Clinicopathological findings in refractory diabetic macular edema: A case report.
Takayuki Tanaka, Satoru Kase, Michiyuki Saito, Ikuyo Hirose, Miyuki Murata, Emi Takakuwa, Susumu Ishida
Biomedical reports, 20, 1, 13, 13, 2024年01月, ［国際誌］
英語, The present study describes the case of a patient with refractory diabetic cystoid macular edema who underwent vitrectomy with en bloc removal of the cystoid lesion component. The current study also performed histopathological and immunohistochemical analyses of the cystoid lesion component to assess fibrin/fibrinogen and advanced glycation end-products (AGEs) immunoreactivity. A 69-year-old Japanese man presented with visual loss in the left eye due to residual cystoid macular edema (CME) refractory to anti-vascular endothelial growth factor therapy. Best-corrected visual acuity was 1.2 in the right eye (OD) and 0.5 in the left eye (OS). Fundus examination showed dot hemorrhages and hard exudates in the peri-macular region with pan-retinal photocoagulation scars in both eye. Swept-source optical coherence tomography revealed CME with slight hyperreflectivity in the cyst OS. A total of 3 months after the initial visit, pars plana vitrectomy was performed, and the translucent solidified component within the cystoid lesion was isolated. Histopathologically, the excised component was elliptical in shape, measuring 0.7x0.4 mm and exhibited homogeneous eosinophilic material without cellular components. No membranous structure was observed surrounding the component. Immunohistochemistry demonstrated that the tissue was positive for fibrin/fibrinogen and weakly positive for AGEs, but was negative for glial fibrillary acidic protein, type 1 collagen and receptor for AGEs. To the best of our knowledge, the present case report is the first to histopathologically examine the contents of refractory CME, and to immunohistochemically demonstrate that fibrin in diabetic CME may be post-translationally modified by AGEs. These results suggested that fibrin in CME may escape degradation by plasmin due to post-translational modifications.

Phosphorylation of αB-Crystallin Involves Interleukin-1β-Mediated Intracellular Retention in Retinal Müller Cells: A New Mechanism Underlying Fibrovascular Membrane Formation.
Taku Yamamoto, Satoru Kase, Akihiro Shinkai, Miyuki Murata, Kasumi Kikuchi, Di Wu, Yasushi Kageyama, Masami Shinohara, Tomohiko Sasase, Susumu Ishida
Investigative ophthalmology & visual science, 64, 10, 20, 20, 2023年07月03日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Chronic inflammation plays a pivotal role in the pathology of proliferative diabetic retinopathy (PDR), in which biological alterations of retinal glial cells are one of the key elements. The phosphorylation of αB-crystallin/CRYAB modulates its molecular dynamics and chaperone activity, and attenuates αB-crystallin secretion via exosomes. In this study, we investigated the effect of phosphorylated αB-crystallin in retinal Müller cells on diabetic mimicking conditions, including interleukin (IL)-1β stimuli. METHODS: Human retinal Müller cells (MIO-M1) were used to examine gene and protein expressions with real-time quantitative PCR, enzyme linked immunosorbent assay (ELISA), and immunoblot analyses. Cell apoptosis was assessed by Caspase-3/7 assay and TdT-mediated dUTP nick-end labeling staining. Retinal tissues isolated from the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic animal model with obesity, and fibrovascular membranes from patients with PDR were examined by double-staining immunofluorescence. RESULTS: CRYAB mRNA was downregulated in MIO-M1 cells with the addition of 10 ng/mL IL-1β; however, intracellular αB-crystallin protein levels were maintained. The αB-crystallin serine 59 (Ser59) residue was phosphorylated with IL-1β application in MIO-M1 cells. Cell apoptosis in MIO-M1 cells was induced by CRYAB knockdown. Immunoreactivity for Ser59-phosphorylated αB-crystallin and glial fibrillary acidic protein was colocalized in glial cells of SDT fatty rats and fibrovascular membranes. CONCLUSIONS: The Ser59 phosphorylation of αB-crystallin was modulated by IL-1β in Müller cells under diabetic mimicking inflammatory conditions, suggesting that αB-crystallin contributes to the pathogenesis of PDR through an anti-apoptotic effect.

A Case of Intraocular Metastasis of Lung Cancer Diagnosed Using Cell Block Preparation of the Vitreous Humor.
Kohei Matsumoto, Satoru Kase, Kenichi Namba, Daiju Iwata, Yoshihiro Matsuno, Susumu Ishida
Cancer diagnosis & prognosis, 3, 1, 130, 134, 2023年, ［国際誌］
英語, BACKGROUND/AIM: Masquerade syndrome is characterized by uveitis-like manifestations caused by tumor cell infiltration into the ocular tissues. The aim of the study was to report a lung cancer patient with persistent unilateral vitreous opacity, who was eventually diagnosed with masquerade syndrome using cell block preparation. CASE REPORT: An 82-year-old female complained of blurred vision in her left eye (OS). Because of pulmonary adenocarcinoma, she had previously received anticancer drug treatment at another Hospital and achieved partial remission. Ophthalmic examinations revealed anterior chamber inflammation and vitreous opacity OS. Corticosteroid eye drops were administered, but the inflammation did not improve, and was referred to the Hokkaido University Hospital. The left best-corrected visual acuity was 0.1 with normal intraocular pressure. Anterior chamber inflammation was 2+ cells, and vitreous haze was 4+ OS. B-mode ultrasonography showed diffuse heterogeneous high echoic changes in the vitreous cavity. She underwent vitrectomy, and cell block preparation of the vitreous infusion fluids was performed. Cytopathology revealed adenocarcinoma cells with a high nuclear/cytoplasmic ratio and glandular formation. The immunocytochemical study showed that tumor cells were positive for thyroid transcription factor-1 (TTF-1), napsin A, and CK7, therefore diagnosis of masquerade syndrome due to intraocular metastasis of pulmonary adenocarcinoma was reached. Chemoradiotherapy was administered, and the eye got phthisis bulbi after irradiation 2 years after diagnosis. CONCLUSION: Cell block preparation using vitreous humor may be useful in the diagnosis and management of intraocular metastasis of pulmonary adenocarcinoma in patients with prolonged vitreous opacity.

Clinical significance of serum and vitreous soluble interleukin-2 receptor in patients with intraocular lymphoma.
Kayo Suzuki, Kenichi Namba, Satoru Kase, Yo Ogino, Keitaro Hase, Daiju Iwata, Kazuomi Mizuuchi, Miki Hiraoka, Nobuyoshi Kitaichi, Susumu Ishida
BMC ophthalmology, 22, 1, 428, 428, 2022年11月10日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Intraocular lymphoma (IOL) is a masquerade syndrome that mimics uveitis, making diagnosis difficult. The serum soluble interleukin-2 receptor (sIL-2R), which is cleaved by matrix metalloproteinase (MMP) -2 and MMP-9, has been recognized as a tumor-related biomarker of malignant lymphomas. The aim of this study was to review the reliability of serum and vitreous sIL-2R for distinguishing IOL from uveitis. METHODS: Patients who underwent diagnostic vitrectomy for marked vitreous haze at Hokkaido University Hospital between April 2014 and June 2019 were enrolled. The patients were divided into an IOL group and a uveitis group, according to the pathology of their vitreous samples. The IOL group was further divided at the time of vitrectomy into patients who already had extraocular involvement (IOL with extraocular involvement group) and patients with no evidence of having extraocular involvement (IOL without extraocular involvement group). Serum sIL-2R, and intravitreal sIL-2R, MMP-2, and MMP-9 levels were assessed. RESULTS: Twenty-five eyes of 25 patients, and 15 eyes of 15 patients were included in the IOL group and uveitis group, respectively. The serum sIL-2R levels were significantly lower in the IOL group than in the uveitis group (P < 0.05), and 20.0% and 66.7% in the IOL and the uveitis group showed high sIL-2R value above the normal range. Vitreous sIL-2R tended to be higher in the IOL group than in the uveitis group (P = 0.80). Serum sIL-2R was significantly lower in the IOL without extraocular involvement group than in the IOL with extraocular involvement group (P < 0.05); 5.9% in the IOL without extraocular involvement group and 50.0% in the IOL with extraocular involvement group showed high sIL-2R value above the normal range. Vitreous sIL-2R, MMP-2, and MMP-9 tended to be higher in the IOL with extraocular involvement group than in the IOL without extraocular involvement group (P = 0.30, < 0.05, 0.16). CONCLUSIONS: Serum sIL-2R is often within the normal range in IOL patients. Even if it is within the normal range, the possibility of IOL should be considered. Serum sIL-2R is not a reliable biomarker for IOL, whereas vitreous sIL-2R may be useful for the diagnosis of IOL.

Relationship between Brachial-Ankle Pulse Wave Velocity and Fundus Arteriolar Area Calculated Using a Deep-Learning Algorithm.
Kanae Fukutsu, Michiyuki Saito, Kousuke Noda, Miyuki Murata, Satoru Kase, Ryosuke Shiba, Naoki Isogai, Yoshikazu Asano, Nagisa Hanawa, Mitsuru Dohke, Manabu Kase, Susumu Ishida
Current eye research, 47, 11, 1534, 1537, 2022年11月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Retinal vessels reflect alterations related to hypertension and arteriosclerosis in the physical status. Previously, we had reported a deep-learning algorithm for automatically detecting retinal vessels and measuring the total retinal vascular area in fundus photographs (VAFP). Herein, we investigated the relationship between VAFP and brachial-ankle pulse wave velocity (baPWV), which is the gold standard for arterial stiffness assessment in clinical practice. METHODS: Retinal photographs (n = 696) obtained from 372 individuals who visited the Keijinkai Maruyama Clinic for regular health checkups were used to analyze VAFP. Additionally, the baPWV was measured for each patient. Automatic retinal-vessel segmentation was performed using our deep-learning algorithm, and the total arteriolar area (AA) and total venular area (VA) were measured. Correlations between baPWV and several parameters, including AA and VA, were assessed. RESULTS: The baPWV was negatively correlated with AA (R = -0.40, n = 696, P < 2.2e-16) and VA (R = -0.36, n = 696, P < 2.2e-16). Independent variables (AA, sex, age, and systolic blood pressure) selected using the stepwise method showed a significant correlation with baPWV. The estimated baPWV, calculated using a regression equation with variables including AA, showed a better correlation with the measured baPWV (R = 0.70, n = 696, P < 2.2e-16) than the estimated value without AA (R = 0.68, n = 696, P < 2.2e-16). CONCLUSIONS: AA and VA were significantly correlated with baPWV. Moreover, baPWV estimated using AA correlated well with the actual baPWV. VAFP may serve as an alternative biomarker for evaluating systemic arterial stiffness.

Diffuse large b-cell lymphoma of the ocular adnexa with flow cytometry analysis and review of the literature.
Mizuho Mitamura, Satoru Kase, Yasuo Suzuki, Takatoshi Sakaguchi, Yuka Suimon, Toshiya Sinohara, A I Shimizu, Yoshihiro Matsuno, Hajime Sakai, Manabu Kase, Susumu Ishida
European journal of ophthalmology, 11206721221127053, 11206721221127053, 2022年09月16日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aim of this study was to evaluate the clinicopathological features and flow cytometry (FCM) of tumor tissues in ocular adnexal diffuse large B-cell lymphoma (DLBCL). METHODS: This retrospective, multicenter case study was designed to evaluate the clinical and immunohistochemical features of tumors. DLBCL was diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM in all surgically removed periocular tumor tissues. This study involved assessing percentages (%) of B-cell/T-cell markers, a natural killer cell marker, and cell-surface Ig kappa/lambda (κ/λ) expression measured by FCM analysis in tumor tissues. RESULTS: Eleven DLBCL patients (4 men and 7 women) with 11 tumors were enrolled in this study. The median age at the time of initial presentation was 73 years. The tumor cells were immunohistochemically positive for cluster of differentiation (CD) 20, while CD5 was negative in all 8 cases tested. At the time of ophthalmic diagnosis, two cases already showed systemic dissemination of DLBCL throughout the body. FCM of tumor tissues detected a high percentage of B-cell markers including CD19 and CD20 in all 11 tumors. One case with high CD10 levels in FCM was histologic transformation from follicular lymphoma. One case with a relatively low CD20 population involved a history of systemic treatments including intravenous rituximab. CONCLUSION: Although caution should be exercised when interpreting the data, FCM is useful for not only supportive diagnosis complementary to immunohistochemistry, but also facilitates a better understanding of immunopathology including histologic transformation of follicular lymphoma to DLBCL in the ocular adnexa.

Placental growth factor stabilizes VEGF receptor-2 protein in retinal pigment epithelial cells by downregulating glycogen synthase kinase 3 activity.
Miyuki Murata, Kousuke Noda, Satoru Kase, Keitaro Hase, Di Wu, Ryo Ando, Susumu Ishida
The Journal of biological chemistry, 298, 9, 102378, 102378, 2022年09月, ［国際誌］
英語, 研究論文（学術雑誌）, Placental growth factor (PlGF) belongs to the vascular endothelial growth factor (VEGF) family of proteins that participate in angiogenesis and vasculogenesis. Anti-VEGF therapy has become the standard treatment for ocular angiogenic disorders in ophthalmological practice. However, there is emerging evidence that anti-VEGF treatment may increase the risk of atrophy of the retinal pigment epithelium (RPE), which is important for the homeostasis of retinal tissue. Whereas the cytoprotective role of VEGF family molecules, particularly that of VEGF A (VEGFA) through its receptor VEGF receptor-2 (VEGFR-2), has been recognized, the physiological role of PlGF in the retina is still unknown. In this study, we explored the role of PlGF in the RPE using PlGF-knockdown RPE cells generated by retrovirus-based PlGF-shRNA transduction. We show that VEGFA reduced apoptosis induced by serum starvation in RPE cells, whereas the antiapoptotic effect of VEGFA was abrogated by VEGFR-2 knockdown. Furthermore, PlGF knockdown increased serum starvation-induced cell apoptosis and unexpectedly reduced the protein level of VEGFR-2 in the RPE. The antiapoptotic effect of VEGFA was also diminished in PlGF-knockdown RPE cells. In addition, we found that glycogen synthase kinase 3 activity was involved in proteasomal degradation of VEGFR-2 in RPE cells and inactivated by PlGF via AKT phosphorylation. Overall, the present data demonstrate that PlGF is crucial for RPE cell viability and that PlGF supports VEGFA/VEGFR-2 signaling by stabilizing the VEGFR-2 protein levels through glycogen synthase kinase 3 inactivation.

Serum advanced glycation end-products and αB-crystallin in diabetic retinopathy patients.
Taku Yamamoto, Satoru Kase, Miyuki Murata, Susumu Ishida
Biomedical reports, 16, 4, 28, 28, 2022年04月, ［国際誌］
英語, 研究論文（学術雑誌）, αB-crystallin, one of the small heat shock proteins, which is also known as HSPB5, has cytoprotective effects under inflammatory conditions. Advanced glycation end-products (AGE) are produced through non-enzymatic glycation under conditions of hyperglycemia and they contribute to angiogenesis and inflammation. The aim of this study was to examine the levels of serum αB-crystallin and AGE concentrations in blood samples collected from proliferative diabetic retinopathy (PDR) patients. Blood samples were collected from seven diabetic patients with PDR and eight patients without diabetes mellitus who underwent vitrectomy due to PDR and idiopathic macular diseases, respectively, in a single center. The levels of serum αB-crystallin and AGE were measured by ELISA and correlations were assessed statistically. The serum levels (mean ± SEM) of AGE were significantly higher in PDR patients (28.41±0.46 µg/ml) than in patients with non-diabetic macular diseases (25.76±0.60 µg/ml; P=0.015), whereas there was no significant difference in serum αB-crystallin levels. There was one patient with an extremely high level of αB-crystallin, who was treated with systemic corticosteroid due to chronic autoimmune inflammatory diseases. The current prospective study showed that serum AGE levels were significantly higher in PDR patients; however, no correlations between serum AGE and αB-crystallin levels were identified.

Diagnostic Accuracy of Cell Block Preparations and Clinical Features Affecting It in Vitreoretinal Lymphoma.
Satoru Kase, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Kayo Suzuki, Takako Ito, Keitaro Hase, Nobuyoshi Kitaichi, Susumu Ishida
Journal of clinical medicine, 11, 5, 2022年03月03日, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: The purpose of this study was to examine the diagnostic accuracy of the cell block (CB) method and clinical features affecting it in patients with vitreoretinal lymphoma (VRL). Methods: This study enrolled 38 eyes in 33 VRL patients, and 7 eyes in 7 patients with idiopathic uveitis who underwent diagnostic vitrectomy. Medical records including the results of CB cytology, interleukin (IL)-10/-6 concentrations, and immunoglobulin heavy chain gene (IgH) rearrangement were retrospectively searched. Results: Patients with VRL comprised 16 women and 17 men, and the age of onset ranged from 44 to 85 years (mean: 70 years). CB preparations detected large malignant cells in 35 eyes (92%), whereas the other 3 VRL eyes were negative. Two of the latter three eyes showed subretinal infiltrates, which existed in 7 of 35 CB-positive eyes. Intravitreal IL-10 and -6 concentrations were 1866 ± 4088 pg/mL and 98 ± 139 pg/mL, respectively, and the rate of IL-10/-6 >1 was 86.9%. The presence of IgH monoclonality was 63.2%. In patients with uveitis, CB specimens revealed no atypical but small inflammatory cells. IL-6 concentration was 311.1 ± 240 pg/mL, whereas IL-10 was undetectable in six eyes, and the IL-negative rate was 85.7%. Six eyes (85.7%) with uveitis showed no IgH monoclonality. Conclusions: Diagnostic accuracy of CB preparations in VRL could achieve an equivalent outcome to IL ratio calculation and IgH monoclonality detection. The appearance of subretinal infiltrates may diminish the CB positivity.

The Expression of Matrix Metalloproteinases in Eyes with Intraocular Lymphoma.
Kanae Fukutsu, Satoru Kase, Daiju Iwata, Kayo Suzuki, Kenichi Namba, Susumu Ishida
Ocular immunology and inflammation, 30, 7-8, 1798, 1802, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The purpose of this study is to investigate matrix metalloproteinases (MMPs) expression in human intraocular lymphoma (IOL). METHODS: Two enucleated eyes and seven cell-block samples obtained from patients with IOL who underwent vitrectomy were used. Immunopathological examinations were performed for detection of MMP-2, MMP-9, and TIMP-4 expressions. RESULTS: In the enucleated eye with primary IOL (PIOL), MMP-2 was negative, and MMP-9 and TIMP-4 were positive in the lymphoma cells, while in the enucleated eye with secondary IOL (SIOL), all the molecules were positive. Among the cell-block samples with PIOL, the positive rate in lymphoma cells of MMP-2, MMP-9, and TIMP-4 was 75%, 100%, and 75%, respectively. In the cell-block samples with SIOL, the positive rates of MMP-2, MMP-9, and TIMP-4 were all 100%. CONCLUSIONS: MMP-2, MMP-9, and TIMP-4 were expressed in lymphoma cells using the specimens of human IOL, suggesting that MMPs may play an important role in the development of IOL.

Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related Stimuli In Vivo and In Vitro.
D I Wu, Satoru Kase, Y E Liu, Atsuhiro Kanda, Miyuki Murata, Susumu Ishida
In vivo (Athens, Greece), 36, 1, 132, 139, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: AlphaB-crystallin plays a pivotal role in many diseases. However, the involvement of alphaB-crystallin in retinal pigment epithelial (RPE) cells with diabetes stimuli remains unknown. The aim of this study is to examine the alterations of RPE cells and alphaB-crystallin expression in diabetic models in vivo and in vitro. MATERIALS AND METHODS: Diabetic conditions in mice were induced by streptozotocin (STZ). The thickness of the RPE/choroid complex was measured by optical coherence tomography (OCT). Periodic acid-Schiff (PAS) staining was used to investigate the choriocapillaris in histological sections of murine eyeballs and oxidative stress was evaluated using immunofluorescence with anti-4-hydroxynonenal (HNE) antibody. AlphaB-crystallin expression was examined in the RPE/choroid complex using ELISA. Real-Time PCR was performed to evaluate the alphaB-crystallin expression in cultured human RPE cells with high glucose or following advanced glycation end-products (AGE) stimulation. RESULTS: In diabetic mice, OCT-based RPE/choroidal layers were thickened 2 months after STZ stimulation, where PAS-positive dilated choriocapillaris was noted. Immunoreactivity of 4-HNE was strongly observed in the RPE layer, from which a significant number of RPE cells was lost. Meanwhile, alphaB-crystallin expression in 2-month STZ mice was significantly lower compared to controls. In accordance with these results, in vitro data showed that the alphaB-crystallin expression was also significantly lower in RPE cells with high glucose or following AGE stimulation compared to untreated cells. CONCLUSION: In both types of diabetic models the expression of alphaB-crystallin was found to be downregulated in RPE cells and was associated with increased levels of oxidative stress.

Gliotic opaque posterior hyaloid membrane separation: report of two cases
Fumio Hosaka, Wataru Saito, Satoru Kase, Susumu Ishida
BMC Ophthalmology, 21, 1, BioMed Central Ltd, 2021年12月01日
英語, 研究論文（学術雑誌）, Background: To report two cases with idiopathic unilateral diffuse opacification of the posterior hyaloid membrane (PHM) completely separated from the retina, the mechanism of which is possibly due to glial cell proliferation and migration. Case presentation: Two Japanese women at age 75 and 84 with no systemic or ocular history developed diffuse opacification in one eye resembling a ground glass sheet almost all over the surface of the PHM, but not within the vitreous gel or fluid. The retinas were funduscopically normal
however, optical coherence tomography demonstrated hyperreflective icicle-like anterior protrusions from the surface of the fovea. The patients received pars plana vitrectomy, resulting in visual improvement. Cell block preparations of the vitreous in one case revealed a cluster of cells immunoreactive for glial fibrillary acidic protein in consistence with gliosis, while denying vitreoretinal lymphoma from lack of atypical cells and vitreous amyloidosis due to no staining for Congo red or direct fast scarlet. The lesions did not recur during follow-up with no new funduscopic abnormalities. Conclusions: To our knowledge, this is the first to demonstrate such peculiar cases of vitreous opacity with idiopathic and unilateral onset. Histological assessments revealed the possible pathogenesis of gliotic opaque PHM separation to cause its ground-glass-sheet appearance.

Factors based on optical coherence tomography correlated with vision impairment in diabetic patients
Hiroaki Endo, Satoru Kase, Hikari Tanaka, Mitsuo Takahashi, Satoshi Katsuta, Yasuo Suzuki, Minako Fujii, Susumu Ishida, Manabu Kase
Scientific Reports, 11, 1, Nature Research, 2021年12月01日
英語, 研究論文（学術雑誌）, The aim of this study is to evaluate the relationship between retinal structures and visual acuity in diabetic patients using optical coherence tomography (OCT) and OCT angiography (OCTA). This study was a retrospective observational study conducted at a single medical center in Japan. Evaluation of retinal images was analyzed using spectral domain OCT. Twelve factors including central retinal thickness, length of disorganization of retinal inner layer (DRIL), number of inner hyperreflective foci, number of outer hyperreflective foci, height of intraretinal fluid, height of subretinal fluid, length of external limiting membrane disruption, length of external ellipsoid zone (EZ) disruption, vessel density of superficial capillary plexus (SCP), foveal avascular zone (FAZ) area, and FAZ circularity were analyzed based on OCT/OCTA findings. Multivariate analysis was used to investigate the OCT-based factors that could be correlated with poor visual acuity in treatment-naïve diabetic eyes. A total of 183 eyes of 123 diabetic patients with type 2 diabetes (mean age 61.9 ± 12.3 years, 66 men and 57 women) and 62 eyes of 55 control subjects (mean age 64.4 ± 12.5 years, 15 men and 40 women) was enrolled in this study. Multiple regression analysis showed that OCT-based factors correlated with visual acuity were length of DRIL (β = 0.24, P <
0.01), length of EZ disruption (β = 0.35, P <
0.001), and FAZ circularity (β = − 0.14, P <
0.05). The other factors showed no significant correlation. In conclusion, the length of DRIL, length of EZ disruption, and FAZ circularity measured by OCT were identified as related factors for visual impairment in treatment-naïve diabetic eyes.

A case of pterygium-like proliferation containing postoperative limbal dermoid remnants: a clinicopathological study
Mizuho Mitamura, Satoru Kase, Takeshi Ohguchi, Susumu Ishida
BMC Ophthalmology, 21, 1, BioMed Central Ltd, 2021年12月01日
英語, 研究論文（学術雑誌）, Background: This study reports a case of pterygium-like proliferation containing postoperative limbal dermoid remnants and its clinicopathological features. Case presentation: A 79-year-old Japanese woman, with a history of congenital limbal dermoid resection at age 12, presented with a pterygium-like tissue growth in the left eye. Its temporal location and marked thickness with abundant fatty droplets were atypical of primary pterygium. We performed pterygium surgery and ocular surface reconstruction. Pathological findings included squamous metaplasia, neovessels, and elastic degeneration, as well as prominent subepithelial and stromal accumulation of collagen fibers, adipose tissue formation, and presence of a peripheral nerve corresponded with the frequent findings of limbal dermoid. Ki67, a marker for cell proliferation, was immunopositive in pterygial epithelial cells and neovascular endothelial cells, but not in dermoid components. Conclusions: Although the pathological finding of degenerative elastic fibers indicated the common feature of ultraviolet-induced pterygium, clinical appearances were atypical possibly due to modification with dermoid remnants.

Expression of vascular endothelial growth factor-c in the trabecular meshwork of patients with neovascular glaucoma and primary open-angle glaucoma
Keitaro Hase, Satoru Kase, Atsuhiro Kanda, Yasuhiro Shinmei, Kousuke Noda, Susumu Ishida
Journal of Clinical Medicine, 10, 13, MDPI, 2021年07月01日
英語, 研究論文（学術雑誌）, Purpose To investigate the expression of vascular endothelial growth factor (VEGF)-C and vascular endothelial growth factor receptor (VEGFR)3 in the trabecular meshwork (TM) of patients with glaucoma and cultured TM cells. Methods: The expressions of VEGF-C in angle tissues collected by trabeculectomy from patients with glaucoma and non-glaucomatous choroidal malignant melanoma were analyzed by immunohistochemistry. Additionally, VEGF-C concentrations were determined in the aqueous humor of patients with glaucoma by ELISA. The expressions of VEGFR3, which is a receptor of VEGF-C in cultured TM cells, were analyzed by Western blot analysis and immunocytochemistry. Cultured TM cells were stimulated by oxidative stress, hypoxia, or high glucose conditions, and VEGF-C concentrations in supernatants and cell lysates were determined by ELISA. Results: VEGF-C immunoreactivity was positive in TM tissues of glaucoma patients, but not in those of non-glaucomatous controls. VEGF-C concentrations in the aqueous humor of patients with neovascular glaucoma and primary open-angle glaucoma were lower than those with non-glaucoma patients. VEGFR3 was expressed in cultured TM cells. VEGF-C concentrations in supernatants or cell lysates of TM cells cultured under oxidative stress and hypoxia were significantly elevated compared with those under steady conditions (p <
0.05). VEGF-C concentrations in supernatants and cell lysates of TM cells cultured in high glucose were significantly higher than those in low glucose (p <
0.01). Conclusions: VEGF-C was expressed in TM tissues of patients with glaucoma, which was secreted from cultured TM cells under various pathological conditions. These results suggest that VEGF-C may be involved in the pathology of glaucoma.

Hypoxia Induces Galectin-1 Expression Via Autoinduction of Placental Growth Factor in Retinal Pigment Epithelium Cells.
Taku Yamamoto, Atsuhiro Kanda, Satoru Kase, Susumu Ishida
Investigative ophthalmology & visual science, 62, 2, 22, 22, 2021年02月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: Galectin-1/LGALS1, a β-galactoside-binding protein, contributes to angiogenesis and fibrosis in various ocular diseases. Hypoxia-dependent and -independent pathways upregulate galectin-1/LGALS1 expression in Müller glial cells. Here, we present novel findings on the galectin-1/LGALS1 regulatory system in human retinal pigment epithelium (RPE) cells, the major cellular participant in the pathogenesis of neovascular age-related macular degeneration (nAMD). Methods: Human RPE cells were used to evaluate changes in gene and protein expression with real-time quantitative PCR and immunoblot analyses, respectively. The promoter and enhancer regions of LGALS1 were analyzed by reporter assay and chromatin immunoprecipitation. Immunofluorescence analysis of nAMD patient specimens was used to confirm the in vitro findings. Results: Hypoxia induced galectin-1/LGALS1 expression via binding of hypoxia-inducible factor 1α (HIF-1α) to hypoxia-responsive elements in the LGALS1 promoter region. Blockade of vascular endothelial growth factor receptor 1 (VEGFR1) partially decreased hypoxia-induced galectin-1/LGALS1 expression. Among several VEGFR1 ligands induced by hypoxia, placental growth factor (PlGF)/PGF alone upregulated galectin-1/LGALS1 expression via phosphorylation of activator protein 1 (AP-1) subunits following AKT and p38 mitogen-activated protein kinase (MAPK) activation. An AP-1 site in the LGALS1 enhancer region was required for PlGF-induced galectin-1/LGALS1 expression in RPE cells. PlGF application upregulated PGF expression via extracellular signal-regulated kinase 1 and 2, AKT, and p38 MAPK pathways. nAMD patient specimens demonstrated co-localization of galectin-1 with HIF-1α, PlGF, and VEGFR1 in RPE cells. Conclusions: Our present findings implicate the significance of hypoxia as a key inducer of galectin-1/LGALS1 in RPE cells and the autoinduction of hypoxia-induced PlGF as a vicious cycle amplifying the pathogenesis of nAMD.

A Novel Deep Learning Architecture for Vascular Area Measurement in Fundus Images
Kanae Fukutsu, Michiyuki Saito, Kousuke Noda, Miyuki Murata, Satoru Kase, Ryosuke Shiba, Naoki Isogai, Yoshikazu Asano, Nagisa Hanawa, Mitsuru Dohke, Manabu Kase, Susumu Ishida
Ophthalmology Science, 100004, 100004, Elsevier BV, 2021年02月
研究論文（学術雑誌）

Clinical Features of Primary Vitreoretinal Lymphoma: A Single-center Study.
Satoru Kase, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Takako Ito, Keitaro Hase, Kayo Suzuki, Masahiro Onozawa, Nobuyoshi Kitaichi, Susumu Ishida
Cancer diagnosis & prognosis, 1, 2, 69, 75, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: This study aimed to demonstrate the clinical outcomes of primary vitreoretinal lymphoma (PVRL). PATIENTS AND METHODS: Seventeen patients with PVRL who had been treated at Hokkaido University Hospital were enrolled in this study. They were diagnosed based on their cytology, interleukin-10/-6 ratio, and immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Diagnostic tests detected cytological malignancy among 14 cases (82.3%), high interleukin-10/-6 ratios among 16 cases (94.1%), and IgH monoclonality in 13 cases (76.5%). Systemic corticosteroids were given to seven (41.2%) patients before their diagnosis of PVRL. Treatments after diagnosis comprised intravitreal methotrexate injection, local radiation, and intravenous chemotherapy for 11, seven, and five cases, respectively. Central nervous system and systemic involvements were observed in nine and one case, respectively, and these complications occurred at 3 to 43 months (mean=16 months) after initial ocular presentation. CONCLUSION: Many of our patients did not receive any systemic intervention, and almost half of patients with PVRL developed central nervous system involvement during their follow-up period.

Choroidal structure changes in chronic myeloid leukemia by binarization method　　　　　　　　　　　　　　　
Yuki Ito, Michiyuki Saito, Hiroaki Endo, Satoru Kase, Mitsuo Takahashi, Masayo Maemori, Manabu Kase
Japanese Journal of Clinical Ophthalmology, 75, 3, 319, 325, Igaku-Shoin Ltd, 2021年
日本語, 研究論文（学術雑誌）, Purpose • To investigate the choroidal structure before and after chemotherapy in a patient with chronic myeloid leukemia (CML) using a binarization method of EDI-OCT Case report-A 30-year-old man had blurred vision in the right eye and was referred to the Department of Ophthalmology, Teine Keijinkai Hospital, for further examinations of fundus hemorrhages in both eyes. The best-corrected visual acuity at the first visit was 0.2 right eye and 1.2 left eye. Based on the fundus examination findings, a high leukocyte count of 501,310///!, and positive detection of BCR-ABL translocation on FISH testing, he was diagnosed with CML and immediately underwent chemotherapy. OCT analysis conducted one month after the treatment revealed that the thickness of the choroidal, luminal, and stromal areas rapidly decreased, whereas the luminal-choroidal area (L/C) ratio showed a flat line during the follow-up period. Conclusion 1 In the acute phase of CML in the present patient, both the luminal and stromal areas, but not the L/C ratio in the choroid, were enlarged. After initiation of chemotherapy, these values improved, whereas the leucocyte count decreased.

A case of pleomorphic adenoma of the lacrimal gland invading the lower orbit
Ryosei Kado, Satoru Kase, Yuka Suimon, Susumu Ishida
Orbit (London), Taylor and Francis Ltd., 2021年
英語, 研究論文（学術雑誌）, Pleomorphic adenoma is a benign tumor that originates from the lacrimal gland and typically develops in the upper orbit. There is a risk of postoperative recurrence due to capsule damage by biopsy or incomplete tumor resection. Here, we report a case of primary lacrimal gland pleomorphic adenoma that extended to the lower orbit. A 76-year-old man visited a nearby clinic with swelling of the right eyelid, and was referred to our department because of decreased vision in the right eye and marked chemosis. At the initial presentation, external eye findings showed swelling of the right eyelid, and elastic hard masses were palpable beneath the skin of the upper and lower eyelids. Magnetic resonance imaging revealed a multinodular tumor in the upper and lower orbits, measuring about 2 cm in the long axis. Excision was attempted by a transcutaneous approach from the upper eyelid, and the tumor was totally removed as a mass without damage to the capsule. The orbital mass was histologically diagnosed as pleomorphic adenoma of the lacrimal gland. We encountered a rare morphological variation of pleomorphic adenoma of the lacrimal gland that extended to the lower orbit. When diagnosing large tumors extending to the upper and lower orbits, total tumor resection should be attempted without biopsy due to the possibility of pleomorphic adenoma.

Involvements of choroidal vascular structures with local treatments in patients with diabetic macular edema
Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Masahiko Yokoi, Yuki Ito, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase
European Journal of Ophthalmology, SAGE Publications Ltd, 2021年
英語, 研究論文（学術雑誌）, Purpose: To examine changes of the choroidal morphology in patients with diabetic macular edema (DME) before and after local treatments. Methods: This study was on 20 eyes with DME, observed for more than 24 months. All patients underwent laser photocoagulation (Laser), sub-tenon triamcinolone acetonide injection (TA), or intravitreal aflibercept injection (IVA). Central macular and choroidal thicknesses (CMT/CCT), and choroidal vascular structures consisting of the total choroidal area (TCA), luminal area (LA), and stromal area (SA) were measured by a binarization method. The ratios of LA in TCA were eventually determined as the L/C ratio in each case. Results: The L/C ratio significantly decreased for 24 months in patients with DME (p = 0.01), whereas no significant differences were noted in other parameters including TCA, LA, SA, or CCT. Among patients treated with Laser ± TA ± IVA, a significant correlation was found between a high L/C ratio at pretreatment and a lower cumulative number of injections (1–2 times/24 months) (p = 0.04). The L/C ratio in pretreatment showed a significantly inverse correlation with CMT (−0.60, p = 0.02) and subsequent BCVA (logMAR) (−0.59, p = 0.03). Conclusion: This study highlighted that the L/C ratio in pretreatment might predict a change of the visual acuity in DME.

Follicular lymphoma of the ocular adnexa: Clinicopathological findings with flow cytometry analysis of eight cases
Mizuho Mitamura, Satoru Kase, Yasuo Suzuki, Takatoshi Sakaguchi, Yuka Suimon, Yoko Dong, Kanako C Hatanaka, Toshiya Sinohara, Manabu Kase, Susumu Ishida
European Journal of Ophthalmology, SAGE Publications Ltd, 2021年
英語, 研究論文（学術雑誌）, Purpose: Flow cytometry (FCM) is used to evaluate cell surface markers of various leukocyte populations quantitatively. However, little is known about the usefulness of FCM in follicular lymphoma (FL) of the ocular adnexa. The aim of this study was to evaluate the clinicopathological features and FCM results in ocular adnexal FL. Materials: This is a retrospective multicenter case study on clinical and immunohistochemical features. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin heavy chain gene rearrangement, and FCM. The percentages (%) of B-cell markers, T-cell markers, a natural killer cell marker, and cell surface kappa/lambda measured by FCM analysis in tumor tissues were searched based on medical records. Results: This study enrolled nine tumors in eight FL patients (three men and five women). The median age at the time of initial presentation was 74 years. All the tumors surgically excised histologically exhibited cluster of differentiation (CD)10, CD20, and BCL2-positive cells. At the time of ophthalmic diagnosis, lymphomas were already disseminated throughout the body in five cases. FCM demonstrated high percentage of B-cell markers including CD10, CD19, CD20, and CD23 in all nine tumors. CD10 population was 73.5% ± 11.9% in seven out of nine tumors, while that in the other two tumors was particularly low being 11.7% ± 1.13%, which showed the relatively high T-cell lineages compared to the other seven tumors. Conclusion: For ophthalmologists involving managements of ocular adnexal tumors, FCM can provide useful information for complementing the diagnosis and understanding pathophysiology of FL.

Morphological features of macular telangiectasia type 2 in Japanese patients.
Akihiro Shinkai, Wataru Saito, Yuki Hashimoto, Michiyuki Saito, Satoru Kase, Kousuke Noda, Susumu Ishida
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2020年11月04日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: This study aimed to demonstrate the clinical course of Japanese patients with macular telangiectasia type 2 (MacTel-2). METHODS: This retrospective observational case series included 16 eyes of 8 Japanese patients (3 men and 5 women) with MacTel-2. The mean age and follow-up duration was 66.9 years and 42.8 months, respectively. Differences in best-corrected visual acuity (BCVA), funduscopic macular findings, central macular thickness (CMT), and the length of macular ellipsoid zone (EZ) loss were compared between the initial/baseline and final visits. Optical coherence tomographic changes in CMT by ≥ 20% and in EZ loss by ≥ 20% or ≥ 100 μm were defined as improved or worsened. RESULTS: Numerical changes in BCVA and EZ loss during follow-up were not statistically significant. However, the mean CMT at baseline, which was lower than that of healthy control eyes (P < 0.001), significantly increased during follow-up (P = 0.041). A certain proportion of eyes showed improvement in several parameters: funduscopic findings (both parafoveal retinal graying and foveal retinal pigment epithelium depigmentation) in 29% of eyes, CMT in 21% of eyes, and EZ loss in 43% of eyes. CONCLUSIONS: The non-negligible proportion of eyes with improved parameters, marked especially by macular EZ loss, suggests that Japanese patients with MacTel-2 have milder clinical features than Caucasian patients reported in the literature.

Solitary Fibrous Tumor of the Orbit: A Clinicopathologic Study of Two Cases with Review of the Literature
Mizuho Mitamura, Satoru Kase, Yasuo Suzuki, Takatoshi Sakaguchi, Yuka Suimon, Yoko Dong, Kanako C. Hatanaka, Toshiya Sinohara, Manabu Kase, Susumu Ishida
In Vivo, 34, 6, 3649, 3654, International Institute of Anticancer Research, 2020年11月01日
英語, 研究論文（学術雑誌）, Background/Aim: Orbital solitary fibrous tumor (SFT) is a rare lesion among orbital tumors, which can be misdiagnosed as another mesenchymal tumor. In this study we report two cases of orbital SFT, focusing on the imaging and pathological findings of the vascular structure inside the tumor. Case Report: A 26-year-old woman and 43-year-old man presented with orbital SFT. The pathological findings revealed a patternless growth pattern of the tumor cells and hemangiopericytoma-like vascularity as well as thickened, dilated blood vessels within the tumor tissue. Tumor cells revealed a diffuse strong positivity for cluster of differentiation 34 (CD34) and signal transducer and activator of transcription 6 (STAT6) in both cases, while B-cell lymphoma 2 (bcl-2) and CD99 were positive in one case. Characteristic findings within the tumor were the arterial components, where a variety of STAT6, CD99 and bcl-2-positive smooth muscle cells were intermingled. Conclusion: Histologically, the tumor tissues might be characterized by not only conventional hemangiopericytoma-like vasculature but also dilated arterial vessels, which were shown to be part of the tumor components.

硝子体内鉄片異物を経前房的に摘出した3例　　　　　　　　　　　　　　　
長谷川 綾華, 清水 啓史, 柴田 有紀子, 品川 真有子, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋
眼科臨床紀要, 13, 11, 739, 739, 眼科臨床紀要会, 2020年11月
日本語

脈絡膜瘢痕病巣を生じた急性特発性黄斑症の1例　　　　　　　　　　　　　　　
大田 翔一郎, 齋藤 理幸, 鈴木 智浩, 清水 啓史, 橋本 勇希, 加瀬 諭, 野田 航介, 石田 晋
眼科臨床紀要, 13, 11, 743, 743, 眼科臨床紀要会, 2020年11月
日本語

Pachychoroid関連疾患と鑑別を要したchoroidal macrovesselの1例　　　　　　　　　　　　　　　
片岡 慶次, 加瀬 諭, 長谷川 綾華, 柴田 有紀子, 品川 真有子, 清水 啓史, 齋藤 理幸, 野田 航介, 石田 晋
眼科臨床紀要, 13, 11, 749, 749, 眼科臨床紀要会, 2020年11月
日本語

ポリープ状脈絡膜血管症に対するphotodynamic therapyトリプル療法におけるpachychoroidの有無での治療成績の比較　　　　　　　　　　　　　　　
柴田 有紀子, 安藤 亮, 野田 航介, 廣岡 季里子, 長谷川 綾華, 品川 真有子, 清水 啓史, 齋藤 理幸, 加瀬 諭, 齋藤 航, 石田 晋
眼科臨床紀要, 13, 11, 752, 752, 眼科臨床紀要会, 2020年11月
日本語

Laser speckle flowgraphy in juxtapapillary retinal capillary hemangioblastoma: a case report on natural course and therapeutic effect
Mizuho Mitamura, Satoru Kase, Kiriko Hirooka, Susumu Ishida
Oncotarget, 11, 42, 3800, 3804, Impact Journals LLC, 2020年10月20日
英語, 研究論文（学術雑誌）, Juxtapapillary retinal capillary hemangioblastoma (JRCH), a benign intraocular vascular tumor, is usually progressive and may lead to severe vision loss due to various complications. We herein present a case of JRCH observed with laser speckle flowgraphy (LSFG) before and after laser photocoagulation (LPC). A 21-year-old Japanese woman underwent LSFG evaluations. Right eye showed an orange-colored tumor consistent with JRCH on the papillomacular bundle, where LSFG showed a mild warm-color blood flow signal. Eight months after the first examination, JRCH in the right eye increased redness with vasodilatation, and the size enlarged, where LSFG showed a stronger warm-color blood flow signal. She underwent direct yellow laser ablation for the JRCH lesion. One week after LPC, JRCH became paler and LSFG eventually depicted a weakened blood flow signal at the same site. In conclusion, noninvasive and reproducible LSFG is a useful tool for assessing not only JRCH activity but also therapeutic effect.

機械学習によって自動算出された網膜動静脈面積と血圧脈波の関係　　　　　　　　　　　　　　　
福津 佳苗, 齋藤 理幸, 野田 航介, 村田 美幸, 加瀬 諭, 柴 涼介, 磯貝 直己, 道家 充, 石田 晋
眼科臨床紀要, 13, 10, 683, 684, 眼科臨床紀要会, 2020年10月
日本語

抗carbonic anhydrase II抗体陽性自己免疫性網膜症の臨床像　　　　　　　　　　　　　　　
安藤 亮, 齋藤 航, 平形 寿彬, 藤波 芳, 角田 和繁, 加瀬 諭, 野田 航介, 神田 敦宏, 石田 晋
眼科臨床紀要, 13, 10, 684, 684, 眼科臨床紀要会, 2020年10月
日本語

Choroidal Thickness in Diabetic Patients Without Diabetic Retinopathy: A Meta-analysis.
Hiroaki Endo, Satoru Kase, Michiyuki Saito, Masahiko Yokoi, Mitsuo Takahashi, Susumu Ishida, Manabu Kase
American journal of ophthalmology, 218, 68, 77, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To evaluate the relationship between diabetic eyes without diabetic retinopathy and healthy eyes in subfoveal choroidal thickness. DESIGN: Systematic review and meta-analysis. METHODS: An independent retrospective or prospective clinical study comparing diabetic eyes without diabetic retinopathy and healthy control eyes in the subfoveal choroidal thickness was selected. This study compiled data from publications in PubMed and Web of Science between January 1, 2008, and November 15, 2019. Heterogeneity was statistically quantified by I2 statistics, and meta-analysis was performed using a random-effects model. RESULTS: Seventeen related studies were identified, including a total of 4,213 eyes, which consisted of 1,197 diabetic eyes without diabetic retinopathy and 3,016 healthy eyes. Meta-analysis clearly showed that the subfoveal choroidal thickness of diabetic eyes without retinopathy was significantly thinner than that of healthy control eyes (weighted mean difference = -14.34 μm; 95% confidence interval: -24.37 to -4.32 μm; P < .005). Similar results were obtained in sub-analysis based on the adjustment of the axial length. CONCLUSIONS: This study suggests that the subfoveal choroidal thickness was thin in diabetic eyes without retinopathy compared to healthy eyes. Subfoveal choroidal thickness might be an important parameter for the development of diabetic retinopathy in diabetic eyes without retinopathy.

機械学習によるFA画像からの網膜静脈分枝閉塞症の視力予後の推量　　　　　　　　　　　　　　　
品川 真有子, 齋藤 理幸, 高橋 光生, 伊藤 有希, 遠藤 弘毅, 加瀬 諭, 野田 航介, 石田 晋
眼科臨床紀要, 13, 9, 638, 638, 眼科臨床紀要会, 2020年09月
日本語

A case of metastatic iris tumor observed with anterior segment optical coherence tomography before and after radiation therapy
Mizuho Mitamura, Satoru Kase, Yuka Suimon, Takako Ito, Susumu Ishida
In Vivo, 34, 4, 2159, 2162, International Institute of Anticancer Research, 2020年08月01日
英語, 研究論文（学術雑誌）, Background/Aim: Metastatic iris tumors are relatively rare entities that are often treated with radiation therapy
however, it remains difficult to evaluate the effectiveness of treatment. Anterior segment optical coherence tomography (AS-OCT) provides high-resolution crosssectional images with no dye injection, and may thus be useful for evaluating iris tumors. Herein, we report a case of metastatic iris tumor examined with AS-OCT before and after radiation therapy. Case Report: A 56-year-old Japanese woman complained of ocular hyperemia and pain in her right eye, and was referred to our hospital because of uveitis and an iris mass. One year before the initial visit, the patient was diagnosed with lung adenocarcinoma, and treated with chemotherapy. She also underwent radiation therapy 4 months ago due to multiple bone metastases. Slit-lamp microscopy revealed a 2×2 mm elevated lesion with partial depigmentation on the lower iris. AS-OCT examination revealed that the mass was located in the iris stroma with an irregular anterior surface. Based on fine needle aspiration cytology, she was diagnosed with metastatic iris tumor derived from lung adenocarcinoma, leading to local radiotherapy. Seven months later, AS-OCT showed shrinkage and atrophy of the iris tumor with peripheral anterior synechia formation. Conclusion: We report a case of cytology-proven metastatic iris tumor observed with AS-OCT before and after radiation therapy. This study highlights the potential usefulness of ASOCT for monitoring changes in tumor size and configuration following radiotherapy.

A Case of IgG4-Related Ophthalmic Disease With Coronary Arteritis.
Yuka Suimon, Satoru Kase, Shuhei Shimoyama, Susumu Ishida
Ophthalmic plastic and reconstructive surgery, 2020年07月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, often with elevated serum IgG4. Multiple organs may be affected. Coronary arteritis may be one form of fatal involvement in IgG4-RD. IgG4-RD can manifest as periocular lesions, called IgG4-related ophthalmic disease (IgG4-ROD). Here, the authors describe a patient with asymptomatic coronary arteritis detected after the diagnosis of IgG4-ROD. A 58-year-old male complained of eyelid swelling and diplopia without systemic symptoms. Swelling of bilateral lacrimal glands and infraorbital nerves, high serum IgG4 levels, and histopathology of lacrimal gland tissue fulfilled diagnostic criteria for IgG4-ROD. After diagnosis, systemic and coronary CT showed coronary lesions and coronary artery stenosis. After prednisolone at 40 mg/day was administered, swelling of the lacrimal glands, diplopia, and coronary lesions improved. This case emphasizes the importance of systemic screening, even if initial symptoms are solely associated with periocular regions.

Multimodal imaging in sclerochoroidal calcification: a case report and literature review.
Mizuho Mitamura, Satoru Kase, Susumu Ishida
BMC ophthalmology, 20, 1, 248, 248, 2020年06月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Sclerochoroidal calcification (SCC), a rare condition found in elderly people, is idiopathic or occasionally secondary to disorders affecting calcium metabolism. Findings of multimodal imaging including choroidal circulation are, however, largely unknown. We present a patient of SCC with systemic background, who underwent multimodal imaging evaluations. CASE PRESENTATION: A 70-year-old Japanese man was referred to our clinic because of bilateral fundus lesions. He had a history of chronic kidney disease (CKD) and secondary hyperparathyroidism. Fundus photography showed a cluster of choroidal folds in the superotemporal extra-macular region OS. Swept-source optical coherence tomography demonstrated ellipsoid zone disruption OD, retinal pigment epithelium undulation OS, dilated Haller layer veins OU, and central choroidal thickening OU and thinning of the overlying choroid due to scleral elevation OS. Fluorescein angiography detected macular hyperfluorescence OD. Indocyanine green angiography demonstrated choroidal vascular hyperpermeability together with numerous scattered hypofluorescent lesions OU. Fundus autofluorescence showed multiple hypoautofluorescent spots surrounded by hyperautofluorescent areas OD. Laser speckle flowgraphy exhibited choroidal blood flow reduction represented by a cold color pattern OU. B-mode echography displayed hyperechoic solid lesions with acoustic shadowing and orbital computed tomography revealed high density areas in the sclera, both of which were consistent with calcification. The patient was diagnosed with SCC, and these imaging findings remained unchanged 7 months after the diagnosis. CONCLUSIONS: We reported a case of SCC with the background of CKD. Our detailed multimodal observations indicated choroidal hypoperfusion possibly caused by mechanical compression due to calcium deposition in the sclera.

Laser Speckle Flowgraphy Findings in a Patient with Choroidal Macrovessel.
Keiji Kataoka, Satoru Kase, Kousuke Noda, Susumu Ishida
Ophthalmology. Retina, 4, 11, 1123, 1124, 2020年06月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Alteration of choroidal vascular structure in diabetic macular edema.
Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Yuki Ito, Michiyuki Saito, Masahiko Yokoi, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 258, 5, 971, 977, 2020年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aim of this study was to analyze choroidal structures in healthy subjects and patients with/without diabetic macular edema (DME). METHODS: This was a retrospective observation case control study. Four hundred and two eyes of patients with diabetes mellitus (DM), and 124 age-matched eyes of healthy subjects were enrolled in this study. DM patients were divided into 3 groups: presence of central-involved (CI) DME (n = 81) and nonCI-DME/non-DME (n = 321), based on OCT findings. Central choroidal thickness (CCT) and total choroidal, luminal, and stromal areas were determined using EDI-OCT and a binarization method, respectively. The luminal area expressed as a ratio of the total choroidal area was defined as the L/C ratio. RESULTS: DM eyes showed a significantly lower L/C ratio than control eyes, whereas there was no significant difference in CCT or total choroidal, luminal, or stromal areas. There was no significant difference between CI-DME and non-DME groups in HbA1c, blood pressure, dyslipidemia, or renal function. CCT and total choroidal, luminal, and stromal areas were significantly greater in the CI-DME group than non-DME group (each P < 0.05). CONCLUSIONS: These results suggest that CCT was thickened in the presence of DME, associated with both increased luminal and stromal areas, which might be related to the pathology of DME.

Alteration of Cell Surface Markers CD38 and CD138 in Lymphoproliferative Disorders in the Ocular Adnexa.
Yuka Suimon, Satoru Kase, Ichiro Miura, Kan Ishijima, Susumu Ishida
Anticancer research, 40, 4, 2019, 2023, 2020年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: CD38 is a cell surface marker commonly present in plasma cells and activated T cells, while CD138 is a representative plasma cell marker. The aim of this study was to describe the expression of cell surface markers including CD38 and CD138, in the tumors of patients with IgG4-related ophthalmic disease (IgG4-ROD) and extranodal marginal zone B-cell lymphoma (EMZL) of the ocular adnexa. MATERIALS AND METHODS: Twenty-four consecutive patients of whom 12 had IgG4-ROD and 12 EMZL were enrolled in this study. Medical records were reviewed for flow cytometry (FCM) results on conventional T-cell markers, B-cell markers, CD38 and CD138. RESULTS: Positive rates of T-cell markers, CD38 and CD138 were significantly higher in IgG4-ROD than in EMZL (p<0.01 and p<0.05, respectively). CONCLUSION: Our FCM results on CD38 and CD138 showed that the lymphocyte populations were different between IgG4-ROD and EMZL, which may reflect the different pathophysiology of the two diseases.

Pseudo-inflammatory manifestations of choroidal lymphoma resembling Vogt-Koyanagi-Harada disease: case report based on multimodal imaging.
Kanae Fukutsu, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Satoru Kase, Kayo Suzuki, Hiroshi Shimizu, Yukiko Shibata, Fumihiko Yamawaki, Masahiro Onozawa, Susumu Ishida
BMC ophthalmology, 20, 1, 94, 94, 2020年03月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Hematologic malignancies occasionally cause serous retinal detachment (SRD); however, its pathogenesis remains unclear. Here we present the imaging characteristics of metastatic choroidal lymphoma masquerading as Vogt-Koyanagi-Harada (VKH) disease. CASE PRESENTATION: A 45-year-old Japanese woman was referred to our clinic because of bilateral SRD with blurred vision. Fluorescein angiography revealed multiple pinpoint leakage followed by pooling OU. Enhanced depth imaging optical coherence tomography showed marked choroidal thickening OU. Laser speckle flowgraphy detected choroidal circulation impairment OU. Although these results totally agreed with the inflammatory manifestations of acute VKH disease, indocyanine green angiography demonstrated various sizes of sharply marginated hypofluorescent lesions that seemed atypical for the finding of VKH disease, i.e., vaguely marginated hypofluorescent small dots. Cerebrospinal fluid pleocytosis was not detected. Blood tests revealed leukocytosis together with elevation of lactate dehydrogenase and soluble interleukin-2 receptor levels. Corticosteroid pulse therapy did not improve any ocular findings. Bone marrow biopsy was then performed, leading to a definite diagnosis of diffuse large B-cell lymphoma. After starting systemic chemotherapy, both SRD and choroidal thickening resolved rapidly with visual recovery. However, choroidal hypoperfusion persisted, which contrasted distinctly with the inflammatory pattern of VKH disease, i.e., the restoration of choroidal blood flow in parallel with normalization of choroidal thickness. CONCLUSIONS: Our detailed multimodal observations highlighted the differential imaging features of choroidal lymphoma despite close resemblance to VKH disease especially at the initial stage. Impaired circulation in the thickened choroid marked the pseudo-inflammatory pathogenesis of SRD due to choroidal involvement with neoplastic, but not inflammatory cells.

Waardenburg症候群と網膜芽細胞腫を合併した13番染色体長腕部分欠失の1例　　　　　　　　　　　　　　　
赤岡 さくら, 安藤 亮, 加瀬 諭, 外木 秀文, 長 祐子, 藤井 史彦, 太田 亨, 石田 晋
日本眼科学会雑誌, 124, 臨増, 231, 231, (公財)日本眼科学会, 2020年03月
日本語

SDT fattyラット水晶体におけるポリオール経路と酸化ストレスの継時的解析　　　　　　　　　　　　　　　
菊地 香澄, 村田 美幸, 野田 航介, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋
日本眼科学会雑誌, 124, 臨増, 242, 242, (公財)日本眼科学会, 2020年03月
日本語

Waardenburg症候群と網膜芽細胞腫を合併した13番染色体長腕部分欠失の1例　　　　　　　　　　　　　　　
赤岡 さくら, 安藤 亮, 加瀬 諭, 外木 秀文, 長 祐子, 藤井 史彦, 太田 亨, 石田 晋
日本眼科学会雑誌, 124, 臨増, 231, 231, (公財)日本眼科学会, 2020年03月
日本語

Alteration of choroidal vascular structure in diabetic retinopathy.
Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Michiyuki Saito, Masahiko Yokoi, Yuki Ito, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase
The British journal of ophthalmology, 104, 3, 417, 421, 2020年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aim of this study was to analyse choroidal structures in normal patients and patients with diabetes with various severities of diabetic retinopathy (DR). METHODS: This is a retrospective observation case control study. Three hundred and forty-two diabetic eyes, and age-matched 112 eyes without diabetes mellitus (DM) were enrolled in this study. Patients with DM were classified into no DR, mild/moderate non-proliferative DR (mNPDR), severe NPDR and proliferative DR (PDR). Patients with DM were further divided into two groups based on information regarding systemic DM treatment situation: DM-treated and untreated groups. Central choroidal thickness (CCT), and total choroidal area (TCA), luminal area (LA) and stromal area (SA) were determined using enhanced depth imaging optical coherence tomography and a binarisation method, respectively. The ratio of LA in the TCA was defined as L/C ratio. RESULTS: The haemoglobin A1c (HbA1c) value was significantly higher in the DM-untreated than in the DM-treated subjects. L/C ratio was significantly lower in all the diabetic eyes than control eyes (p<0.05). TCA, LA, L/C ratio and CCT were significantly greater in the DM-untreated than treated group (each p<0.05). In the DM-untreated group, TCA and LAs (p<0.05) and L/C ratio (p<0.01) were significantly lower in mNPDR subjects than normal controls (p<0.05). PDR in the DM-untreated group showed significantly larger SA and LA, and greater CCT than normal controls (each p<0.05). CONCLUSIONS: These results suggest that choroidal vasculature was initially involved at an early DR, whereas thickened LA and SA were noted in advanced DR.

EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION IN A CASE OF FOCAL NODULAR GLIOSIS OF THE RETINA.
Mizuki Tagami, Norihiko Misawa, Saki Noma-Ishikura, Satoshi Honda, Satoru Kase, Shigeru Honda
Retinal cases & brief reports, 16, 3, 375, 378, 2020年02月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To describe the immunohistochemical profile in a case with focal nodular gliosis (FNG) of the retina. METHODS: A 56-year-old female patient presented with vitreoretinal tractional syndrome with FNG of the retina. After resection of the retinal tumor tissue during the 25-G pars plana vitrectomy, immunohistochemistry using anti-epidermal growth factor receptor (EGFR), p-53, Ki67, glial fibrillary acid protein (GFAP), CD34, and vascular endothelial growth factor antibodies was performed in the excised tissue of the FNG of the retina. RESULTS: Histopathological analysis of the tumor led to a diagnosis of FNG of the retina. Spindle cells of the tumor exhibited strong positive staining for glial fibrillary acid protein, and there was local staining for CD34 in the endothelial cells in the blood vessels. The epidermal growth factor receptor and vascular endothelial growth factor immunoreactivity were strongly observed in the endothelial cells. CONCLUSION: This study demonstrated epidermal growth factor receptor expression in eyes with FNG of the retina. Oncogenic epidermal growth factor receptor might trigger and amplify the expression and function of endothelial vascular endothelial growth factor.

Supplemental Restraint Systemエアバッグによる網膜再剥離と気胸を発症した1例
新海 晃弘, 加瀬 諭, 山下 優, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋
あたらしい眼科, 37, 2, 230, 234, (株)メディカル葵出版, 2020年02月
日本語, 背景:運転席用supplemental restraint system(SRS)エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。症例:73歳、男性。北海道大学病院眼科で左眼裂孔原性網膜剥離(RRD)に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。術後8日目に、突然の胸痛と動悸を発症した。右気胸と診断され、治療された。受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。(著者抄録)

Supplemental Restraint Systemエアバッグによる網膜再剥離と気胸を発症した1例　　　　　　　　　　　　　　　
新海 晃弘, 加瀬 諭, 山下 優, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋
あたらしい眼科, 37, 2, 230, 234, (株)メディカル葵出版, 2020年02月, ［査読有り］
日本語, 背景:運転席用supplemental restraint system(SRS)エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。症例:73歳、男性。北海道大学病院眼科で左眼裂孔原性網膜剥離(RRD)に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。術後8日目に、突然の胸痛と動悸を発症した。右気胸と診断され、治療された。受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。(著者抄録)

A case of giant orbital conjunctival cyst mimicking lymphatic malformation
Yuka Suimon, Satoru Kase, Takako Ito, Susumu Ishida
European Journal of Ophthalmology, SAGE Publications Ltd, 2020年
英語, 研究論文（学術雑誌）, A conjunctival inclusion cyst is a colorless or whitish translucent cystic lesion, frequently occurring on the conjunctiva. Here, we describe a patient with a giant conjunctival cyst, mainly existing in the orbit, which clinically resembled lymphatic malformation. A 34-year-old male complained of a subconjunctival mass on his left infero-medial side persisting since childhood. It had gradually enlarged over the 3 months before the initial visit. He had no history of trauma, surgery, or conjunctivitis. The mass was dark red, with superficial dilated blood vessels. Magnetic resonance imaging showed a well-circumscribed mass in the inferior orbit, measuring 12 × 25 mm, which had an internal septum. The lesion was completely resected without rupture of the mass through a transcutaneous approach. Histopathologically, the mass was a cyst composed of columnar epithelium with goblet cells and lymphoid follicles adjacent to the wall. In conclusion, a giant orbital conjunctival cyst and a lymphatic malformation should be differentiated at diagnosis.

Relationship between diabetic macular edema and choroidal layer thickness.
Hiroaki Endo, Satoru Kase, Mitsuo Takahashi, Michiyuki Saito, Masahiko Yokoi, Chisato Sugawara, Satoshi Katsuta, Susumu Ishida, Manabu Kase
PloS one, 15, 1, e0226630, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate the relationship between diabetic macular edema (DME) and the choroidal layer thickness in diabetic patients. METHODS: This is a retrospective observation study. Three hundred eighteen eyes of 159 diabetes mellitus (DM) patients and age-matched 100 eyes of 79 healthy controls were enrolled. DME was defined as over 300 μm in the central retinal subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid sector. The central choroidal thickness (CCT), as well as inner and outer layers were determined based on enhanced depth imaging (EDI)-OCT. Diabetic patients with/without systemic diabetic treatments (DT) at the start of this study was defined as DT+ and DT-, respectively. The number of eyes examined was 62 and 256 eyes in DME+and DME-groups, respectively. DM patients were further subdivided into 4 groups with/without DME and DT; DME+DT+(35 eyes), DME-DT+(159 eyes), DME+DT-(27 eyes), and DME-DT-group (97 eyes). Multiple comparisons on CCT layers including control and each DM group were statistically examined. RESULTS: The total CCT layer was 254±83, 283±88, and 251±70 μm in the control, DME+, and DME-group, respectively. A total CCT layer in DME+was significantly thicker than the DME-group (P < 0.05). The outer CCT layer was 195±75, 222±83, and 193±63 μm in the control, DME+, and DME-group, respectively. The outer CCT layer in DME+ was significantly thicker than the DME-group (P < 0.05). In the subdivided groups, the total CCT layers in the control, DME+DT+, DME-DT+, DME+DT-and DME-DT-groups were 254±83, 274±88, 247±66, 290±84 and 258±75 μm, respectively. The outer CCT layers in each group were 195±75, 214±83, 189±58, 228±77, and 201±70 μm, respectively. Total CCT and the outer layer in DME+DT-was significantly thicker than the DME-DT+group (each P < 0.05). In contrast, there was no significant difference in inner layer between the groups. CONCLUSIONS: The total and outer CCT layers of diabetic eyes were significantly thickened in the DME+DT-as compared with the DME-DT+group, suggesting that CCT may be related to the pathology of DME.

Histological observation of trabecular meshwork in a patient with Axenfeld-Rieger syndrome-a new theory for the mechanism of ectropion uvea in congenital glaucoma.
Satoru Kase, Shinki Chin, Teruhiko Hamanaka, Yasuhiro Shinmei, Takeshi Ohguchi, Susumu Ishida
International journal of ophthalmology, 13, 7, 1167, 1169, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Diabetic Cataract in Spontaneously Diabetic Torii Fatty Rats.
Kasumi Kikuchi, Miyuki Murata, Kousuke Noda, Satoru Kase, Yoshiaki Tagawa, Yasushi Kageyama, Masami Shinohara, Tomohiko Sasase, Susumu Ishida
Journal of diabetes research, 2020, 3058547, 3058547, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Spontaneously Diabetic Torii (SDT) fatty rat is a novel animal model of type 2 diabetes with obesity. SDT fatty rats develop hyperglycemia, dyslipidemia, and other diabetic complications including ocular disorders; however, diabetic cataract formation in SDT fatty rats has not been fully investigated. The aim of the current study was to investigate the characteristics of cataract in the SDT fatty rats. The mean body weight of SDT fatty rats is larger than that of age-matched Sprague-Dawley (SD) rats and control animals until 8 weeks of age, and thereafter the growing speed decreased until the end of observation at 16 weeks of age. Blood glucose levels in SDT fatty rats were significantly higher than those in SD rats throughout the observational period. Slit-lamp examination revealed that no rats showed cataract formation at 5 weeks of age; however, SDT fatty rats gradually developed cortical cataract and posterior subcapsular cataract, both of which are the common types of cataract in patients with type 2 diabetes. The levels of glucose, sorbitol, and fructose were higher in the lens tissues of SDT fatty rats in comparison with that of SD rats. Furthermore, the level of 4-hydroxynonenal (4-HNE) was higher in the lens of SDT fatty rats than in that of SD rats. By contrast, total glutathione (GSH) concentration was lower in the lens of SDT fatty rats than in that of SD rats. The present study demonstrated that the cataractogenesis in SDT fatty rats resembled human diabetic cataract formation, indicating that SDT fatty rats serve as a potential animal model in researches on human cataract associated with type 2 diabetes and obesity.

ポリープ状脈絡膜血管症に対する光線力学的療法トリプル療法の5年成績　　　　　　　　　　　　　　　
安藤 亮, 野田 航介, 廣岡 季里子, 柴田 有紀子, 橋本 勇希, 鈴木 智浩, 清水 啓史, 藤谷 顕雄, 董 震宇, 加瀬 諭, 吉澤 史子, 齋藤 航, 石田 晋
眼科臨床紀要, 12, 11, 832, 832, 眼科臨床紀要会, 2019年11月
日本語

網膜変性を認めたDanon病の1例　　　　　　　　　　　　　　　
長谷川 綾華, 藤谷 顕雄, 柴田 有紀子, 鈴木 智浩, 清水 啓史, 董 震宇, 加瀬 諭, 野田 航介, 石田 晋
眼科臨床紀要, 12, 11, 854, 854, 眼科臨床紀要会, 2019年11月
日本語

術後細菌性眼内炎との鑑別を要した水晶体起因性眼内炎の1例　　　　　　　　　　　　　　　
清水 啓史, 加瀬 諭, 柴田 有紀子, 鈴木 智浩, 董 震宇, 藤谷 顕雄, 野田 航介, 石田 晋
眼科臨床紀要, 12, 11, 856, 856, 眼科臨床紀要会, 2019年11月
日本語

Suppression of Choroidal Neovascularization and Fibrosis by a Novel RNAi Therapeutic Agent against (Pro)renin Receptor.
Ye Liu, Atsuhiro Kanda, Di Wu, Erdal Tan Ishizuka, Satoru Kase, Kousuke Noda, Atsuhiro Ichihara, Susumu Ishida
Molecular therapy. Nucleic acids, 17, 113, 125, 2019年09月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The receptor-associated prorenin system refers to the pathogenic mechanism whereby prorenin binding to (pro)renin receptor [ (P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent signaling, and its activation contributes to the molecular pathogenesis of various ocular diseases. We recently developed a new single-stranded RNAi agent targeting both human and mouse (P)RR ((P)RR-proline-modified short hairpin RNA [ (P)RR-PshRNA]), and confirmed its therapeutic effect on murine models of ocular inflammation. Here, we investigated the efficacy of (P)RR-PshRNA against laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which are involved in the pathogenesis of age-related macular degeneration (AMD). Administration of (P)RR-PshRNA in mice significantly reduced CNV formation, together with the expression of inflammatory molecules, macrophage infiltration, and extracellular signal-regulated kinase (ERK) 1/2 activation. In addition, (P)RR-PshRNA attenuated subretinal fibrosis, together with epithelial-mesenchymal transition (EMT)-related markers including phosphorylated SMAD2. The suppressive effect of (P)RR-PshRNA is comparable with aflibercept, an anti-vascular endothelial growth factor drug widely used for AMD therapy. AMD patient specimens demonstrated (P)RR co-localization with phosphorylated ERK1/2 in neovascular endothelial cells and retinal pigment epithelial cells. These results indicate that (P)RR contributes to the ocular pathogenesis of both inflammation-related angiogenesis and EMT-driven fibrosis, and that (P)RR-PshRNA is a promising therapeutic agent for AMD.

Adenosquamous Carcinoma Arising in Bulbar Conjunctiva
Satoru Kase, Susumu Ishida
Ophthalmic plastic and reconstructive surgery, 35, 5, e109, e110, NLM (Medline), 2019年09月01日
英語, 研究論文（学術雑誌）, Adenosquamous carcinoma is a highly aggressive tumor, which can rarely arise from the ocular surface. The authors herein report a patient who presented with a 5 mm mass on the temporal conjunctiva that was clinically diagnosed as squamous cell carcinoma. The lesion was surgically resected with cryopexy to the conjunctival wound edges. Histopathology and immunoractivity confirmed the diagnosis of adenosquamous carcinoma. Following topical interferon alpha 2b for 3 months, there has been no recurrence or distant metastsis during a follow-up of 12 months.

網膜上下の増殖組織が連続していた黄斑円孔網膜剥離併発の増殖糖尿病網膜症の1例　　　　　　　　　　　　　　　
柴田 有紀子, 清水 啓史, 長谷川 綾華, 品川 真有子, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋
糖尿病合併症, 33, Suppl.1, 266, 266, (一社)日本糖尿病合併症学会, 2019年09月
日本語

Spontaneously Diabetic Torii fattyラット網膜における炎症性サイトカインの発現解析　　　　　　　　　　　　　　　
菊地 香澄, 野田 航介, 村田 美幸, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋
糖尿病合併症, 33, Suppl.1, 271, 271, (一社)日本糖尿病合併症学会, 2019年09月
日本語

抗α-enolase抗体陽性自己免疫性網膜症の網膜電図所見　　　　　　　　　　　　　　　
安藤 亮, 齋藤 航, 神田 敦宏, 加瀬 諭, 藤波 芳, 菅原 道孝, 中村 洋介, 江口 秀一郎, 野田 航介, 篠田 啓, 石田 晋
眼科臨床紀要, 12, 8, 642, 643, 眼科臨床紀要会, 2019年08月, ［査読有り］
日本語

Relationship between choroidal structure and duration of diabetes.
Hiroaki Endo, Satoru Kase, Yuki Ito, Mitsuo Takahashi, Masahiko Yokoi, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 257, 6, 1133, 1140, 2019年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The aim of this study was to evaluate the relationship between the choroidal structure of diabetic patients without diabetic retinopathy (DR) and duration of diabetes. METHODS: This study is a retrospective observational study in diabetic patients without DR. Eyes with diabetes mellitus (DM) (n = 105) were divided into two groups based on the duration: long duration group (over 10 years, n = 31) and short duration group (less than 10 years, n = 74). One hundred seventeen eyes of non-diabetic patients were used as control group. All patients underwent enhanced depth imaging optical coherence tomography, and the choroidal structure was analyzed using a binarization method. RESULTS: There was no significant difference in areas of total choroid and lumina/stroma or central choroidal thickness (CCT) between control and DM groups. In contrast, lumina/total choroidal (L/C) ratio was significantly lower in diabetic eyes than in control eyes (P = 0.02). Although there was no significant difference in the areas or CCT between short and long duration groups, L/C ratio was significantly lower in the long duration group than in the short duration group (P = 0.03). CONCLUSIONS: The current study suggests that choroidal vasculature is involved in the diabetic eyes and that the choroidal structure has changed with duration of diabetes. Our study points out that L/C ratio is a new potential biomarker in monitoring choroidal vascular disorders in diabetic eyes without DR.

Photocoagulation for juxtapapillary retinal hemangioma in a young girl: A case report.
Satoru Kase, Susumu Ishida
Molecular and clinical oncology, 10, 5, 521, 523, 2019年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, von Hippel Lindau (VHL) disease is caused by inactivation of the VHL tumor suppressor gene, resulting in formation of multiple systemic tumors. Juxtapapillary retinal capillary hemangioma (JRCH) is one of the major manifestations in VHL disease; however, treatments are challenging, especially in children. The present study reports the case of a 6-year-old girl with suspected VHL disease presenting with JRCH. Fluorescein angiography demonstrated marked dye leakage from the tumor. Retinal hemorrhage occurred around the tumor 7 months later. Laser photocoagulation of the tumor tissue was safely and successfully conducted without general anesthesia. The hemorrhage diminished after laser photocoagulation. Optical coherence tomography demonstrated mild resolution of an elevated lesion in JRCH with contraction of the vitreoretinal interface over the tumor. Laser photocoagulation may be considered the first-line treatment for young patients with JRCH, although the primary physicians must have the necessary skills and be able to establish good doctor-patient relationships, even with children.

Involvement of circulatory disturbance in optic disk melanocytoma with visual dysfunction.
Iku Kikuchi, Satoru Kase, Yuki Hashimoto, Kiriko Hirooka, Susumu Ishida
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 257, 4, 835, 841, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: This study aims to examine the relationship between ocular circulation changes and visual field defects in optic disk melanocytoma (ODM). METHODS: Five eyes of five patients were enrolled in this study. All patients were diagnosed with ODM in the Department of Ophthalmology, Hokkaido University Hospital from March 2009 to November 2017. Ophthalmological data including optical coherence tomography angiography (OCTA) and laser speckle flowgraphy (LSFG) findings were retrospectively analyzed. RESULTS: The five ODM cases consisted of two females and three males. Ages of the patients ranged from 47 to 82 years (mean 54 years). Follow-up periods were from 4 to 105 months. Fluorescein angiography showed hypo-fluorescence throughout the examination in all four eyes examined with this modality. OCTA detected dense blood vessel networks in the tumor in two out of the five eyes. Nasal visual field defects were found in two other eyes, which were correlated with locations of tumors free of vessel networks. One ODM eye without marked visual field defects and pigmentations showed lower mean blur rates determined by LSFG in optic disk vessels and tissue circulations than those in the contralateral eye. During follow-up, there was no tumor enlargement in any case. CONCLUSIONS: This study showed the relationship between the deficit of blood vessel networks and visual field defects in ODM patients. LSFG demonstrated reduced blood flow in the tumor, suggesting that circulatory disorder caused by the optic disk tumor might be correlated with visual field defect.

Spontaneously Diabetic Torii fattyラットにおける糖尿病白内障の検討　　　　　　　　　　　　　　　
菊地 香澄, 野田 航介, 村田 美幸, 田川 義晃, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋
日本眼科学会雑誌, 123, 臨増, 166, 166, (公財)日本眼科学会, 2019年03月
日本語

Usefulness of topical interferon alpha-2b eye drop as an adjunctive therapy following surgical resection in ocular surface squamous neoplasia
Rina Kanaya, Satoru Kase, Kan Ishijima, Susumu Ishida
In Vivo, 33, 6, 2211, 2215, International Institute of Anticancer Research, 2019年
英語, 研究論文（学術雑誌）, Aim: To report the clinical course of patients with ocular surface squamous neoplasia treated with topical interferon α-2b (IFNα-2b) after local excision of the tumor. Patients and Methods: This study enrolled four consecutive Japanese patients comprising one eye with conjunctival carcinoma in situ, and three eyes with squamous cell carcinoma (SCC) diagnosed histopathologically. All of them initially visited Hokkaido University Hospital in 2016. After resecting the tumor tissues, topical IFNα-2b eye drops were given to the eye four times a day. This study retrospectively analyzed the ophthalmological and imaging findings before and after the surgery, based on the patients'medical records. Results: The mean follow-up duration was 37.8 months. All cases were males, and the mean age was 62.3 years. The tumor was located in the bulbar conjunctiva in three cases. Local pedunculated rotation flap, and free conjunctival flap were performed in one and two patients, respectively. In one case with SCC, the tumor involved the lower palpebral conjunctiva, already invading into the orbit at the first visit. The patient underwent extended resection of the lower lid, and reconstruction of the posterior lobe of the eyelid with Hughes flap. Cataract surgery was successfully conducted 18 months after tumor resection. All patients remain well without local recurrence or distant metastasis. Conclusion: Topical IFNα-2b treatment contributed to suppression of tumor recurrence and improvement of quality of vision in patients after local resection of ocular surface squamous neoplasia.

Clinicopathological features of cystic lesions in the eyelid
Yuka Suimon, Satoru Kase, Kan Ishijima, Hiromi Kanno-Okada, Susumu Ishida
Biomedical Reports, 10, 2, 92, 96, Spandidos Publications, 2019年
英語, 研究論文（学術雑誌）, The aim of the present study was to investigate the clinicopathological features of cystic lesions in the eyelid. Clinicopathological profiles were retrospectively searched based on medical records of 35 patients with cystic lesions of the eyelids, which were surgically resected from January 2003 to June 2016. The cohort consisted of 16 men and 19 women. The mean age of the patients was 57±24 years. The main locations of the cysts were the upper eyelid in 22 patients, followed by the lower eyelid in 5 patients. Eyelid skin and its appendages were the most common as the origin of cysts, followed by the tarsus, palpebral conjunctiva and lacrimal gland. The histopathological diagnoses were 16 epidermal cysts, 5 intratarsal keratinous cysts, 3 conjunctival cysts, 2 trichilemmal cysts, 1 dermoid cyst, 1 apocrine hidrocystoma, 1 lacrimal gland cyst and 6 unclassifiable cysts. All cysts did not recur following resection. In summary, cystic lesions of the eyelid were frequently observed in the upper eyelid. The most frequent diagnoses were epidermal cysts, followed by intratarsal keratinous cysts, while a definitive diagnosis in some cysts could not be pathologically determined, as they lacked epithelia and/or the contents or they resembled apocrine hidrocystoma and intratarsal keratinous cysts with atypical findings. The results of the current study indicate that the incidence and differential diagnosis of eyelid cystic lesions may contribute to the application of appropriate treatment for patients with eyelid tumors.

A case of nodular posterior scleritis simulating intraocular tumor.
Yukiko Shibata, Satoru Kase, Kenichi Namba, Susumu Ishida
International journal of ophthalmology, 12, 4, 685, 688, 2019年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Rhegmatogenous retinal detachment in a patient with choroidal melanoma simulating choroidal detachment: A case report
Satoru Kase, Yuka Suimon, Kan Ishijima, Susumu Ishida
Journal of Medical Case Reports, 12, 1, BioMed Central, 2018年12月25日
英語, 研究論文（学術雑誌）, Background: Ophthalmologists and retina specialists may consider choroidal detachment if patients with rhegmatogenous retinal detachment present with choroidal elevation. That misdiagnosis may lead to inappropriate treatments, development of tumor cell dissemination, and eventual promotion of patient death. We report a case of a patient with rhegmatogenous retinal detachment associated with choroidal melanoma simulating choroidal detachment according to fundus findings. Case presentation: A 78-year-old Japanese woman with blurred vision in her right eye was referred to our hospital because of rhegmatogenous retinal detachment with complicated atypical choroidal detachment. Her intraocular pressure was normal with clear anterior chamber. Retinal detachment involving the inferior and nasal retina was observed, and a retinal hole was noted in the same quadrant. A small yellowish choroidal elevation was located in the inferonasal site. Gadolinium-enhanced magnetic resonance imaging revealed enhancement corresponding to the elevation, leading to the identification of a choroidal tumor. Enucleation of the patient's right eye was eventually performed. The enucleated eye histologically demonstrated malignant melanoma. Conclusions: If hypotony or an inflammatory sign is absent, ophthalmologists should pay attention to the differential diagnosis of choroidal elevations observed in such patients.

Changes in blood flow velocity and thickness of the choroid in a patient with leukemic retinopathy.
Takita A, Hashimoto Y, Saito W, Kase S, Ishida S
American journal of ophthalmology case reports, 12, 68, 72, 2018年12月, ［査読有り］

Acute macular neuroretinopathyにおける脈絡膜層別厚の経時変化　　　　　　　　　　　　　　　
橋本 勇希, 齋藤 航, 滝田 亜かり, 長谷川 裕香, 鈴木 智浩, 安藤 亮, 藤谷 顕雄, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋
眼科臨床紀要, 11, 11, 836, 837, 眼科臨床紀要会, 2018年11月
日本語

MPO-ANCA陽性を示したparacentral acute middle maculopathyの1例　　　　　　　　　　　　　　　
福津 佳苗, 安藤 亮, 新明 康弘, 鈴木 智浩, 藤谷 顕雄, 森 祥平, 加瀬 諭, 阿部 早和子, 齋藤 航, 野田 航介, 石田 晋
眼科臨床紀要, 11, 11, 837, 837, 眼科臨床紀要会, 2018年11月
日本語

エアバッグによる網膜再剥離と気胸を発症した1例　　　　　　　　　　　　　　　
新海 晃弘, 加瀬 諭, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋
眼科臨床紀要, 11, 11, 846, 846, 眼科臨床紀要会, 2018年11月
日本語

Galectin-1 promotes choroidal neovascularization and subretinal fibrosis mediated via epithelial-mesenchymal transition.
Wu D, Kanda A, Liu Y, Kase S, Noda K, Ishida S
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 2, fj201801227R, 2513, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, VEGFA and TGF-β are known major angiogenic and fibrogenic factors. Galectin-1, encoded by lectin, galactoside-binding, soluble ( LGALS) 1, has attracted growing attention for its facilitatory role in angiogenesis and fibrosis through its modification of VEGFA and TGF-β receptor signaling pathways. We reveal galectin-1 involvement in the mouse model of laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which represent the pathogenesis of age-related macular degeneration (AMD). Neither deletion nor overexpression of Lgals1 affected physiologic retinal development or visual function. Galectin-1/ Lgals1 was upregulated by CNV induction, whereas deletion of Lgals1 suppressed CNV together with downstream molecules of VEGF receptor (VEGFR)2. Loss of Lgals1 also attenuated subretinal fibrosis, expression of epithelial-mesenchymal transition (EMT) markers including Snai1, and phosphorylation of SMAD family member 2. Supporting these in vivo findings, silencing of LGALS1 in human retinal pigment epithelial (RPE) cells inhibited TGF-β1-induced EMT-related molecules and cell motilities. Conversely, overexpression of Lgals1 enhanced CNV and subretinal fibrosis. Specimens from patients with AMD demonstrated colocalization of galectin-1 with VEGFR2 in neovascular endothelial cells and with phosphorylated SMAD2 in RPE cells. These results suggested a biologic significance of galectin-1 as a key promotor for both angiogenesis and fibrosis in eyes with AMD.-Wu, D., Kanda, A., Liu, Y., Kase, S., Noda, K., Ishida, S. Galectin-1 promotes choroidal neovascularization and subretinal fibrosis mediated via epithelial-mesenchymal transition.

Immunohistochemical and Immunocytochemical Analyses in Patients with Vitreoretinal Lymphoma.
Kase S, Namba K, Kanno-Okada H, Onozawa M, Hidaka D, Iwata D, Mizuuchi K, Fukuhara T, Fukuhara J, Kitaichi N, Matsuno Y, Ishida S
Ocular immunology and inflammation, 1, 9, 2018年10月, ［査読有り］

Clinical features of Japanese patients with anti-α-enolase antibody-positive autoimmune retinopathy: Novel subtype of multiple drusen.
Ando R, Saito W, Kanda A, Kase S, Fujinami K, Sugahara M, Nakamura Y, Eguchi S, Mori S, Noda K, Shinoda K, Ishida S
American journal of ophthalmology, 196, 181, 196, 2018年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To evaluate clinical features of Japanese patients with anti-α-enolase antibody-positive autoimmune retinopathy (anti-enolase AIR). DESIGN: Multicenter retrospective observational case series. METHODS: Forty-nine eyes of 25 Japanese anti-enolase AIR patients (16 female and 9 male; mean age at first visit, 60.8 years) were included. Fundus characteristics, perimetry, spectral-domain optical coherence tomography (SD-OCT), electroretinography (ERG), best-corrected visual acuity (BCVA), and complicating systemic tumors were assessed. Protein localization of α-enolase was examined by immunohistochemistry in an enucleated eye of 1 patient. RESULTS: Patients were classified into 3 groups: multiple drusen (48%), retinal degeneration (36%), and normal fundus (16%). Drusen varied in size from small deposits to vitelliform-like lesions. Images on SD-OCT revealed dome-shaped hyperreflectivity beneath the retinal pigment epithelium (RPE), corresponding to drusen. Perimetry showed that ring scotoma was the most frequent (39%). Rod-system and/or single-flash cone responses revealed decreased responses in 81% of the eyes. Combined rod and cone system responses demonstrated significantly lower a-wave amplitudes in the degeneration group than in the drusen group (P = .005). BCVA was improved or maintained in 80% of the eyes during follow-up. Malignant or benign tumors were detected in 30% of patients. The RPE and photoreceptor layers were immunopositive for α-enolase. CONCLUSIONS: The drusen subtype, scarcely described in the literature, is suggested to characterize Japanese patients with anti-enolase AIR. The different funduscopic features with different functional severities may have resulted from antibody-mediated damage to RPE as well as photoreceptor cells.

糖尿病網膜症の増殖組織における分子シャペロンαB-クリスタリンのリン酸化　　　　　　　　　　　　　　　
加瀬 諭, 董 陽子, 神田 敦宏, 野田 航介, 石田 晋
日本糖尿病眼学会誌, 22, 133, 133, 日本糖尿病眼学会, 2018年09月
日本語

The clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma
Kanae Fukutsu, Satoru Kase, Kan Ishijima, Rumiko Kinoshita, Susumu Ishida
Radiation Oncology, 13, 1, 95, BioMed Central Ltd., 2018年05月16日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: To examine the clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. Methods: Twenty-one patients with 26 eyes diagnosed with ocular adnexal MALT lymphoma (26 eyes), who were treated in Hokkaido University Hospital, were retrospectively reviewed based on medical records. Results: Out of the 21 patients, 16 patients (21 eyes) received radiation therapy (RT) with a total dose of 30 Gy. All cases eventually achieved complete remission. Eight of these patients (11 eyes: 52.3%) required cataract surgery after RT. The mean age at surgery was 56.8 (40-70) years. The mean latency between RT and the indication for surgery was 43.3 months. The percentage of females was significantly higher in patients who required surgery (P <
0.01), compared with those without surgery. The eyes of patients who received bolus technique on radiation treatment developed cataract more frequently (P <
0.05). In contrast, none of the patients without RT required cataract surgery. Conclusions: Patients with ocular adnexal MALT lymphoma who underwent surgery for radiation cataract were seen more often in relatively young, female patients, and surgery was required about 3 years after RT. A long-term observation may be needed for patients after RT for a tumor. A female sex and the bolus technique may be risk factors for radiation cataract.

Alteration of layer thickness in the choroid of diabetic patients.
Endo H, Kase S, Takahashi M, Yokoi M, Isozaki C, Katsuta S, Kase M
Clinical & experimental ophthalmology, 2018年05月, ［査読有り］

Anterior proliferative vitreoretinopathy in a patient with Coats disease
Satoru Kase, Shohei Mori, Kousuke Noda, Susumu Ishida
International Journal of Ophthalmology, 11, 2, 343, 345, International Journal of Ophthalmology (c/o Editorial Office), 2018年, ［査読有り］
英語

Role of the Epipapillary Membrane in Maculopathy Associated with Cavitary Optic Disc Anomalies: Morphology, Surgical Outcomes, and Histopathology.
Tanaka A, Saito W, Kase S, Ishijima K, Noda K, Ishida S
Journal of ophthalmology, 2018, 5680503, 5680503, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: To evaluate the surgical outcomes of pars plana vitrectomy (PPV) with epipapillary membrane removal in patients with maculopathy associated with cavitary optic disc anomalies. Methods: Eight patients (8 eyes) with cavitary optic disc anomaly-associated maculopathy who underwent PPV with epipapillary membrane removal were retrospectively reviewed. The best-corrected visual acuity (BCVA) and macular and papillary morphologies using enhanced depth imaging optical coherence tomography (EDI-OCT) were evaluated before and after treatment. Immunohistochemistry for an intraoperatively excised epipapillary membrane tissue was also performed. Results: Before surgery, EDI-OCT revealed that epipapillary membrane was observed in all patients. Retinoschisis was resolved with no recurrence in all patients following vitrectomy regardless of a disease type or the presence or absence of preoperative posterior vitreous detachment. The mean final BCVA and central retinal thickness significantly improved compared with pretreatment values (P = 0.008 and 0.004, resp.). Immunoreactivity for S100 protein and glial fibrillary acidic protein, markers of astrocytes, was positive in the resected membrane tissues. Conclusions: These results suggest that epipapillary membrane is involved in the pathogenesis of some patients with cavitary optic disc anomaly-associated maculopathy as well as posterior hyaloid membrane. PPV with epipapillary membrane removal may be a useful treatment option for this maculopathy. This trial is registered with UMIN000011123.

A clinicopathological study on IgG4-related ophthalmic disease.
Suimon Y, Kase S, Ishijima K, Kanno-Okada H, Ishida S
International journal of ophthalmology, 11, 9, 1539, 1544, 2018年, ［査読有り］

Expression of VEGF in human conjunctival melanoma analyzed with immunohistochemistry
Satoru Kase, Iku Kikuchi, Susumu Ishida
Clinical Ophthalmology, 12, 2363, 2367, Dove Medical Press Ltd, 2018年
英語, 研究論文（学術雑誌）, Purpose: The aim of this study was to examine the immunolocalization of VEGF-A and CD34, a marker of endothelial cells, in human conjunctival melanoma. Methods: This study retrospectively analyzed primary conjunctival melanoma patients who underwent surgical resection of the tumor. All excised tissues were fixed with paraformalde-hyde and embedded in paraffin, which were then submitted for immunohistochemistry with anti-VEGF and CD34 antibodies. Results: The study sample comprised 4 female and two male melanoma patients. The age of the patients ranged from 64 to 84 (average age, 73) years. Histopathology of the surgically resected tumor tissues demonstrated accumulation of polygonal atypical malignant cells producing melanin. Cytoplasmic immunoreactivity for VEGF was clearly observed in tumor cells of all six tumors. In contrast, CD34-positive endothelial cells were less marked in the melanoma tissues than in the adjacent noncancerous subconjunctival stroma. Conclusion: VEGF immunoreactivity was observed in conjunctival melanoma tissues, in which endothelial cells were hardly observed. These results suggest that although VEGF is expressed, conjunctival melanoma is a hypovascular tumor.

Usefulness of PET/CT for early detection of internal malignancies in patients with Muir-Torre syndrome: report of two cases.
Ishiguro Y, Homma S, Yoshida T, Ohno Y, Ichikawa N, Kawamura H, Hata H, Kase S, Ishida S, Okada-Kanno H, Hatanaka KC, Taketomi A
Surgical case reports, 3, 1, 71, 71, Springer, 2017年12月, ［査読有り］
英語, Background: Muir-Torre syndrome (MTS) is a rare autosomal dominant genodermatosis caused by mutations in mismatch repair genes. It is characterized by the presence of at least one sebaceous skin tumor associated with internal malignancies. Whether positron emission tomography/computed tomography (PET/CT) is useful for the detection of malignancies in patients with MTS has not been determined. We herein report two cases in which PET/CT was useful for the diagnosis and follow-up of internal malignancies in patients with MTS. Case presentation: In case 1, a 57-year-old woman underwent excision of a sebaceous carcinoma on the left upper eyelid. She underwent follow-up PET/CT once yearly thereafter. Forty-two months after the eyelid surgery, PET/CT showed intense tracer uptake in the right lower abdomen. An ascending colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. In case 2, a 77-year-old man presented for evaluation of three continuous papules with telangiectasia on his right cheek. Examination of a skin biopsy specimen of the cheek papule revealed a sebaceous carcinoma. He underwent PET/CT to detect other malignancies. PET/CT showed intense tracer uptake in the sigmoid colon. A sigmoid colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. Both patients underwent resection of their tumors, and both were still free of recurrence of the sebaceous and colon carcinomas at the time of this writing. Conclusion: PET/CT is a reliable imaging modality for the detection of internal malignancies and is useful for the diagnosis and follow-up of MTS.

Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection
Iku Kikuchi, Satoru Kase, Kan Ishijima, Susumu Ishida
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 255, 11, 2271, 2276, SPRINGER, 2017年11月, ［査読有り］
英語, 研究論文（学術雑誌）, The purpose of this study was to report the clinical outcomes of patients with conjunctival melanoma treated with interferon (IFN) alpha-2b eye drops following local tumor resection.
Five eyes of five patients were enrolled in this study. All patients underwent the local resection of tumors, and topical IFN alpha-2b eye drops were subsequently administered 4 times/day until the complete disappearance of the pigmented lesions determined by slit-lamp examination. Ophthalmological findings, histopathological findings, and imaging modalities were retrospectively analyzed.
The age of the patients ranged from 65 to 84 years (mean: 75.4 years). Locations of the tumor were the bulbar conjunctiva in three eyes, multiple palpebral conjunctivas in one eye, and palpebral conjunctiva and caruncle in one eye. All patients received topical IFN alpha-2b eye drop treatment for 6-10 months. Follow-up periods after resection ranged from 18 to 78 months. Histologically, all excised conjunctival tumors were diagnosed with malignant melanoma, where the surgical margins were completely negative in one patient. No patients had suffered from severe adverse effects related to IFN alpha-2b. Four out of five patients consequently achieved complete remission. Since one eye in one case showed resistance to the local chemotherapy containing IFN alpha-2b eye drops and the subconjunctival injection of IFN-beta, orbital exenteration was eventually required 12 months after local resection.
Topical IFN alpha-2b eye drops may be safe and one of the useful adjunctive treatments following surgical resection for patients with conjunctival melanoma.

Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa
Satoru Kase, Kan Ishijima, Takehiko Uraki, Yuka Suimon, Yasuo Suzuki, Manabu Kase, Susumu Ishida
ANTICANCER RESEARCH, 37, 9, 5001, 5004, INT INST ANTICANCER RESEARCH, 2017年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Background/Aim: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). Materials and Methods: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. Results: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. Conclusion: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM.

Cytopathologic findings of cell block materials from the vitreous: Diagnostic distinction between intraocular lymphoma and non-lymphomatous diseases
Hiromi Kanno-Okada, Emi Takakuwa, Yoshiaki Tagawa, Satoru Kase, Kanako C. Hatanaka, Yutaka Hatanaka, Kenichi Namba, Tomoko Mitsuhashi, Yoshihiro Matsuno
PATHOLOGY INTERNATIONAL, 67, 7, 342, 349, WILEY, 2017年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Intraocular lymphoma is a rare neoplasm that occurs only in the eyes and/or central nervous system. Diagnosis of intraocular lymphoma is difficult because its clinical manifestations mimic chronic uveitis. Pathological examination of the vitreous is one of the main diagnostic tools for intraocular lymphoma, but this is challenging due to the sparse cellularity and specimen degeneration. Here, we reviewed 33 cell block preparations from vitreous perfusion fluid in order to examine the significance of cytopathological findings for differential diagnosis using vitreous samples. The cases comprised 12 intraocular lymphomas and 21 non-lymphomatous diseases. Cytologically, vitreous samples from non-lymphoma cases showed lower cellularity than the lymphoma cases. Whereas vitreous material from cases with infectious endophthalmitis showed prominent neutrophilic infiltration, material from sarcoidosis cases showed infiltration of small lymphoid cells, especially CD4-positive T cells. On the other hand, lymphoma cases showed higher cellularity, with large, irregular and atypical lymphoid cells, frequent necrotic cells in the background, and less pronounced neutrophil infiltration. Immunocytochemically, 11 of the 12 lymphoma cases were of the B-cell phenotype and the remaining case was of the T/NK-cell phenotype. In conclusion, careful cytopathological examination or immunocytochemistry of vitreous material facilitates appropriate diagnosis of intraocular lymphoma.

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva
Satoru Kase, Toshiya Shinohara, Manabu Kase, Susumu Ishida
EXPERIMENTAL AND THERAPEUTIC MEDICINE, 13, 6, 3516, 3522, SPANDIDOS PUBL LTD, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.

Catastrophic Thermal Corneoscleral Injury Treated with Transplantation of Donor Scleral Graft.
Kase S, Ohguchi T, Ishida S
Case reports in ophthalmology, 8, 2, 349, 352, 2017年05月, ［査読有り］

Vascular anomaly in the levator aponeurosis of neurofibromatosis type 1
Satoru Kase, Toshiya Shinohara, Mika Noda, Susumu Ishida, Manabu Kase
INTERNATIONAL JOURNAL OF OPHTHALMOLOGY, 10, 4, 656, 657, IJO PRESS, 2017年04月, ［査読有り］
英語, 研究論文（学術雑誌）

Serial Frequencies and Clinical Features of Uveitis in Hokkaido, Japan
Daiju Iwata, Kazuomi Mizuuchi, Koki Aoki, Yukihiro Horie, Satoru Kase, Kenichi Namba, Shigeaki Ohno, Susumu Ishida, Nobuyoshi Kitaichi
OCULAR IMMUNOLOGY AND INFLAMMATION, 25, sup1, S15, S18, TAYLOR & FRANCIS INC, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: Environmental and lifestyle changes influence the clinical features of uveitis. This study reviewed the epidemiologic trends of uveitis in the Japanese population.Methods: A retrospective review of the past 80 years of reports from Hokkaido University Hospital.Results: In the 1930s, tuberculosis accounted for 46% and syphilitic uveitis for 31% of cases. The frequency of these diseases decreased to 12% in the 1950s; 8% in 1969; 0.6% in the 1990s; and 0.8% in the 2000s, while the rate of non-infectious uveitis increased. The three most common specific diagnoses were: sarcoidosis, Vogt-Koyanagi-Harada disease, and Behcet disease. Although Behcet disease was the most frequent non-infectious uveitis until the 1980s, sarcoidosis is now the most frequent cause of newly diagnosed non-infectious uveitis.Conclusions: The etiology of uveitis has changed with the times. Tubercular and syphilitic cases have greatly decreased, and sarcoidosis is the most frequent type of uveitis today.

Histological Findings in the Trabecular Meshwork of a Patient with Atopic Glaucoma.
Kase S, Chin S, Hamanaka T, Shinmei Y, Ohguchi T, Kijima R, Matsuda A, Ishida S
The open ophthalmology journal, 11, 103, 106, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aim of this study was to report a case of atopic dermatitis showing elevated intraocular pressure (IOP) beyond the baseline levels followed by a modified 360-degree suture trabeculotomy, and to analyze the histological findings in the trabecular meshwork. METHODS: A 40-year-old male suffered from blurred vision in the right eye (OD). He had a medical history of severe atopic dermatitis and intraocular lens implantation OU due to atopic cataract. At the initial presentation, the visual acuity was 0.03, and IOP was 35 mmHg OD. Slit-lamp examination demonstrated corneal epithelial edema OD. Increased IOP was refractory to several topical medications. The patient underwent a modified 360-degree suture trabeculotomy. The visual field defect, however, deteriorated with persistently high IOP. The patient underwent trabeculectomy together with drainage implant surgery. In the outflow routes, although there seemed to be an opening of Schlemm's canal into the anterior chamber, there was no endothelium of the canal in the region of its opening. The fibrotic changes were conspicuous around Schlemm's canal. CONCLUSION: The histological results indicated that trabeculotomy might not be an appropriate treatment for patients with atopic glaucoma, possibly because of excessive repair to the newly created uveoscleral outflow in addition to the increased postoperative fibrosis in the trabecular meshwork and Schlemm's canal.

Clinical and histological evaluation of large macular hole surgery using the inverted internal limiting membrane flap technique.
Kase S, Saito W, Mori S, Saito M, Ando R, Dong Z, Suzuki T, Noda K, Ishida S
Clinical ophthalmology (Auckland, N.Z.), 11, 9, 14, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aims of this study were to analyze optical coherence tomography (OCT) imaging of large macular holes (MHs) treated with inverted internal limiting membrane (ILM) flap technique and to perform a histological examination of an ILM-like membrane tissue obtained during vitrectomy. PATIENTS AND METHODS: This is a retrospective observational case study. Nine patients, comprising of five males and four females, showing large and myopic MHs, underwent pars plana vitrectomy (PPV) with inverted ILM flap technique assisted by brilliant blue G (BBG) staining. Ophthalmological findings including visual acuity and OCT were investigated based on medical records. Formalin-fixed paraffin-embedded tissue section of an ILM-like membrane was submitted for immunohistochemistry with glial fibrillary acidic protein (GFAP). RESULTS: ILM was clearly stained with BBG in eight patients, whereas the ILM in one case revealed no staining with BBG during PPV. Visual acuities improved to >0.2 LogMAR in six patients. The complete closure of MH following PPV with inverted ILM technique was eventually achieved in all patients determined by OCT imaging (100%). Only one patient showed recovery of ellipsoid zone and interdigitation zone following the surgery. Elongation of outer nuclear layer was noted in three eyes. The ILM-like membrane not stained with BBG histologically revealed an amorphous structure admixed with GFAP-positive mononuclear cell infiltration. CONCLUSION: PPV with inverted ILM flap technique achieved 100% closure rates with favorable configuration at an initial surgery in large MHs. Our histopathological data also suggest that even BBG staining-negative membrane may be a useful material for autologous transplantation to the hole.

Coincidence of Inflamed Conjunctival Carcinoma in situ and Primary Pterygium
Hiroaki Endo, Satoru Kase, Yasuo Suzuki, Manabu Kase
Case Reports in Ophthalmology, 7, 3, 208, 212, S. Karger AG, 2016年09月09日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: We report a rare case of carcinoma in situ (CIS) in conjunction with a primary pterygium that exhibited characteristic angiographic and histopathological findings. Case: A 78-year-old man presented with a pterygium and a whitish tumor adjacent to the pterygium in his right eye. Indocyanine green angiography displayed that feeder vessels within the primary pterygium spread to the whitish tumor. The tumor and pterygial tissues were surgically removed. Histologically, the resected tissue contained CIS as well as squamous metaplasia. There was a marked inflammatory cell infiltration within the tumor and beneath the epithelium. Topical interferon alfa-2b was given 4 times per day for 2 months. The patient has been well without local recurrence of tumor or distal metastases to 54 follow-up months after surgery. Conclusions: Because CIS can occur adjacent to pterygial tissues, long-term follow-up is necessary in patients with pterygia.

【網膜硝子体疾患の薬物療法-どこまでできるか?-】各種脈絡膜新生血管に対する薬物療法
加瀬 諭, 野田 航介
OCULISTA, 41, 31, 38, (株)全日本病院出版会, 2016年08月
日本語, 脈絡膜新生血管(CNV)は加齢黄斑変性のみならず、さまざまな炎症疾患、変性疾患に発生し得る。近視性CNVでは、抗VEGF薬治療によりCNVの活動性を制御することが可能であるが、治療後の再発や網脈絡膜萎縮による視力障害が問題である。ぶどう膜炎や点状網膜内層症における炎症性CNVにおいては、副腎皮質ステロイド薬や抗VEGF薬治療がCNVの制御に有用であるが、依然確立された治療法は存在しない。網膜色素線条に伴うCNVに対しては、抗VEGF薬治療により視力を維持することが可能になってきているが、Bruch膜断裂に対する根本的な治療は存在しない。特発性CNVは概して抗VEGF薬治療に対して良好な反応を示すが、治療回数や若年者の中心窩下CNV症例における視力不良例が問題である。以上より、抗VEGF薬治療は、加齢黄斑変性以外のCNVに対しても、有効性を示す眼疾患が多々存在するが、課題も残されている。(著者抄録)

Regulation of vascular endothelial growth factor-C by tumor necrosis factor-α in the conjunctiva and pterygium.
Dong Y, Kase S, Dong Z, Fukuhara J, Tagawa Y, Ishizuka ET, Murata M, Shinmei Y, Ohguchi T, Kanda A, Noda K, Ishida S
International journal of molecular medicine, 38, 2, 545, 550, 2016年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Vascular endothelial growth factor C (VEGF-C) plays an important role in the development of a pterygium through lymphangiogenesis. We examined the association between VEGF-C and tumor necrosis factor-α (TNF-α) in the pathogenesis of pterygia. Cultured conjunctival epithelial cells were treated with TNF-α, and the gene expression levels of VEGFC were evaluated by quantitative polymerase chain reaction (qPCR) and VEGF-C protein expression levels were measured using an enzyme-linked immunosorbent assay (ELISA). In addition, using ELISA, we evaluated the VEGF-C protein expression in the supernatants of cultured conjunctival epithelial cells, in which we neutralized TNF-α using anti‑TNF-α antibody. The gene expression of tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), known as TNF receptor 1 (TNFR1), was confirmed using reverse transcription PCR in cultured conjunctival epithelial cells. Immunofluorescence microscopy was used to examine the localization of VEGF-C and TNFR1 in pterygium tissues and TNFR1 expression in cultured conjunctival epithelial cells. Immunohistochemistry was used to examine the localization of TNFR1 in pterygia and normal conjunctival tissues. VEGFC gene expression increased in cultured conjunctival epithelial cells 24 h after the addition of TNF-α. The secretion of VEGF-C protein was significantly increased 48 h after the stimulation of cultured conjunctival epithelial cells with TNF-α. Increased VEGF-C protein secretion stimulated by TNF-α was significantly reduced by anti-TNF-α neutralizing antibody treatment. In cultured conjunctival epithelial cells, TNFRSF1A and TNFR1 were expressed. TNFR1 was immunolocalized in normal conjunctival tissues and in human pterygium tissues as well as in VEGF‑C‑positive epithelial cells from human pterygia. Our data demonstrate that TNF-α mediates VEGF-C expression, which plays a critical role in the pathogenesis of pterygia.

Diagnostic efficacy of cell block method for vitreoretinal lymphoma
Kase Satoru, Namba Kenichi, Iwata Daiju, Mizuuchi Kazuomi, Kitaichi Nobuyoshi, Tagawa Yoshiaki, Okada-Kanno Hiromi, Matsuno Yoshihiro, Ishida Susumu
Diagnostic pathology, 11, 29, 29, BioMed Central, 2016年03月, ［査読有り］
英語, Background: Vitreoretinal lymphoma (VRL) is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. Methods: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin (IL)-10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. Results: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL (positive rate: 93.3 %), but in 5 out of 14 eyes in conventional smear cytology (positive rate: 35.7 %). Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block-positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. Conclusions: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity.背景：眼内リンパ腫（VRL）は視力・生命予後に影響を及ぼす疾患である。本研究ではVRLの診断における細胞塊（セルブロック）標本の有用性を検討することを目的とした。症例と方法：北海道大学病院眼科および他院を受診したVRL12例16眼、および硝子体混濁を呈した特発性ぶどう膜炎4例4眼を対象とした。小切開硝子体手術により、無希釈硝子体液および硝子体灌流液を採取した。19眼で、硝子体灌流液を用いたセルブロック標本を作製した。これらの標本を用いて特殊染色、およびB細胞マーカーである抗CD20抗体の免疫細胞化学的検討を行った。14眼では無希釈硝子体液を用いた塗抹細胞診を併せて行った。VRLの診断は、細胞診、無希釈硝子体液のIL-10, -6濃度、灌流液沈殿物から遺伝子再構成部位のモノクローナリティについて検討して行った。結果：VRLの15眼中14眼でセルブロック標本にて悪性リンパ腫細胞が検出された（陽性率：93.3％）。一方、塗抹細胞診では5眼で悪性細胞が検出された（陽性率：35.7％）。塗抹細胞診で陰性、セルブロックで陽性を示したIOL症例は7例8眼であった。特発性ぶどう膜炎では、悪性細胞が検出された症例はなかった（陽性率：0％）。VRL細胞はCD20陽性を示したが、特発性ぶどう膜炎ではCD20陽性細胞は検出されなかった。結語：硝子体灌流液を用いたセルブロック細胞診は、これまでの塗抹細胞診よりVRLの陽性率が高く、偽陽性も無かった。セルブロックは、VRLとぶどう膜炎との鑑別にも有用であることが示唆された。

Phosphorylation of alphaB-crystallin in epiretinal membrane of human proliferative diabetic retinopathy.
Dong Y, Dong Z, Kase S, Ando R, Fukuhara J, Kinoshita S, Inafuku S, Tagawa Y, Ishizuka ET, Saito W, Murata M, Kanda A, Noda K, Ishida S
International journal of ophthalmology, 9, 8, 1100, 1105, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: To examine phosphorylation of alphaB-crystallin (p-αBC), a vascular endothelial growth factor (VEGF) chaperone, and immunohistochemically investigate relationship between p-αBC, VEGF and phosphorylated p38-mitogen-activated protein kinase (p-p38 MAPK) in the epiretinal membrane of human proliferative diabetic retinopathy (PDR). METHODS: Eleven epiretinal membranes of PDR surgically excised were included in this study. Two normal retinas were also collected from enucleation tissues due to choroidal melanoma. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with anti-p-αBC, VEGF, CD31, and p-p38 MAPK antibodies. RESULTS: Immunoreactivity for p-αBC was observed in all of the epiretinal membranes examined, where phosphorylation on serine (Ser) 59 showed strongest immunoreactivity in over 70% of the membranes. The immunolocalization of p-αBC was detected in the CD31-positive endothelial cells, and co-localized with VEGF and p-p38 MAPK in PDR membranes. Immunoreactivity for p-αBC, however, was undetectable in endothelial cells of the normal retinas, where p-p38 MAPK immunoreactivity was less marked than PDR membranes. CONCLUSION: Phosphorylation of αBC, in particular, phosphorylation on Ser59 by p-p38 MAPK may play a potential role as a molecular chaperon for VEGF in the pathogenesis of epiretinal membranes in PDR.

Measurement of interleukins in vitreous infusion fluid.
Kase S, Yokoi M, Ishida S, Kase M
Biomedical reports, 3, 6, 818, 820, Spandidos Publications, 2015年11月, ［査読有り］
英語, Measurements of interleukin (IL)-6 and -10 concentrations in the vitreous can be used to differentiate intraocular lymphoma (IOL) from uveitis. This is the first study reporting the IL-6 and -10 concentrations in the undiluted vitreous fluid and vitreous infusion fluid, which were simultaneously examined in the patients. A total of 2 females presented with intraocular inflammation, and underwent pars plana vitrectomy. Undiluted anterior vitreous and vitreous infusion fluid were collected simultaneously. IL concentrations were determined by enzyme-linked immunosorbent assay systems. Vitreous infusion fluid of 20 ml was eventually collected following completion of core vitrectomy in the two patients. IL-6 concentrations of the first patient were 513 and 106 pg/ml in the undiluted vitreous and the infusion fluid, respectively, while those of the second patient were 263 and 29 pg/ml. By contrast, IL-10 was under the detectable levels in all the fluids. The IL-10/-6 ratio was <1 in both fluids in the patients. Cytological examination revealed the presence of reactive inflammatory cells in the vitreous fluid. The two patients were eventually diagnosed with uveitis. Measurements of IL concentrations in the vitreous infusion fluid provided significant evidence on the differential diagnosis between IOL and uveitis, when considering how vitreous infusion fluid was diluted. The present study highlighted a novel application of cytokine analyses using the vitreous infusion fluid, which may contribute to the development of future translational researches on uveitis/IOL patients.

A case of choroidal malignant melanoma with vitreal dissemination　　　　　　　　　　　　　　　
Hanae Yokoyama, Satoru Kase, Yasuo Suzuki, Satoshi Katsuta, Mitsuo Takahashi, Toshiya Shinohara, Susumu Ishida, Manabu Kase
Japanese Journal of Clinical Ophthalmology, 69, 10, 1545, 1550, Igaku-Shoin Ltd, 2015年10月01日
日本語, 研究論文（学術雑誌）, Background: Choroidal malignant melanoma is rear in the Japanese. Its incidence has been reported to be 0.25 among general population of 1, 000, 000. Association of vitreal dissemination was reported in only 3 cases in Japan. Purpose: To report a case of choroidal malignant melanoma with vitreal dissemination. Case: A 31-year-old male was referred to us for elevated lesion in the left fundus. He had had myodesopsia since 2 years before. Findings and Clinical Course: Best corrected visual acuity was 0.6 in either eye. The left eye showed pigmented floaters in the anterior vitreous. An elevated brown tumor was present with black area in its apex in the left temporal fundus. This tumor showed dye leakage in the late phase of fluorescein angiography and hyperfluorescence by indocyanine angiography. The black area in the apex remained hypofluorescent throughout. The fundus lesion was diagnosed with choroidal malignant melanoma, leading to enucleation. Histopathology confirmed the diagnosis. The tumor measured 8 mm × 8 mm × 5 mm. Tumor cells perforated the retina into the vitreous at the apex corresponding to the site of black area. Conclusion: The present caae was choroidal malignant melanoma with vitreal dissemination.

Choroidal thickness in diabetic retinopathy in relation to long-term systemic treatments for diabetes mellitus
Satoru Kase, Hiroaki Endo, Masahiko Yokoi, Masako Kotani, Satoshi Katsuta, Mitsuo Takahashi, Manabu Kase
European Journal of Ophthalmology, 26, 2, 158, 162, Wichtig Publishing Srl, 2015年09月29日
英語, 研究論文（学術雑誌）, Purpose: To measure central choroidal thickness (CCT) in patients with diabetic retinopathy (DR) and analyze the correlation with clinical backgrounds regarding medications for diabetes mellitus (DM). Methods: We retrospectively identified 86 patients with DR (172 eyes) and 43 healthy subjects (57 eyes) who underwent spectral-domain optical coherence tomography. Among the 86 patients with DM who had received no intraocular treatments, 61 were diabetic patients who had continuously received systemic treatments for DM (under treatment group). Twenty-five were patients who had discontinued the treatments or had not received any treatment for DM until this study started (no treatment group). Results: The results of CCT acquired by 2 masked raters showed a significant correlation coefficient (r = 0.98), indicating high reproducibility in this study. No correlation of CCT was noted between normal (272 ± 71 μm) and DM eyes (264 ± 77 μm), the presence of diabetic macular edema, or CCT and the severity of DR in the patients examined. Interestingly, there was a significant decrease in CCT (175 ± 42 μm) in eyes with mild/moderate nonproliferative DR (NPDR) in the no treatment group (p<
0.05), whereas CCT was prominently thicker in eyes with severe NPDR (354 ± 76 μm) and proliferative DR (286 ± 74 μm) than in eyes without DR. Conclusions: This study demonstrated that CCT was significantly decreased in the presence of mild/moderate NPDR in the no treatment group, suggesting that a continuously high blood sugar state caused by insufficient treatments for DM may facilitate vascular damage in the choroid in the early stage of DR.

Histological observation of goblet cells following topical rebamipide treatment of the human ocular surface: A case report
Satoru Kase, Toshiya Shinohara, Manabu Kase
EXPERIMENTAL AND THERAPEUTIC MEDICINE, 9, 2, 456, 458, SPANDIDOS PUBL LTD, 2015年02月, ［査読有り］
英語, 研究論文（学術雑誌）, The topical administration of rebamipide (Mucosta (R)), an antiulcer agent, clinically increases the mucin level of tear film. The aim of this study was to report the histological changes of goblet cells following the topical administration of rebamipide to a patient with nevus of the lacrimal caruncle. A 62-year-old male exhibited a pigmented nodule located in the lacrimal caruncle in the left eye. An excisional biopsy and subsequent surgical resection were conducted at the caruncle, prior to and three months after topical rebamipide administration. Histologically, a biopsy specimen revealed a pigmented nevus beneath the caruncle epithelium containing a few goblet cells [4 cells/high power field (HPF)]. A few nevus cells were present at the surgical margin. By contrast, the secondary resected specimen obtained three months after the initiation of topical rebamipide treatment revealed the epithelium and nevus, where numerous goblet cells were present (28 cells/HPF), and mucin-like substances were markedly secreted from the goblet cells. Topical rebamipide markedly increased the number of goblet cells and stimulated the secretion of mucin-like substances in the caruncular tissue of a human patient. These results suggest that topical rebamipide is useful in patients following surgery and/or biopsy to support tissue repair of the ocular surface.

Involvement of the receptor-associated prorenin system in the pathogenesis of human conjunctival lymphoma.
Ishizuka ET, Kanda A, Kase S, Noda K, Ishida S
Investigative ophthalmology & visual science, 56, 1, 74, 80, 2014年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Extranodal marginal zone B-cell lymphoma (EMZL) is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin-angiotensin system (RAS) and (pro)renin receptor ([P]RR) in the pathogenesis of conjunctival lymphoma. METHODS: Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of (P)RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II (Ang II), and gene expression levels were analyzed using real-time quantitative PCR (qPCR). In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components. RESULTS: Gene expression and immunohistochemical analyses revealed the expression of RAS components, including (P)RR and angiotensin II type 1 receptor (AT1R), in EMZL tissues. Double-labeling analyses demonstrated that (P)RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 (FGF2), while angiotensin II treatment upregulated the expression levels of basigin (BSG), matrix metallopeptidase (MMP)2, 9, and 14, which were abolished by (P)RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of (P)RR and AT1R with the products of these upregulated genes. CONCLUSIONS: The present study suggests that activation of (P)RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs.

Oxidative stress in the levator aponeurosis in Asian involutional blepharoptosis.
Kase S, Noda M, Yoshikawa H, Yamamoto T, Ishijima K, Ishida S
Ophthalmic plastic and reconstructive surgery, 30, 4, 290, 294, 2014年07月, ［査読有り］

Adenosquamous carcinoma of the conjunctiva: A case report.
Kase S, Yoshikawa H, Nakajima Y, Noda M, Ishida S
Oncology letters, 7, 6, 1941, 1943, Spandidos Publications, 2014年06月, ［査読有り］
英語, Adenosquamous carcinoma (ASC) is a rare form of malignancy which consists of two types of cell, including squamous cells and glandular-like cells. The current report presents the first known case of ASC in the conjunctiva and analyzes the histological findings. A 76-year-old female presented with right eyelid swelling in 2001. A right conjunctival tumor was noted and a biopsy was performed. Histologically, the tumor was diagnosed as a squamous cell carcinoma. The patient underwent radiotherapy, but the tumor rapidly relapsed. Subsequently, the patient underwent orbital exenteration. Histologically, the conjunctival tissues had been replaced with invasive tumor cells. A number of tumor cells demonstrated squamous differentiation with a keratinizing tendency, while other tumor cells exhibited mucin-producing activity with glandular formation. The conjunctival tumor was diagnosed as an ASC. At the time of writing, the patient is well without local recurrence or distant metastases. ASC typically exhibits aggressive biological behavior, and is associated with worse prognosis than conventional adenocarcinoma. Therefore, complete surgical excision is considered a key treatment for ASC of the conjunctiva.

Expression of vascular endothelial growth factor in human ocular adnexal lymphoma.
Kinoshita S, Kase S, Ando R, Dong Z, Fukuhara J, Dong Y, Inafuku S, Noda K, Noda M, Kanda A, Ishida S
Investigative ophthalmology & visual science, 55, 6, 3461, 3467, 2014年05月, ［査読有り］

IgG4-related lacrimal sac diverticulitis
Satoru Kase, Yasuo Suzuki, Toshiya Shinohara, Manabu Kase
Orbit, 33, 3, 217, 219, Informa Healthcare, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, IgG4-related disease is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. We herein report a case of lacrimal sac diverticulitis with marked IgG4-positive plasma cell infiltration. An 89-year-old woman presenting with right lower eyelid mass. Imaging modalities demonstrated a cystic orbital mass located beneath the globe and adjacent to enlarged lacrimal sac. Serological tests showed high IgG4 and normal IgG levels, measuring 242 and 1603mg/dl, respectively. The orbital mass was surgically excised. Histologically, the excised tissue demonstrated marked inflammation with fibrosis surrounded by mononuclear epithelial cells. A variety of IgG and IgG4-positive plasma cells infiltrated the stroma. This patient was diagnosed as an IgG4-related lacrimal sac diverticulitis, based on current diagnostic criteria of IgG4-related disease. It is likely that IgG4-related inflammation occurs in a lacrimal sac diverticulum, which should be considered a differential diagnosis in inferior orbital tumors. © 2014 Informa Healthcare USA, Inc.

Expression of vascular endothelial growth factor and intravitreal anti-VEGF therapy with bevacizumab in vasoproliferative retinal tumors.
Saito W, Kase S, Fujiya A, Dong Z, Noda K, Ishida S
Retina (Philadelphia, Pa.), 33, 9, 1959, 1967, 2013年10月, ［査読有り］

Spontaneous regression of IgG4-related dacryoadenitis.
Kase S, Yamamoto T, Ishijima K, Noda M, Ishida S
Modern rheumatology, 23, 5, 1018, 1021, 2013年09月, ［査読有り］
英語

Expression of αB-crystallin and vascular endothelial growth factor in conjunctival squamous cell carcinoma.
Dong Z, Kase S, Ando R, Fukuhara J, Kinoshita S, Dong Y, Takashina S, Kanda A, Noda M, Noda K, Ishida S
Anticancer research, 33, 9, 3745, 3751, 2013年09月, ［査読有り］

Clinical features of human T lymphotropic virus type 1-associated uveitis in Hokkaido, Japan.
Kase S, Namba K, Kitaichi N, Iwata D, Ohno S, Ishida S
Japanese journal of ophthalmology, 57, 4, 379, 384, Springer, 2013年07月, ［査読有り］
英語

IgG4-related inflammation of the orbit simulating malignant lymphoma.
Kase S, Noda M, Ishijima K, Yamamoto T, Hatanaka K, Ishida S
Anticancer research, 33, 6, 2779, 2783, 2013年06月, ［査読有り］

Autoimmune retinopathy associated with colonic adenoma.
Saito W, Kase S, Ohguro H, Ishida S
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 251, 5, 1447, 1449, Springer, 2013年05月, ［査読有り］
日本語

Stevens-Johnson syndrome/toxic epidermal necrolysis mouse model generated by using PBMCs and the skin of patients
Nao Saito, Naoya Yoshioka, Riichiro Abe, Hongjiang Qiao, Yasuyuki Fujita, Daichi Hoshina, Asuka Suto, Satoru Kase, Nobuyoshi Kitaichi, Michitaka Ozaki, Hiroshi Shimizu
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 131, 2, 434, +, MOSBY-ELSEVIER, 2013年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions caused by drugs or infections and exhibiting widespread epidermal necrosis. Currently, there is no animal model that reproduces SJS/TEN symptoms.
Objective: We sought to develop a novel mouse model of SJS/TEN by using PBMCs and skin from patients who had recovered from SJS/TEN.
Methods: For our mouse model, patients' PBMCs were injected intravenously into immunocompromised NOD/Shi-scid, IL-2R gamma(null) (NOG) mice, followed by oral administration of a causative drug. Subsequently, to replace human skin, unaffected skin specimens obtained from patients who had recovered from SJS/TEN were grafted onto NOG mice, after which patient-derived PBMCs and the causative drug were applied.
Results: Mice injected with PBMCs from patients with SJS/TEN and given the causative drug showed marked conjunctival congestion and numerous cell death of conjunctival epithelium, whereas there were no symptoms in mice injected with PBMCs from patients with ordinary drug skin reactions. CD8(+) T lymphocyte-depleted PBMCs from patients with SJS/TEN did not elicit these symptoms. In addition, skin-grafted mice showed darkening of the skin-grafted areas. Cleaved caspase-3 staining showed that dead keratinocytes were more numerous in the skin-grafted mice than in the healthy control animals.
Conclusion: We have established a novel human-oriented SJS/TEN mouse model and proved the importance of CD8(+) T lymphocytes in SJS/TEN pathogenesis. The mouse model promises to promote diagnostic and therapeutic approaches. (J Allergy Clin Immunol 2013;131:434-41.)

Expression of vascular endothelial growth factor C in human pterygium.
Fukuhara J, Kase S, Ohashi T, Ando R, Dong Z, Noda K, Ohguchi T, Kanda A, Ishida S
Histochemistry and cell biology, 139, 2, 381, 389, 2, 2013年02月, ［査読有り］
英語, Purpose: Vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3 mediate lymphangiogenesis. In this study, we analyzed the expression of VEGF-C and VEGFR-3 as well as lymphatic vessels in the pterygium and normal conjunctiva of humans. Methods: Fifteen primary nasal pterygia and three normal bulbar conjunctivas, surgically removed, were examined in this study. The lymphatic vessel density (LVD) and blood vessel density (BVD) were determined by the immunolabeling of D2-40 and CD31, markers for lymphatic and blood vessels, respectively. VEGF-C and VEGFR-3 expression in pterygial and conjunctival tissue proteins was detected by Western blotting. Expressions of VEGF-C and VEGFR-3 were evaluated using immunohistochemistry. Results: The LVD was significantly higher in the pterygium than normal conjunctiva (p<0.05). Western blot demonstrated high-level expression of VEGF-C and VEGFR-3 in the pterygium compared with normal conjunctiva. VEGF-C immunoreactivity was detected in the cytoplasm of pterygial and normal conjunctival epithelial cells. The number of VEGF-C-immunopositive cells in pterygial epithelial cells was significantly higher than in normal conjunctival cells (p<0.05). VEGFR-3 immunoreactivity was localized in the D2-40-positive lymphatic endothelial cells. Conclusions: The present findings suggest the potential role of VEGF-C in the pathogenesis and development of a pterygium through lymphangiogenesis and the VEGF-C/VEGFR-3 pathway as a novel therapeutic target for the human pterygium.

Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice.
Lennikov A, Kitaichi N, Kase S, Noda K, Horie Y, Nakai A, Ohno S, Ishida S
International journal of molecular sciences, 14, 1, 2175, 2189, MDPI, 2013年01月, ［査読有り］
英語, Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP) 70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400 mJ/cm2), GGA-untreated UVB-exposed (400 mJ/cm2), GGA-treated (500 mg/kg/mouse) but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). HSP70, reactive oxygen species (ROS) production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and protein kinase B (Akt) expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01). Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01). Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05). ROS signal was not affected by GGA. NF-κB activation was reduced but phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-κB activation and possibly increased Akt phosphorilation.

TNF-α decreases VEGF secretion in highly polarized RPE cells but increases it in non-polarized RPE cells related to crosstalk between JNK and NF-κB pathways.
Terasaki H, Kase S, Shirasawa M, Otsuka H, Hisatomi T, Sonoda S, Ishida S, Ishibashi T, Sakamoto T
PloS one, 8, 7, e69994, 2013年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Asymmetrical secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells in situ is critical for maintaining the homeostasis of the retina and choroid. VEGF is also involved in the development and progression of age-related macular degeneration (AMD). We studied the effect of tumor necrosis factor-α (TNF-α) on the secretion of VEGF in polarized and non-polarized RPE cells (P-RPE cells and N-RPE cells, respectively) in culture and in situ in rats. A subretinal injection of TNF-α caused a decrease in VEGF expression and choroidal atrophy. Porcine RPE cells were seeded on Transwell™ filters, and their maturation and polarization were confirmed by the asymmetrical VEGF secretion and trans electrical resistance. Exposure to TNF-α decreased the VEGF secretion in P-RPE cells but increased it in N-RPE cells in culture. TNF-α inactivated JNK in P-RPE cells but activated it in N-RPE cells, and TNF-α activated NF-κB in P-RPE cells but not in N-RPE cells. Inhibition of NF-κB activated JNK in both types of RPE cells indicating crosstalk between JNK and NF-κB. TNF-α induced the inhibitory effects of NF-κB on JNK in P-RPE cells because NF-κB is continuously inactivated. In N-RPE cells, however, it was not evident because NF-κB was already activated. The basic activation pattern of JNK and NF-κB and their crosstalk led to opposing responses of RPE cells to TNF-α. These results suggest that VEGF secretion under inflammatory conditions depends on cellular polarization, and the TNF-α-induced VEGF down-regulation may result in choroidal atrophy in polarized physiological RPE cells. TNF-α-induced VEGF up-regulation may cause neovascularization by non-polarized or non-physiological RPE cells.

Expression of vascular endothelial growth factor in eyes with Coats' disease.
Kase S, Rao NA, Yoshikawa H, Fukuhara J, Noda K, Kanda A, Ishida S
Investigative ophthalmology & visual science, 54, 1, 57, 62, 1, 2013年01月, ［査読有り］

Conjunctival lymphoma arising from reactive lymphoid hyperplasia.
Fukuhara J, Kase S, Noda M, Ishijima K, Yamamoto T, Ishida S
World journal of surgical oncology, 10, 194, 194, BioMed Central, 2012年09月, ［査読有り］
英語, Extra nodal marginal zone B-cell lymphoma (EMZL) of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia (RLH) of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque (OU). Specimens from conjunctival tumors in the right eye, oculus dexter (OD), revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin (Ig) light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister (OS), and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region (JH) region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy.

Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Behçet's disease with infliximab.
Iwata D, Namba K, Mizuuchi K, Kitaichi N, Kase S, Takemoto Y, Ohno S, Ishida S
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 250, 7, 1081, 1087, Springer Berlin / Heidelberg, 2012年07月, ［査読有り］
英語, Background: Infliximab, an anti-TNF-α monoclonal antibody, administered to Behçet's disease (BD) patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody (ANA) titers in patients with BD who were undergoing infliximab therapy. Methods: Seventeen patients (14 males and 3 females) with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records. Results: One patient (5.9%) was ANA-positive prior to the initiation of infliximab, and 11 patients (64.7%) developed positive ANA during the therapy. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titres gradually increased. None of the patients showed lupus symptoms. Five patients (29.4%) have suffered from ocular inflammatory attacks since 6th month from the initiation of infliximab treatment and all of them were ANA-positive. In contrast, 4 patients (23.5%) who were ANA-negative experienced no ocular attacks during the follow-up period. Conclusions: Here we report the positive conversion and subsequent elevation of serum ANA titres in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titre may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-α antibody therapies.

Alphab-crystallin expression in epiretinal membrane of human proliferative diabetic retinopathy.
Dong Z, Kase S, Ando R, Fukuhara J, Saito W, Kanda A, Murata M, Noda K, Ishida S
Retina (Philadelphia, Pa.), 32, 6, 1190, 1196, 6, 2012年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To examine the expression of alphaB-crystallin and its colocalization with vascular endothelial growth factor in the epiretinal membrane of human proliferative diabetic retinopathy. METHODS: Ten epiretinal membranes of proliferative diabetic retinopathy and three normal retinas surgically excised were included in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with alphaB-crystallin, vascular endothelial growth factor, and CD31 antibodies. RESULTS: AlphaB-crystallin was expressed in all epiretinal membranes examined. The immunolocalization of alphaB-crystallin was detected in the cytoplasm of CD31-positive endothelial cells, but not in normal retinal blood vessels. Furthermore, alphaB-crystallin immunoreactivity was colocalized in vascular endothelial growth factor-positive endothelial cells in proliferative diabetic retinopathy membranes. CONCLUSION: AlphaB-crystallin was expressed in proliferative diabetic retinopathy membranes, and colocalized with vascular endothelial growth factor-positive neovessels. AlphaB-crystallin may play a potential role in the pathogenesis of epiretinal membranes in proliferative diabetic retinopathy, together with vascular endothelial growth factor.

Soluble vascular adhesion protein-1 accumulates in proliferative diabetic retinopathy.
Murata M, Noda K, Fukuhara J, Kanda A, Kase S, Saito W, Ozawa Y, Mochizuki S, Kimura S, Mashima Y, Okada Y, Ishida S
Investigative ophthalmology & visual science, 53, 7, 4055, 4062, 7, 2012年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Vascular adhesion protein (VAP)-1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy (PDR) with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells. METHODS: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. The mechanism of VAP-1 shedding under diabetic condition, exposure to high glucose and/or inflammatory cytokines, was explored using cultured retinal capillary endothelial cells. RESULTS: Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-α and IL-1β in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells. CONCLUSIONS: Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR.

Spontaneous regression of intraocular lymphoma.
Kase S, Namba K, Jin XH, Kubota KC, Ishida S
Ophthalmology, 119, 5, 1083, 1084, 2012年05月, ［査読有り］

眼窩IgG4関連疾患を背景に発生したと考えたIgG4陽性形質細胞を伴う節外性濾胞辺縁帯B細胞性リンパ腫の1例　　　　　　　　　　　　　　　
久保田 佳奈子, ヘールナンデス 真子, 藤田 裕美, 山田 洋介, 加瀬 諭, 畑中 豊, 高桑 恵美, 三橋 智子, 松野 吉宏
日本病理学会会誌, 101, 1, 381, 381, (一社)日本病理学会, 2012年03月, ［査読有り］
日本語

Expression of α-crystallin in the retina of human sympathetic ophthalmia.
Kase S, Meghpara BB, Ishida S, Rao NA
Molecular medicine reports, 5, 2, 395, 399, 2012年02月, ［査読有り］

Ectopic cilia: a histopathological study.
Hase K, Kase S, Noda M, Ohashi T, Shinkuma S, Ishida S
Case reports in dermatology, 4, 1, 37, 40, 1, 2012年01月, ［査読有り］, ［国際誌］
英語, Cilia are normally found at the eyelid margin, while ectopic cilia are one or more lash follicles appearing in an abnormal position within the eyelid. We herein report two cases of cilia located in the palpebral conjunctiva. A 31-year-old female and a 46-year-old male presented with ectopic cilia in the superior palpebral conjunctiva. Histopathological study of the excised ectopic cilia and related lesions showed the cilia-related lesion to be located in the epithelial pit that contains goblet cells, which is consistent with the crypts of Henle. The hair follicle was surrounded by granulation tissue, while a dermal papilla and a hair matrix, which are known to produce hair follicles, did not exist in the excised tissue. While anterior ectopic cilia are congenital, ectopic cilia in the palpebral conjunctiva may be acquired, and these aberrant cilia are associated with crypts of Henle and chronic inflammation.

Abnormalities of fundus autofluorescence in pigmented paravenous chorioretinal atrophy.
Hashimoto Y, Kase S, Saito W, Ishida S
The open ophthalmology journal, 6, 125, 128, 2012年, ［査読有り］

Immunolocalization of vascular adhesion protein-1 in human conjunctival tumors.
Fukuhara J, Kase S, Noda K, Murata M, Noda M, Ando R, Dong Z, Kanda A, Ishida S
Ophthalmic research, 48, 1, 33, 37, 1, 2012年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: We analyzed the expression and immunolocalization of vascular adhesion protein (VAP)-1 in conjunctival tumors and normal conjunctival tissue of humans. METHODS: Nine conjunctival tumors, including pyogenic granuloma and extranodal marginal zone B-cell lymphoma (EMZL), and 2 normal conjunctivas were analyzed by immunohistochemistry for VAP-1 and CD31 expression. RESULTS: Immunoreactivity for VAP-1 was detected in the lumen of microvessels in pyogenic granuloma and in EMZLs. In contrast, normal bulbar conjunctival tissues demonstrated weak cytoplasmic immunoreactivity for VAP-1 in the blood vessels. CONCLUSIONS: The immunolocalization of VAP-1 varied in the histopathology of the conjunctiva, involving the pathology of inflammatory conjunctival disorders.

Intraocular neovascularization associated with choroidal ganglioneuroma in neurofibromatosis type 1.
Ishijima K, Kase S, Noda M, Ishida S
European journal of ophthalmology, 21, 6, 837, 840, 2011年11月, ［査読有り］

Increased expression of αA-crystallin in human diabetic eye.
Kase S, Ishida S, Rao NA
International journal of molecular medicine, 28, 4, 505, 511, 2011年10月, ［査読有り］

A case of herpes zoster ophthalmicus with acute dacryoadenitis as the initial manifestation　　　　　　　　　　　　　　　
Chiaki Yokoyama, Shohei Mori, Asako Kamada, Satoru Kase, Susumu Ishida
Japanese Journal of Clinical Ophthalmology, 65, 6, 945, 948, 2011年06月15日
日本語, 研究論文（国際会議プロシーディングス）, Purpose: To report a case of herpes zoster ophthalmicus presenting acute dacryoadenitis as the initial manifestation. Case: An 82-year-old female presented with right periocular pain since 2 days before. Her right eye showed hyperemia and swelling with no eruption. Findings by magnetic resonance imaging (MRI) were suggestive of acute dacryoadenitis and led to systemic treatment with antibiotics. Swelling of lacrimal gland exacerbated 4 days later. The right eye showed punctate lesions in the corneal epithelium and signs of inflammation in the anterior chamber 2 days later. Treatment with antiviral medications was started. Herpes zoster ophthalmicus was diagnosed another 2 days later after the right forehead showed rash with scarring and erosion. Signs of dacryoadenitis, inflammation in the anterior chamber and skin lesions subsided 15 days after her initial visit. Conclusion: This case illustrates that herpes zoster ophthalmicus may manifest, initially, signs of acute dacryoadenitis resistant to antibiotics without typical rash or ocular manifestations.

Extranodal marginal zone B-cell lymphoma involving superior rectus muscle: A clinicopathological case report.
Fukuhara J, Kase S, Noda M, Ishijima K, Ishida S
Oncology letters, 2, 3, 489, 491, Spandidos, 2011年05月, ［査読有り］
英語, A 66-year-old female had suffered from proptosis in the left eye (OS) and double vision for 1 month due to abnormality of the superior rectus muscle. Visual acuity was noted as 20/20 in both eyes (OU). Eye movement showed limited OS supraduction. Magnetic resonance imaging revealed an indistinct mass in the orbit involving the superior rectus muscle. A biopsy specimen of the orbital tumor led to the histological diagnosis of extranodal marginal zone B-cell lymphoma. Radiotherapy with a total dosage of 30 Gy was administered, which subsequently resolved the tumor. However, the supraduction limitation of ocular movement remained unchanged. Supraduction limitation is due to muscular contraction disorder of the superior rectus muscle, caused by direct lymphoma cell invasion.

Conjunctival lymphoproliferative disorder.
Fukuhara J, Kase S, Ishijima K, Noda M, Ishida S
Ophthalmology, 118, 2, 423.e1, 2, 2011年02月, ［査読有り］

Diffuse infiltrating retinoblastoma invading subarachnoid space.
Kase S, Yoshida K, Suzuki S, Ohshima K, Ohno S, Ishida S
Clinical ophthalmology (Auckland, N.Z.), 5, 861, 863, Dove Medical Press, 2011年, ［査読有り］
英語, We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient's death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD) in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinalelevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescencein the peripapillary region at an early-phase OD. Because the size of the subretinal lesion andvitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the midperipheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinaldetachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed.

Tissue factor expression in human pterygium.
Ando R, Kase S, Ohashi T, Dong Z, Fukuhara J, Kanda A, Murata M, Noda K, Kitaichi N, Ishida S
Molecular vision, 17, 63, 69, Molecular vision, 2011年01月, ［査読有り］
英語, Purpose: A pterygium shows tumor-like characteristics, such as proliferation, invasion, and epithelial–mesenchymal transition (EMT). Previous reports suggest that tissue factor (TF) expression is closely related to the EMT of tumor cells, and subsequent tumor development. In this study, we analyzed the expression and immunolocalization of TF in pterygial and normal conjunctival tissues of humans. Methods: Eight pterygia and three normal bulbar conjunctivas, surgically removed, were used in this study. Formalinfixed, paraffin-embedded tissues were submitted for immunohistochemical analysis with anti-TF antibody. Double staining immunohistochemistry was performed to assess TF and alpha-smooth muscle actin (α-SMA) or epidermal growth factor receptor (EGFR) expression in the pterygia. Results: Immunoreactivity for TF was detected in all pterygial tissues examined. TF immunoreactivity was localized in the cytoplasm of basal, suprabasal, and superficial epithelial cells. The number of TF-immunopositive cells in pterygialepithelial cells was significantly higher than in normal conjunctival epithelial cells (p<0.001). TF immunoreactivity was detected in α-SMA-positive or -negative pterygial epithelial cells. EGFR immunoreactivity was detected in pterygial epithelium, which was colocalized with TF. Conclusions: These results suggest that TF plays a potential role in the pathogenesis and development of a pterygium, and that TF expression might be involved through EMT-dependent and -independent pathways.

Intravitreal anti-vascular endothelial growth factor therapy with bevacizumab for tuberous sclerosis with macular oedema
Wataru Saito, Satoru Kase, Kazuhiro Ohgami, Shohei Mori, Shigeaki Ohno
ACTA OPHTHALMOLOGICA, 88, 3, 377, 380, WILEY-BLACKWELL, 2010年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose:
To describe two patients with macular oedema secondary to tuberous sclerosis complex (TSC) who were treated with intravitreal bevacizumab injection.
Methods:
Interventional case reports. Bevacizumab 1.25 mg was injected into the vitreous of two patients with TSC-associated macular oedema / exudative retinal detachment. Vascular endothelial growth factor (VEGF) concentration in the vitreous fluid was measured by enzyme-linked immunosorbent assay (ELISA) in one of these patients.
Results:
Patient 1: a 22-year-old woman with TSC was diagnosed as having multiple retinal hamartomas in both eyes. Eleven years later, the patient developed macular oedema with epiretinal membrane formation in the right eye. The patient underwent pars-plana vitrectomy with retinal photocoagulation for retinal tumours. VEGF concentration in the vitreous fluid was high compared to that in patients without retinal vascular diseases. Recurrent macular oedema disappeared by intravitreal injection of bevacizumab. Patient 2: a 32-year-old woman with TSC-associated retinal hamartoma, temporally showing macular exudative retinal detachment, developed neovascularization originated from the tumour. By intravitreal bevacizumab injection, the tumour size reduced markedly with regression of neovascularization.
Conclusion:
These results suggest that VEGF derived from retinal hamartomas causes macular oedema associated with TSC. Intravitreal injections of bevacizumab may be a useful therapeutic option for macular oedema secondary to TSC.

Cyclo-oxygenase-2 expression in human idiopathic epiretinal membrane.
Kase S, Saito W, Ohno S, Ishida S
Retina (Philadelphia, Pa.), 30, 5, 719, 723, 2010年05月, ［査読有り］

Merkel cell carcinoma of the conjunctiva.
Kase S, Ishijima K, Ishida S, Rao NA
Ophthalmology, 117, 3, 637.e1, 2, 2010年03月, ［査読有り］

Pyoderma Gangrenosum of the Eyelid: Report of Two Cases and Review of the Literature
N. Saito, T. Yanagi, M. Akiyama, H. Y. Lin, S. Kasai, Y. Fujita, N. Yamane, D. Inokuma, S. Kase, K. Ono, H. Minakawa, H. Shimizu
DERMATOLOGY, 221, 3, 211, 215, KARGER, 2010年, ［査読有り］
英語, 研究論文（学術雑誌）, Pyoderma gangrenosum (PG) of the eyelid is extremely rare, and its proper management is essential for the preservation of visual function. Here, we report 2 cases of PG of the eyelid with intraorbital involvement. In both cases, the skin and intraorbital lesions improved after systemic immunosuppressive therapies; however, corneal perforation occurred in 1 case. In order to assess the clinical features of PG of the eyelid and to obtain clues for optimal treatment, we reviewed 15 well-documented cases in the literature, including the present cases. Corneal perforation occurred in 4 cases and defective ocular motility in 1 case. Three patients eventually underwent enucleation of the affected eye. Our cases and the literature review clearly indicate that MRI is a powerful tool for evaluating the extent of extracutaneous PG lesions around the eye and that early diagnosis and immediate immunosuppressive therapy are crucial for the preservation of visual acuity. Copyright (C) 2010 S. Karger AG, Basel

Proliferative diabetic retinopathy with lymphocyte-rich epiretinal membrane associated with poor visual prognosis.
Kase S, Saito W, Ohno S, Ishida S
Investigative ophthalmology & visual science, 50, 12, 5909, 5912, 2009年12月, ［査読有り］

Microphthalmia and lack of vitreous body in transgenic mice expressing the first immunoglobulin-like domain of nectin-1
Kazuhiko Yoshida, Yukiko Tomioka, Satoru Kase, Masami Morimatsu, Kyoko Shinya, Shigeaki Ohno, Etsuro Ono
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 246, 4, 543, 549, SPRINGER, 2008年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background Nectins are Ca2+-independent immunoglobulin (Ig)-like cell-cell-adhesion molecules. We have generated transgenic mice expressing a series of soluble forms of nectin-1, and investigated special effects of each soluble form of nectin-1 in vivo. In the course of generating transgenic mice expressing a soluble form of nectin-1 consisting of the first Ig-like domain of nectin-1 and the Fc portion of human IgG1 (PHveC-VhIg), we found that all of the transgenic founder mice showed a microphthalmia. The purpose of this study is to examine functions of the extracellular domains of nectin-1 in eye development using transgenic technology.
Methods Eyes of four different transgenic mouse lines expressing each soluble form of nectin-1 were analyzed histologically. Tissue sections were processed with hematoxylin-eosin staining and indirect immunoperoxidase technique.
Results All of five transgenic mouse founders expressing PHveC-VhIg, and of three lines expressing PHveC-VpIg made of the first Ig-like domain fused to porcine Fc portions at 5 weeks showed a microphthalmia, but not all of the transgenic mouse lines expressing PHveCIg or PHveCpIg made of the entire ectodomain fused to human or porcine Fc portions. In the abnormal eyes, the vitreous body was almost absent. In PHveC-VhIg-expressing mice at postnatal day 6, each vitreous space was very small. In the neonatal transgenic mice, the vitreous body was almost the same as that of control mice, and PHveC-VhIg was expressed in the optic nerve, conjunctival epithelium, ciliary body, corneal and lens epithelium. At this stage, nectin-1, -3 and -4 were stained in the optic nerve of control mice as well as in that of the transgenic mice. Nectin-1 is faintly stained in the epithelium of the cornea and lens epithelium, but not in the ciliary body.
Conclusion Soluble forms of the first Ig-like domain of nectin-1 (PHveC-VhIg and PHveC-VpIg), but not those of the entire ectodomain (PHveCIg and PHveCpIg), lead to microphthalmia and lack of vitreous body in the transgenic mice.

Increased expression of erythropoietin receptor Increased expression of erythropoietin receptor in human pterygial tissuesin human pterygial tissues
Satoru Kase, Mitsuhiko Osaki, Xue-Hai Jin, Kazuhiro Ohgami, Kazuhiko Yoshida, Wataru Saito, Shuji Takahashi, Katsuya Nakanishi, Hisao Ito, Shigeaki Ohno
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 20, 5, 699, 702, PROFESSOR D A SPANDIDOS, 2007年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Erythropoietin (Epo) induces physiological activities such as cell proliferation, migration, and angiogenesis in Epo receptor (EpoR)-expressing vascular endothelial and tumor cells. Recently, it has been demonstrated that growth factor-independent proliferation is frequently observed during the cell transformation process. Pterygium is a fibrovascular proliferating tissue that includes transformed cells. The aim of this study was to examine the localization of Epo and EpoR proteins in human pterygial tissues. Eleven samples including nine pterygia and two normal bulbar conjunctivas, which were surgically excised, were studied. Formalin-fixed, paraffin-embedded tissue sections were constructed and then were examined by immunohistochemistry with anti-Epo and EpoR antibodies. Cytoplasmic immunoreactivity for EpoR was heterogeneously detected in basal and suprabasal cells of the pterygium epithelium. In the pterygium stroma, a variety of endothelial cells forming vascular cavities showed cytolasmic immunoreactivity for EpoR. In normal conjunctival epithelium, a few basal cells showed a weak homogeneous immunoreactivity for EpoR in the cytoplasm. The number of EpoR-expressing epithelial cells was much higher in the pterygiurn compared to the normal conjunctiva. EpoR expression was marginally detected in stromal microvessels of the normal conjunctiva. Immunoreactivity for Epo was not noted in pterygiurn epithelium and stroma, and in normal conjunctiva. These results suggest that the Epo-independent EpoR-signaling pathway plays a potential role in cell proliferation and angiogenesis in human pterygium.

Expression of erythropoietin receptor in human epiretinal membrane of proliferative diabetic retinopathy
Satoru Kase, Wataru Saito, Kazuhiro Ohgami, Kazuhiko Yoshida, Naoki Furudate, Akari Saito, Masahiko Yokoi, Manabu Kase, Shigeaki Ohno
BRITISH JOURNAL OF OPHTHALMOLOGY, 91, 10, B M J PUBLISHING GROUP, 2007年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: It is widely accepted that intravitreous levels of erythropoietin ( Epo) are elevated in patients with ischaemic retinal diseases such as proliferative diabetic retinopathy ( PDR). The aim of this study was to examine the expression of Epo and the Epo receptor ( EpoR) in epiretinal membranes with and without diabetes.
Methods: Eighteen epiretinal membranes ( PDR ( n = 10), idiopathic epiretinal membranes ( IERMs) without diabetes ( n = 4) and inner limiting membranes ( ILMs) ( n = 4)) were obtained during pars plana vitrectomy. Formalin-fixed and paraffin-embedded tissues were examined by immunohistochemistry with anti-Epo and EpoR antibodies.
Results: The histopathological findings demonstrated that PDR membranes consisted of a variety of endothelial cells forming a microvascular cavity with red blood cells and non-vascular stromal mononuclear cells. Membranous and cytoplasmic immunoreactivity for EpoR was strongly detected in endothelial cells and stromal cells in all PDR patients. Although microvessels were not observed in IERMs and ILMs, immunoreactivity for EpoR was noted in the cellular component of IERMs, and was weakly detected in ILMs. Epo was not expressed in any membrane.
Conclusion: EpoR was strongly expressed in microvessels of all PDR membranes. The in vivo evidence in this study suggests that Epo in the vitreous binds to EpoR in PDR membranes, which subsequently leads to the proliferation of new retinal vessels. EpoR immunoreactivity in non-vascular stromal cells in PDR membranes, and IERMs and ILMs might be indirectly correlated with ischaemia.

Inhibition of nuclear factor-kappa B activation attenuates hydrogen peroxide-induced cytotoxicity in human lens epithelial cells
Jin Xue-Hai, Ohgami Kazuhiro, Shiratori Kenji, Koyama Yoshikazu, Yoshida Kazuhiko, Kase Satoru, Ohno Shigeaki
British Journal of Ophthalmology, 91, 3, 369, 371, BMJ Publishing Group, 2007年03月
英語, Aims: Hydrogen peroxide (H2O2) is the major oxidant involved in cataract formation. Lens epithelial cells have been suggested to be the first site of oxidative damage. The authors investigated the relationship between H2O2-induced cytotoxicity and activation of nuclear factor kappa B (NF-B) in human lens epithelial (HLE) cells. Methods: HLE B-3 cells were stimulated by various concentrations of H2O2 in the presence or absence of pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-B. H2O2-induced cytotoxicity was measured by lactate dehydrogenase cytotoxicity assay. Translocation of NF-B was examined by Western blot and immunocytochemistry using anti-p65 antibody. Results: H2O2-induced cytotoxicity increased in a concentration-dependent manner. PDTC treatment significantly suppressed the cytotoxicity induced by H2O2. After stimulated with H2O2, NF-B was found translocated from cytoplasm into the nuclei. PDTC treatment also inhibited the translocation of NF-B. Conclusions: NF-B signal pathway may be important in the development of H2O2-induced damage in HLE cells that is involved in cataractogenesis.

Repeated exacerbations of ocular inflammation with vitreous hemorrhage in a patient with HLA-B27 associated uveitis
Satoru Kase, Kenichi Namba, Yukihiro Horie, Satoshi Kotake, Shigeaki Ohno
Journal of Medical Investigation, 54, 3-4, 350, 353, 3-4, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, HLA-B27 associated uveitis is characterized by recurrent alternating acute unilateral attacks of intraocular inflammation in the anterior chamber. The aim of this study was to report an unusual case of repeated exacerbations with vitreous hemorrhage in HLA-B27 associated uveitis. Thirty four-year-old man was diagnosed as HLA-B27 associated uveitis in his right eye. He showed repeated exacerbation of ocular inflammation with retinal vein dilation and small retinal hemorrhage following vitreous hemorrhage. Fluorescein fundus angiography a week before the appearance of vitreous hemorrhage showed no neovascularization. Oral prednisolone administration was started from 40 mg/day with gradual tapering. About 3 weeks after the onset, most of the vitreous hemorrhage disappeared and visual acuity was improved to 20/20. Through the decreased vitreous hemorrhage, Weiss ring was detected later. The vitreous hemorrhage found in this patient is a severe exacerbation, and might be a consequence of the vitritis that leads to posterior vitreous detachment.

Tyrosinase gene family and Vogt-Koyanagi-Harada disease in Japanese patients.
Yukihiro Horie, Yuko Takemoto, Akiko Miyazaki, Kenichi Namba, Satoru Kase, Kazuhiko Yoshida, Masao Ota, Yukiko Hasumi, Hidetoshi Inoko, Nobuhisa Mizuki, Shigeaki Ohno
Molecular vision, 12, 12, 1601, 5, 2006年12月20日, ［査読有り］, ［国際誌］
英語, PURPOSE: The aim of the present study was to examine the genetic background of Vogt-Koyanagi-Harada (VKH) disease in a Japanese population by analyzing the tyrosinase gene family (TYR, TYRP1, and dopachrome tautomerase (DCT)). METHODS: 87 VKH patients and 122 healthy controls were genotyped using seven microsatellite markers on the candidate loci. We analyzed microsatellite (MS) polymorphisms at regions within tyrosinase gene family loci. In addition, the haplotype frequencies were also estimated and statistical analysis was performed. HLA-DRB1 genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. RESULTS: No significant evidence for an association was found. HLA-DRB1*0405 showed a highly significant association with VKH disease compared with the healthy controls (Pc=0.000000079), as expected. CONCLUSIONS: We concluded that there is no genetic susceptibility or increased risk attributed to the tyrosinase gene family. Our results suggest the need for further genetic study and encourage a search for novel genetic loci and predisposing genes in order to elucidate the genetic mechanisms underlying VKH disease.

Phosphorylation of p27(KIP1) in lens epithelial cells after extraction of fiber cells.
Satoru Kase, Kazuhiko Yoshida, Xue-Hai Jin, Yoshikazu Koyama, Nobuyoshi Kitaichi, Kazuhiro Ohgami, Kenji Shiratori, Iliyana Ilieva, Shigeaki Ohno
International journal of molecular medicine, 18, 6, 1187, 91, 2006年12月, ［査読有り］, ［国際誌］
英語, Opacification of the posterior capsule depends on replication of the residual lens epithelial cells lining the capsule. However, the mechanisms in the regulation of lens cell proliferation have not been determined. The purpose of this study is to examine the expression of p27(KIP1), a cyclin-dependent kinase inhibitor, and its phosphorylation, and cyclin D1 in lens epithelial cells after extraction of fiber cells. C57Bl6 mice (12 weeks old) were anesthetized, and the lens fiber cells were surgically extracted. Eyeballs were collected and fixed at 15 min and 24 h after extraction with and without injection of a specific phosphorylated extracellular signal-regulated kinase (pERK) 1/2 inhibitor (PD98059) to the anterior chamber. Collected tissues were analyzed using immunohistochemistry with anti-p27(KIP1), anti-phosphorylated p27(KIP1) on serine 10 (s10-phospho-p27) and cyclin D1 antibodies. Human lens epithelial cells were cultured, and then were treated with and without 40 ng/ml human recombinant basic fibroblast growth factor (bFGF), which was analyzed by Western blot analysis. In the untreated lens, p27(KIP1) was not phosphorylated in the lens epithelial cells, although p27(KIP1)-positive nuclei were detected in the lens cells of the equatorial region. Immunoreactivity for cyclin D1 was hardly detected in the lens. Nuclear immunoreactivity for p27(KIP1) and s10-phospho-p27 was observed in several lens cells of the equatorial region 15 min after extraction of fiber cells. Western blotting demonstrated that the p27(KIP1) phosphorylation form was upregulated 15 min after bFGF treatment in cultured lens epithelial cells. Many cyclin D1-positive nuclei were noted 24 h after the surgery. p27(KIP1) phosphorylation and cyclin D1 induction were inhibited by PD98059. s10-phospho-p27 and p27(KIP1) immunoreactivity was undetected in the lens cells 24 h after the extraction of fiber cells. It is possible that the phosphorylation of p27(KIP1), and cyclin D1 expression are regulated by the ERK pathway in lens cells after the extraction of fiber cells.

Captopril suppresses inflammation in endotoxin-induced uveitis in rats
Ilieva Iliyana, Ohgami Kazuhiro, Jin Xue-Hai, Suzuki Yukari, Shiratori Kenji, Yoshida Kazuhiko, Kase Satoru, Ohno Shigeaki
Experimental Eye Research, 83, 3, 651, 657, Elsevier B.V., 2006年09月
英語, Captopril is an inhibitor of angiotensin-converting enzyme (ACE) that is largely used in the treatment of cardiovascular diseases. Several previous studies have demonstrated that captopril exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the efficacy of captopril on endotoxin induced uveitis (EIU) in rats. We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), monocyte chemoattractant protein-1 (MCP-1) in the anterior chamber. In addition, we checked its effect on activation of nuclear factor kappa B (NF-κB) in iris and ciliary body (ICB) cells in vivo. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour after the LPS inoculation, either 1 mg/kg, 10 mg/kg or 100 mg/kg captopril were injected intravenously. 24 h later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-α, PGE2, NO and MCP-1 were determined by enzyme-linked immunosorbent assay. On some eyes, after enucleation, immunohistochemical staining with a monoclonal antibody against activated NF-κB was performed. Captopril treatment significantly decreased the inflammatory cells infiltration, the level of protein, concentrations of TNF-α, PGE2, NO and MCP-1 in the aqueous humor. The number of activated NF-κB-positive cells was lower in ICB of the rats treated with captopril 3 h after the LPS injection. The present results indicate that captopril suppresses the inflammation in EIU by inhibiting the NF-κB-dependent pathway and the subsequent production of pro-inflammatory mediators.

Usefulness of quantifying serum KL-6 levels in the follow-up of uveitic patients with sarcoidosis.
Nobuyoshi Kitaichi, Toshihide Ariga, Satoru Kase, Kauzhiko Yoshida, Kenichi Namba, Shigeaki Ohno
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 244, 4, 433, 7, 2006年04月, ［査読有り］, ［国際誌］
英語, BACKGROUND: KL-6 is a human glycoprotein secreted by type II alveolar cells in the lung, and its serum levels increase in pneumonia of various causes. We previously reported that serum KL-6 levels in uveitis patients with sarcoidosis were significantly higher than those of other uveitis patients and healthy controls. Additionally, the combined measurement of serum KL-6 and angiotensin converting enzyme (ACE) was useful for screening uveitic patients to diagnose sarcoidosis. The purpose of the present study was to investigate the clinical usefulness of quantifying serum KL-6 levels for following-up the patients with sarcoidosis. METHODS: Sera were obtained from 36 uveitic patients diagnosed with sarcoidosis and the same number of healthy volunteers. To examine the influence of systemic medication, we also collected blood samples from four more sarcoidosis patients, who were systemically treated with corticosteroid or angiotensin converting enzyme (ACE) inhibitor, an anti-hypertensive drug. The serum concentration of KL-6 was measured by a human KL-6 electrochemiluminescence immunoassay (ECLIA). RESULTS: The mean KL-6 concentrations of sarcoidosis patients and healthy controls were 449.3+/-66.3 (mean+/-SE) and 192.1+/-11.3, respectively. The average levels of serum KL-6 were significantly elevated in sarcoidosis patients compared with healthy control subjects (P<0.001), and there were significant correlations between serum KL-6 and ACE levels in the patients with sarcoidosis (r=0.70 and P<0.0001). Moreover, serum KL-6 concentrations were less affected by systemic corticosteroid, and unaffected by ACE inhibitory drugs in contrast to ACE levels. CONCLUSIONS: Measurement of serum KL-6 in the uveitic patients may be useful to follow-up the diagnosed sarcoidosis, as well as for diagnosing sarcoidosis, because the serum KL-6 level was well correlated with the ACE level, and less affected by systemic medication than ACE levels.

Phosphorylation of extracellular signal-regulated kinase and p27(KIP1) after retinal detachment
S Kase, K Yoshida, T Harada, C Harada, K Namekata, Y Suzuki, K Ohgami, K Shiratori, KI Nakayama, S Ohno
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 244, 3, 352, 358, SPRINGER, 2006年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: The roles of the extracellular signal-regulated kinase (ERK) pathway in the expression of cyclin D1 and p27(KIP1), the phosphorylation of p27(KIP1), and proliferation activity were examined after retinal detachment. Methods: Normal eyes and eyes at 15 min, 2 and 4 days after retinal detachment in C57Bl6 mice were examined by immunohistochemistry using anti-phosphorylated (p) ERK1/2, anti-cyclin D1, anti-p27(KIP1), anti-p27(KIP1) phosphorylated at serine 10 (S10-phospho-p27), and anti-proliferating cell nuclear antigen (PCNA) antibodies with or without treatment with a specific ERK inhibitor, PD98059. Mouse Muller cells were isolated and examined for alteration of p27(KIP1) and cyclin D1 after exposure of basic fibroblast growth factor (bFGF) with and without treatment of PD98059 using Western blotting. Results: In the normal retina, nuclear immunoreactivity for p27(KIP1), but not S10-phospho-p27 or pERK1/2, was observed in the middle sublayer of the inner nuclear layer (INL), where Muller glial cells are situated. At 15 min after the retinal detachment, p27(KIP1), S10-phospho-p27 and pERK1/2-positive nuclei were noted in the INL, whereas immunoreactivity for pERK1/2 or S10-phospho-p27 was not observed after treatment with PD98095. Cyclin D1 was induced in the INL 2 days after the retinal detachment, and the induction was inhibited by PD98059. At 4 days after the detachment, p27(KIP1) immunoreactivity was not observed, and cyclin D1 and PCNA were expressed. The disappearance of p27(KIP1) was suppressed, whereas expression of cyclin D1 and PCNA was not observed in mice treated with PD98059. Exposure of bFGF relatively decreased the expression level of p27(KIP1) and increased the level of cyclin D1 in mouse Muller cells, compared with control level. Induction of cyclin D1 and decrease in p27(KIP1) were inhibited with treatment of PD98059. Conclusion: Phosphorylation of ERK and expression of p27(KIP1) and cyclin D1 are involved in the proliferation of Muller cells after retinal detachment.

Suppressive effects of astaxanthin against rat endotoxin-induced uveitis by inhibiting the NF-κB signaling pathway
Suzuki Yukari, Ohgami Kazuhiro, Shiratori Kenji, Jin Xue-Hai, Ilieva Iliyana, Koyama Yoshikazu, Yazawa Kazunaga, Yoshida Kazuhiko, Kase Satoru, Ohno Shigeaki
Experimental Eye Research, 82, 2, 275, 281, Elsevier Ltd., 2006年02月
英語, We investigated the effects of astxanthin (AST), a carotenoid, on endotoxin-induced uveitis (EIU), and measured the expression of inflammatory cytokines and chemokines in the presence or absence of AST over the course of the disease. EIU was induced in male Lewis rats by footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, either 1, 10, or 100 mg/kg of AST were injected intravenously. Aqueous humor was collected at 6, 12 and 24 hours after LPS inoculation and the number of infiltrating cells in the anterior chamber were counted. In addition, we assayed the concentration of protein, nitric oxide (NO), tumor necrosis factor (TNF)- and prostaglandin (PG) E2. Immunohistochemical staining with a monoclonal antibody against activated NF-B was performed in order to evaluate the effects of AST on NF-B activation. Rats injected with AST showed a significant decrease in the number of infiltrating cells in anterior chamber. Moreover, AST-treated rats with EIU showed significantly lower concentrations of protein, NO, TNF- and PGE2 in the aqueous humor. Even the early stages of EIU were suppressed by injection of AST. The number of activated NF-B-positive cells was lower in iris-ciliary bodies treated with 10 or 100 mg/kg AST at 3 hours after LPS injection. These results suggest that AST reduces ocular inflammation in eyes with EIU by downregulating proinflammatory factors and by inhibiting the NF-B-dependent signaling pathway.

Expression of glutamine synthetase and cell proliferation in human idiopathic epiretinal membrane
Kase S, Saito W, Yokoi M, Yoshida K, Furudate N, Muramatsu M, Saito A, Kase M, Ohno S
British Journal of Ophthalmology, 90, 1, 96, 98, BMJ Publishing Group, 2006年01月
英語, Background/aim: The mechanisms of the cellular origin and cell proliferation in the idiopathic epiretinal membrane (ERM) are unsolved. The aim of this study was to examine the expression of cell cycle related molecules and glutamine synthetase (GS), which is expressed in Müller cells and their processes, in ERM tissues. Methods: The ERMs were surgically removed using pars plana vitrectomy. Formalin fixed, paraffin embedded ERM tissues were analysed by immunohistochemistry with anti-cyclin D1, p27 (KIP1), proliferating cell nuclear antigen (PCNA), and GS antibodies. Results: The histopathological findings showed that all the ERMs consisted of oval or spindle mononuclear cells with thin collagen-like tissues. Immunoreactivity for GS was detected in collagen-like tissues of ERM, presenting a continuous, isodense pattern. GS immunopositive cells in all cases expressed PCNA in their nuclei. Nuclear immunoreactivity for cyclin D1 was noted in the ERM constituent cells, whereas p27 (KIP1) positive nuclei were not detected. Conclusion: Cyclin D1 and PCNA were expressed in the idiopathic ERM, which was mainly derived from Müller cells and extensions of their processes.

Immunolocalization of cyclin D1 in the developing lens of c-maf -/- mice.
Satoru Kase, Kazuhiko Yoshida, Masaharu Sakai, Kazuhiro Ohgami, Kenji Shiratori, Nobuyoshi Kitaichi, Yukari Suzuki, Takayuki Harada, Shigeaki Ohno
Acta histochemica, 107, 6, 469, 72, 2006年, ［査読有り］, ［国際誌］
英語, The maf gene encodes a transcription factor protein containing a typical basic/leucine zipper domain structure, a motif for protein dimerization and DNA binding. It has been demonstrated that maf family genes have important roles in embryonic development and cellular differentiation. In this study, localization of cyclin D1, one of the cell cycle-related molecules, was examined immunohistochemically in developing lens cells of c-maf knockout (-/-) mice. At embryonic day 14 in wild-type mice, lens cells consisted of round epithelial cells in a single layer and regularly arranged elongated lens cells, indicating primary lens fiber cells. Cyclin D1-positive nuclei were observed in the lens epithelial cells, whereas cyclin D1 was not detected in the primary lens fiber cells. In c-maf -/- mice, a variety of round epithelial cells were located in the anterior and posterior lens. Many cyclin D1-positive nuclei were observed in lens epithelial cells as well as posterior lens cells. These results are consistent with c-maf playing a role in the regulation of cyclin D1 in developing lens cells.

Expression of p27(KIP1) and cell proliferation in human retina and retinoblastoma
S Kase, K Yoshida, K Ohgami, K Shiratori, T Harada, S Ohno
ANTICANCER RESEARCH, 25, 6B, 3843, 3846, INT INST ANTICANCER RESEARCH, 2005年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Retinoblastoma is a rare cancer of the eye, in which biallelic inactivation of the retinoblastoma gene is a hallmark. Although retinoblastoma protein (Rb) and p27(KIP1) block the cell cycle transition from G1- to S-phase, the interaction has not been confirmed in vivo. The aim of this study was to examine the correlation between the expression of p27(K[PI) and cell proliferation in human retina and retinoblastoma.
Materials and Methods: Human retinoblastoma, surgically removed, was fixed by 4% paraformaldehyde. Then, paraffin-embedded tissue sections were examined using immunohistochemistry with antip27(KIP1) and anti-proliferating cell nuclear antigen (PCNA) antibodies.
Results: Retinoblastoma tissue was adjacent to the normal retina in which tumor cells with homogeneous nuclei proliferated and it was impossible to identify the layer structure of the inner nuclear layer (INL) and the outer nuclear layer (ONL). In normal retina, PCNA-positive nuclei were not observed, whereas nuclear immunoreactivity for PCNA was detected in a variety of tumor cells. Many p27(KIP1) -positive nuclei were detected in INL and ONL, while p27(KIP1) immunoreactivity was not detected in retinoblastoma cells.
Conclusion: The correlation between disappearance of p27(KIP1) and induction of proliferation activity suggests that functional loss of Rb leads to down-regulation of p27(K[P1) and uncontrolled retinal cell proliferation.

Bilateral diffuse uveal melanocytic proliferation in a patient with cancer-associated retinopathy
W Saito, S Kase, K Yoshida, H Ohguro, M Yokoi, H Iwaki, S Ohno
AMERICAN JOURNAL OF OPHTHALMOLOGY, 140, 5, 942, 945, ELSEVIER SCIENCE INC, 2005年11月, ［査読有り］
英語, 研究論文（学術雑誌）, PURPOSE: To describe a patient with bilateral diffuse uveal melanocytic proliferation (BDUMP) and cancer-associated retinopathy (CAR).
DESIGN: Interventional case report.
METHODS: A 66-year-old woman developed progressive vision loss 4 months after total hysterectomy. Ophthalmologic examination, Western blot test of sera and aqueous humor, and immunohistochemistry of carcinoma cells were performed.
RESULTS: Testing revealed BDUMP and severe retinal dysfunction. Autoantibodies against recoverin and heat shock cognate protein 70 (hsc 70) were detected in serum. Cytoplasmic immunoreactivity for recoverin and hsc 70 was observed in endometrioid carcinoma cells.
CONCLUSIONS: Simultaneous cases of BDUMP and CAR are rare. Aberrantly expressed recoverin and hsc 70 triggered serum autoantibody production, which caused photoreceptor degeneration.

Expression of thymidine phosphorylase in choroidal malignant melanoma associated with neovascular glaucoma.
Satoru Kase, Wataru Saito, Kazuhiko Yoshida, Kenichi Namba, Mitsuhiko Osaki, Kazuhiro Ohgami, Kenji Shiratori, Nobuyoshi Kitaichi, Hironobu Adachi, Hisao Ito, Shigeaki Ohno
Pathology international, 55, 9, 569, 73, 2005年09月, ［査読有り］, ［国際誌］
英語, Reported herein is a case of 62-year-old man who complained of blurred vision and ocular pain in his right eye. The patient was diagnosed with choroidal melanoma complicated by neovascular glaucoma (NVG) and total retinal detachment, and he underwent enucleation of the eye. The isolated tumor was 2.5 x 2.5 cm in size. It was accompanied by intratumoral calcification, and consisted of epithelioid and spindle melanoma cells. There were a variety of microvessels in the stroma of the iris. The expression of thymidine phosphorylase (dThdPase), an angiogenic factor, was examined immunohistochemically. Cytoplasmic immunoreactivity for dThdPase was more prominent in the epithelioid cells than in spindle tumor cells. Another case of choroidal melanoma without NVG had less marked immunoreactivity. These results suggest that the production of dThdPase by melanoma cells correlates with the pathogenesis of NVG.

Phosphorylation of p27(KIP1) in the developing retina and retinoblastoma.
Kase Satoru, Yoshida Kazuhiko, Nakayama Keiichi I, Nakayama Keiko, Ikeda Hiromi, Harada Takayuki, Harada Chikako, Ohgami Kazuhiro, Shiratori Kenji, Ohno Shigeaki
Int J Mol Med, 16, 2, 257, 262, 2005年08月, ［査読有り］
英語, 研究論文（学術雑誌）

Disappearance of p27(KIP1) and increase in proliferation of the lens cells after extraction of most of the fiber cells of the lens.
Kase Satoru, Yoshida Kazuhiko, Ikeda Hiromi, Harada Takayuki, Harada Chikako, Imaki Junko, Ohgami Kazuhiro, Shiratori Kenji, Nakayama Keiichi I, Nakayama Keiko, Ohno Shigeaki
Curr Eye Res, 30, 6, 437, 442, 2005年06月, ［査読有り］
英語, 研究論文（学術雑誌）

Clinicopathological features of primary choroidal malignant melanoma　　　　　　　　　　　　　　　
Satoru Kase, Kazuhiko Yoshida, Wataru Saito, Ken-Ichi Namba, Naoko Tsujino, Masahiro Muramatsu, Naoki Furudate, Shigeaki Ohno
Japanese Journal of Clinical Ophthalmology, 59, 5, 705, 709, 2005年05月
日本語, 研究論文（学術雑誌）, Purpose: To describe clinicopathological findings in 4 eyes of primary choroidal malignant melanoma. Cases and Method: Four eyes of 4 patients with primary choroidal malignant melanoma underwent histopathological examinations. They were 29-year-old male, 50-year-old female, 62-year-old male, and 66-year-old female. Enucleated eyes were fixed in 4% paraformaldehyde and embedded in paraffin. Sliced specimens were stained by hematoxylin-eosin and by hematoxylin after demelanization. Findings: All the eyes had bullous retinal detachment. Total retinal detachment was present in 1 eye. The tumor size ranged from 13 × 13 mm to 25 × 25 mm. The interval between visual impairment and enucleatrion ranged from 2 to 9 months. Cases enucleated later tended to have larger tumor with advanced stage. All the eyes showed massive deposit of melanin in the tumor. Demelanization facilitated observation of morphological features of the tumor including mitosis. Tumor cells with spindle-shaped nuclei were the prevalent features in 2 eyes. The other 2 eyes showed mixture of epithelioid cells. Conclusion: While primary choroidal malignant melanoma is relatively rare in Japan. Detailed clinicopathological evaluation is mandatory.

Epstein-Barr virus infected cells in the aqueous humour originated from nasal NK/T cell lymphoma
Kase S, Namba K, Kitaichi N, Ohno S
British Journal of Ophthalmology, 90, 2, 244, 245, BMJ Publishing Group Ltd, 2005年
英語, Nasal natural killer (NK)/T cell lymphoma is a definitive diagnostic entity in the World Health Organization lymphoma classification.1 In many cases, NK/T cell lymphoma is invariably associated with Epstein-Barr virus (EBV). Although ocular involvement is found in less than 10% of patients with systemic lymphoma,2 because of its anatomical proximity, nasal NK/T lymphoma can sometimes complicate uveitis and orbital infiltration.3 We experienced a case of nasal NK/T lymphoma, and the cells collected from the aqueous humour originated from the lymphoma which was infected by EBV.

Anti-inflammatory effects of aronia extract on rat endotoxin-induced uveitis.
Kazuhiro Ohgami, Iliyana Ilieva, Kenji Shiratori, Yoshikazu Koyama, Xue-Hai Jin, Kazuhiko Yoshida, Satoru Kase, Nobuyoshi Kitaichi, Yukari Suzuki, Tsuneo Tanaka, Shigeaki Ohno
Investigative ophthalmology & visual science, 46, 1, 275, 81, 2005年01月, ［査読有り］, ［国際誌］
英語, PURPOSE: Aronia crude extract (ACE) with high levels of polyphenol compounds has been reported to have antioxidative effects in vitro and in vivo. In this study, attention was focused on the antioxidant effect of ACE. The purpose of the present study was to investigate the effect of ACE on endotoxin-induced uveitis (EIU) in rats. In addition, the endotoxin-induced expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 proteins was investigated in a mouse macrophage cell line (RAW 264.7) treated with ACE in vitro, to clarify the anti-inflammatory effect. METHODS: EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, 1, 10, or 100 mg ACE or 10 mg prednisolone was injected intravenously. After 24 hours, the aqueous humor was collected from both eyes, and the number of infiltrating cells, protein concentration, nitric oxide (NO), prostaglandin (PG)-E2, and TNF-alpha levels in the aqueous humor were determined. RAW 264.7 cells treated with various concentrations of ACE were incubated with 10 mug/mL LPS for 24 hours. Levels of NO, PGE2, and TNF-alpha were determined by an enzyme-linked immunosorbent assay. The expression of iNOS and COX-2 proteins was analyzed by Western blot analysis. RESULTS: The number of inflammatory cells, the protein concentrations, and the levels of NO, PGE2, and TNF-alpha in the aqueous humor in the groups treated with ACE were significantly decreased in a dose-dependent manner. In addition, the anti-inflammatory effect of 100 mg ACE was as strong as that of 10 mg prednisolone. The anti-inflammatory action of ACE was stronger than that of either quercetin or anthocyanin administered alone. ACE also suppressed LPS-induced iNOS and COX-2 protein expressions in RAW 264.7 cells in vitro in a dose-dependent manner. CONCLUSIONS: The results suggest that ACE has a dose-dependent anti-ocular inflammatory effect that is due to the direct blocking of the expression of the iNOS and COX-2 enzymes and leads to the suppression of the production of NO, PGE2, and TNF-alpha.

Expression of maf-B mRNA in the epithelium around the eyelid closure of the mouse eye at embryonic day IS
S Kase, J Imaki, T Harada, C Harada, K Ohgami, K Shiratori, M Sakai, S Nishi, S Ohno, K Yoshida
ANATOMY AND EMBRYOLOGY, 209, 2, 153, 156, SPRINGER, 2004年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Maf encodes a transcription factor protein containing a typical basic leucine zipper domain structure, a motif for protein dimerization and DNA binding. We examined the expression of maf-B mRNA in the epithelium around the eyelid closure. Expression of maf-B mRNA was examined in C57Bl6 mice at the embryonic stages in 12.5 days of gestation (E12.5) and E18 using in situ hybridization with S-35-labeled antisense riboprobes. In embryos studied 12.5 days postconception, a message specific for maf-B was not detected around the developing eyelid. In contrast, maf-B was strongly expressed in the epithelium of the eyelid closure at E18. Expression of maf-B was strongly noted in the suprabasal differentiating cells derived from the basal layer of the conjunctiva and epidermis. In contrast, basal cells in the eyelid closure and in the epidermis, as well as keratinizing cells, did not express maf-B. These data indicate that maf-B mRNA is expressed during development of the eyelid closure.

Activation of nuclear factor-kappa B in the conjunctiva with the epithelial scraping of the mouse cornea and human epidemic keratoconjunctivitis
S Kase, K Aoki, T Harada, C Harada, K Ohgami, K Shiratori, S Nishi, S Ohno, K Yoshida
BRITISH JOURNAL OF OPHTHALMOLOGY, 88, 7, 947, 949, B M J PUBLISHING GROUP, 2004年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Aim: To examine the expression of p65, one of nuclear factor-kappa B (NF-kappaB), in the conjunctival epithelium of the C57Bl6 mouse and a patient with epidemic keratoconjunctivitis (EKC).
Methods: Normal and epithelial scraped cornea obtained 6 hours after the injury were processed for paraffin section. Samples of a normal and an EKC conjunctival epithelium were obtained using impression cytology. Both samples were analysed by immunocytochemistry using anti-p65 antibody.
Results: Immunocytochemistry with the anti-NF-kappaB p65 antibody revealed that p65 was localised in the cytoplasm of the conjunctival epithelium in the C57Bl6 mouse without the treatment. Six hours after the scraping of the cornea, p65 protein was expressed in the nuclei of the conjunctival epithelium. p65 was localised in the cytoplasm of the conjunctival epithelium in the human normal eye. p65 protein was expressed in the nuclei of the conjunctival epithelial cells in the EKC patient.
Conclusion: These findings suggest that NF-kappaB was activated in the conjunctiva in the epithelial scraping of the mouse cornea and in human EKC.

Involvement of p27KIP1 in the proliferation of the developing corneal endothelium.
Yoshida Kazuhiko, Kase Satoru, Nakayama Keiko, Nagahama Hiroyasu, Harada Takayuki, Ikeda Hiromi, Harada Chikako, Imaki Junko, Ohgami Kazuhiro, Shiratori Kenji, Ilieva Iliyana Bozhidarova, Ohno Shigeaki, Nishi Shinzo, Nakayama Keiichi I
Invest Ophthalmol Vis Sci, 45, 7, 2163, 2167, 2004年07月, ［査読有り］
英語, 研究論文（学術雑誌）

Distribution of p27(KIP1), cyclin D1, and proliferating cell nuclear antigen after retinal detachment.
Yoshida Kazuhiko, Kase Satoru, Nakayama Keiko, Nagahama Hiroyasu, Harada Takayuki, Ikeda Hiromi, Harada Chikako, Imaki Junko, Ohgami Kazuhiro, Shiratori Kenji, Ohno Shigeaki, Nakayama Keiichi I
Graefes Arch Clin Exp Ophthalmol, 242, 5, 437, 441, 2004年05月, ［査読有り］
英語, 研究論文（学術雑誌）

Involvement of p27(KIP1) in proliferation of the retinal pigment epithelium and ciliary body.
Yoshida Kazuhiko, Nakayama Keiko, Kase Satoru, Nagahama Hiroyasu, Harada Takayuki, Ikeda Hiromi, Harada Chikako, Imaki Junko, Ohgami Kazuhiro, Shiratori Kenji, Ohno Shigeaki, Nishi Shinzo, Nakayama Keiichi I
Anat Embryol (Berl), 208, 2, 145, 150, 2004年05月, ［査読有り］
英語, 研究論文（学術雑誌）

Choroidal vascular structures in diabetic patients: a meta-analysis
Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Masahiko Yokoi, Yuki Ito, Michiyuki Saito, Susumu Ishida, Manabu Kase, Graefe's Archive for Clinical and Experimental Ophthalmology, 259, 12, 3537, 3548, 2021年12月01日
Purpose: Choroidal vascular structures are likely to be affected in diabetic patients. The aim of this study was to conduct a meta-analysis of choroidal vascular structures in diabetic eyes with no diabetic retinopathy (NDR) and healthy control eyes, which was systematically evaluated by various factors involving the measurements. Methods: This study identified clinical data from publications in PubMed and web of science until May 2020. Independent retrospective or prospective clinical studies comparing NDR and healthy control eyes regarding choroidal vascular structures were extracted. Five related studies were enrolled, cumulating in a total of 282 diabetic eyes and 511 control eyes examined in this study. Heterogeneity was statistically quantified by I2 statistics, and meta-analysis was performed using a random effects model. This study included 2 different algorisms of binarization determining the ratio of luminal areas in total choroidal areas, both of which were consolidated and called “choroidal vascular ratio.” Results: Meta-analysis clearly showed that the choroidal vascular ratio was significantly lower in NDR eyes than in healthy control eyes (weighted mean difference = − 2.16
95%CI: − 3.19 to − 1.13
P <
0.005). Similar results were obtained in sub-analysis based on adjustment of serum HbA1c levels and duration of diabetes. Conclusions: The choroidal vascular ratio of NDR eyes was significantly lower than that of healthy control eyes. The ratio might contribute to a better understanding of the pathophysiology involved in the development of diabetic retinopathy, although there was some heterogeneity in primary analysis studies.[Figure not available: see fulltext.], Springer Science and Business Media Deutschland GmbH, 英語, 書評論文,書評,文献紹介等

Histological observation in pachyvessels in a patient with choroidal melanoma
Satoru Kase, Kousuke Noda, Susumu Ishida, International Journal of Ophthalmology, 14, 5, 777, 779, 2021年05月01日
International Journal of Ophthalmology (c/o Editorial Office), 英語, 速報，短報，研究ノート等（学術雑誌）

ニューラルネットワークによる眼底写真の網膜動静脈検出
福津佳苗, 齋藤理幸, 野田航介, 村田美幸, 加瀬諭, 柴涼介, 磯貝直己, 道家充, 石田晋, 日本眼循環学会講演抄録集, 36th, 2019年

眼科のトランスレーショナルリサーチ 多機能蛋白質に着目した糖尿病網膜症に対する創薬研究
野田 航介, 村田 美幸, 稲福 沙織, 松田 剛, 吉田 志帆, 董 陽子, 木下 哲志, 安藤 亮, 藤谷 顕雄, 齋藤 理幸, 董 震宇, 森 祥平, 加瀬 諭, 吉澤 史子, 齋藤 航, 神田 敦宏, 石田 晋, 眞島 行彦, 笹瀬 智彦, 天野 麻穂, 大橋 哲, 西村 伸一郎, 今川 貴仁, 白仁田 明生, 日本眼科学会雑誌, 122, 3, 223, 248, 2018年03月
近年の基礎研究は、血管内皮増殖因子(vascular endothelial growth factor:VEGF)が糖尿病網膜症の病態形成に主要な役割を演じることを明らかとした。そして、同分子群に対する阻害薬の臨床応用は糖尿病網膜症の治療予後を劇的に改善し、現在我々はanti-VEGF eraと呼ばれるこの時代において同疾患の治療体系が刻々と変貌するのを目の当たりにしている。かつては光凝固と硝子体手術のみが進行した糖尿病網膜症に対する治療手段であったことを考えると隔世の感がある。しかしながらその一方で、情報システムの革新と研究技術の進歩を背景に蓄積される基礎および臨床研究の成果は、網膜症病態の複雑さ、VEGF単独阻害による治療の限界、そしてその弊害の可能性なども浮き彫りにした。そして、その必然としてVEGF以外の病態責任分子を標的とした糖尿病網膜症に対する創薬研究が全世界で現在行われ、複数の分子標的製剤が糖尿病網膜症の治療オプションとなるpost anti-VEGF eraが目前に迫ってきている。糖尿病網膜症の発症および進展には、慢性炎症、そして酸化ストレスの関与が知られている。本研究においては、糖鎖など新規標的分子の探索的研究を行うとともに、この二つの病態に関わる分子としてvascular adhesion protein-1(VAP-1)/semicarbazide sensitive amine oxidase(SSAO)の糖尿病網膜症病態における役割についての検討を主に行った。VAP-1/SSAOは血管内皮細胞に発現する白血球接着分子だが、その一方で酵素活性も持つ多機能蛋白質"moonlighting protein"であり、慢性炎症と酸化ストレスの双方に関わる重要な分子の一つである。本研究ではVAP-1/SSAOが糖尿病網膜症の病態形成に白血球接着分子として関与する一方、遊離型蛋白質としてその眼内に蓄積すること、そしてその機序にVEGFや蛋白質分解酵素matrix metalloproteinasesが関与することを明らかにした。また、VAP-1/SSAOは酵素として過酸化水素および不飽和アルデヒドの一種アクロレインを産生し、血管内皮細胞における酸化ストレス亢進に寄与することとその機序を見出した。以上の検討結果に基づいて、本稿では糖尿病網膜症におけるVAP-1/SSAO阻害剤による治療可能性について述べたい。(著者抄録), (公財)日本眼科学会, 日本語

視神経乳頭黒色細胞腫のOCT angiography所見　　　　　　　　　　　　　　　
菊地 郁, 加瀬 諭, 石田 晋, 日本眼科学会雑誌, 122, 臨増, 279, 279, 2018年03月
(公財)日本眼科学会, 日本語

増殖糖尿病網膜症患者の硝子体中アクロレイン結合蛋白FDP-lysine濃度　　　　　　　　　　　　　　　
森 祥平, 村田 美幸, 野田 航介, 鈴木 智浩, 齋藤 理幸, 安藤 亮, 加瀬 諭, 齋藤 航, 神田 敦宏, 石田 晋, 眼科臨床紀要, 10, 11, 920, 921, 2017年11月
眼科臨床紀要会, 日本語

PDTトリプル療法を行った加齢黄斑変性における治療2年後視力の規定因子　　　　　　　　　　　　　　　
安藤 亮, 野田 航介, 廣岡 季里子, 橋本 勇希, 鈴木 智浩, 森 祥平, 齋藤 理幸, 吉澤 史子, 加瀬 諭, 齋藤 航, 石田 晋, 眼科臨床紀要, 10, 11, 940, 940, 2017年11月
眼科臨床紀要会, 日本語

ステロイドパルス療法が著効した脈絡膜新生血管とAZOORを伴った点状脈絡膜内層症の1例　　　　　　　　　　　　　　　
鈴木 智浩, 加瀬 諭, 森 祥平, 安藤 亮, 齋藤 理幸, 野田 航介, 石田 晋, 眼科臨床紀要, 10, 11, 949, 950, 2017年11月
眼科臨床紀要会, 日本語

難治性黄斑円孔に対する内境界膜自家移植変法　　　　　　　　　　　　　　　
柴田 有紀子, 齋藤 理幸, 藤谷 顕雄, 鈴木 智浩, 安藤 亮, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋, 眼科臨床紀要, 10, 10, 843, 843, 2017年10月
眼科臨床紀要会, 日本語

Pachychoroid pigment epitheliopathyの臨床像　　　　　　　　　　　　　　　
廣岡 季里子, 齋藤 航, 齋藤 理幸, 森 祥平, 安藤 亮, 橋本 勇希, 加瀬 諭, 野田 航介, 石田 晋, 眼科臨床紀要, 10, 10, 860, 860, 2017年10月
眼科臨床紀要会, 日本語

糖尿病眼における熱ショック蛋白α-クリスタリンと最終糖化産物の発現　　　　　　　　　　　　　　　
加瀬 諭, 石田 晋, 糖尿病合併症, 31, Suppl.1, 341, 341, 2017年10月
(一社)日本糖尿病合併症学会, 日本語

瞼板内角質嚢胞との鑑別を要した眼瞼結膜嚢胞性病変の1例　　　　　　　　　　　　　　　
水門 由佳, 加瀬 諭, 石嶋 漢, 高桑 恵美, 石田 晋, 日本眼腫瘍学会誌, 6, 1, 4, 2017年09月
【緒言】瞼板内角質嚢胞は、瞼板内に発生する腫瘤性病変において代表的な嚢胞性疾患である。今回我々は、瞼板内角質嚢胞と鑑別を要し、眼瞼結膜に発生した嚢胞性病変の1例を経験したので報告する。【症例】62歳女性。6年前から右上眼瞼の腫脹と自然排膿があり、前医にて経過観察を行ってきた。腫瘤が増大傾向を示したため、眼瞼脂腺癌などの悪性疾患が疑われ、当科紹介となった。初診時、右眼の上眼瞼結膜側に突出する黄色腫瘤がみられた。同日、眼瞼結膜から腫瘤の切除生検を行った。腫瘤の本体は瞼板内にみられ、病理組織検査では、一部に顆粒層を有する異型に乏しい重層扁平上皮が嚢胞状構造を形成しており、眼瞼結膜に隣接していた。嚢胞内腔には層板状の角化物が見られ、病理組織学的には表皮嚢胞を考える所見であった。【結論】上眼瞼の代表的な嚢胞性疾患として、表皮嚢胞、瞼板内角質嚢胞が挙げられる。本症例は、臨床的に開口部が結膜と考えられること、嚢胞壁に顆粒層を有することから表皮嚢胞、瞼板内角質嚢胞とは異なる結膜嚢胞性病変である。(著者抄録), 日本眼腫瘍学会, 日本語

非典型的所見を呈した片眼性網膜芽細胞腫の1例　　　　　　　　　　　　　　　
安藤 亮, 加瀬 諭, 野崎 真世, 石田 晋, 眼科臨床紀要, 10, 6, 517, 517, 2017年06月
眼科臨床紀要会, 日本語

翼状片に対する新たな無切除Z型切開回転術の手術成績 (第70回 日本臨床眼科学会講演集(3))
堤 雅幸, 堀江 幸弘, 加瀬 諭, 北市 伸義, 臨床眼科, 71, 5, 789, 794, 2017年05月
医学書院, 日本語

眼付属器MALTリンパ腫の診断におけるフローサイトメトリの有用性　　　　　　　　　　　　　　　
加瀬 諭, 石嶋 漢, 浦木 健彦, 鈴木 康夫, 石田 晋, 日本眼科学会雑誌, 121, 臨増, 201, 201, 2017年03月
(公財)日本眼科学会, 日本語

多発消失性白点症候群における脈絡膜層別厚の経時変化　　　　　　　　　　　　　　　
橋本 勇希, 齋藤 航, 長谷川 裕香, 齋藤 理幸, 安藤 亮, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋, 日本眼科学会雑誌, 121, 臨増, 218, 218, 2017年03月
(公財)日本眼科学会, 日本語

腫瘍性病変が疑われた結節性後部強膜炎の1例　　　　　　　　　　　　　　　
柴田 有紀子, 加瀬 諭, 南場 研一, 石田 晋, 日本眼科学会雑誌, 121, 臨増, 329, 329, 2017年03月
(公財)日本眼科学会, 日本語

睫毛乱生に対するラジオ波メス睫毛根焼灼の治療効果　　　　　　　　　　　　　　　
浦木 健彦, 加瀬 諭, 木下 哲志, 石嶋 漢, 石田 晋, 眼科手術, 30, 1, 187, 190, 2017年01月
目的:睫毛乱生に対するラジオ波メスを用いた睫毛根焼灼の治療成績を報告する。方法:2015年3〜12月に帯広協会病院にてラジオ波メスを用いた睫毛根焼灼を施行し睫毛乱生13例21側を対象とした。機器はサージトロンEMC(Ellman社)を使用し、焼灼条件は止血・凝固モード、パワーは2W、焼灼時間は1秒とした。焼灼後56日間で再発がみられない場合に寛解と定義した。結果:初回治療では151本中111本が寛解した(寛解率:73.5%)。再発した40本に対し2回目の治療を施行し、32本が寛解した(寛解率:80%)。再度、再発した8本に3回目の治療を施行し、結果的に100%の寛解率を得た。治療回数が多い眼瞼では、有意に睫毛数が増加していた。合併症では21側中2側(9.5%)に軽微な色素沈着や陥凹瘢痕がみられた。結論:本研究により、睫毛乱生に対するラジオ波焼灼は、有用な治療法の一つであることが示された。(著者抄録), (公社)日本眼科手術学会, 日本語

PDTトリプル療法を行ったポリープ状脈絡膜血管症における治療1年後視力の規定因子　　　　　　　　　　　　　　　
安藤 亮, 齋藤 航, 廣岡 季里子, 鈴木 智浩, 吉澤 史子, 齋藤 理幸, 加瀬 諭, 森 祥平, 野田 航介, 石田 晋, 眼科臨床紀要, 9, 11, 930, 930, 2016年11月
眼科臨床紀要会, 日本語

アフリベルセプト併用PDTトリプル療法1年後の治療成績　　　　　　　　　　　　　　　
鈴木 智浩, 齋藤 航, 森 祥平, 齋藤 理幸, 安藤 亮, 加瀬 諭, 廣岡 季里子, 吉澤 史子, 野田 航介, 石田 晋, 眼科臨床紀要, 9, 11, 931, 931, 2016年11月
眼科臨床紀要会, 日本語

ベバシズマブ硝子体内注射が奏効した血管増殖性網膜腫瘍の3例　　　　　　　　　　　　　　　
川向 友子, 齋藤 航, 加瀬 諭, 石田 晋, 眼科臨床紀要, 9, 11, 934, 934, 2016年11月
眼科臨床紀要会, 日本語

Alterations of Choroidal Thickness and Circulation in Patients with Hypertensive Choroidopathy
Michiyuki Saito, Kousuke Noda, Yuki Hashimoto, Kiriko Hirooka, Zhenyu Don, Ryo Ando, Shohei Mori, Satoru Kase, Wataru Saito, Susumu Ishida, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 57, 12, 2016年09月
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 英語, 研究発表ペーパー・要旨（国際会議）

糖尿病網膜症の増殖組織における分子シャペロンαB-クリスタリンのリン酸化　　　　　　　　　　　　　　　
加瀬 諭, 董 陽子, 神田 敦宏, 野田 航介, 石田 晋, 糖尿病合併症, 30, Suppl.1, 249, 249, 2016年09月
(一社)日本糖尿病合併症学会, 日本語

中心性漿液性脈絡網膜症における中心窩脈絡膜厚と黄斑部脈絡膜血流の変化　　　　　　　　　　　　　　　
齋藤 理幸, 野田 航介, 橋本 勇希, 廣岡 季里子, 安藤 亮, 森 祥平, 加瀬 諭, 齋藤 航, 石田 晋, 日本眼科学会雑誌, 120, 臨増, 188, 188, 2016年03月
(公財)日本眼科学会, 日本語

慢性中心性漿液性脈絡網膜症における脈絡膜循環と形態の経時変化　　　　　　　　　　　　　　　
廣岡 季里子, 齋藤 航, 齋藤 理幸, 橋本 勇希, 森 祥平, 加瀬 諭, 安藤 亮, 野田 航介, 石田 晋, 日本眼科学会雑誌, 120, 臨増, 242, 242, 2016年03月
(公財)日本眼科学会, 日本語

カラー臨床報告 硝子体浸潤を伴った脈絡膜悪性黒色腫の1例
横山 英恵, 加瀬 諭, 鈴木 康夫, 勝田 聡, 高橋 光生, 篠原 敏也, 石田 晋, 加瀬 学, 臨床眼科, 69, 10, 1545, 1550, 2015年10月
背景:硝子体浸潤を伴う脈絡膜悪性黒色腫はわが国では稀である。目的:硝子体浸潤を伴う脈絡膜悪性黒色腫の1例の報告。症例:73歳の男性が左眼の眼底の隆起性病変で紹介受診した。2年前から左眼の飛蚊症を自覚していた。所見と経過:矯正視力は左右眼とも0.6であった。左眼には前部硝子体に色素細胞が浮遊し,眼底耳側に3乳頭径大の茶褐色隆起性病変があり,その頂点に黒褐色病巣があった。この隆起性病変は,フルオレセイン蛍光眼底造影の後期で色素漏出,インドシアニングリーン蛍光造影で過蛍光であり,黒褐色病巣は終始低蛍光であった。悪性黒色腫と診断し,左眼を摘出した。病理学的に,類上皮型の脈絡膜悪性黒色腫であり,腫瘍の大きさは8mm×8mm×5mmで,腫瘤の頂点で腫瘍細胞が網膜を穿破して硝子体腔に浸潤していた。結論:本症例はわが国では稀な,硝子体浸潤を伴う脈絡膜悪性黒色腫であった。(著者抄録), (株)医学書院, 日本語

【抗VEGF薬による治療】 抗VEGF薬の治療 種々の眼疾患、眼腫瘍への応用
加瀬 諭, 石田 晋, あたらしい眼科, 32, 8, 1075, 1081, 2015年08月
(株)メディカル葵出版, 日本語

結膜節外辺縁帯B細胞性リンパ腫におけるレニン・アンジオテンシン系の病態への関与　　　　　　　　　　　　　　　
石塚 タンエルダル, 神田 敦宏, 加瀬 諭, 安藤 亮, 董 陽子, 稲福 沙織, 田川 義晃, 野田 航介, 石田 晋, 日本眼科学会雑誌, 119, 臨増, 180, 180, 2015年03月
(公財)日本眼科学会, 日本語

Effect of Topical Rebamipide on Human Conjunctival Goblet Cells
Satoru Kase, Toshiya Shinohara, Manabu Kase, JAMA OPHTHALMOLOGY, 132, 8, 1021, 1022, 2014年08月
AMER MEDICAL ASSOC, 英語, 速報，短報，研究ノート等（学術雑誌）

診断に苦慮した毛様体平滑筋腫の一例　　　　　　　　　　　　　　　
石嶋 漢, 加瀬 諭, 吉川 洋, 鈴木 茂伸, 新明 康弘, 南場 研一, 山本 哲平, 野崎 真世, 野田 実香, 石田 晋, 日本眼科学会雑誌, 118, 臨増, 304, 304, 2014年03月
(公財)日本眼科学会, 日本語

癌関連網膜症の臨床像　　　　　　　　　　　　　　　
齋藤 理幸, 齋藤 航, 加瀬 諭, 野田 航介, 吉沢 史子, 藤谷 顕雄, 大黒 浩, 石田 晋, 眼科臨床紀要, 6, 10, 808, 809, 2013年10月
眼科臨床紀要会, 日本語

中心窩に多発性裂孔を呈した黄斑円孔の1例　　　　　　　　　　　　　　　
鈴木 智浩, 野田 航介, 齋藤 航, 齋藤 理幸, 加瀬 諭, 藤谷 顕雄, 吉澤 史子, 石田 晋, 眼科臨床紀要, 6, 10, 830, 830, 2013年10月
眼科臨床紀要会, 日本語

ラニビズマブ併用PDTトリプル療法1年後の治療成績　　　　　　　　　　　　　　　
吉澤 史子, 齋藤 航, 加瀬 諭, 齋藤 理幸, 藤谷 顕雄, 橋本 勇希, 野田 航介, 石田 晋, 眼科臨床紀要, 6, 10, 837, 838, 2013年10月
眼科臨床紀要会, 日本語

新しい展望 眼腫瘍
辻 英貴, 鈴木 茂伸, 加瀬 諭, 眼科, 55, 8, 865, 904, 2013年08月
金原出版, 日本語

黄斑円孔網膜剥離に対する硝子体手術成績 黄斑バックル使用の効果　　　　　　　　　　　　　　　
藤谷 顕雄, 齋藤 航, 齋藤 理幸, 吉沢 史子, 野田 航介, 加瀬 諭, 石田 晋, 眼科手術, 26, 2, 279, 283, 2013年04月
目的:黄斑円孔網膜剥離(MHRD)に対する硝子体手術(PPV)成績を検討すること。対象および方法:2003年12月から2011年8月に北海道大学病院眼科でPPVを施行したMHRD20例20眼(男性3例、女性17例、平均年齢69.5歳)を対象とした。初回術式として15眼に内境界膜(ILM)剥離併用PPV(PPV群)、5眼に黄斑バックル(MB)併用PPV(MB群)が施行された。網膜復位率、視力の推移、黄斑円孔閉鎖率などについて、診療録より後ろ向きに検討した。結果:PPV群の初回網膜復位率は66.7%であり、MHが再開通した3眼にMB併用PPVを追加し、全例で網膜復位を得た。一方、MB群の初回網膜復位率は80%、最終網膜復位術は100%であった。最終的に19眼(95%)で網膜は復位した。最終平均視力は有意に改善し(p=0.0007)、最終的にMB併用群は、非併用群より良好な傾向があった(p=0.069)。黄斑円孔閉鎖率は、MB併用群、非併用群でそれぞれ71.4%、40.0%であった。結論:MHRDに対するPPVにおける、長眼軸長眼でもMBを併用することで良好な網膜腹位率と良好な黄斑円孔閉鎖率が得られた。(著者抄録), (公社)日本眼科手術学会, 日本語

網膜血管増殖性腫瘍に対する硝子体手術成績と血管内皮増殖因子の発現　　　　　　　　　　　　　　　
齋藤 航, 藤谷 顕雄, 加瀬 諭, 董 震宇, 石田 晋, 眼科臨床紀要, 5, 10, 942, 942, 2012年10月
眼科臨床紀要会, 日本語

DNAメチル化阻害剤による脈絡膜血管内皮細胞の増殖抑制効果　　　　　　　　　　　　　　　
加瀬 諭, 園田 祥三, ヘー・シクン, ステファン・ライアン, ヒントン・デービット, 石田 晋, 眼科臨床紀要, 5, 10, 954, 954, 2012年10月
眼科臨床紀要会, 日本語

強度近視眼に発症したタモキシフェン網膜症の1例　　　　　　　　　　　　　　　
吉澤 史子, 加瀬 諭, 齋藤 航, 石田 晋, 眼科臨床紀要, 5, 10, 971, 971, 2012年10月
眼科臨床紀要会, 日本語

小児Coats病に対するbevacizumab硝子体内注射併用網膜光凝固
橋本 勇希, 野田 航介, 齋藤 航, 藤谷 顕雄, 齋藤 理幸, 加瀬 諭, 吉澤 史子, 石田 晋, 眼科臨床紀要, 5, 7, 651, 655, 2012年07月
背景:小児Coats病に対してbevacizumab硝子体内注射(以下;IVB)併用網膜光凝固を施行した一例の臨床経過報告。症例:12歳、男児。初診時矯正視力は右0.04で、眼底には右耳側周辺部に網膜毛細血管拡張と瘤状の異常網膜血管があった。異常血管周囲には強度の網膜浮腫があり、後極部および中心窩に硬性白斑が集積していた。フルオレセイン蛍光眼底造影(FA)では異常血管に一致した強い蛍光漏出を示した。Coats病stage 2Bと診断し、全身麻酔下でIVB(1.25mg)および網膜光凝固を施行した。治療4日後には黄斑浮腫と硬性白斑は軽減し、視力は0.3に改善した。その後、異常網膜血管に対する網膜光凝固を追加したところ、硬性白斑と網膜浮腫は著明に減少し、視力は1.0に改善した。結論:IVBを併用した網膜光凝固は、小児のCoats病において有効な治療法であることが示唆された。(著者抄録), 眼科臨床紀要会, 日本語

加瀬諭
加瀬 諭, あたらしい眼科 = Journal of the eye, 29, 5, 649, 650, 2012年05月30日
日本語

眼内血管新生の治療標的としてのクリスタリン蛋白
加瀬 諭, あたらしい眼科 = Journal of the eye, 29, 3, 361, 363, 2012年03月30日
メディカル葵出版, 日本語

ヒト結膜MALTリンパ腫におけるVEGFの発現　　　　　　　　　　　　　　　
木下 哲志, 加瀬 諭, 安藤 亮, 董 震宇, 福原 淳一, アントン・レニコフ, 神田 敦宏, 野田 航介, 石田 晋, 日本眼科学会雑誌, 116, 臨増, 278, 278, 2012年03月
(公財)日本眼科学会, 日本語

漿液性網膜色素上皮剥離がある滲出型加齢黄斑変性の臨床経過　　　　　　　　　　　　　　　
吉澤 史子, 齋藤 航, 藤谷 顕雄, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋, 日本眼科学会雑誌, 116, 臨増, 334, 334, 2012年03月
(公財)日本眼科学会, 日本語

自己免疫性網膜症疑い患者におけるWestern blot法を用いた抗網膜抗体陽性率　　　　　　　　　　　　　　　
齋藤 理幸, 齋藤 航, 加瀬 諭, 野田 航介, 吉沢 史子, 藤谷 顕雄, 大黒 浩, 石田 晋, 日本眼科学会雑誌, 116, 臨増, 337, 337, 2012年03月
(公財)日本眼科学会, 日本語

健康成人の片眼に発症した内因性真菌性眼内炎
宇野 友絵, 南場 研一, 加瀬 諭, 齋藤 航, 北市 伸義, 大野 重昭, 石田 晋, あたらしい眼科 = Journal of the eye, 29, 1, 135, 138, 2012年01月30日
メディカル葵出版, 日本語

涙嚢様腺管組織を呈した涙腺嚢胞の1例
山本 和幸, 加瀬 諭, 野田 実香, 岩口 佳史, 後藤田 裕子, 石田 晋, 臨床眼科, 66, 1, 57, 60, 2012年01月
目的:涙腺嚢胞の1症例の報告。症例:80歳男性が右の上眼瞼腫脹で受診した。40年前に涙嚢炎で右の涙嚢摘出を受けていた。所見:右の上眼瞼の耳側に直径10mmの表面が平滑な軟性腫瘤が触知された。周囲組織との癒着はなかった。磁気共鳴画像検査(MRI)のT2強調画像で,内部が均一な高信号を示す嚢胞様病変があった。血液検査でCRPとIgGの上昇があった。摘出した腫瘤は,病理組織学的に大小の嚢胞腔腫瘤からなり,嚢胞内腔は多列線毛円柱上皮を示し,断頭分泌を伴っていた。嚢胞の上皮下にリンパ球とIgG陽性の形質細胞浸潤があった。結論:本症例は涙嚢様組織を呈する涙腺嚢胞と考えられる。血液のCRPとIgG値の上昇,嚢胞の上皮下に浸潤した形質細胞がIgG陽性であったことから,その発生に慢性炎症が関与した可能性がある。(著者抄録), (株)医学書院, 日本語

糖尿病網膜症における増殖組織の病理組織学的所見と視力予後の相関
加瀬 諭, 日本眼科學会雜誌, 115, 11, 998, 1006, 2011年11月10日
日本眼科学会, 日本語

インターフェロンα-2b点眼液を補助療法として使用した結膜悪性黒色腫の2例
加瀬 諭, 石嶋 漢, 野田 実香, 石田 晋, 日本眼科學会雜誌, 115, 11, 1043, 1047, 2011年11月10日
日本眼科学会, 日本語

狭心症を合併した乳頭血管炎患者における冠動脈の病理学的検討　　　　　　　　　　　　　　　
加瀬 諭, 齋藤 航, 吉沢 史子, 矢野 俊之, 石田 晋, 眼科臨床紀要, 4, 10, 1002, 1002, 2011年10月
眼科臨床紀要会, 日本語

網膜芽細胞腫の診断と臨床経過の検討
野崎 真世, 加瀬 諭, 吉田 和彦, 石嶋 漢, 野田 実香, 鈴木 茂伸, 東 範行, 石田 晋, 臨床眼科, 65, 7, 1123, 1127, 2011年07月
目的:網膜芽細胞腫の診断と臨床経過の報告。症例:過去8年間の網膜芽細胞腫の自験例7症例を検索した。結果:男児2例,女児5例で,5例が片眼性,2例が両眼性であった。年齢は6例が4歳以下で,1例が7歳であった。主訴は白色瞳孔と斜視が5例,視力低下が1例,結膜充血と眼瞼腫脹が1例にあった。国際分類での病期はB〜Eの範囲にあり,3例がE期であった。初回治療として眼球摘出術を5眼,眼窩内容除去術を1眼に行った。眼球を温存した3眼中,2眼では後に眼球摘出を必要とし,1眼では再発がなかった。眼球摘出術または眼窩内容除去術を行った6眼では転移はなかった。眼球外に浸潤した2例は不帰の転帰をとった。この2例は,初診時に網膜芽細胞腫の典型的所見がなかった。結論:網膜芽細胞腫の初診時の臨床像は,必ずしも予後を示さない。(著者抄録), (株)医学書院, 日本語

急性涙腺炎を初発症状とした眼部帯状疱疹の1例
横山 千秋, 森 祥平, 鎌田 麻子, 加瀬 諭, 石田 晋, 臨床眼科, 65, 6, 945, 948, 2011年06月
目的:急性涙腺炎を初発症状とした眼部帯状疱疹の1例の報告。症例:82歳女性が2日前からの右眼周囲の痛みで受診した。圧痛を伴う右眼瞼の発赤と腫脹があり,皮疹はなかった。磁気共鳴画像検査(MRI)の所見から急性涙腺炎を疑い,抗生物質を点滴した。4日後に涙腺腫脹が増悪し,その2日後に右角膜上皮に点状混濁と前房炎症が生じ,抗ウイルス薬治療を開始した。さらに2日後に右前額部に痂皮を伴う皮疹とびらんが生じ,帯状疱疹と診断した。初診から15日後に涙腺炎,前房の炎症,皮疹は寛解した。結論:典型的な皮疹や眼病変がなく,抗生物質に反応しない急性涙腺炎では,稀ではあるが眼部帯状疱疹による可能性がある。(著者抄録), (株)医学書院, 日本語

ヒト翼状片におけるTissue Factorの発現　　　　　　　　　　　　　　　
安藤 亮, 加瀬 諭, 大橋 勉, 董 震宇, 福原 淳一, アントン・レニコフ, 神田 敦宏, 村田 美幸, 野田 航介, 石田 晋, 日本眼科学会雑誌, 115, 臨増, 203, 203, 2011年04月
(公財)日本眼科学会, 日本語

AlphaB-crystallinによる実験的脈絡膜新生血管の制御　　　　　　　　　　　　　　　
加瀬 諭, 園田 祥三, 北村 瑞, Stephen Ryan, David Hinton, 石田 晋, 日本眼科学会雑誌, 115, 臨増, 219, 219, 2011年04月
(公財)日本眼科学会, 日本語

増殖糖尿病網膜症の線維血管膜におけるalphaB-crystallinの発現　　　　　　　　　　　　　　　
董 震宇, 加瀬 諭, 安藤 亮, 福原 淳一, アントン・レニコフ, 神田 敦宏, 村田 美幸, 野田 航介, 斎藤 航, 石田 晋, 日本眼科学会雑誌, 115, 臨増, 231, 231, 2011年04月
(公財)日本眼科学会, 日本語

角結膜上皮内新生物術後に急速に増大した化膿性肉芽腫の1例
石嶋 漢, 加瀬 諭, 野田 実香, 石田 晋, 日本眼科學会雜誌, 114, 12, 1036, 1039, 2010年12月10日
日本眼科学会, 日本語

特発性網膜上膜におけるCyclooxygenase(COX)-2の発現　　　　　　　　　　　　　　　
加瀬 諭, 齋藤 航, 石田 晋, 眼科臨床紀要, 3, 10, 996, 996, 2010年10月
眼科臨床紀要会, 日本語

熱ショックタンパク質70発現量増加によるマウス紫外線角膜炎の回復(Amelioration of UV-photokeratitis in mice by heat shock protein 70 upregulation)　　　　　　　　　　　　　　　
アントン・レニコフ, 北市 伸義, 加瀬 諭, 石田 晋, 大野 重昭, 日本眼科学会雑誌, 114, 臨増, 246, 246, 2010年03月
(公財)日本眼科学会, 日本語

くも膜下腔に浸潤したびまん性浸潤型網膜芽細胞腫の一例　　　　　　　　　　　　　　　
吉田 和彦, 加瀬 諭, 野崎 真世, 石田 晋, 日本眼科学会雑誌, 114, 臨増, 258, 258, 2010年03月
(公財)日本眼科学会, 日本語

眼瞼脂腺癌におけるalpha-crystallinの発現　　　　　　　　　　　　　　　
加瀬 諭, 吉田 和彦, 野田 実香, Rao Narsing, 石田 晋, 日本眼科学会雑誌, 114, 臨増, 336, 336, 2010年03月
(公財)日本眼科学会, 日本語

炎症性眼疾患の診療(23)Stevens-Johnson 症候群(皮膚粘膜眼症候群)
加瀬 諭, 北市 伸義, 大野 重昭, 臨床眼科, 64, 2, 172, 176, 2010年02月
医学書院, 日本語

Uveal effusion syndrome caused by choroidal invasion of malignant lymphoma
Satoru Kase, Wataru Saito, Akari Saito, Shigeaki Ohno, JAPANESE JOURNAL OF OPHTHALMOLOGY, 54, 1, 109, 110, 2010年01月
SPRINGER TOKYO, 英語, 速報，短報，研究ノート等（学術雑誌）

マウス酸素誘導網膜症の病理学的所見と臨床応用の可能性
加瀬 諭, 坂本 泰二, あたらしい眼科 = Journal of the eye, 25, 11, 1533, 1535, 2008年11月30日
メディカル葵出版, 日本語

Comment on the recent publication "Conjunctival nodules associated with Vogt-Koyanagi-Harada disease"
Satoru Kase, Narsing A. Rao, GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 246, 2, 323, 323, 2008年02月
SPRINGER, 英語, 速報，短報，研究ノート等（学術雑誌）

ヒト初発翼状片の病理組織学的検討
加瀬 諭, 佐藤 出, 中西 勝也, 安藤 亮, 小原 睦子, 高橋 秀史, 札幌社会保険総合病院医誌 = Journal of Sapporo Social Insurance General Hospital (JSSIGH), 16, 1, 13, 18, 2007年12月01日
翼状片は眼球結膜に連続して発生し、角膜輪部を超えて角膜中央へ進入する増殖組織である。本研究では初発翼状片の病理組織学的所見を解析した。bare-sclera法により切除術を行った8例10眼を検討した。切除した組織をフォルマリン固定、パラフィン胞埋、未染標本作製後、ヘマトキシリンーエオジン染色、PAS染色、マッソントリクローム染色、エラスチカワンギーソン染色を行った。10眼とも上皮は細胞異型のない扁平上皮化生を来した円柱上皮であり、基底層に褐色色素沈着があった。8眼で杯細胞過形成、2眼で嚢胞の形成があった。問質には多数の微小血管が分布し、7眼で上皮内へ微小血管が進入していた。6眼で炎症細胞浸潤が強く、リンパ濾胞様の構造を呈していた。10眼で間質に変性した弾性線維の集塊があった。翼状片の病理組織学的所見は多彩であり、その発生病理に関与するもの、および増殖、進展に伴い検出される所見が混在していることが示唆された。, 札幌社会保険総合病院, 日本語

Slowly progressive cancer-associated retinopathy
Wataru Saito, Satoru Kase, Naoki Furudate, Shigeaki Ohno, ARCHIVES OF OPHTHALMOLOGY, 125, 10, 1431, 1433, 2007年10月
AMER MEDICAL ASSOC, 英語, その他

強い黄斑浮腫と閉塞性網膜血管炎を合併した乳頭血管炎の1症例　　　　　　　　　　　　　　　
齋藤 理幸, 齋藤 航, 加瀬 諭, 古舘 直樹, 眼科臨床医報, 101, 9, 966, 967, 2007年09月
眼科臨床医報会, 日本語

網膜の細胞増殖制御におけるp27(KIP 1)の役割
加瀬 諭, 吉田 和彦, 大野 重昭, 日本眼科學会雜誌 = Journal of Japanese Ophthalmological Society, 111, 8, 577, 586, 2007年08月10日
日本眼科学会, 日本語

Increased osteopontin levels in the vitreous of patients with diabetic retinopathy
Satoru Kase, Masahiko Yokoi, Wataru Saito, Naoki Furudate, Kazuhiro Ohgami, Mizuki Kitamura, Nobuyoshi Kitaichi, Kazuhiko Yoshida, Manabu Kase, Shigeaki Ohno, Toshimitsu Uede, OPHTHALMIC RESEARCH, 39, 3, 143, 147, 2007年
Purpose: Osteopontin ( OPN) has diverse functions such as cell adhesion, chemoattraction, immunomodulation, and angiogenesis. The aim of this study is to analyze the OPN levels in vitreous fluid obtained from diabetic retinopathy ( DR) and non- DR patients. Methods: Nineteen patients out of 11 with DR and 8 without DR underwent pars plana vitrectomy and vitreous fluid was obtained simultaneously. Two distinct sandwich enzyme- linked immunosorbent assay systems ( systems 1 and 2) were applied, which have been developed in our laboratories to quantify the OPN concentrations in vitreous fluid. Results: The non- thrombin- cleaved full- length OPN levels in the vitreous fluid were 921.63 8 45.38 ng/ ml in DR and 632.80 +/- 83.43 ng/ ml in non- DR using system 1. Also, vitreous thrombin- cleaved and noncleaved OPN levels were increased to 2,109.22 +/- 151.651 and 1,651.13 +/- 229.82 ng/ ml in patients with DR and non- DR using system 2. The vitreous OPN levels were significantly higher in DR than those in non- DR ( p < 0.01 by system 1 and p < 0.05 by system 2). Conclusion: Thrombin- cleaved and noncleaved vitreous OPN levels in patients with DR were increased compared with control subjects, suggesting that OPN plays a potential role in the pathogenesis of diabetic retinal ischemia. Copyright (c) 2007 S. Karger AG, Basel., KARGER, 英語

Elevation of serum Krebs von den Lunge-6 levels in patients with tubulointerstitial nephritis and uveitis syndrome.
Satoru Kase, Nobuyoshi Kitaichi, Kenichi Namba, Akiko Miyazaki, Kazuhiko Yoshida, Kenji Ishikura, Masahiro Ikeda, Taiji Nakashima, Shigeaki Ohno, American journal of kidney diseases : the official journal of the National Kidney Foundation, 48, 6, 935, 41, 2006年12月, ［国際誌］
BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is characterized by a combination of idiopathic acute tubulointerstitial nephritis and uveitis. Krebs von den Lunge-6 (KL-6) is a human glycoprotein secreted by type II alveolar cells in the lung, and its serum levels increase in patients with pneumonia of various causes, as well as ocular sarcoidosis. The aim of the present study is to quantify serum KL-6 levels in patients with TINU syndrome, which has no pulmonary and sarcoid lesions, and elucidate the usefulness of KL-6 for the diagnosis and follow-up of this syndrome. METHODS: Serum and urinary samples were obtained from 17 patients with TINU syndrome and 36 age-matched patients with uveitis from other causes. Sarcoidosis was eliminated because serum KL-6 levels increased during their lung lesion. Serum KL-6 level was determined by using a human KL-6 electrochemiluminescence immunoassay. Formalin-fixed paraffin-embedded renal tissue sections were incubated with anti-KL-6 monoclonal antibody, then examined immunohistochemically. RESULTS: Mean serum KL-6 levels for patients with TINU syndrome and those with uveitis from other causes were 363.35 +/- 51.06 and 213.19 +/- 10.28 U/mL, respectively (P < 0.001). Urinary beta(2)-microglobulin levels of patients with TINU syndrome and uveitis from other causes were 4.06 +/- 1.31 and 0.16 +/- 0.20 mg/L, respectively (P < 0.001). All patients with TINU syndrome showed a simultaneous decrease in serum KL-6 and urinary beta(2)-microglobulin levels after the beginning of treatment. Strong immunoreactivity for KL-6 was observed in renal distal tubules in biopsy tissue of patients with TINU syndrome. CONCLUSION: We show a significant increase in serum KL-6 levels in patients with TINU syndrome, whereas levels were normal in patients with other causes of uveitis without nephritis. Renal distal tubules stained strongly with anti-KL-6 antibody, suggesting that high KL-6 levels may reflect the renal lesion of TINU syndrome. Serum KL-6 may be a potential laboratory parameter for the diagnosis and follow-up of patients with TINU syndrome that could complement urinary beta(2)-microglobulin measurements., 英語

Chronic panuveitis and scleritis in a patient with cryptogenic organizing pneumonia
Wataru Saito, Akari Saito, Kenichi Namba, Satoru Kase, Masanori Shiratori, Shigeaki Ohno, JAPANESE JOURNAL OF OPHTHALMOLOGY, 50, 6, 558, 561, 2006年11月
ELSEVIER SCIENCE INC, 英語, 速報，短報，研究ノート等（学術雑誌）

Expression of erythropoietin receptor in human Merkel cell carcinoma of the eyelid
Kase Satoru, Yoshida Kazuhiko, Osaki Mitsuhiko, Adachi Hironobu, Ito Hisao, Ohno Shigeaki, Anticancer Research, 26, 6, 4535, 4537, 2006年
Background: Merkel cell carcinoma (MCC) of the eyelid is a rare malignant solid tumor of the elderly, which demonstrates a large, firm, reddish nodule mimicking an angiomatous lesion. The expression of erythropoietin (Epo) and Epo receptor (EpoR), as well as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) and basic fibroblast growth factor (bFGF) were examined in human MCC tissues. Materials and Methods: Three patients diagnosed with MCC of the eyelid underwent surgical excision. Isolated tissues were fixed by 4% paraformaldehyde and then were examined using immunohistochemistry. Results: The carcinoma cells consisted of irregular tumor nests with linear stroma and showed hypercellularity indicated by small round nuclei with several mitoses. While immunoreactivity of Epo was undetectable, an increased expression of EpoR was noted in the carcinoma cells. Cytoplasmic immunoreactivity for EpoR was detected in a variety of carcinoma cells, including mitotic cells. VEGF, VEGFR, and bFGF, other angiogenic factors were not expressed in the MCC tissues. Conclusion: EpoR was highly expressed in MCC of the eyelid, suggesting that the Epo-EpoR pathway plays an important role in the formation of MCC., International Institute of Anticancer Research, 英語

脈絡膜原発悪性黒色腫の臨床病理学的検討 (特集 第58回日本臨床眼科学会講演集(3))
加瀬 諭, 吉田 和彦, 齋藤 航, 臨床眼科, 59, 5, 705, 709, 2005年05月
医学書院, 日本語

角膜上皮剥離後および発生過程の水晶体の細胞増殖における細胞周期調節蛋白の役割
吉田 和彦, 原田 高幸, 原田 知加子, 加瀬 諭, 池田 裕美, 酒井 正春, 西 信三, 今城 純子, 中山 啓子, 永濱 裕康, 中山 敬一, 大野 重昭, 日本眼科學会雜誌, 107, 11, 678, 686, 2003年11月10日
日本語

網膜ミュラー細胞のグリア間葉移行におけるアルファBクリスタリンの関与
科学研究費助成事業
2024年04月01日 - 2027年03月31日
加瀬 諭, 村田 美幸
日本学術振興会, 基盤研究(C), 北海道大学, 24K12797

加齢黄斑変性におけるセリン/スレオニンキナーゼLRRK2の病態意義解明
科学研究費助成事業
2021年04月01日 - 2025年03月31日
野田 航介, 村田 美幸, 矢部 一郎, 加瀬 諭
加齢黄斑変性(AMD)の病態基盤には網膜色素上皮細胞(RPE)の変性や細胞死が関与している。AMD患者ではパーキンソン病の発症リスクが有意に高いとする報告が近年相次いでおり、パーキンソン病が神経変性疾患であることから、この2つの疾患には共通病態が存在する可能性があると仮説を立てた。本研究の目的は、「AMDにおけるパーキンソン病との共通病態を探索すること」である。
Leucine-rich repeat kinase 2(LRRK2)は、パーキンソン病の重要な病態責任分子の1つである。令和4年度は、ヒト摘出眼球切片を用いた免疫染色を行い、RPEにLRRK2が局在することが確認された。次に、培養RPE細胞株を用いたin vitro実験を行った。RPEに酸化ストレスを負荷すると、LRRK2のmRNAおよび蛋白の増加が認められた。続いて、RPEにおけるLRRK2発現増加が細胞機能に及ぼす影響を解析するため、哺乳細胞用バキュロウイルスBacMamシステムを用いてLRRK2を過剰発現させた。RPEにおけるLRRK2の過剰発現により、細胞生存性の低下とCaspase3/7活性の亢進が生じていた。また、LRRK2を過剰発現したRPEではαシヌクレイン蛋白量の増加とリン酸化の亢進が認められた。αシヌクレインのmRNAは変化しなかったことから、このαシヌクレインの増加は蛋白レベルの変化であると考えられた。更に、in vivo実験においてLRRK2の活性が亢進する遺伝子変異であるLRRK2-G2019Sを導入したトランスジェニックマウスでは野生型と比較し網膜電図の振幅の低下が認められた。これらの結果から、LRRK2の増加がRPE細胞死を引き起こし、in vivoにおいてはLRRK2活性の亢進により網膜機能の障害が生じる可能性が示された。
日本学術振興会, 基盤研究(B), 北海道大学, 23K21479

加齢黄斑変性におけるセリン/スレオニンキナーゼLRRK2の病態意義解明
科学研究費助成事業
2021年04月01日 - 2025年03月31日
野田 航介, 村田 美幸, 矢部 一郎, 加瀬 諭
加齢黄斑変性(AMD)の病態基盤には網膜色素上皮細胞(RPE)の変性や細胞死が関与している。興味深いことに、AMD患者ではパーキンソン病の発症リスクが有意に高いとする報告が近年相次いでおり、パーキンソン病が神経変性疾患であることから、この2つの疾患には共通病態が存在する可能性があると仮説を立てた。本研究の目的は、「AMDにおけるパーキンソン病との共通病態を探索すること」である。
研究開始初年度は、まずヒト摘出眼球切片を用いてRPEにおけるαシヌクレインおよびリン酸化αシヌクレインの局在を免疫組織染色によって検討した。その結果、ヒト眼球組織のRPEにおいてαシヌクレインとリン酸化αシヌクレインの比較的強い染色シグナルが確認された。次に、RPEにおけるαシヌクレインおよびリン酸化αシヌクレインの産生機序を検討するため、in vitro実験系を用いて検討を行なった。血清除去条件下でヒト培養RPE株hTERT RPE-1を24時間培養した後のαシヌクレインおよびリン酸化αシヌクレインの変化をwestern blottingで検討した。その結果、血清除去によってhTERT RPE-1におけるαシヌクレインおよびリン酸化αシヌクレインのタンパク量は増加していた。また同条件下では、パーキンソン病発症に重要な役割を演じているとされるleucine-rich repeat kinase 2 (LRRK2)のmRNA発現およびタンパク量も増加した。
リン酸化αシヌクレインはオリゴマーを形成することで神経細胞の変性を引き起こすとされる。また、αシヌクレインのリン酸化およびその蓄積には前述のLRRK2が関与するとする報告がある。以上のことは、パーキンソン病と同様に、加齢などの要因によるRPEの変性にもリン酸化αシヌクレインが関与している可能性を示している。
日本学術振興会, 基盤研究(B), 北海道大学, 21H03091

糖尿病網膜症病態におけるミュラー細胞のαBークリスタリンの発現
科学研究費助成事業
2021年04月01日 - 2024年03月31日
加瀬 諭, 神田 敦宏
増殖糖尿病網膜症（PDR）における網膜のグリア細胞のαBクリスタリンの発現とその機能解析を行ってきた。糖尿病網膜症の初期病態を反映するSDT fattyラットの網膜組織切片を用いて免疫染色を行った。SDT fattyラットの網膜組織において、ミュラー細胞でのαBクリスタリンとGFAPの共局在を確認した。次に硝子体手術を行ったヒトPDRの増殖組織において免疫組織化学的検討をおこなったところ、増殖組織にグリア細胞マーカーであるGFAP陽性のグリア細胞が存在し、そのグリア細胞におけるαBクリスタリンとGFAPの局在が一致することを確認した。次にヒト培養ミュラー細胞であるMIO-M1を用いて、リアルタイムPCR法、ELISA法、イムノブロット法にて遺伝子およびタンパク発現を解析した。高グルコース条件で培養したミュラー細胞では、αBクリスタリンのタンパク発現は低下した。これまでの研究から、αBクリスタインのセリン59残基のリン酸化はそのシャペロン能やアポトーシス耐性などの機能変化に関与することが知られている。糖尿病網膜症と関連がある炎症性サイトカインのIL-1β、IL-6、TNF-αをMIO-M1に投与したところ、IL-1β投与にてαBクリスタリンのセリン59残基のリン酸化がみられた。
以上の結果より、糖尿病モデルラットのミュラー細胞でαBクリスタリンが発現しており、培養ミュラー細胞ではIL-1β刺激によりαBクリスタリンのセリン59残基のリン酸化を生じた。ミュラー細胞でのαBクリスタリンの発現・リン酸化による、糖尿病網膜症病態への関与が示唆される。
日本学術振興会, 基盤研究(C), 北海道大学, 21K09668

糖尿病の脈絡膜厚調節に対するVEGF-αB-クリスタリン系の関与
科学研究費助成事業
2018年04月01日 - 2021年03月31日
加瀬 諭, 神田 敦宏
培養網膜色素上皮(RPE）細胞を用いて、高血糖負荷を行なったところ、αBークリスタリンの発現は予想に反し、低下した。一方、αA-クリスタリンの発現に変化はなかった。血糖下降薬であるメトフォルミンを投与すると、高血糖負荷によるαBークリスタリンの発現はさらに低下した。加えて、高血糖負荷により、培養RPE細胞におけるαBークリスタリンの上清中の分布を検討したが、有意な分泌上昇はみられなかった。以上より、RPE細胞における高血糖負荷後のαBークリスタリンは、細胞の保護的な機能よりも高血糖による細胞障害を反映する可能性が示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 18K09394

糖尿病網膜症におけるαークリスタリンのリン酸化機序
科学研究費助成事業
2015年04月01日 - 2018年03月31日
加瀬 諭, 神田 敦宏
STZ誘導糖尿病マウスでは、誘導後８週をピークに脈絡膜厚が有意に肥厚することが示唆された。病理組織所見としては、STZ誘導８週では、脈絡膜に間質成分の増加、色素沈着の増加と微小血管の増加もみられた。脈絡膜組織におけるVEGF、αB－クリスタリン濃度は、STZ誘導４－８週にかけて、有意に低下していることが判明した。同様の結果は、網膜組織においてもみられた。今後は糖尿病モデルマウスの進行におけるVEGF、αBークリスタリンの発現低下の意義について検討を行う予定である。
日本学術振興会, 基盤研究(C), 北海道大学, 15K10856

αＢーｃｒｙｓｔａｌｌｉｎによる脈絡膜血管新生の制御機構
科学研究費助成事業
2012年04月01日 - 2014年03月31日
加瀬 諭
ヒトの脈絡膜新生血管膜を採取するのは困難であった。他方、ヒト増殖糖尿病網膜症の硝子体手術の際に、繊維血管増殖組織を採取した。この検体を用いて、代表的な血管新生因子であるVEGFの分子シャペロンαＢークリスタリンの発現、およびそのリン酸化について検討したところ、増殖組織の新生血管にαＢークリスタリンの発現がみられた。併せて、αＢ－クリスタリンとVEGFの共発現も確認された。加えて、αＢ－クリスタリンのセリンリン酸化とVEGFの関連が示唆された。
日本学術振興会, 若手研究(B), 北海道大学, 24791822

白血球接着分子VAP-1の眼窩腫瘍における予後予測因子としての検討
科学研究費助成事業
2010年 - 2012年
野田 実香, 加瀬 諭, 野田 航介
眼科領域における眼付属器腫瘍の中で結膜腫瘍は臨床上よく遭遇する疾患である。その中で、良性腫瘍である化膿性肉芽腫と悪性腫瘍である節外性B細胞性リンパ腫は炎症細胞浸潤をともなっているが、その病態における炎症の関与は明らかとされていない。そこで、本研究では両腫瘍組織における白血球接着分子vascularadhesionprotein(VAP)-1の発現および局在について検討した。VAP-1は、正常結膜では血管内皮細胞の細胞質に存在したが、化膿性肉芽腫と節外性B細胞性リンパ腫の双方では血管の内腔側に局在していた。これらのことは、VAP-1の発現様式は腫瘍によって異なるが、炎症病態に関与していると考えられた。本研究により、眼付属器腫瘍におけるVAP-1の病態関与が示唆され、今後の更なる検討の手がかりを得ることができた。
日本学術振興会, 基盤研究(C), 北海道大学, 22591926

糖尿病網膜症の血管新生におけるalphaB-crystallinの役割
科学研究費助成事業
2010年 - 2011年
加瀬 諭
ヒト糖尿病網膜症の線維血管増殖組織において、熱ショック蛋白であるalphaB-crystallinがCD31陽性を示す微小血管の内皮細胞に発現していたが、正常網膜血管には発現はなかった。AlphaB-crystallin陽性を示す糖尿病網膜症の増殖組織の微小血管では、血管新生因子VEGFとの供発現もみられた。
新生血管に対するαクリスタリンの研究は、直接的なVEGF蛋白質を標的とするのではなく、その蛋白分解を制御している分子を治療標的にすることにより、抗VEGF抗体治療の効果の増強、反復投与の軽減効果が期待される。
日本学術振興会, 研究活動スタート支援, 北海道大学, 22890006

ヒト網膜芽細胞腫の核分裂における細胞周期関連蛋白の発現
科学研究費助成事業
2006年 - 2006年
加瀬 諭
日本学術振興会, 若手研究(B), 北海道大学, 18791252

修士課程, 医学院

博士課程, 医学院