Publications by authors named "Kinya Tsubota"

25 Publications

  • Page 1 of 1

Intraocular surgery under adalimumab therapy in patients with refractory uveitis: a single center study of 23 eyes.

Jpn J Ophthalmol 2021 Sep 7. Epub 2021 Sep 7.

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

Purpose: We assessed the efficacy and safety of performing intraocular surgery for refractory uveitis under adalimumab (ADA) therapy.

Study Design: Single-center cohort study between 2016 and 2019.

Methods: In uveitis patients undergoing intraocular surgery under ADA treatment, we collected clinical data before surgery, and at the first visit, 6 months and last visit after surgery (follow-up 19.3 ± 8.1 months). Primary outcomes were visual acuity (VA) improvement in patients after cataract surgery, intraocular pressure (IOP) in patients after trabeculectomy and intraocular inflammation in all patients. Secondary outcomes were activated inflammation, vitreous opacity (OCV), uveitic macula edema (UME) and infection.

Results: Of 81 patients (161 eyes) initiated ADA therapy for uveitis, 19 patients (23 eyes) underwent intraocular surgery and were analyzed. Twelve of 18 eyes (66.6%) that underwent cataract surgery or vitrectomy with/without cataract surgery had improved VA at the last visit compared to before surgery. All 5 eyes that underwent trabeculectomy showed controlled IOP 6 months after surgery. Intraocular inflammation was resolved in 22 of 23 eyes at the first postoperative visit. Postoperative intraocular inflammation recurred in 3 eyes; 2 with UME, 1 with OCV. No eyes developed infection postoperatively. Preoperative ADA therapy duration was unrelated to relapse of intraocular inflammation.

Conclusion: Surgery for refractory uveitis under ADA treatment is safe and achieves good visual outcome and uveitis control if inflammation exists before surgery. ADA does not increase the risk of infections. Intraoperative findings of UME at surgery requires attention for postoperative relapse.
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http://dx.doi.org/10.1007/s10384-021-00871-3DOI Listing
September 2021

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

Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis.

J Clin Med 2020 Dec 17;9(12). Epub 2020 Dec 17.

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

Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features.

Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored.

Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement ( < 0.001). The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D ( = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement (25% versus 6%, = 0.004). Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA (37% versus 5%, ≤ 0.001).

Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients.
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http://dx.doi.org/10.3390/jcm9124084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766793PMC
December 2020

Serum Metabolomic Profiling of Patients with Non-Infectious Uveitis.

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

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

The activities of various metabolic pathways can influence the pathogeneses of autoimmune diseases, and intrinsic metabolites can potentially be used to diagnose diseases. However, the metabolomic analysis of patients with uveitis has not yet been conducted. Here, we profiled the serum metabolomes of patients with three major forms of uveitis (Behҫet's disease (BD), sarcoidosis, and Vogt-Koyanagi-Harada disease (VKH)) to identify potential biomarkers. This study included 19 BD, 20 sarcoidosis, and 15 VKH patients alongside 16 healthy control subjects. The metabolite concentrations in their sera were quantified using liquid chromatography with time-of-flight mass spectrometry. The discriminative abilities of quantified metabolites were evaluated by four comparisons: control vs. three diseases, and each disease vs. the other two diseases (such as sarcoidosis vs. BD + VKH). Among 78 quantified metabolites, 24 kinds of metabolites showed significant differences in these comparisons. Four multiple logistic regression models were developed and validated. The area under the receiver operating characteristic (ROC) curve (AUC) in the model to discriminate disease groups from control was 0.72. The AUC of the other models to discriminate sarcoidosis, BD, and VKH from the other two diseases were 0.84, 0.83, and 0.73, respectively. This study provides potential diagnostic abilities of sarcoidosis, BD, and VKH using routinely available serum samples that can be collected with minimal invasiveness.
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http://dx.doi.org/10.3390/jcm9123955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762156PMC
December 2020

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

Comprehensive miRNA Analysis Using Serum From Patients With Noninfectious Uveitis.

Invest Ophthalmol Vis Sci 2020 09;61(11)

Department of Ophthalmology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Purpose: MicroRNAs (miRNAs) are noncoding RNAs and have attracted attention as a biomarker in a variety of diseases. However, extensive unbiased miRNAs analysis in patients with uveitis has not been completely explored. In the present study, we comprehensively analyzed the deregulated miRNAs in three major forms of uveitis (Behҫet's disease [BD], sarcoidosis and Vogt-Koyanagi-Harada disease [VKH]) to search for potential biomarkers.

Methods: This study included 10 patients with BD, 17 patients with sarcoidosis, and 13 patients with VKH. Eleven healthy subjects were used as controls. The miRNAs expression levels were studied by microarray using serum samples from patients with uveitis and healthy controls.

Results: A total of 281 upregulated miRNAs and 137 downregulated miRNAs were detected in patients with BD, 35 upregulated miRNAs and 86 downregulated miRNAs in patients with sarcoidosis, and 153 upregulated miRNAs and 35 downregulated miRNAs in patients with VKH. Some deregulated miRNAs were involved in the mitogen-activated protein kinase signaling pathway and inflammatory cytokine pathways. Furthermore, we identified miR-4708-3p, miR-4323, and let-7g-3p as the best predictor miRNAs for BD, sarcoidosis, and VKH, respectively. Panels of miRNAs with diagnostic potential for the three diseases were generated using machine learning.

Conclusions: In this study, comprehensive miRNA analysis identified deregulated miRNAs in three major forms of noninfectious uveitis. This study provides new insights into molecular pathogenetic mechanisms and useful information toward developing novel diagnostic biomarkers and therapeutic targets for BD, sarcoidosis, and VKH.
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http://dx.doi.org/10.1167/iovs.61.11.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476662PMC
September 2020

Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients.

Ocul Immunol Inflamm 2020 Aug 20:1-8. Epub 2020 Aug 20.

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

Purpose: The efficacy of infliximab (IFX) and adalimumab (ADA) for treating Behçet's syndrome (BS) and sarcoidosis has not been compared adequately.

Methods: We reviewed the medical records of patients with uveitis diagnosed at Tokyo Medical University Hospital and compared the efficacy of IFX and ADA for BS and the efficacy of ADA for sarcoidosis and BS.

Results: 68 patients in IFX group and 63 patients in ADA group were analyzed. In BS patients, IFX and ADA were both effective in improving uveitic macular edema (UME). ADA improved UME in BS but not in sarcoidosis patients. The efficacy of ADA in reducing doses of corticosteroids and glaucoma medications was better in sarcoidosis than in the BS group.

Conclusion: Both IFX and ADA are efficacious in improving UME in BS patients. The reason that ADA improves UME better in BS than in sarcoidosis may be due to the difference in pathogenesis between these diseases.
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http://dx.doi.org/10.1080/09273948.2020.1791346DOI Listing
August 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

Identification of Prognostic Markers in Patients with Primary Vitreoretinal Lymphoma by Clustering Analysis Using Clinical Data.

J Clin Med 2020 Jul 20;9(7). Epub 2020 Jul 20.

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

(1) Purpose: Primary vitreoretinal lymphoma (PVRL) is associated with poor prognosis because most of the patients with PVRL develop central nerve system lymphoma. The prognostic biomarker of PVRL is largely unknown. Cluster analysis has been used to identify phenotypic groups within various diseases. In this study, we aimed to describe clinical features of patients with PVRL grouped by clustering analysis and to identify biomarkers for predicting survival prognosis in patients with PVRL. (2) Materials and Methods: Forty patients with PVRL were divided into two groups by clustering analysis using clinical data. Clinical features of the two groups were compared. (3) Result: Clustering analysis classified patients into groups A and B. The survival rate during the follow-up period was significantly lower in group B than in group A ( = 0.03). Serum IgG, serum IgA, vitreous IL-10 and vitreous IL-10 to IL-6 ratio were significantly different between groups A and B ( = 0.03, 0.005, 0.008 and 0.03, respectively). Receiver operating characteristic (ROC) curves generated for the four variables indicated that serum IgA was most suitable for the prediction of prognosis. Patients with serum IgA below 184 mg/dL obtained from the ROC curve had a lower three-year survival rate ( = 0.03) and more episodes of recurrence of lymphoma (3.2 times versus 1.8 times, = 0.02) compared with patients with serum IgA above 184 mg/dL. (4) Conclusion: The survival rate was significantly different in PVRL patients classified into two groups by clustering analysis. Patients with lower serum IgA had more recurrences and poorer survival than patients with higher IgA.
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http://dx.doi.org/10.3390/jcm9072298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409000PMC
July 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

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.

Elife 2020 03 31;9. Epub 2020 Mar 31.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.
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http://dx.doi.org/10.7554/eLife.49392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108862PMC
March 2020

Changes in Etiology of Uveitis in a Single Center in Japan.

Ocul Immunol Inflamm 2020 Feb 18:1-6. Epub 2020 Feb 18.

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

: We investigated the changes in etiology of uveitis at the Uveitis Clinic of Tokyo Medical University Hospital in recent years.: Medical records of patients with uveitis diagnosed between 2011 and 2017 (Group A) and between 2001 and 2007 (Group B) were reviewed.: 1,587 patients in group A and 1,507 patients in group B were analyzed. For noninfectious uveitis, frequencies of Vogt-Koyanagi-Harada disease, intraocular lymphoma (IOL) and iridocyclitis in young girls increased, while those of sarcoidosis and Behçet's disease decreased in the recent era. For infectious uveitis, herpetic iridocyclitis, ocular toxoplasmosis, ocular syphilis, and bacterial endophthalmitis increased, while acute retinal necrosis and ocular toxocariasis decreased. Unclassified uveitis decreased, whereas infectious uveitis and IOL increased due to the availability of new diagnostic tests.: Etiologies of uveitis have changed over the years. Further development of novel tests and diagnostic criteria would increase definitive diagnosis for unclassified uveitis. (147/150 words).
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http://dx.doi.org/10.1080/09273948.2019.1709649DOI Listing
February 2020

Effectiveness of prophylactic intravitreal bevacizumab injection to proliferative diabetic retinopathy patients with elevated preoperative intraocular VEGF in preventing complications after vitrectomy.

Clin Ophthalmol 2019 28;13:1063-1070. Epub 2019 Jun 28.

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

Purpose: This study aimed to elucidate the effects of intravitreal bevacizumab (IVB) injections for the prevention of post-vitrectomy complications in proliferative diabetic retinopathy (PDR) patients with elevated vitreous vascular endothelial growth factor (VEGF) concentration.

Design: Prospective case series.

Methods: Thirty-three patients (42 eyes) with PDR who underwent primary vitrectomy in the Department of Ophthalmology, Tokyo Medical University Hospital were studied. We measured VEGF concentrations in vitreous humor collected at the time of vitrectomy using ELISA. IVB injections were performed after vitrectomy in patients with vitreous VEGF levels exceeding 1,000 pg/mL. New bleeding occurring within 1 month of vitrectomy was defined as early vitreous hemorrhage (VH).

Main Outcome Measure: The incidence of complications after vitrectomy including postoperative early VH.

Results: IVB injections were administered to 11 eyes (26%) with vitreous VEGF concentrations exceeding 1,000 pg/mL. None of the 11 eyes that received an IVB injection developed early VH. Among 31 eyes (74%) with vitreous VEGF concentrations lower than 1,000 pg/mL, two eyes (6%) developed early VH after vitrectomy.

Conclusions: Prophylactic IVB injections administered to patients with elevated preoperative intraocular VEGF concentrations were effective in preventing post-vitrectomy early VH.
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http://dx.doi.org/10.2147/OPTH.S203921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605036PMC
June 2019

A highly efficient murine model of experimental myopia.

Sci Rep 2018 02 1;8(1):2026. Epub 2018 Feb 1.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Despite the global pandemic of myopia, the precise molecular mechanism of the onset of myopia remains largely unknown. This is partially because of the lack of efficient murine myopic models that allow genetic manipulation at low cost. Here we report a highly practical and reproducible lens-induced myopia model by specially designed frames and lenses for mice. A lens power dependent myopic induction in mice was shown until minus 30 diopter lenses. The phenotype was significantly stronger than form-deprivation myopia. We presented the protocol for precise evaluations of the state of myopia, including refraction, corneal curvature and axial length using up-to-date devices. We also found that myopic mouse eyes showed decreased visual acuity on optokinetic response examination. Finally, we confirmed the anti-myopic effect of 1% atropine using this model, which showed its potential in drug screening. The strong phenotype, stable evaluation and the potential for gene manipulation utilizing the presented method in mice will accelerate the translational research of myopia.
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http://dx.doi.org/10.1038/s41598-018-20272-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794929PMC
February 2018

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

Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression.

EBioMedicine 2017 Feb 16;15:210-219. Epub 2016 Dec 16.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address:

Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression.
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http://dx.doi.org/10.1016/j.ebiom.2016.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233810PMC
February 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

Global metabolomics reveals metabolic dysregulation in ischemic retinopathy.

Metabolomics 2016 18;12:15. Epub 2015 Nov 18.

Department of Cell and Molecular Biology, The Scripps Research Institute, MB 28, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA.

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets. Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (n = 9) and non-diabetic controls (n = 11) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (n = 11) and non-diabetic controls (n = 20)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to-proline pathway could be used as a therapeutic target in diabetic retinopathy.
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http://dx.doi.org/10.1007/s11306-015-0877-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651979PMC
November 2015

Differences in the clinical features of two types of Vogt-Koyanagi-Harada disease: serous retinal detachment and optic disc swelling.

Jpn J Ophthalmol 2015 Mar 3;59(2):103-8. Epub 2014 Dec 3.

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

Purpose: To elucidate the clinical differences between serous retinal detachment (RD)-type and optic disc (OD) swelling-type Vogt-Koyanagi-Harada (VKH) disease.

Methods: We performed a retrospective review of 96 patients with new-onset, active VKH disease. Patients were classified into serous RD-type or OD swelling-type VKH disease groups by means of optical coherence tomography and fluorescein angiography, and the differences between the 2 groups were analyzed.

Results: Eighty-two patients were classified as having RD-type VKH disease (34 men and 48 women, aged 40.5 ± 12.6 years) and 14 patients as having OD swelling-type VKH disease (1 man and 13 women, aged 54.6 ± 11.6 years). Patients with the OD swelling type had older onset (P < 0.001) and were more proportionately female (P = 0.02) than those with the RD type. OD swelling-type VKH disease had a longer interval between disease onset and treatment initiation (22.4 ± 14.0 days vs 12.6 ± 14.7 days; P = 0.02) and a higher frequency of chronic disease (64.3 vs 30.5 %; P = 0.03) than did serous RD-type VKH disease. In the OD swelling type, patients with pretreatment visual acuity (VA) lower than 20/20 developed chronic disease more frequently than did those with VA of 20/20 or better (P = 0.02).

Conclusions: Patients with OD swelling-type VKH disease are more likely to be female, have older onset, and develop chronic disease than patients with RD-type VKH disease. In OD swelling-type VKH disease, worse VA before treatment is associated with the development of chronic disease.
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http://dx.doi.org/10.1007/s10384-014-0367-8DOI Listing
March 2015

Retrospective study of threshold time for the conventional treatment of branch retinal artery occlusion.

Clin Ophthalmol 2014 22;8:1877-81. Epub 2014 Sep 22.

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

Purpose: To investigate the medical backgrounds of patients and the treatment periods from the onset of branch retinal artery occlusion to obtaining improved final visual acuity.

Methods: This was a retrospective case series study. A total of 68 consecutive patients (69 eyes) with branch retinal artery occlusion who visited Tokyo Medical University Hospital from 2007 to 2012 were included in this study. All patients underwent ophthalmic examinations and visual acuity tests. We reviewed their medical records for systemic conditions, as well as the periods from onset of symptoms to treatment. Participants were categorized into 2 groups: group A (n=36), which received any treatment within 24 hours from onset, and group B (n=33), which visited our hospital after 24 hours from onset. Best corrected visual acuity (BCVA) changes from the first to final visit and the relationships between systemic condition and visiting time to BCVA were assessed.

Results: At the first visit, 59% of the patients had BCVA over 20/40; the ratio was increased to 74% at the final visit. BCVA improved more than 2 lines for 35% of the patients and was unchanged for 57% of those receiving conventional treatment. BCVA over 20/40 was significantly lower in hyperlipidemia patients. Hypertension, diabetes mellitus, and significant carotid stenosis were not correlated. The mean BCVA at baseline (0.91±1.03) significantly recovered to 0.35±0.91 after treatment in group A (P<0.001, Student's t-test). The mean BCVA at baseline (0.30±0.64) was 0.25±0.61 at the final visit in group B (no significant change).

Conclusion: Conventional treatment within 24 hours from onset was acceptable for branch retinal artery occlusion.
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http://dx.doi.org/10.2147/OPTH.S70468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181636PMC
October 2014
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