyeball (53 cases), local resection of the tumor (4 cases), heavy particle beam therapy (18 cases), and brachytherapy (4 cases). Extraocular metastasis was detected in 22% of the patients, and 89% of them died within 5 years. Five-year survival rate was 20% in 6 cases (13.6%) in whom histopathologic studies revealed extrascleral invasions. Conclusions: Prognosis of patients with metastatic uveal melanoma is extremely poor. Early diagnosis and treatment, and establishment of follow-up system after local treatment are critical. Further development and dissemination of novel treatment for metastatic melanoma is desired.
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May 2017

EFFICACY OF THE INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE WITH VITRECTOMY FOR RETINAL DETACHMENT ASSOCIATED WITH MYOPIC MACULAR HOLES.

Retina 2017 Mar;37(3):466-471

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To evaluate the anatomical and functional outcome of the inverted internal limiting membrane (ILM) flap technique with vitrectomy for retinal detachment associated with macular hole (MHRD) in highly myopic eyes.

Methods: In this retrospective observational study, 21 eyes with MHRD that underwent vitrectomy with conventional ILM peeling (ILM-peeling group, n = 11) or the inverted ILM flap technique (ILM flap group, n = 10) combined with C3F8 tamponade were enrolled in this study. The initial retinal reattachment rate, macular hole closure rate, and postoperative visual acuity at the final visit were compared between the ILM-peeling group and ILM flap group.

Results: There was no significant difference in the retinal reattachment rate between ILM-peeling and ILM flap groups (91% and 100%, respectively). The macular hole closure rate in the ILM flap group was 80% (8 of 10 eyes), and was significantly higher than 36% (4 of 11 eyes) in the ILM-peeling group (P = 0.039). Among 12 eyes that achieved macular hole closure, there was no significant difference in median visual acuity after vitrectomy between the ILM flap group and ILM-peeling group (logMAR unit [Snellen acuity]: 1.0 [20/200] and 0.76 [20/125], respectively, P = 0.300).

Conclusion: Compared with conventional ILM peeling, the inverted ILM flap technique was more effective for macular hole closure after vitrectomy for MHRD in myopic eye but showed no advantage in the postoperative visual outcome in this study.
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http://dx.doi.org/10.1097/IAE.0000000000001211DOI Listing
March 2017

PERSISTENT OVERPRODUCTION OF INTRAOCULAR VASCULAR ENDOTHELIAL GROWTH FACTOR AS A CAUSE OF LATE VITREOUS HEMORRHAGE AFTER VITRECTOMY FOR PROLIFERATIVE DIABETIC RETINOPATHY.

Retina 2017 Dec;37(12):2317-2325

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: The purpose of this study was to investigate whether vitreous levels of vascular endothelial growth factor (VEGF) predict late vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy, and how VEGF level changes in patients with postoperative late VH.

Methods: Eighty-five eyes of 68 patients with proliferative diabetic retinopathy who underwent vitrectomy were analyzed retrospectively. Vitreous samples were collected from eyes undergoing primary vitrectomy and from eyes with late VH undergoing second vitrectomy. Vitreous VEGF levels were measured using enzyme-linked immunosorbent assay. The relationship between VEGF level and late VH (>4 weeks) occurring during follow-up as well as clinical findings, and changes in VEGF level in eyes with late VH undergoing second vitrectomy were analyzed.

Results: Late VH occurred in 20 (24%) of 85 eyes, and 9 eyes required second vitrectomy. Vitreous levels of VEGF were significantly higher (median: 1,945 pg/mL; P < 0.0001) in eyes with late VH than in those without. Preexisting iris neovascularization (P < 0.0001), hypertension (P = 0.002), and proteinuria (P = 0.040) were also significant risk factors of late VH. Multivariate logistic regression analysis showed that a higher vitreous VEGF level was independently associated with a risk of postoperative late VH in patients with proliferative diabetic retinopathy (odds ratio: 20.8, 95% confidence interval: 2.72-159.47; P = 0.003). Vitreous VEGF level at second vitrectomy in patients with late VH was significantly lower compared with that at primary vitrectomy, but remained elevated (median: 1,610 pg/mL; P = 0.023).

Conclusion: In patients with proliferative diabetic retinopathy, high intraocular VEGF level at primary vitrectomy was identified as an independent risk factor of postoperative late VH. Persistent overproduction of intraocular VEGF may be associated with postoperative late VH.
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http://dx.doi.org/10.1097/IAE.0000000000001490DOI Listing
December 2017

Aqueous immune mediators in malignant uveal melanomas in comparison to benign pigmented intraocular tumors.

Graefes Arch Clin Exp Ophthalmol 2017 Feb 22;255(2):393-399. Epub 2016 Nov 22.

Department of Ophthalmology, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Background: To examine the usefulness of measuring immune mediators in aqueous humor samples for differentiating malignant uveal melanoma from benign pigmented intraocular tumors.

Methods: Thirteen eyes of 13 patients with uveal melanoma were studied, and 13 eyes of 13 patients with benign pigmented intraocular tumors served as controls. Undiluted samples of aqueous humor were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 35 immune mediators comprising 14 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T cell expressed and secreted, monokine induced by interferon-γ, basic fibroblast growth factor, Fas ligand, granzyme A, granzyme B, eotaxin, interferon-inducible T-cell alpha chemoattractant, fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, vascular endothelial growth factor, angiogenin, tumor necrosis factor-α, lymphotoxin-α, and CD40L.

Results: Aqueous humor levels of angiogenin, IL-8, and MCP-1 were significantly higher in eyes with malignant melanoma than in those with benign tumors (p < 0.05).

Conclusions: Angiogenin, IL-8, and MCP-1 levels in aqueous humor may be potential markers for distinguishing malignant uveal melanoma from benign pigmented intraocular tumors, and may be a useful adjunct to histomorphology, diagnostic imaging, and other biomarkers for the diagnosis and appropriate clinical management of malignant uveal melanoma.
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http://dx.doi.org/10.1007/s00417-016-3541-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285432PMC
February 2017

Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa.

Sci Rep 2016 11 10;6:36621. Epub 2016 Nov 10.

Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.

Infectious agents have been identified as a major cause of specific types of human cancers worldwide. Several microorganisms have been identified as potential aggravators of ocular adnexal neoplasms; however, given the rarity of these neoplasms, large epidemiological studies are difficult to coordinate. This study aimed to conduct an exhaustive search for pathogenic DNA in lymphoproliferative disorders (LPD) of the ocular adnexa in a total of 70 patients who were diagnosed with LPD of the ocular adnexa between 2008 and 2013. Specimens were screened for bacterial, viral, fungal, and parasitic DNA by multiplex polymerase chain reaction (PCR) and quantitative real-time PCR. Among cases of conjunctival mucosa-associated lymphoid tissue lymphoma, human herpes virus (HHV)-6, HHV-7, chlamydia, Epstein-Barr virus (EBV) and bacterial 16S ribosomal DNA were detected. In cases of IgG4-related ocular disease, similar pathogens were detected but in a larger number of patients. Our PCR assays detected DNAs of various infectious agents in tumor specimens, especially HHV6, HHV7, and EBV, with different positive rates in various types of LPD. Chronic inflammatory stimulation or activation of oncogenes from these infectious agents might be involved in the pathogenesis of LPD of the ocular adnexa.
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http://dx.doi.org/10.1038/srep36621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103257PMC
November 2016

Possible Relation between Lack of Posterior Vitreous Detachment and Severe Endogenous Endophthalmitis.

J Ophthalmol 2016 27;2016:8561379. Epub 2016 Sep 27.

Department of Ophthalmology and Visual Sciences, Tokyo Medical University, Tokyo, Japan.

. Endogenous endophthalmitis (EE) is a rare ocular disease caused by bacterial or fungal infection of intraocular spaces by hematogenous spread of pathogens from distant infectious loci in the body. We investigated the clinical characteristics and management of eyes with EE in ten consecutive patients. . Ten patients (10 eyes) with EE treated at Tokyo Medical University Hospital in 2014 were reviewed. We retrospectively studied the causative organisms, systemic complications, pre/postoperative mean best-corrected visual acuity (BCVA), and status of posterior vitreous detachment (PVD). . The 10 patients comprised 8 males and 2 females, with mean age of 71.2 years. The causative organisms were bacteria in 6 eyes and fungi in 4 eyes. Systemic complications included septicemia or disseminated intravascular coagulation in 5 patients and diabetes mellitus in 4 patients. Postoperative BCVA was improved by 0.2log⁡MAR or greater in 4 eyes and decreased in 4 eyes. Vitrectomy was performed in all eyes, and 4 required multiple surgeries. During vitrectomy, PVD was absent in 8 eyes, 4 of which showed retinal necrosis. The mean age of patients with no PVD was 71.2 years. . Despite an advanced age, PVD was absent in the majority of patients with EE. PVD may be related to the pathogenesis and aggravation of EE.
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http://dx.doi.org/10.1155/2016/8561379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059565PMC
September 2016

Dasatinib affects focal adhesion and myosin regulation to inhibit matrix contraction by Müller cells.

Exp Eye Res 2015 Oct 1;139:90-6. Epub 2015 Aug 1.

Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA; Department of Biochemistry and Molecular Genetics, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA. Electronic address:

Epiretinal membrane (ERM) contraction is associated with a variety of ocular diseases that cause macular dysfunction. Trans-differentiated Müller cells have been identified in ERMs, and have been implicated to be involved in the contractile process. In this study, we tested the effect of dasatinib, an FDA-approved tyrosine kinase inhibitor, on matrix contraction caused by Müller cells, and examined molecular mechanism of action. Type I collagen matrix contraction assays were used to examine the effect of drugs on matrix contraction by trans-differentiated Müller cells. Fluophore-conjugated phalloidin was used for the detection of actin cytoskeleton, and Western-blot analyses were carried out to examine protein expression and phosphorylation status. Dasatinib inhibited collagen matrix contraction by trans-differentiated Müller cells that was associated with decreased cell spreading and reduction of actomyosin stress fibers. Concomitantly, dasatinib-treated Müller cells had reduced phosphorylation of Src family kinase, paxillin, as well as myosin II light chain. Specific inhibitors of Rho/ROCK and myosin II confirmed the critical role played by this pathway in Müller cell contraction. Our data demonstrate that dasatinib significantly reduced matrix contraction by Müller cells via inhibition of focal adhesion, as well as actomyosin contraction.
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http://dx.doi.org/10.1016/j.exer.2015.07.019DOI Listing
October 2015

Profile of intraocular immune mediators in patients with age-related macular degeneration and the effect of intravitreal bevacizumab injection.

Retina 2014 Sep;34(9):1811-8

*Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan; and †Department of Ophthalmology, National Defense Medical College, Saitama, Japan.

Purpose: To measure intraocular cytokine levels in patients with exudative age-related macular degeneration and analyze changes in the cytokine profile 2 days after intravitreal bevacizumab injection.

Methods: This prospective case-control study enrolled 37 patients (37 eyes) with age-related macular degeneration including polypoidal choroidal vasculopathy. Twenty-eight age-matched patients (28 eyes) who underwent cataract surgery were used as controls. Undiluted aqueous humor samples were collected after intravitreal bevacizumab injection. Two days after intravitreal bevacizumab injection, cataract surgery was performed and undiluted aqueous humor samples were collected at the beginning of surgery (10 eyes). Twenty-three cytokines were measured using flow cytometry. P values were corrected in multiple comparisons using the conservative Bonferroni-Holm method. The level of significance was set at 0.0022 (0.05/23).

Results: At baseline, aqueous humor levels of vascular endothelial growth factor, angiogenin, interferon gamma-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1β, monokine induced by interferon γ (Mig), and monocyte chemotactic protein (MCP)-1 were significantly higher in the age-related macular degeneration group than in the control group (P < 0.0022). The result of exploratory multivariate analysis showed that elevated angiogenin level was an important factor that discriminates the two groups (P = 0.0004). Two days after intravitreal bevacizumab injection, vascular endothelial growth factor levels tended to be reduced (P = 0.049), whereas interleukin (IL)-6 and IL-8 levels increased significantly (P < 0.0022).

Conclusion: Vascular endothelial growth factor and also angiogenin, IP-10, MCP-1, MIP-1β, and Mig may be related to the pathogenesis of age-related macular degeneration. Intravitreal bevacizumab injection increases inflammatory cytokine levels, suggesting the induction of an inflammatory process.
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http://dx.doi.org/10.1097/IAE.0000000000000157DOI Listing
September 2014

Role of retinal pigment epithelial cell β-catenin signaling in experimental proliferative vitreoretinopathy.

Am J Pathol 2014 May 18;184(5):1419-28. Epub 2014 Mar 18.

Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky. Electronic address:

Proliferative vitreoretinopathy is caused by the contraction of fibrotic membranes on the epiretinal surface of the neurosensory retina, resulting in a traction retinal detachment and loss of visual acuity. Retinal pigment epithelial (RPE) cells play an important role in formation of such fibrotic, contractile membranes. We investigated the role of Wnt/β-catenin signaling, a pathway implicated in several fibrotic diseases, in RPE cells in proliferative vitreoretinopathy. In vitro culture of swine RPE sheets resulted in nuclear translocation of β-catenin in dedifferentiated RPE cells. FH535, a specific inhibitor of β-catenin signaling, reduced the outgrowth of cultured RPE sheets and prevented dedifferentiated RPE cell proliferation and migration. It also inhibited formation of contractile membranes by dedifferentiated RPE cells on collagen I matrices. Expression and function of the β-catenin signaling target connexin-43 were down-regulated by FH535, and functional blockade of connexins with carbenoxolone also prevented the in vitro formation of fibrotic, contractile membranes. Intravitreal injection of FH535 in swine also inhibited formation of dense, contractile membranes on the epiretinal surface and prevented development of traction retinal detachment. These findings demonstrate that β-catenin signaling is involved in formation of contractile membranes by dedifferentiated RPE cells and suggest that adjunctive treatment targeting this pathway could be useful in preventing proliferative vitreoretinopathy.
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http://dx.doi.org/10.1016/j.ajpath.2014.01.022DOI Listing
May 2014

Axial length as a factor associated with visual outcome after vitrectomy for diabetic macular edema.

Invest Ophthalmol Vis Sci 2013 Oct 21;54(10):6834-40. Epub 2013 Oct 21.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To investigate whether axial length predicts visual acuity outcome after vitrectomy for diffuse macular edema secondary to diabetic retinopathy.

Methods: Fifty-one eyes of 41 patients with diabetic macular edema (DME) who underwent vitrectomy were reviewed retrospectively. Clinical data, including axial length measured by partial coherence interferometry, postoperative best-corrected visual acuity (BCVA), and postoperative status of integrity of the photoreceptor layer observed by optical coherence tomography, were recorded. The relationship between axial length and postoperative BCVA or visibility of the junction between the inner and outer segment (IS/OS) line at 12 months after surgery were analyzed. Logistic regression analyses were performed to examine predictors related to postoperative BCVA.

Results: Median BCVA improved significantly (P < 0.0001) after surgery (0.4 logMAR units; range, 0-1.5) compared to baseline (0.69 logMAR units; range, 0.22-1.22). Median axial length was significantly longer (P = 0.017) when postoperative BCVA was below 0.4 logMAR units (23.51 mm; range, 22.30-26.10) compared to over 0.4 logMAR units (23.02 mm; range, 22.10-24.65). A significant negative correlation was observed between postoperative logMAR and axial length (n = 51, rs = -0.35, P = 0.012). Median axial length was significantly longer (P = 0.039) in eyes with visible IS/OS line (23.54 mm; range, 22.39-26.10) than in those without visible IS/OS line (23.02 mm; range, 22.13-24.65) at 12 months after surgery. Multivariate logistic regression analysis showed that short axial length (odds ratio: 0.3, P = 0.009) increased the risk of poor visual outcome after surgery.

Conclusions: Longer axial length predicts better postoperative BCVA after vitrectomy for diffuse macular edema secondary to diabetic retinopathy.
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http://dx.doi.org/10.1167/iovs.13-12519DOI Listing
October 2013

Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine.

Invest Ophthalmol Vis Sci 2013 Feb 1;54(2):1150-9. Epub 2013 Feb 1.

Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40202, USA.

Purpose: We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR).

Methods: The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.

Results: Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.

Conclusions: Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR.
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http://dx.doi.org/10.1167/iovs.12-10418DOI Listing
February 2013

Effects of soluble CD14 and cytokine levels on diabetic macular edema and visual acuity.

Retina 2013 May;33(5):1020-5

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: The pathogenesis of diabetic retinopathy has been suggested to be associated with ocular inflammation. Macrophages and monocytes that infiltrate the eye are known to express CD14. After shedding from the membrane-bound CD14, soluble CD14 (sCD14) is released, which could potentially activate inflammatory signaling. In this study, the authors investigated ocular fluid and serum levels of vascular endothelial growth factor (VEGF), sCD14, and other inflammatory cytokines in patients with diabetic macular edema (DME). Furthermore, the authors determined any potential correlation between these factors and visual acuity.

Methods: Vitreous fluid, aqueous humor, and serum samples from 14 eyes with DME and 24 control eyes were investigated. Soluble CD14, interleukin 8, interferon-inducible protein 10, monocyte chemotactic protein 1, monokine induced by interferon γ, and VEGF were measured simultaneously by FACSCalibur flow cytometer. Visual acuity was measured in all patients with DME before surgery, with the assessors being blinded to the patients' diagnoses.

Results: All factors were significantly elevated in vitreous fluid of DME eyes. Soluble CD14 and VEGF levels in vitreous fluid and aqueous humor were significantly higher in patients with DME than in nondiabetic controls (P < 0.05). In patients with DME, vitreous and aqueous humor concentrations of sCD14 correlated significantly. In these patients, vitreous fluid concentration of sCD14 correlated significantly with that of VEGF or interleukin 8 or monocyte chemotactic protein 1. In addition, there was a significant positive correlation between preoperative visual acuity and intraocular sCD14 concentrations.

Conclusion: Soluble CD14 may act as key regulator of VEGF production and contribute to the pathogenesis of diabetic retinopathy.
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http://dx.doi.org/10.1097/IAE.0b013e31826f0688DOI Listing
May 2013

Proliferative vitreoretinopathy in the Swine-a new model.

Invest Ophthalmol Vis Sci 2012 Jul 24;53(8):4910-6. Epub 2012 Jul 24.

Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY, USA.

Purpose: To develop a large animal model of proliferative vitreoretinopathy (PVR) in the swine to eventually study disease pathophysiology, as well as novel therapies.

Methods: PVR was induced in domestic swine by creation of a posterior vitreous detachment, creation of a retinal detachment by the injection of subretinal fluid, and intravitreal injection of green fluorescent protein-positive retinal pigment epithelial (GFP+ RPE) cells. Control eyes had the same surgical procedures without RPE cell injection. PVR was clinically graded on days 3, 7, and 14. Animals were euthanized on day 14, and enucleated eyes were analyzed by light microscopy and immunohistochemistry.

Results: Injection of GFP+ RPE cells into the vitreous cavity produced localized, traction retinal detachments by day 14 in all eyes (14 of 14); in contrast, the retina spontaneously reattached by day 3 and remained attached in all control eyes (10 of 10). Contractile epiretinal membranes on the inner retinal surface that caused the traction retinal detachments consisted predominantly of GFP+ RPE cells. These cells stained positive for cytokeratin, confirming their epithelial origin, and also expressed α-SMA and fibronectin, markers for myofibroblasts and fibrosis, respectively.

Conclusions: We established a swine PVR model that recapitulates key clinical features found in humans and, thus, can be used to study the pathophysiology of PVR, as well as new novel therapies. GFP+ RPE cells injected into the vitreous cavity formed contractile membranes on the inner retinal surface and caused localized traction retinal detachments.
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http://dx.doi.org/10.1167/iovs.12-9768DOI Listing
July 2012

[Review of clinical features of circumscribed choroidal hemangioma in 28 cases].

Nippon Ganka Gakkai Zasshi 2011 May;115(5):454-9

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.

Purpose: To review the clinical features and management of circumscribed choroidal hemangioma.

Methods: Twenty eight cases of circumscribed choroidal hemangioma diagnosed at Tokyo Medical University Hospital from 1991 through 2008 were reviewed. We retrospectively studied the frequency of the individual tumors, gender, age, size of tumors, presence of serous detachment and hyperopia, management and outcome.

Results: Sixteen patients were men and 12 cases were women. The average age was 55 years. The average basal diameter of the tumors was 3.3 optic disc. Serous retinal detachment was observed in 19 cases (70%). Seventeen eyes agreed with the definition of hyperopia, 10 cases (59%) developed hyperopia. Thirteen cases (46%) were observed without any treatment, 10 cases(36%) were treated with transpupillary thermotherapy (TTT) and 5 cases (18%) were treated with dye laser. Thirteen cases (46%) showed improvement, 13 cases (46%) remained constant and 2 cases (7%) showed deterioration.

Conclusion: Circumscribed choroidal hemangioma is a relatively rare clinical entity. The management should be tailored to the individual patients including the tumor size presence of serous detachement and visual acuity.
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May 2011
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