Chi-Chun Lai

Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3′-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.

Effects and Complications of Bevacizumab Use in Patients with Retinopathy of Prematurity: A Multicenter Study in Taiwan

PURPOSE To investigate the effects and complications of the anti-vascular endothelial growth factor agent bevacizumab in the treatment of retinopathy of prematurity (ROP) in Taiwanese patients. DESIGN A multicenter, retrospective case series study. PARTICIPANTS Twenty-seven patients (49 eyes) from 4 medical centers across Taiwan. METHODS This study included patients receiving intravitreal injections of bevacizumab (IVB) (0.625 mg) for the treatment of ROP between 2007 and 2009 at 4 major medical centers in Taiwan. The effects and complications associated with this treatment were analyzed. Patients were followed for at least 6 months after bevacizumab injection. MAIN OUTCOME MEASURES Regression of ROP and the complications associated with the injection of bevacizumab. RESULTS Forty-nine eyes of 27 patients (18 male and 9 female) were included in the study. Mean gestational age and birth weight were 26.0 ± 2.4 weeks and 971.6 ± 589.6 g, respectively. There were 41 eyes (23 patients) with stage 3 ROP, 6 eyes (3 patients) with stage 4A ROP, and 2 eyes (1 patient) with stage 5 ROP. All of the eyes received only a single injection of IVB. The mean injection time was 36.8 ± 2.6 weeks postmenstrual age for eyes with stage 3 ROP. A total of 37 of 41 eyes (90%) with stage 3 ROP regressed after bevacizumab injection only. Four eyes (10%) required additional laser treatment to regress the ROP. Of 6 eyes (3 patients) with stage 4A ROP, 2 eyes (1 patient; 33%) regressed after bevacizumab injection and 4 eyes (67%) regressed after bevacizumab injection and subsequent vitrectomy. The 2 eyes with stage 5 ROP exhibited decreased vascular tortuosity after bevacizumab injection, but the retina failed to reattach after vitrectomy surgeries. Major complications included vitreous or pre-retinal hemorrhage in 4 eyes (8%) and transient vascular sheathing in 2 eyes (4%). CONCLUSIONS Bevacizumab injection seems effective and well tolerated in some cases of ROP, especially in stage 3 ROP. Ocular complications could result from the injection of bevacizumab in pediatric eyes.

An Updated Study of the Use of Bevacizumab in the Treatment of Patients with Prethreshold Retinopathy of Prematurity in Taiwan

PURPOSE To investigate the effectiveness and complications associated with the use of bevacizumab, an anti-vascular endothelial growth factor agent, in the treatment of prethreshold retinopathy of prematurity (ROP). DESIGN A multicenter, retrospective case series. METHODS Data from patients who had received intravitreal bevacizumab (IVB) injections for the treatment of ROP were collected from 4 medical centers in Taiwan. The main outcome measures were the regression of ROP and the complications that were associated with the IVB injections. RESULTS In total, 162 eyes from 85 patients were included in the study. After receiving IVB injections, 143 eyes (88%) exhibited ROP regression. Fourteen eyes (9%) required additional laser treatment for ROP regression after the absence of a positive response to the IVB injections. Three eyes (2%) progressed to stage 4 ROP and required vitrectomies to reattach the retinas. Two eyes (1%) received 1 additional IVB injection to decrease persistent plus disease. All of the eyes (100%) had attached retinas after the various treatments that they received. The major ocular complications that were associated with IVB injections included vitreous or preretinal hemorrhage in 2 eyes (1%); cataract in 1 eye (1%); and exotropia in 1 eye (1%). No notable systemic complications related to the IVB injections were observed. CONCLUSIONS IVB injection seems to be an effective and well-tolerated method of treating prethreshold ROP. Laser therapy may still be required as a backup treatment for patients who do not respond to an IVB injection or for those in whom ROP worsens after an IVB injection.

Visual Acuity, Optical Components, and Macular Abnormalities in Patients with a History of Retinopathy of Prematurity

PURPOSE To examine the optical components and spectral-domain optical coherence tomography (OCT) findings in children with a history of retinopathy of prematurity (ROP) and to identify any associations between the OCT findings and the visual acuities of the patients. DESIGN Prospective, case-controlled study. PARTICIPANTS AND CONTROLS Children who were between 6 and 14 years of age were divided into the following 4 groups: Patients with a history of threshold ROP who had been treated using laser therapy or cryotherapy (group 1), patients with regressed ROP who had not received any treatment (group 2), patients who were born prematurely but who had no history of ROP (group 3), and normal full-term children (group 4). The posterior poles of the eyes of all of the patients seemed to be normal. METHODS Visual acuities, optical components, and macular thicknesses were measured in 4 groups of patients, and comparisons between the groups were made. Macular thicknesses were measured using OCT. MAIN OUTCOME MEASURES Visual acuity (VA), optical components, and OCT findings. RESULTS We enrolled 133 patients in the study. Patients in group 1 had significantly thicker foveas than the other patients, as demonstrated by OCT, and this finding was negatively correlated with gestational age. The incidence of abnormal foveal contours among patients in group 1 was significantly higher than among the rest of the patients. Retention of the inner retinal layers was noted in group 1 patients; however, the structure of the outer retina remained intact. Greater degrees of myopic shift and astigmatism, steeper corneal curvatures, shallower anterior chamber depths, and thicker lenses were noted in previously treated ROP patients. These findings corresponded with poor VA and high refractive errors in group 1 patients. CONCLUSIONS Patients with a history of threshold ROP are more likely to show abnormal foveal development and have a poorer visual prognosis than other patient groups despite a fundus with no macular dragging, disc dragging, or retinal detachment. A steeper corneal curvature, shallower anterior chamber, and greater lens thickness are the main changes in the optical components in these patients.

Transplantation of Reprogrammed Embryonic Stem Cells Improves Visual Function in a Mouse Model for Retinitis Pigmentosa

Background. To study whether C57BL/6J-Tyrc−2j/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65rd12/Rpe65rd12 C57BL6 mice. Methods. Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell-derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65rd12/Rpe65rd12 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation. Results. RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65rd12/Rpe65rd12 mice transplanted with RPE-like cells showed significant visual recovery during a 7-month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue. Conclusions. ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials.

Treatment of retinal detachment resulting from posterior staphyloma-associated macular hole in highly myopic eyes.

Purpose: To evaluate the surgical outcome of retinal detachment resulting from a posterior staphyloma–associated macular hole in highly myopic eyes. Methods: Fifty-seven consecutive highly myopic eyes with retinal detachment resulting from a posterior staphyloma–associated macular hole diagnosed between January 1993 and June 2003 were retrospectively studied. Anatomical reattachment of the retina and best-corrected visual acuity were measured. Results: Six different operative methods were used to treat this condition with diverse retinal reattachment rates: long-acting gas tamponade only (12.5%); pars plana vitrectomy (PPV) with long-acting gas tamponade (42.8%); PPV with epiretinal membrane (ERM) peeling and long-acting gas tamponade (50.0%); encircling scleral buckling combined with PPV and long-acting gas tamponade (57.1%); encircling scleral buckling combined with PPV, ERM peeling, and long-acting gas tamponade (40.0%); and encircling scleral buckling combined with PPV and silicone oil tamponade (75.0%). Overall, successful retinal reattachment was achieved in 25 (43.9%) of 57 eyes after the first surgery. However, the ultimate success rate of retinal reattachment was 77.2% (44 of 57 eyes) after subsequent surgery. The mean preoperative visual acuity ± SEM (in logarithm of the minimal angle of resolution units) was 2.08 ± 0.55, and the mean postoperative visual acuity ± SEM was significantly increased to 1.87 ± 0.54 at the last follow-up (P = 0.038). The major cause of recurrent retinal detachment in the long-acting gas tamponade group was nonclosure of the macular hole. For vitrectomized eyes, the major cause was reopening of the macular hole, even with ERM formation and proliferative vitreoretinopathy. There was no obvious correlation between the extent of the detachment or lens status and the reattachment rate. Conclusions: The major causes of recurrent retinal detachment in the long-acting gas tamponade and vitrectomized groups were nonclosure of the macular hole and reopening of the macular hole, respectively. Furthermore, a lesser extent of retinal detachment was not associated with a higher anatomical success rate. More aggressive treatment such as silicone oil tamponade may need to be performed to overcome reduced natural adhesion due to posterior staphyloma with marked chorioretinal atrophy. Failure to initiate aggressive treatment can result in an unsatisfactory outcome and repeated surgery.

Choroidal Thickness and Biometric Markers for the Screening of Lacquer Cracks in Patients with High Myopia

Objectives Validation of choroidal thickness and other biometrics measured by spectral domain optical coherence tomography (SD-OCT) in predicting lacquer cracks formation in highly myopic eyes. Methods Patients with a refractive error worse than −8 diopters and moderate myopic maculopathy were recruited into two groups based on the presence or absence of lacquer cracks (36 eyes without and 33 eyes with lacquer cracks). Choroidal thickness, refractive error, and axial length were measured and subjected to receiver operating characteristic curve analysis to identify the optimal cutoff values at predicting lacquer crack formation. The width of the retinal pigment epithelium (RPE), RPE to the inner segment/outer segment line, RPE to the external limiting membrane were also measured and compared to the subfoveal choroidal thickness to assess their relationships as potential markers of lacquer crack formation. Results Lacquer crack is associated with decreased choroidal thickness, lower best-corrected visual acuity, longer axial length and higher refractive errors. Choroidal thickness has the strongest association with lacquer crack formation versus axial length and refractive error. In eyes with lacquer cracks, stellate lacquer cracks are associated with thinner choroidal thickness compared to eyes with linear lacquer cracks. Subfoveal choroidal thickness less than the width of the retinal pigment epithelium to the inner segment/outer segment line is also associated with lacquer crack formation (sensitivity 78.8%, specificity 88.3%, and accuracy 81.2%). Conclusions This study suggests that choroidal thickness and other SD-OCT measurements could be employed clinically to predict the development and severity of lacquer cracks in patients with high myopia.

Serum Levels of Vascular Endothelial Growth Factor and Related Factors After Intravitreous Bevacizumab Injection for Retinopathy of Prematurity

IMPORTANCE Intravitreous injections of bevacizumab (IVB) have been found to be effective for the treatment of retinopathy of prematurity (ROP). However, serum levels of vascular endothelial growth factor (VEGF) have been found to be suppressed for 2 weeks after IVB in patients with ROP. Changes in serum VEGF levels after IVB in patients with ROP may be important because VEGF also plays a role in the neurodevelopment of newborns. OBJECTIVE To investigate the correlation of levels of VEGF and related growth factors with bevacizumab levels in the systemic circulation after IVB in patients with type 1 ROP. DESIGN, SETTING, AND PARTICIPANTS We studied a prospective case series at an institutional referral center from December 1, 2011, through February 28, 2013. We enrolled patients with type 1 ROP who received IVB. We collected blood samples before and for as long as 8 weeks after IVB. The samples were tested for serum levels of bevacizumab and growth factors, including VEGF, VEGF receptor 1 (VEGFR1), VEGFR2, Tie2, erythropoietin, transforming growth factor β1, insulinlike growth factor type 1, angiopoietin 1, angiopoietin 2, angiopoietinlike 3, and angiopoietin 4. The serum concentrations of these factors were measured using enzyme-linked immunosorbent assays. MAIN OUTCOMES AND MEASURES Serum levels of VEGF, bevacizumab, and the other growth factors before and for as long as 8 weeks after IVB. RESULTS We enrolled 8 patients with type 1 ROP. Bevacizumab levels were elevated 1 day after IVB in the 3 patients for whom measurements were available (mean [SD], 1425 [1010 (95% CI, 0-3934)] ng/mL; P = .13) and remained detectable in the serum as long as 8 weeks after IVB (285 ng/mL for the 1 patient with a measurement available). Serum VEGF levels were suppressed for the same period (mean [SD] level at 1 day after IVB, 379 [226 (95% CI, 190-568)] pg/mL for the 3 patients with measurements available; at 8 weeks, 216 pg/mL for the 1 patient with a measurement available). We found a negative correlation between the serum levels of bevacizumab and VEGF in the patients with ROP who received IVB (r = -0.43 [95% CI, -0.67 to -0.10]; P = .01). No changes were identified in the serum levels of any of the other factors after IVB. Bevacizumab may interfere with the actual level of VEGF in the serum, and the total VEGF level in the serum cannot be determined when bevacizumab is present. Wide CIs were noted in the measurement of these factors, probably owing to the small number of patients enrolled in this study. CONCLUSIONS AND RELEVANCE Serum VEGF levels were suppressed for 2 months after IVB in patients with type 1 ROP owing to the leakage of bevacizumab into the systemic circulation.

Classification of Early Dry-Type Myopic Maculopathy with Macular Choroidal Thickness

PURPOSE To compare the macular choroidal thickness in 2 types of early dry-type myopic maculopathy. DESIGN Prospective, observational, comparative study. METHODS Patients with a refractive error of less than -8 diopters were included and were classified into 2 groups. Group 1 consisted of 24 eyes with a tessellated fundus, and group 2 consisted of 33 eyes with diffuse chorioretinal atrophy, but not to the extent of patchy chorioretinal atrophy. These 2 groups were compared with regard to their clinical characteristics, refractive error, axial length, macular choroidal thickness, and best-corrected visual acuity (BCVA). Linear regression was used to evaluate the explanatory variables in terms of macular choroidal thickness and BCVA. RESULTS Patients in group 1 were significantly younger and had better BCVA, less myopia, shorter axial length, and less staphyloma than those in group 2. Refractive error, axial length, and BCVA correlated significantly with macular choroidal thickness in group 2. However, no such significant correlations were observed in group 1. Multiple linear regression analysis showed that age and macular choroidal thickness were the variables that associated most strongly with BCVA, whereas neither refractive error nor axial length was a significant predictor of BCVA. In group 2, eyes with lacquer cracks showed worse BCVA and thinner macular choroidal thickness than eyes without lacquer cracks. CONCLUSIONS Macular choroidal thickness is an important factor in myopic maculopathy and can be a better indicator of its severity. These findings suggest that BCVA reduction in eyes with dry-type myopic maculopathy can be related to a thinner macular choroidal thickness and to the development of lacquer cracks.

Neurodevelopmental Outcomes in Infants with Retinopathy of Prematurity and Bevacizumab Treatment

Purpose The current study aims to investigate the neurodevelopment of premature infants after intravitreal injections of bevacizumab (IVB) for the treatment of retinopathy of prematurity (ROP) up to the age of 2 years. Methods The study design was retrospective observational case series conducted at an institutional referral center. Infants with type 1 ROP were classified into 3 groups: laser only, IVB only, and a combination of IVB and laser treatment. Main Outcome Measures were neurodevelopmental outcomes of the patients after treatment were assessed by Bayley Scales for Infant Development. Results Sixty-one patients who finished the neurodevelopmental survey were included. No detrimental effects on neurodevelopment were found in IVB group compared with the patients who received laser treatment only. The patients in the IVB + laser group had a higher incidence of significant mental (p = 0.028) and psychomotor (p = 0.002) impairment at 24 months than the patients in the laser group. The odds ratio of having severe psychomotor defects in the IVB + laser group was 5.3 compared with the laser group (p = 0.041). The causal source for the differences that were detected remained unknown due to lack of randomization in the study and accompanying bias in patient selection. Conclusions Two years after laser and/or intravitreal injections of bevacizumab for infants with retinopathy of prematurity, no difference on neurodevelopment for those who received only bevacizumab versus only laser treatment were found. Those infants who required rescue therapy with laser or bevacizumab injection after initial, unsuccessful treatment showed some detrimental, neurodevelopmental effects.