FIVE-YEAR VISUAL OUTCOME OF TREATMENT FOR RETINOPATHY OF PREMATURITY IN INFANTS WEIGHING <500 G AT BIRTH: A Multicenter Cohort Study From J-CREST.

PURPOSE: To investigate the 5-year treatment outcomes of retinopathy of prematurity in infants <500 g birth weight and compare laser and anti-vascular endothelial growth factor therapies. METHODS: A multicenter retrospective study comprised 24 eyes of 13 patients treated for Type 1 retinopathy of prematurity, followed for 5 years. Initial treatment was laser and anti-vascular endothelial growth factor in 13 and 11 eyes, respectively. Data collected included sex, birth characteristics, retinopathy of prematurity characteristics at the time of treatment, best-corrected visual acuity (BCVA), spherical equivalent, and astigmatism at 5 years posttreatment. RESULTS: Median BCVA was 0.15 logarithm of the minimum angle of resolution (interquartile range, 0.0-0.5). Snellen BCVA was ≥20/40 in 73% and ≥20/20 in 27% of eyes. Median spherical equivalent was -2.37 (interquartile range, -6.1 to -0.1); 75% had myopia (≤-0.5 D), and 25% had high myopia (≤-6.0 D). Median astigmatism was 1.25 (interquartile range, 0.9-3.0); 46% had ≥1.5 D. Anti-vascular endothelial growth factor-treated eyes showed less myopia ( P < 0.009), with no BCVA or astigmatism difference ( P = 0.997, P = 0.271) compared with laser-treated eyes. CONCLUSION: One-quarter of the eyes exhibited good visual acuity (Snellen BCVA of ≥20/20) 5 years after retinopathy of prematurity treatment. Refractive errors were common. Anti-vascular endothelial growth factor therapy may be superior to laser therapy in myopic refractive error.

Correlation between Residual Sensitivity in the Central Inferior Nasal Visual Field and Visual Function in Chronic Leber Hereditary Optic Neuropathy Patients.

INTRODUCTION: Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, optic neuropathy. The typical symptoms include reduced visual acuity and central scotoma. Despite the presence of deep central scotoma, some patients with LHON are able to perform daily activities. This study aimed to investigate the correlation between the residual visual field and visual acuity, critical flicker frequency, and fixation ellipse in patients with chronic LHON. METHODS: Residual visual function (defined as sensitivity points where patients sensed the size V stimulus) of both eyes was evaluated in 10 patients with LHON carrying the m.11778 mitochondrial DNA mutation and with median age of onset and disease duration of 29 and 16.5 years, respectively. The central visual field was measured as static perimetry using the Humphrey visual field testing 30-2 program with the size III or V stimulus. Moreover, best-corrected visual acuity, critical flicker frequency, and the correlation between fixation ellipse and residual central visual fields were determined. The analysis was performed through a linear mixed-effects model. RESULTS: The residual visual sensitivity in the inferior nasal visual field was significantly correlated with the logMAR (p < 0.05). The fixation ellipse fell within the residual visual field region with higher sensitivity. CONCLUSIONS: Patients with chronic LHON tended to retain the sensitivity detectable with the size V stimulus at the central inferior nasal visual field regions, where the fixation ellipse fell. Visual acuity, which influences daily activity, was spatially correlated with residual visual sensitivity.

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma.

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

Favorable effect of ripasudil use on surgical outcomes of microhook ab interno trabeculotomy.

PURPOSE: We have previously demonstrated that prolonged use of glaucoma medications was associated with a poor surgical outcome of ab interno trabeculotomy (µTLO). Given that almost all types of glaucoma eye drop either enhance the drainage through the uveoscleral pathway or reduce aqueous humor production, we hypothesized that prolonged use of these medications might cause disuse atrophy of the conventional pathway. In contrast, ripasudil increases the conventional outflow and eventually shows a favorable outcome of µTLO. This study aimed to evaluate the effect of ripasudil use on µTLO outcomes. METHOD: The medical charts of 218 patients who underwent µTLO were analyzed retrospectively. We compared the 1-year outcome between ripasudil users versus nonusers by using propensity score matching. We set the covariates as age, sex, glaucoma types, preoperative intraocular pressure (IOP), the mean deviation values of visual field tests, the presence or absence of concomitant cataract surgery, trabecular meshwork incision range, the presence or absence of any glaucoma medication except ripasudil and duration of glaucoma medical therapy. Success was defined as a postoperative IOP between 5 and 21 mmHg, a ≥ 20% IOP reduction from baseline, and no additional glaucoma surgery at postoperative 1 year. RESULT: Fifty-seven patients each were allocated to the ripasudil users or nonusers. The 1-year success rates were 74% in ripasudil users and 51% in nonusers (p = 0.01). Kaplan‒Meier survival curves also showed that the ripasudil users had a higher survival distribution (p = 0.01). CONCLUSION: The patients who took ripasudil showed a favorable 1-year outcome of µTLO.

Factors influencing postoperative bleeding after dental extraction in older adult patients receiving anticoagulation therapy.

OBJECTIVES: To investigate factors influencing postoperative bleeding occurrence after dental extraction in older patients receiving anticoagulation therapy. MATERIALS AND METHODS: This retrospective study included patients aged ≥ 65 years receiving one of the following anticoagulants: apixaban, edoxaban, rivaroxaban, and warfarin. Patients who underwent one to multiple tooth extractions in the geriatric dentistry clinic at Tokyo Medical and Dental University Hospital between August 1, 2016, and November 30, 2020, were included. The outcome variable was postoperative bleeding occurrence. Logistic regression analysis was performed with the following ten factors as explanatory variables: age, sex, maximum systolic blood pressure during the extraction, type of local anesthesia, vertical incision, osteotomy, usage of surgical splints, the mesiodistal width of the extracted tooth on a radiograph, use of antiplatelet agents, and history of diabetes requiring medication. RESULTS: Among 395 participants (mean age, 82.3 ± 6.5 years) included in this study, 75 patients experienced postoperative bleeding after tooth extraction. Logistic regression analysis revealed that the odds ratios for the vertical incision (18.400, p < 0.001), osteotomy (3.630, p = 0.00558), usage of surgical splints (1.860, p = 0.0395), and the mesiodistal width of the extracted tooth on a radiograph (1.060, p = 0.0261) were statistically significant. CONCLUSIONS: For dental extraction in older patients receiving anticoagulants, postoperative bleeding is more likely to occur in patients with vertical incision, osteotomy, and posterior or multiple tooth extractions. CLINICAL RELEVANCE: Dentists should consider suturing and adjunctive hemostatic procedures for patients undergoing vertical incision, osteotomy, and multiple tooth extractions while receiving anticoagulation therapy to minimize the risk of postoperative bleeding.

Risk of surgical failure and hemorrhagic complications associated with antithrombotic medication in glaucoma surgery.

PURPOSE: The purpose of this retrospective study was to determine the extent to which the use of antithrombotic drugs during glaucoma surgery contributes to surgical failure and postsurgical hemorrhagic complications. METHODS: Glaucoma surgeries were categorized into three groups: trabeculotomy (TLO), trabeculectomy (TLE), and long-Tube shunt surgery (Tube). At 1 year after surgery, the following criteria for surgical success were met: intraocular pressure (IOP) in the 5-21-mmHg range, IOP reduction of at least 20% from the preoperative level, and no additional glaucoma surgeries. We compared the percentages of the success rates and hemorrhagic complications between antithrombotic medication experiencers and non-experiencers. Furthermore, we adjusted the preoperative factors between the two groups using a propensity score analysis in TLO and TLE surgeries. RESULTS: A total of 910 glaucoma surgeries were included, with TLO, TLE, and Tube accounting for 353, 444, and 113 surgeries, respectively. Preoperative antithrombotic medications were administered to 149 patients in all glaucoma surgeries: 37 patients used only anticoagulants, 102 used only antiplatelets, and 10 used both. There was no significant difference in the success rates of any of the procedures. The hemorrhagic complications (hyphema and vitreous hemorrhage rate) were significantly higher in the patients who underwent TLE and Tube. The surgical success rates of TLO and TLE were not significantly different after the two groups were matched by propensity score. CONCLUSION: The perioperative use of antithrombotic drugs did not affect success for any of the procedures. However, it increased early postoperative hemorrhagic complications for TLE and Tube.

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC.

The beneficial impact of filtration surgery on antiviral therapy cessation in patients with cytomegalovirus-related secondary glaucoma.

PURPOSE: Cytomegalovirus (CMV)-related keratouveitis elevates intraocular pressure (IOP). Antiviral therapy does not always control IOP and some patients do not tolerate systemic antiviral therapy because of the side effects. The purpose of this study is to evaluate the clinical characteristics of patients with CMV-related keratouveitis and determine the impact of glaucoma surgeries on the postoperative antiviral therapy regimen. METHODS: We enrolled twenty-two patients with CMV-DNA-positive keratouveitis between June 2012 and July 2019 in Kobe University Hospital. The following clinical parameters were collected: gender, age, history of previous intraocular surgery, antiviral medications, visual acuity, IOP, glaucoma drug score, corneal endothelial cells density, and the mean deviation of a Humphrey visual field test at the first visit and before and 1 year after glaucoma surgery. RESULTS: All twenty-two patients started on oral and/or topical antiviral therapy. Eighteen patients needed glaucoma surgery despite their antiviral medications. Nine patients underwent trabeculotomy (TLO) and nine underwent trabeculectomy (TLE) as the first surgical intervention. Six of patients who initially underwent TLO and two of the patients who initially underwent TLE required additional TLE within 1 year. Each of the 15 patients who underwent at least 1 TLE showed a reduction in the magnitude and variation of IOP and glaucoma drug scores and 13 patients were able to discontinue antiviral therapy. For the remaining 4 patients, IOP and inflammation were controlled but with antiviral medications. CONCLUSIONS: In patients with CMV-related keratouveitis, TLE decreases and stabilizes IOP and contributes to withdrawal from antiviral medications.

Postoperative bleeding after dental extraction among elderly patients under anticoagulant therapy.

OBJECTIVES: This study aimed to assess and compare postoperative bleeding occurrence after dental extraction in medically compromised elderly patients under anticoagulant therapy. MATERIALS AND METHODS: This retrospective study included medically compromised elderly patients aged ≥ 65 years who were taking apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin and had undergone single or multiple dental extractions. The primary outcome measure was postoperative bleeding occurrence, which was defined as oozing or marked hemorrhage from 24 h to 7 days after dental extraction. Postoperative bleeding occurrence was calculated for each anticoagulant and compared using Fisher's exact test, followed by multiple comparisons. RESULTS: Two hundred thirty-two patients met the inclusion criteria. The highest postoperative bleeding occurrence was recorded for rivaroxaban (12/37: 32.4%), followed by apixaban (8/44: 18.2%), warfarin (17/98: 17.3%), and edoxaban (2/35: 5.7%). Patients taking dabigatran did not present postoperative bleeding (0/18: 0%). Fisher's exact test, followed by multiple comparison tests, revealed a significant among-anticoagulant difference (p = 0.0095). Postoperative bleeding was significantly higher in patients taking rivaroxaban than in those taking edoxaban or dabigatran (p = 0.03088). CONCLUSIONS: Within the limitations of this retrospective study design, these findings suggest that different anticoagulants may affect postoperative bleeding occurrence after dental extraction among medically compromised elderly patients. CLINICAL RELEVANCE: Clinicians should carefully consider postoperative bleeding after dental extraction in patients taking anticoagulant therapy, especially rivaroxaban.

Comparison of cardiovascular response between patients on warfarin and hypertensive patients not on warfarin during dental extraction.

OBJECTIVE: To evaluate cardiovascular response in patients on warfarin and hypertensive patients not on warfarin during dental extraction. MATERIALS AND METHODS: This retrospective study included 53 patients who had undergone dental extraction while on warfarin (mean age 78.8 ± 6.3 years, 26 men) and 66 with hypertension who had undergone dental extraction but were not on warfarin (mean age 77.4 ± 6.8 years, 22 men). Vital signs were monitored in both groups during extraction. RESULTS: The highest systolic blood pressure (SBP) values (mean 150.1 ± 21.1 mmHg) were observed in patients on warfarin before (9.0%) and after (10.3%) administration of local anesthesia (LA), during extraction (39.7%), and during (33.3%) and after (7.7%) suturing (n = 78; p < 0.01), and in hypertensive patients not receiving warfarin (160.6 ± 24.8 mmHg) before (19.2%) and after (27.3%) administration of LA, during extraction (29.3%), and during (18.2%) and after (6.1%) suturing (n = 99; p < 0.01). The highest SBP was linearly correlated with SBP before administration of LA in patients on warfarin (highest SBP = 0.9415 × SBP before LA + 23.243, R2 = 0.75481) and in hypertensive patients not on warfarin (highest SBP = 1.0027 × SBP before LA + 15.789, R2 = 0.60341). CONCLUSIONS: The highest SBP was not distributed evenly between patients on warfarin and hypertensive patients not on warfarin during dental extraction and was strongly associated with SBP before LA regardless of anticoagulant status. CLINICAL RELEVANCE: Thorough management of SBP is required in patients on warfarin to avoid thromboembolism and major hemorrhagic complications. Knowing the SBP value before dental treatment would help predict the risk of cardiovascular complications.

Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: A multiinstitutional retrospective study.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC.

Clinicopathological significance of EGFR pathway gene mutations and CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma.

AIMS: Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland carcinomas. Epidermal growth factor receptor (EGFR) signalling pathway gene mutations are important in predicting a patient's prognosis, selecting molecularly targeted drugs and estimating the efficacy of a molecular therapy. However, their significance in MEC have been poorly clarified. CRTC1/3-MAML2 fusions are specific to MEC and may be associated with favourable characteristics in these patients. METHODS AND RESULTS: We looked for CRTC1/3-MAML2 fusions and gene alterations in the EGFR, RAS family (KRAS, HRAS and NRAS), PIK3CA, BRAF and AKT1 in 101 MEC cases. We also examined mutations in TP53. CRTC1/3-MAML2 fusions were found in 62.4% of the cases. KRAS, HRAS and PIK3CA mutations were detected in 6.9%, 2.0% and 6.9%, respectively, but other EGFR pathway genes were not mutated. In total, gene mutations (RAS/PIK3CA) in the EGFR pathway were detected in 14.9% of the cases. TP53 mutations were found in 20.8%. CRTC1/3-MAML2 fusions were associated with a better prognosis and RAS/PIK3CA mutations a worse prognosis of the patients, respectively, and both were selected as independent prognostic factors for the overall survival of the patients. TP53 mutations had no prognostic impact. CRTC1/3-MAML2 fusion-positive rates were inversely associated with the patients' age and the fusions were found in 82% of patients aged < 30 years. CONCLUSIONS: RAS/PIK3CA mutations were frequently detected, and may be a biomarker for a poorer prognosis in MEC patients. CTRC1/3-MAML2 fusions were positive in most of the young MEC patients.

Next-generation sequencing assay in salivary gland cytology: A pilot study.

BACKGROUND: Preoperative diagnosis of salivary gland tumors (SGTs) by fine-needle aspiration (FNA) cytology is challenging. Next-generation sequencing (NGS)-based assays for somatic mutations have a great advantage in that a large number of genes can be analyzed simultaneously. Although NGS may have an enormous diagnostic potential in cytology, to our knowledge, the significance of NGS in SGT cytology remains to be clarified. METHODS: In this pilot study, we retrospectively examined 32 frozen SGT samples obtained at surgery (14 malignant and 18 benign). After the stored frozen tumor tissues were thawed, aspirate samples were obtained using 22-gauge needles and subjected to smear tumor samples and to DNA extraction for an NGS assay employing the Illumina AmpliSeq Cancer Hotspot Panel v2. The results were correlated to preoperative cytological diagnosis. RESULTS: The preoperative diagnoses obtained by FNA cytology included 23 negative lesions (no malignancy in 6 and benign tumor in 17) and nine positive lesions (suspicious for malignancy in 4 and malignancy in five), providing a sensitivity and a specificity of 9/14 (64%) and 18/18 (100%), respectively. The NGS assay detected somatic mutations in 10/14 malignant and 1/18 benign SGT cases, providing a sensitivity and a specificity of 71% and 94%, respectively. CONCLUSION: The NGS assay may be helpful for detecting the malignant potential in SGT cases and can be used as an ancillary test for SGT cytology.

The impact of clinicopathological factors on clinical outcomes in patients with salivary gland adenoid cystic carcinoma: a multi-institutional analysis in Japan.

BACKGROUND: Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified. METHODS: In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy. CONCLUSIONS: A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

Increase in pulse pressure on administration of a dental local anesthetic solution, prilocaine hydrochloride with felypressin in male diabetic patients with coronary heart disease.

OBJECTIVES: This study aimed to evaluate pulse pressure fluctuation on dental local anesthetic administration in diabetic patients with and without coronary heart disease undergoing tooth extraction. MATERIALS AND METHODS: This retrospective study in diabetic patients undergoing tooth extraction included 33 patients with coronary heart disease (mean age 79.3 ± 7.4, 64% male) and 49 patients without coronary heart disease (mean age 78.6 ± 6.5, 29% male). The increase in pulse pressure before and after administration of local anesthetics was compared between diabetic patients with and without coronary heart disease. RESULTS: Pulse pressure was increased in male diabetic patients with coronary heart disease compared with those without coronary heart disease following administration of 3% prilocaine hydrochloride with felypressin 0.03 IU/mL (prilocaine) (15.6 ± 15.4 mmHg in those with coronary heart disease (n = 11) versus 4.3 ± 10.9 mmHg in those without coronary heart disease (n = 13), p = 0.03). CONCLUSIONS: Prilocaine administration increased pulse pressure in male diabetic patients with coronary heart disease compared with those without coronary heart disease. Further study is needed to reveal the mechanisms involved in the increase in pulse pressure. CLINICAL RELEVANCE: This is the first study of pulse pressure fluctuation in diabetic patients with and without coronary heart disease following administration of local anesthetics. Our findings can help guide the choice of local anesthetics and serve as a predictor of coronary vascular condition in diabetic patients during dental treatment.

Generation of three-dimensional retinal organoids expressing rhodopsin and S- and M-cone opsins from mouse stem cells.

PURPOSE: Three-dimensional retinal organoids can be differentiated from embryonic stem cells/induced pluripotent stem cells (ES/iPS cells) under defined medium conditions. We modified the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) culture procedure to obtain retinal organoids expressing more rod photoreceptors and S- and M-cone opsins. METHODS: Retinal organoids differentiated from mouse Nrl-eGFP iPS cells were cultured in various mediums during photoreceptor development. To promote rod photoreceptor development, organoids were maintained in media containing 9-cis retinoic acids (9cRA). To obtain retinal organoids with M-opsin expression, we cultured in medium with 1% fetal bovine serum (FBS) supplemented with T3, BMP4, and DAPT. Section immunohistochemistry was performed to visualize the expression of photoreceptor markers. RESULTS: In three-dimensional (3D) retinas exposed to 9cRA, rhodopsin was expressed earlier and S-cone opsins were suppressed. We could maintain 3D retinas up to DD 35 in culture media with 1% FBS. The 3D retinas expressed rhodopsin, S- and M-opsins, but most cone photoreceptors expressed either S- or M-opsins. CONCLUSION: By modifying culture conditions in the SFEBq protocol, we obtained rod-dominated 3D retinas and S- and M-opsin expressing 3D retinas.

Effectiveness and safety of sulcus fixation of Baerveldt glaucoma implants in glaucomatous eyes in patients who underwent multiple intraocular surgeries.

PURPOSE: The purpose of this study was to evaluate the surgical success of sulcus fixation of Baerveldt glaucoma implant (BGIs) in special reference to corneal damage. METHODS: This observational prospective cohort study included 24 patients who underwent a median of 3.0 previous intraocular surgeries and sulcus fixation of BGIs for the first time. The intraocular pressure (IOP), the number of ocular hypotensives used, corneal endothelial cell density (ECD), and logMAR-converted best-corrected visual acuity (VA) of each patient were measured preoperatively and postoperatively until 12 months after surgery. Surgical success was evaluated after 12 months based on the reduction of IOP (5-21 mmHg and > 20% reduction), corneal damage (postoperative development of decompensation, unmeasurable ECD, or ECD reduction of > 20%), loss of light perception, and need for additional surgeries. RESULTS: Surgical success was noted in 16 (66.7%) patients when corneal damage was included as a failure criterion, whereas surgery was successful in 21 (87.5%) patients when solely judged using IOP control similarly as previous clinical trials. The median IOP decreased from 27.5 mmHg preoperatively to 14.5 mmHg postoperatively (P < 0.0001). The number of ocular hypotensives was significantly reduced postoperatively (P < 0.0001). The median postoperative ECD reduction was only 0.15%, although ECD could not be measured during follow-up or it was significantly reduced by > 20% in six patients. VA was not significantly reduced after surgery. Adverse effects were observed in 15 patients (62.5 cumulative %). CONCLUSION: Sulcus fixation of BGIs may be effective and safe in patients with glaucomatous eyes who underwent multiple prior intraocular surgeries.

Nationwide epidemiological survey of Leber hereditary optic neuropathy in Japan.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy that leads to central loss of vision, predominantly in young males. Most LHON cases have one of three primary point mutations in mitochondrial DNA (mtDNA). The annual incidence and prevalence of LHON in Japan are not known. Thus, we estimated the annual incidence of molecularly confirmed LHON in Japan during 2014. METHODS: Sequential questionnaires were sent to 1397 facilities, which included all of the university hospitals in Japan, and they were certified by either the Japanese Ophthalmological Society or the Japanese Neuro-Ophthalmological Society. We calculated the incidence number (Ir) as the number of patients who developed LHON in 2014 and its 95% confidence interval. RESULTS: We received 861 responses to the first questionnaire, where 49 facilities reported 72 cases (67 were male and 5 were female) of newly developed LHON during 2014. Ir was calculated as 117, and the 95% confidence interval ranged from 81 to 153. For the second questionnaire, responses were received from 30 facilities, where the median age at onset was 38 years for males and 30 years for females, and 86.5% of cases possessed the mtDNA ND4/G11778A mutation. CONCLUSION: Approximately 120 cases of newly developed LHON were reported during 2014 in Japan, and 93.2% were males.

Home Monitoring of Intraocular Pressure and it's Diurnal Patterns Using Icare® HOME.

Purpose: To evaluate Icare® HOME for home monitoring of intraocular pressure (IOP) and to observe diurnal IOP patterns for a short term. Patients and methods: Twenty six eyes of 16 patients with open angle glaucoma were included. After instruction and practice in using Icare® HOME, patients were asked to measure their IOP by themselves at home or in a sick room. Patients measured their IOP four times a day with a four hour interval between each measurement for three days. Patients repeated measurements until three successful measurements were obtained at each time. Intra-rater reliability was assessed calculating intraclass correlation coefficient (ICC) of the three measurements. Diurnal IOP patterns were assessed for three days. Results: No adverse events occurred. ICC of three measurements was 0.76 (95% confidence coefficient; 0.71 to 0.81). The median of the difference between the highest and the lowest IOP during a day was 4.26 mmHg (95% CI; 4.06 to 4.67). Repeatable patterns were not found in diurnal IOP for three days. Three out of ten patients who answered the questionnaire after measurements found difficulties in handling the device. Conclusions: Although Icare® HOME is safe and could be used for home monitoring of IOP, some patients had difficulties in using the instrument. Diurnal IOP patterns did not show repeatability during a short term.

Trabeculotomy with Schlemm's Canal Endothelium Removal and Deep Sclerectomy.

Purpose: To evaluate the effects of trabeculotomy (TLO) combined with Schlemm's canal endothelium removal (SER) and deep sclerectomy (DS). Method: This retrospective study involved 131 adults eyes, diagnosed with glaucoma that were enrolled with at least 1 year follow-up after TLO. Fifty three eyes received TLO+SER+DS and 78 eyes underwent TLO+DS without SER. SER was performed as peeling of Schlemm's canal endothelium opening under the scleral flap. Surgical success was defined by the need for additional glaucoma surgery, or intraocular pressure (IOP) ≤20 mmHg (criterion A) and ≤16 mmHg (criterion B). Results: The occurrence rate of transient ocular hypertension (≥30 mmHg) was significantly less (p<0.001) in SER (3.8%) compared with Non-SER (21.8%). SER decreased IOP at 3 years without significant efficacy in terms of lowered IOP compared with Non-SER. At 3 years, Kaplan-Meier survival analysis revealed that the success rate of SER was higher than Non-SER for criterion A (p=0.008), but comparable for criterion B (p=0.06). Conclusions: SER was effective for reducing the rate of transient ocular hypertension in TLO and controlling IOP≤20 mmHg in adult eyes.