Relationship between Vision-Related Quality of Life and Central 10° of the Binocular Integrated Visual Field in Advanced Glaucoma.

To investigate the relationships between sensitivity loss in various subfields of the central 10° of the binocular integrated visual field (IVF) and vision-related quality of life (VRQoL) in 172 patients with advanced glaucoma. Using the Random Forest algorithm, which controls for inter-correlations among various subfields of the IVF, we analysed the relationships among the Rasch analysis-derived person ability index (RADPAI), age, best-corrected visual acuity (BCVA), mean total deviations (mTDs) of eight quadrant subfields in the IVF measured with the Humphrey Field Analyzer (HFA) 10-2 program (10-2 IVF), and mTDs of the upper/lower hemifields in the IVF measured with the HFA 24-2 program (24-2 IVF). Significant contributors to RADPAIs were as follows: the inner and outer lower-right quadrants of the 10-2 IVF contributed to the dining and total tasks; the lower-left quadrant of the 10-2 IVF contributed to the walking, going out and total tasks; the lower hemifield of the 24-2 IVF contributed to the walking, going out, dining, miscellaneous and total tasks; and BCVA contributed more to the letter, sentence, dressing and miscellaneous tasks than to others. The impact of damage in different 10-2 IVF subfields differed significantly across daily tasks in patients with advanced glaucoma.

Long-term Side Effects Including Blepharitis Leading to Discontinuation of Ripasudil.

PRECIS: Blepharitis was the most common side effect leading to discontinuation of ripasudil therapy. Prior allergic reactions to other topical glaucoma were found to be a risk factor for ripasudil-induced blepharitis. PURPOSE: To report the incidence proportion of blepharitis and its relating factors due to long-term use of 0.4% riapasudil, a Rho-kinase inhibitor, in glaucoma patients of a clinical setting. PATIENTS AND METHODS: One hundred three eyes of 103 consecutive glaucoma patients who started ripasudil treatment between December 2014 and February 2017 at our institute, and who had a follow-up period of over 6 months were enrolled in this study. Incidence proportion, time required for recovery and risk factors associated with blepharitis and other side effects that led to discontinuation of ripasudil treatment were considered. RESULTS: The most frequently observed side effect was blepharitis (25.2%). The 12- and 24-month discontinuation rate due to blepharitis was 21.1%±8.2% and 34.6%±11.8% (average±SE), respectively (Kaplan-Meier analysis). Most patients recovered from blepharitis symptoms within 4 weeks, but 5 patients required over 8 weeks for recovery. Past history of allergic reactions to other topical glaucoma medication was significantly correlated with the manifestation of blepharitis (Cox proportional hazard model, P<0.007) while age, sex, intraocular pressure reduction rate, number of administered eye drops, history of systemic allergic diseases were not. CONCLUSIONS: Blepharitis was the most common reason for discontinuation of ripasudil treatment. Although most cases were resolved spontaneously, prolonged blepharitis was observed in a few patients. A past history of allergic reaction to other glaucoma medication indicates a higher possibility of blepharitis with ripasudil use and warrants careful administration.

Expression of platelet-derived growth factor receptor ß is maintained by Prox1 in lymphatic endothelial cells and is required for tumor lymphangiogenesis.

The lymphatic system plays important roles not only in the physiological processes, such as maintenance of tissue fluid homeostasis, but also in pathological processes including the lymph node metastasis of tumor cells. Therefore, understanding of the molecular mechanisms underlying lymphatic vessel formation is crucial. Previous studies have shown that proliferation and migration of lymphatic endothelial cells (LECs) are activated by multiple types of signals mediated by tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR) 3. Although signals mediated by platelet-derived growth factor receptor ß (PDGFRß) have been implicated in lymphangiogenesis, the mechanisms explaining how PDGFRß expression is maintained in LECs remain to be fully elucidated. In the present study, we show that PDGFRß expression in LECs is maintained by Prox1 transcription factor. Knockdown of Prox1 expression in human dermal LECs decreased the expression of PDGFRß, leading to the lowered migration of human dermal LECs towards PDGF-BB. Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model. Intraperitoneal administration of imatinib, a potent inhibitor of PDGFRß, and transduction of PDGFRß/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice. We also found that the expression of PDGFRß/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model. These findings suggest that PDGFRß is one of the key mediators of lymphatic vessel formation acting downstream of Prox1.

Factors related to future peripheral anterior synechiae formation on ultrasound biomicroscopy: 7-year follow-up in eyes with shallow peripheral anterior chambers.

PURPOSE: To study factors associated with future peripheral anterior synechiae (PAS) formation on ultrasound biomicroscopy (UBM) in eyes with a shallow peripheral anterior chamber. PATIENTS AND METHODS: Fifteen subjects with a shallow peripheral anterior chamber but no PAS in both eyes, in 2001, that had no medical or surgical intervention until 2008 were included in this study. The same examiners performed gonioscopy and UBM at the 3, 6, 9, and 12 o'clock limbal positions under dark and light conditions in 2001 and 2008. A masked examiner performed a quantitative evaluation of the angle configurations in the UBM images. The presence or absence of PAS was determined by compression gonioscopy. The UBM parameters and the number of appositional closures per eye were compared between PAS-positive eyes and PAS-negative eyes. RESULTS: One eye from 15 subjects were randomly selected and included in the analyses. The gonioscopic gradings and UBM parameters did not change significantly (P>0.1) between 2001 and 2008. Seven (47%; 95% confidence interval, 25-70) of 15 eyes developed PAS. In 2001, under dark conditions, the appositional angle closure in 3 to 4 quadrants was found more often (P=0.026) in 7 eyes where PAS developed during the following 7 years than in other 8 eyes. CONCLUSIONS: In eyes with a shallow peripheral anterior chamber but no PAS, PAS developed in 47% of eyes followed without intervention for 7 years. PAS was significantly more likely to develop in eyes with the appositional angle closure found in 3 to 4 quadrants under dark conditions.

Iridotrabecular contact observed using anterior segment three-dimensional OCT in eyes with a shallow peripheral anterior chamber.

PURPOSE: To evaluate the prevalence and range of iridotrabecular contact (ITC) in eyes with a shallow peripheral anterior chamber (AC) by using anterior segment swept-source optical coherence tomography (AS-SS-OCT) and to compare the results with those obtained with ultrasound biomicroscopy (UBM) and gonioscopy. METHODS: Forty-three shallow peripheral AC eyes in 43 consecutive patients underwent gonioscopy. Cross-sectional images throughout the angle circumference (i.e., 360°) were obtained with AS-SS-OCT (SS-1000 noncontact, noninvasive three-dimensional imaging system) and those of the peripheral AC at the 3, 6, 9, and 12 o'clock positions were obtained with UBM (UD-1000). RESULTS: ITC evaluated with AS-SS-OCT included all gonioscopically identified peripheral anterior synechia (PAS) in the area. With AS-SS-OCT, at least one ITC was found in 40 (93.0%) and 42 (97.7%) of the 43 eyes under light and dark conditions, respectively, whereas with UBM, at least one ITC was found in 22 (51.1%) and 36 (83.7%) of the 43 eyes under light and dark conditions. The prevalence of ITC in eyes with AS-SS-OCT was significantly higher than that with UBM under light conditions, but not under dark conditions (P = 0.0001, 0.07, respectively, sign test). The PAS-positive eyes had a significantly greater ITC range than the PAS-negative eyes under light conditions (P = 0.006), but not under dark conditions (P = 0.08). CONCLUSIONS: AS-SS-OCT detected all PAS and the prevalence of ITC detected by AS-SS-OCT in narrow angle eyes was markedly higher than previously thought. A relationship between the ITC range under light conditions and future PAS formation was suggested.

Noninvasive observations of peripheral angle in eyes after penetrating keratoplasty using anterior segment fourier-domain optical coherence tomography.

PURPOSE: To examine iridotrabecular contact (ITC) as a peripheral anterior synechia (PAS) of patients who underwent penetrating keratoplasty (PKP) using anterior segment Fourier-domain optical coherence tomography (OCT). METHODS: Retrospective, observational case series. ITC, ITC index, and ITC area of 60 eyes of 52 patients who underwent PKP at the Department of Ophthalmology in the University of Tokyo Hospital (mean follow-up time 102.8 ± 116.1 months postoperation) were calculated using the angle analysis mode of a commercially available anterior segment Fourier-domain OCT system (CASIA; TOMEY, Nagoya, Japan). We analyzed the occurrence of ITC, ITC index, and ITC area with preoperative diagnosis, lens status, operation method, operation frequency, graft size, and intraocular pressure elevation. RESULTS: ITC was observed in 28 (46.7%) of 60 eyes. Average ITC index was 14.0%, and average ITC area was 5.97 mm. ITC was significantly associated with eyes with bullous keratopathy, infectious keratitis, pseudophakia, PKP with cataract operation, several PKP operations, and large graft size. CONCLUSIONS: Anterior segment Fourier-domain OCT is a useful and innovative tool that enables us to observe the anterior chamber angle and examine ITC as PAS of eyes with corneal opacity, even after PKP.

Identification of Schlemm's canal and its surrounding tissues by anterior segment fourier domain optical coherence tomography.

PURPOSE: To identify Schlemm's canal (SC) and trabecular meshwork (TM) by anterior segment Fourier-domain optical coherence tomography (AS-FD-OCT) with histologic confirmation in enucleated human eyes and to quantitatively evaluate SC and TM in living human eyes. METHODS: In enucleated human eyes, the imaging of the anterior chamber angle by AS-FD-OCT was performed before and after surgical expansion of SC with an injection of a viscoelastic material, followed by histologic examination. In 60 living human eyes, the agreement of identification of SC between examiners was evaluated with the Cohen's κ values, and the lengths of SC and TM and the area of TM were measured on temporal and nasal sections of the AS-FD-OCT images. RESULTS: In enucleated human eyes, SC was observed to be a thin, linear, lucent space in the AS-FD-OCT image obtained with the high-definition raster scan protocol, but not in those obtained with the bi-angle radial scan protocol. This space was enlarged after the SC expansion. In the histologic study, the SC was confirmed to be in the same position as in the AS-FD-OCT images. The κ values of observable SC in living human subjects were 0.92 or higher. The axial length of the SC averaged 347.2 ± 42.3 µm, TM length 466.9 ± 60.7 µm, and TM area 0.0671 ± 0.0058 mm². These measurements showed sufficient repeatability and reproducibility. CONCLUSIONS: Using the high-definition images of the AS-FD-OCT, SC and its surrounding tissues were successfully observed in most of the living eyes and were quantitatively evaluated in a noninvasive manner.

Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis.

During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. Here, we identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, we found that expression of HoxD8 was significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. We also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, we found that HoxD8 induces Prox1 expression in HUVECs and that knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels.

Ultrasound biomicroscopy in narrow peripheral anterior chamber eyes with or without peripheral anterior synechiae.

AIM: To compare the configurations of the anterior ocular segment including the anterior chamber (AC) angle and ciliary body between eyes with a narrow AC angle (ACA) with and without peripheral anterior synechiae (PAS). PATIENTS AND METHODS: One hundred and one eyes of 101 consecutive patients with a temporal peripheral AC depth one-quarter of the corneal thickness or less were included. Gonioscopy and ultrasound biomicroscopy were performed under light and dark conditions. The existence of PAS was further confirmed with compression gonioscopy with indentation. Eyes with findings suggestive of plateau iris configuration or those with glaucomatous optic neuropathy were carefully excluded. The biometric parameters including the ACA, the angle opening distance at 500 mum, the trabecular-ciliary process distance, the iris-zonule distance, and the scleral-ciliary process angle were determined. RESULTS: PAS were found in 43 (43%) of the 101 eyes. There were no differences in age, refractive error, or intraocular pressure between PAS-positive and PAS-negative eyes (P>0.1). ACA, iris-zonule distance, scleral-ciliary process angle under light and/or dark conditions were significantly smaller in the PAS-positive eyes than in the PAS-negative eyes (P<0.05). CONCLUSIONS: Shallow peripheral AC depth and relatively anteriorly located ciliary body was significantly associated with the presence of PAS in eyes with a narrow ACA.

Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades.

During embryonic lymphatic development, a homeobox transcription factor Prox1 plays important roles in sprouting and migration of a subpopulation of blood vessel endothelial cells (BECs) toward VEGF-C-expressing cells. However, effects of Prox1 on endothelial cellular behavior remain to be elucidated. Here, we show that Prox1, via induction of integrin alpha9 expression, inhibits sheet formation and stimulates motility of endothelial cells. Prox1-expressing BECs preferentially migrated toward VEGF-C via up-regulation of the expression of integrin alpha9 and VEGF receptor 3 (VEGFR3). In mouse embryos, expression of VEGFR3 and integrin alpha9 is increased in Prox1-expressing lymphatic endothelial cells (LECs) compared with BECs. Knockdown of Prox1 expression in human LECs led to decrease in the expression of integrin alpha9 and VEGFR3, resulting in the decreased chemotaxes toward VEGF-C. These findings suggest that Prox1 plays important roles in conferring and maintaining the characteristics of LECs by modulating multiple signaling cascades and that integrin alpha9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.

TGF-beta signaling in embryonic stem cell-derived endothelial cells.

The roles of the transforming growth factor (TGF)-beta superfamily in vasculogenesis have been implicated by the findings that mutations in genes encoding for various TGF-beta superfamily signaling components exhibit defects in vascular tissues in humans and mice. Embryonic stem cell (ESC)-derived vascular progenitor cells have been shown to differentiate into both endothelial and mural cells. We showed that members of the TGF-beta superfamily play important roles during differentiation of vascular progenitor cells derived from mouse ESC. TGF-beta inhibited proliferation and sheet formation of ESC-derived endothelial cells. Interestingly, SB-431542, a synthetic molecule that inhibits the kinases of receptors for TGF-beta and activin, facilitated proliferation and sheet formation of ESC-derived endothelial cells. We also found that stimulation of ESC-derived endothelial cells with TGF-beta resulted in phosphorylation of both Smad2 and Smadl/5; BMP induced phosphorylation of Smad1/5. In this chapter, we present how to study the cellular and biochemical effects of TGF-beta signals on endothelial cells derived from mouse ESCs.

Development or existence of non-metastatic lymph nodes in the previously operated neck: a good prognostic sign for oromaxillary squamous cell carcinoma?

The aim of this study is to clarify the clinicopathological features of patients having non-metastatic lymph nodes in the previously operated neck for oromaxillary squamous cell carcinoma (OSCC). The clinicopathological factors of 9 such patients were comparatively analyzed with those of 78 other patients who underwent neck dissection (ND). The following observations were elicited from the data: (1) These 9 patients were alive and without OSCC for periods ranging from 1 year to 15 years and 9 months since their initial cancer treatments. (2) The interval between ND and clinical and/or imaging recognition of newly developed lymph nodes with suspicion of recurrence was significantly longer in these 9 patients. (3) The initially removed lymph nodes tended to be in a less advanced stage of disease. (4) Retrospectively, discrimination of non-metastatic lymph nodes from metastatic nodes was difficult in only one patient. (5) Each of the extirpated lymph nodes from 7 of the 9 patients showed a varying grade of reactive lymphadenitis on histopathology. In conclusion, the occurrence of benign hyperplastic lymph nodes in the previously operated neck region suggested favorable prognosis, though the immunological mechanism is not understood.

Etodolac, a selective cyclo-oxygenase-2 inhibitor, enhances carboplatin-induced apoptosis of human tongue carcinoma cells by down-regulation of FAP-1 expression.

The human tongue well-differentiated squamous carcinoma cell line, SCC-25, shows Fas-dependent apoptosis by treatment with carboplatin (CBDCA). FADD is markedly up-regulated by CBDCA, resulting in the induction of apoptosis. FAP-1, antiapoptotic tyrosine phosphatase, is expressed in the cytosol and blocks the transduction of the "death signal" from Fas to downstream. In this study, we show that etodolac, a selective cyclo-oxygenase-2 inhibitor, enhanced CBDCA-induced apoptosis of SCC-25, although etodolac alone did not induce the apoptosis. In combination with CBDCA, etodolac significantly decreased FAP-1 expression both at protein and mRNA levels, although etodolac by itself did not inhibit FAP-1 expression. These results indicate that etodolac, when combined with CBDCA, can enhance an action of anticancer drug through the suppression of FAP-1 expression.

[An advanced case of squamous cell carcinoma in the left buccal mucosa, upper gingiva, and maxillary sinus (T4N0M0) showing a complete response to chemotherapy with TS-1].

We report a case of advanced squamous cell carcinoma in the left buccal mucosa, upper gingiva, and maxillary sinus (T4N0M0) showing a complete response to oral chemotherapy with TS-1. The patient was an 89-year-old female with severe dementia. We carried out chemotherapy with TS-1 50 mg/day, without surgical treatment. The tumor disappeared clinically at 4 months after 3 courses of the TS-1 administration. Adverse drug reactions, including vomiting, leukopenia and thrombopenia, forced a stop of the administration of TS-1. Although she finally died of in senescence 2 months from the cease of administration, there was no recurrence of the cancer at the time.

TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells.

Recent findings have shown that embryonic vascular progenitor cells are capable of differentiating into mural and endothelial cells. However, the molecular mechanisms that regulate their differentiation, proliferation, and endothelial sheet formation remain to be elucidated. Here, we show that members of the transforming growth factor (TGF)-beta superfamily play important roles during differentiation of vascular progenitor cells derived from mouse embryonic stem cells (ESCs) and from 8.5-days postcoitum embryos. TGF-beta and activin inhibited proliferation and sheet formation of endothelial cells. Interestingly, SB-431542, a synthetic molecule that inhibits the kinases of receptors for TGF-beta and activin, facilitated proliferation and sheet formation of ESC-derived endothelial cells. Moreover, SB-431542 up-regulated the expression of claudin-5, an endothelial specific component of tight junctions. These results suggest that endogenous TGF-beta/activin signals play important roles in regulating vascular growth and permeability.

Carboplatin induces Fas (APO-1/CD95)-dependent apoptosis of human tongue carcinoma cells: sensitization for apoptosis by upregulation of FADD expression.

We examined the apoptosis of tongue carcinoma cells and the effects of anticancer drugs to identify the molecules that mediate apoptotic cascade in the malignancy. Carboplatin (CBDCA) induced apoptosis of SCC-9 and SCC-25, human well-differentiated tongue squamous carcinoma cell lines. Neutralizing anti-Fas (APO-1/CD95) and anti-Fas ligand (FasL) antibodies obliterated the CBDCA-induced cell death. In the absence of CBDCA, cytotoxic anti-Fas antibody, which binds to and activates Fas at the cell surface, failed to induce apoptosis. However, in the presence of CBDCA, the cytotoxic antibody markedly enhanced the apoptosis in a dose-dependent manner. Western blotting and reverse-transcription (RT) PCR revealed that there were no alterations in Fas or FasL expression upon CBDCA treatment. SCC-25 induced apoptosis of Jurkat cells, Fas-sensitive T-lymphatic leukemia cell line, and the apoptosis was inhibited by neutralizing anti-Fas or anti-FasL antibody. These results indicate that the tongue carcinoma cells express nonfunctional Fas and functional FasL, which by themselves fail to induce apoptosis. The expression of FADD in the tongue carcinoma cells was very low and was largely enhanced by CBDCA treatment. Suppression of FADD expression using the specific antisense oligonucleotide resulted in a failure of CBDCA induction of cell death. These results indicate that a deficiency of FADD is involved in the insensitivity of tongue carcinoma cells for Fas activation, and that CBDCA treatment switches nonfunctional Fas to functional Fas by upregulation of FADD expression, resulting in activation of a Fas-sensitive pathway leading to apoptosis.

Clinical characteristics of oral adenosquamous carcinoma: report of a case and an analysis of the reported Japanese cases.

We present a case of adenosquamous carcinoma (ASC) which developed in the floor of the mouth of a 72-year-old Japanese man, and review 19 reported ASC cases in Japan from between 1986 and 2001, including the subject case herein. These ASCs occurred at an average age of 63 years, with 74% of the ASCs occurring in the floor of the mouth (8) and the tongue (6); the other sites of occurrence were the palate (3) and mandibular alveolus (2). Chief complaints were painless mass formation (28%), pain and/or sensational abnormality (28%), painful ulcer or swelling (22%), simple ulcer (11%), and miscellaneous others (11%). The clinical presentations of ASC were tumor with ulceration (58%), tumorous mass (26%), and ulcer (16%). Tumor size at first examination varied from bean-size to approximately 65 x 40 mm. In the pretreatment period, 31.3% were known to have cervical lymph node involvement, and descriptions on distant metastasis were not noted in any of the 19 cases. Some of the ASCs were initially diagnosed as other types of lesions, such as squamous cell carcinoma (SCC; 41%), adenocarcinoma (Ad.C; 12%) mucoepidermoid carcinoma (MEC; 6%), and MEC or SCC (6%). After initial treatments, neck and distant metastases were ascertained in 47.1 and 17.6% of the cases, respectively. Generally, a surgical procedure was performed as one of the most critical methods of treatment. The overall 5-year survival rate was 57.0%, with that of patients who underwent active treatment at 60.6%. Our study demonstrates the extent of the varied nature of ASC.