Use of an Artificial Intelligence-Generated Vascular Severity Score Improved Plus Disease Diagnosis in Retinopathy of Prematurity.

PURPOSE: To evaluate whether providing clinicians with an artificial intelligence (AI)-based vascular severity score (VSS) improves consistency in the diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN: Multireader diagnostic accuracy imaging study. PARTICIPANTS: Eleven ROP experts, 9 of whom had been in practice for 10 years or more. METHODS: RetCam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available examinations, a subset of 150 eye examinations from 110 infants were selected for grading. An AI-based VSS was assigned to each set of images using the i-ROP DL system (Siloam Vision). The clinicians were asked to diagnose plus disease for each examination and to assign an estimated VSS (range, 1-9) at baseline, and then again 1 month later with AI-based VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye examination from the Imaging and Informatics in ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURES: Mean linearly weighted κ value for plus disease diagnosis compared with RSD. Area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPR) for labels 1 through 9 compared with RSD for plus disease. RESULTS: Expert agreement improved significantly, from substantial (κ value, 0.69 [0.59, 0.75]) to near perfect (κ value, 0.81 [0.71, 0.86]), when AI-based VSS was integrated. Additionally, a significant improvement in plus disease discrimination was achieved as measured by mean AUC (from 0.94 [95% confidence interval (CI), 0.92-0.96] to 0.98 [95% CI, 0.96-0.99]; difference, 0.04 [95% CI, 0.01-0.06]) and AUPR (from 0.86 [95% CI, 0.81-0.90] to 0.95 [95% CI, 0.91-0.97]; difference, 0.09 [95% CI, 0.03-0.14]). CONCLUSIONS: Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling as compared with an RSD for plus disease. If implemented in practice, AI-based VSS could reduce interobserver variability and could standardize treatment for infants with ROP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Strabismus management in retinoblastoma survivors.

PURPOSE: To report the result of strabismus surgery in eye-salvaged retinoblastoma (Rb) patients. METHODS: A retrospective case series including 18 patients with Rb and strabismus who underwent strabismus surgery after completing tumor treatment by a single pediatric ophthalmologist. RESULTS: A total of 18 patients (10 females and 8 males) were included with a mean age of 13.3 ± 3.0 (range, 2-39) months at the time tumor presentation and 6.0 ± 1.5 (range, 4-9) years at the time of strabismus surgery. Ten (56%) patients had unilateral and 8(44%) had bilateral involvement and the most common worse eye tumor's group was D (n = 11), C (n = 4), B (n = 2) and E (n = 1). Macula was involved by the tumors in 12 (67%) patients. The tumors were managed by intravenous chemotherapy (n = 8, 47%), intra-arterial chemotherapy (n = 7, 41%) and both (n = 3, 17%). After complete treatment, the average time to strabismus surgery was 29.9 ± 20.5 (range, 12-84) months. Except for one, visual acuity was equal or less than 1.0 logMAR (≤ 20/200) in the affected eye. Seven (39%) patients had exotropia, 11(61%) had esotropia (P = 0.346) and vertical deviation was found in 8 (48%) cases. The angle of deviation was 42.0 ± 10.4 (range, 30-60) prism diopter (PD) for esotropic and 35.7 ± 7.9 (range, 25-50) PD for exotropic patients (P = 0.32) that after surgery significantly decreased to 8.5 ± 5.3 PD in esotropic cases and 5.9 ± 6.7 PD in exotropic cases (P < 0.001). The mean follow-up after surgery was 15.2 ± 2.0 (range, 10-24) months, in which, 3 (17%) patients needed a second surgery. CONCLUSION: Strabismus surgery in treated Rb is safe and results of the surgeries are acceptable and close to the general population. There was not associated with tumor recurrence or metastasis.

Whole-genome sequencing unravels novel genetic determinants and regulatory pathways associated with triamcinolone acetonide-induced ocular hypertension.

Glucocorticosteroids commonly used to treat certain ocular inflammatory conditions cause an unwarranted elevation in intraocular pressure (IOP) leading to steroid-induced ocular hypertension (OHT). This study aims to identify novel genetic variants in the Indian population associated with steroid responsiveness, specifically to that of intravitreal Triamcinolone acetonide (TA) injections, which leads to OHT in 27% of the TA-treated Indian subjects. Genetic determinants and pathways regulating TA-OHT progression were investigated by applying whole-genome sequencing (WGS) on DNA extracted from 53 blood samples that included TA responders and non-responders. Sequencing analysis yielded 45 intronic and 49 exonic variants to be associated with TA-OHT, which are known to play a vital role in eye, heart, brain, and bone deformities. Of these, the most significant genetic variant associated with TA-OHT was further considered for molecular dynamics (MD) simulation studies. Variants in the CRPPA, PLOD1, ARHGAP1, TIMELESS and TNFSF4 genes were found to be directly implicating TA-OHT. Furthermore, these genes were enriched in pathways associated with cardiomyopathy, focal adhesion, extracellular matrix, and actin cytoskeleton reorganization. MD simulation studies revealed that the top significant variant (rs141625803) in the CRPPA gene possesses a high pathogenic and structurally destabilizing effect. Thus, novel genetic variants that could be significantly associated with the TA-OHT progression were identified in this study. Validation of these targets in a larger cohort of patients along with their functional analysis would inform on the disease, thereby adding to the existing knowledge on the pathophysiology of TA-OHT.

Incidence, Risk Factors, Treatment, and Outcome of Ocular Hypertension following Intravitreal Steroid Injections: A Comparative Study.

PURPOSE: To compare the incidence, risk factors, treatment, and outcomes associated with intravitreal triamcinolone-acetonide (TA) and dexamethasone-implant (Dex)-induced ocular hypertension (OHT). METHODS: This retrospective study reviewed 1,549 TA and Dex administrations in 1,075 eyes of 897 patients. Intraocular pressure (IOP) values were monitored for a period of 6 months following intravitreal injection(s) and patients were categorized as steroid-responders (SR): IOP≥21 mm Hg, and steroid non-responders (NR): IOP≤20 mm Hg. Glaucoma patients, glaucoma suspects, uveitis, trauma, and less than 1 month of IOP follow-up cases were excluded from the study. The incidence of IOP rise, time and magnitude of IOP rise, and its management procedures were studied. Ocular and systemic associations with OHT incidence were investigated. Statistical analysis was performed using SPSS.23 and p < 0.05 was considered significant. RESULT: Twenty-eight percent of TA and 17% of Dex administered eyes developed OHT. Male subjects and elderly people (greater than 40 years of age) are at higher risk for OHT following steroid treatment. A high percentage of IOP rise was observed on day 1 (41%) for TA-SR, and after 1 month (50%) for Dex-SR. IOP rise was found to be more severe (>30 mm Hg) for TA-SR compared to Dex-SR (p = 0.006). 6% TA-SR required trabeculectomy with medically uncontrollable IOP. Myopia is a risk factor for secondary OHT, whereas diabetes mellitus and hypercholesterolemia are protective of it. CONCLUSION: Twenty-eight percent of TA and 17% of Dex administrations developed OHT. Early and severe IOP rises were more common in TA than among Dex administrations. Myopia is a risk for Dex-OHT.

Choroidal neovascularization in 111 eyes of children and adolescents.

PURPOSE: To describe the clinical features, management, and outcomes of choroidal neovascularization (CNV) in children less than 18 years of age. METHODS: This was a retrospective, case control study of 111 eyes of 96 patients. CNV was clinically diagnosed in all patients. Eyes were classified as those that were observed (Controls; Group 1) or those that had treatment (Cases; Group 2). CNV was categorized as regressed, persistent, or recurrent in order to evaluate the anatomical outcomes. RESULTS: Of 96 patients, 68(71%) were male. Mean presenting age was 11.4 ± 3.4 years (median = 11 years, range = 1-17 years). CNV was bilateral in 15(16%) patients. Of 111 eyes, 38 eyes had treatment (Cases) and 73 eyes did not (Natural history group or Controls). Subfoveal CNV was seen in majority of cases (59%). Most common etiology was post-inflammatory (38%), followed by trauma (16%). Eyes were classified as those that were observed (controls; Group 1) or those that had treatment (cases; Group 2). In group 1, spontaneous regression of CNV was seen in 26(36%) eyes and there was no recurrence in this group. In group 2 following treatment, 25(66%) of 38 eyes achieved complete regression at mean 4.9 months and was persistent in 5 eyes. CNV recurrence was seen in 10 eyes with the mean time to first recurrence being 9 months. At presentation, mean best-corrected visual acuity (BCVA) of eyes with subfoveal CNV was logMAR 0.99 that improved to logMAR 0.63 with treatment. Mean follow-up was 17 months. CONCLUSION: CNV results in significant visual decline in children; most commonly of post-inflammatory etiology. Treatment achieves high regression rates, albeit with limited visual improvement.

A prospective, interventional study comparing the outcomes of macular hole surgery in eyes randomized to C3F8, C2F6, or SF6 gas tamponade.

PURPOSE: Analysis of outcomes of macular hole (MH) surgery using 12% C3F8, 16% C2F6, or 18% SF6 as randomized gas tamponading agent. METHODS: This is a prospective, randomized, interventional study of 159 eyes with idiopathic MH undergoing 23/25G pars-plana vitrectomy with internal limiting membrane peeling and gas tamponade. Eyes were stratified into two groups: Group I (MH < 800 µ) and group II (MH > 800 µ) according to MH apical diameter. Eyes in group I were randomized to receive either 18% SF6, 16% C2F6, or 12% C3F8. Eyes in group II were randomized to either 16% C2F6 or 12% C3F8. Clinical details, MH parameters on optical coherence tomography, surgical details and complications were analyzed. Outcome measures were type of hole closure (I/II), best corrected visual acuity, intraocular pressure, and cataract progression. RESULTS: In Group I (n = 139), type 1 closure was achieved in 107 (77%) eyes. Type 1 closure rates in group I per gas tamponade were as follows: SF6 (70%), C2F6 (80%), C3F8 (78%) (p = 0.503, chi-square test for independence). There was no statistical difference in MH closure rates between SF6 and C2F6 (p = 0.134), SF6 and C3F8 (p = 0.186), and C2F6 and C3F8 (p = 0.373). In Group II (n = 20), type 1 closure was achieved in 12 (60%) eyes. Type 1 closure rates in group II per gas tamponade were as follows: C2F6 (75%), C3F8 (50%) (p = 0.132, Two proportion Z test). Mean follow-up after surgery was 2.66 ± 2.74 months. CONCLUSION: Given the similar outcomes of using 18% SF6, 16% C2F6, or 12% C3F8 in idiopathic macular hole surgery, the advantage of using a shorter acting tamponade translates into earlier recovery and rehabilitation.

Multimodal imaging characteristics in eyes with vitreoretinal lymphoma treated with intravitreal rituximab.

PURPOSE: To characterize the imaging features in eyes with vitreoretinal lymphoma (VRL) using ultra-widefield fundus photography (UWF-FP), swept-source optical coherence tomography (SSOCT) and fundus autofluorescence (FAF) that are correlated to ongoing treatment with intravitreal Rituximab(IVR). METHODS: Retrospective observational imaging-based study of 15 treatment-naive eyes with VRL treated with IVR. All patients with primary VRL underwent vitreous biopsy using 23/25G microincision vitrectomy system for confirmation of diagnosis. All eyes received monthly IVR (1 mg/0.1 mL) injections till disease remission. Baseline clinical characteristics, treatment details, outcomes, and sequential imaging features on UWF-FP, FAF, and SSOCT were analyzed. OUTCOME MEASURES: Baseline features and changes in UWF-FP, FAF patterns, and SSOCT features in response to treatment RESULTS: Clinically, patients presented with sub-RPE deposits (n = 15), superficial retinal hemorrhages (n = 2), 'giant' RPE (retinal pigment epithelium) holes (n = 2), and anterior segment reaction (n = 1). Eyes were treated with mean 5.7 IVR injections (median: 5; range 1-13) over a mean 7.2 ± 4.9 months. During the course of treatment, two eyes developed superficial retinal hemorrhages with spontaneous resolution, 2 eyes developed CME, and 4 eyes developed characteristic 'leopard skin' pigmentation. Hyper-autofluorescence corresponding to areas of active lesions decreased with each treatment cycle and was finally replaced by hypo-autofluorescence. Serial OCTs showed regression of sub-RPE/subretinal deposits (n = 15), ellipsoid zone disruption (n = 9), and its resolution with treatment (n = 3), epiretinal membrane (ERM; n = 6), choroidal hyperreflective foci (HRF; n = 4), disorganization of retinal inner layers (DRIL; n = 3), RPE-rip (n = 2), cystoid macular edema (CME; n = 2), and hyperreflective lesions in the choroid (n = 1). Complete resolution was observed in all eyes with extensive hypo-AF. The central foveal thickness decreased from 237 ± 113 µ to 182 ± 114 µ (p = 0.1) and subfoveal choroidal thickness decreased from 258 ± 66 µ to 220 ± 64 µ (p = 0.12) at final follow-up. The mean baseline BCVA was logMAR 0.9 ± 0.9 that deteriorated to mean logMAR 1 ± 1 final visit (p = 0.7). The mean recurrence-free follow-up was 5.9 ± 5.1 months CONCLUSION: Multimodal imaging provides novel insights into features of VRL, a better understanding of regression patterns, and prognostication of outcomes when treated with intravitreal rituximab. Larger, multicentric studies with longer follow-up will help unravel imaging biomarkers to understand these aspects better.

Intravitreal rituximab monotherapy for management of eyes with vitreoretinal lymphoma: initial experience from India.

PURPOSE: To evaluate treatment outcomes and complications of intravitreal rituximab (IVR) monotherapy for eyes with vitreoretinal lymphoma (VRL). METHODS: Patients diagnosed with 'isolated primary VRL' or 'VRL with remission of systemic disease' and treated with IVR (1 mg/0.1 ml) between June 2014 and June 2019 were included in this retrospective, interventional case series. Injections were repeated at monthly intervals until complete resolution. All patients signed a written informed consent form. Institutional review board approval was obtained. RESULTS: Twelve eyes of 7 patients with VRL were treated with 77 IVR injections at mean 6.42 injections per eye (median = 5; range = 2-13) for complete resolution at mean 8.16 ± 4.62 months (median = 6.97 months; range = 1.97-14.33 months). Mean age at presentation was 53.3 years (median = 54 years; range = 34-74 years). Patients were co-managed with medical oncologist and periodically evaluated. Complications included anterior uveitis (n = 6), raised intraocular pressure (n = 3), posterior synechiae (n = 2), vitreous haemorrhage (n = 1), pre-retinal haemorrhage (n = 1), retinal detachment (n = 1), posterior subcapsular cataract (n = 2) and sectoral iris atrophy (n = 1). Recurrences were seen in 3 eyes (25%), which eventually achieved complete resolution with treatment. None of the patients had systemic involvement or death during follow-up. Mean follow-up was 18.73 ± 8.83 months (median = 21.60 months; range = 7.37-32.67 months). CONCLUSION: Intravitreal rituximab monotherapy is effective in management of vitreoretinal lymphoma in patients with isolated ocular disease.

Vitreoretinal Complications and Outcomes in 92 Eyes Undergoing Surgery for Modified Osteo-Odonto-Keratoprosthesis: A 10-Year Review.

PURPOSE: To analyze vitreoretinal (VR) complications and treatment outcomes in eyes undergoing modified osteo-odonto-keratoprosthesis (OOKP) surgery. DESIGN: Retrospective case series. PARTICIPANTS: All patients who underwent modified OOKP (mOOKP) surgery at a tertiary eye-care center from March 2003 to February 2013 were included. METHODS: Medical records were reviewed for relevant medical history, best-corrected visual acuity (BCVA), slit-lamp examination, ultrasound scan, oral examination findings, and VR complications. MAIN OUTCOME MEASURES: The BCVA at the last visit. Optimal anatomic outcome was attached retina with a normal intraocular pressure at the last visit. RESULTS: A total of 92 eyes of 90 patients were included. Indications for OOKP included Stevens-Johnson syndrome (n = 53), chemical injury (n = 36), and ocular cicatricial pemphigoid (n = 3). A total of 41 eyes of 39 patients developed VR complications, including vitritis (n = 21), retinal detachment (RD) (n = 12; primary RD = 5), retroprosthetic membrane (RPM) (n = 10; primary RPM = 2), endophthalmitis (n = 8), vitreous hemorrhage (VH) (n = 5; primary VH = 1), serous choroidal detachment (n = 5), hemorrhagic choroidal detachment (n = 2), and leak-related hypotony (n = 1). Mean interval from mOOKP surgery to occurrence of VR complication(s) was 43.8 months (median, 41.9 months; range, 0.2-95.5 months). After treatment of VR complication, visual improvement was seen in 17 eyes (42%) (mean improvement = 1.2 logarithm of the minimum angle of resolution [logMAR]; median, 0.8 logMAR; range, 0.1-2.5 logMAR), visual decline in 7 eyes (14%) (mean decline in BCVA = 0.6 logMAR; median, 0.4 logMAR; range, 0.3-1.8 logMAR), and no change in BCVA in 17 eyes (42%). However, BCVA ≥6/60 was retained in 19 eyes and ≥6/18 was retained in 9 eyes after final VR treatment. CONCLUSIONS: Vitreoretinal complications constitute a significant cause of visual morbidity in eyes undergoing mOOKP surgery and pose a challenging situation to manage. However, appropriate and timely intervention can achieve encouraging results.

Phosphoproteomics of Retinoblastoma: A Pilot Study Identifies Aberrant Kinases.

Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.

Clinical and genetic analysis of Indian patients with NDP-related retinopathies.

PURPOSE: NDP-related retinopathies are a group of X-linked disorders characterized by degenerative and proliferative changes of the neuroretina, occasionally accompanied with varying degrees of mental retardation and sensorineural hearing loss. NDP is the predominant gene associated with NDP-related retinopathies. The purpose of this study was to report the clinical and genetic findings in three unrelated patients diagnosed with NDP-related retinopathies. METHODS: The patients underwent complete ophthalmic examination followed by genetic analyses. NDP gene was screened by direct sequencing approach. Targeted resequencing of several other ocular genes was carried out in patient samples that either indicated NDP gene deletion or tested negative for NDP mutation. Gene quantitation analysis was performed using real-time PCR. RESULTS: The whole NDP gene was deleted in patient I, while a missense NDP mutation, c.205T>C, was identified in patient II, and both had classical Norrie disease ocular phenotype (with no other systemic defects). Patient III who was diagnosed with familial exudative vitreoretinopathy did not show any mutation in the known candidate genes as well as in other ocular genes tested. CONCLUSIONS: The patient with whole NDP gene deletion did not exhibit any apparent extraocular defects (like mental retardation or sensorineural hearing loss) during his first decade of life, and this is considered to be a notable finding. Our study also provides evidence emphasizing the need for genetic testing which could eliminate ambiguities in clinical diagnosis and detect carrier status, thereby aiding the patient and family members during genetic counseling.

Proteomic profiling of retinoblastoma by high resolution mass spectrometry.

BACKGROUND: Retinoblastoma is an ocular neoplastic cancer caused primarily due to the mutation/deletion of RB1 gene. Due to the rarity of the disease very limited information is available on molecular changes in primary retinoblastoma. High throughput analysis of retinoblastoma transcriptome is available however the proteomic landscape of retinoblastoma remains unexplored. In the present study we used high resolution mass spectrometry-based quantitative proteomics to identify proteins associated with pathogenesis of retinoblastoma. METHODS: We used five pooled normal retina and five pooled retinoblastoma tissues to prepare tissue lysates. Equivalent amount of proteins from each group was trypsin digested and labeled with iTRAQ tags. The samples were analyzed on Orbitrap Velos mass spectrometer. We further validated few of the differentially expressed proteins by immunohistochemistry on primary tumors. RESULTS: We identified and quantified a total of 3587 proteins in retinoblastoma when compared with normal adult retina. In total, we identified 899 proteins that were differentially expressed in retinoblastoma with a fold change of ≥2 of which 402 proteins were upregulated and 497 were down regulated. Insulin growth factor 2 mRNA binding protein 1 (IGF2BP1), chromogranin A, fetuin A (ASHG), Rac GTPase-activating protein 1 and midkine that were found to be overexpressed in retinoblastoma were further confirmed by immunohistochemistry by staining 15 independent retinoblastoma tissue sections. We further verified the effect of IGF2BP1 on cell proliferation and migration capability of a retinoblastoma cell line using knockdown studies. CONCLUSIONS: In the present study mass spectrometry-based quantitative proteomic approach was applied to identify proteins differentially expressed in retinoblastoma tumor. This study identified the mitochondrial dysfunction and lipid metabolism pathways as the major pathways to be deregulated in retinoblastoma. Further knockdown studies of IGF2BP1 in retinoblastoma cell lines revealed it as a prospective therapeutic target for retinoblastoma.

VITREORETINAL COMPLICATIONS IN EYES WITH BOSTON KERATOPROSTHESIS TYPE I.

PURPOSE: To describe the spectrum of vitreoretinal complications in eyes with Boston keratoprosthesis type I and evaluate the treatment outcomes. METHODS: This was a retrospective interventional case series of 23 of 45 eyes that underwent Boston keratoprosthesis from April 2003 to December 2013 and developed vitreoretinal complications. Types of vitreoretinal complications, surgical techniques, and anatomical and visual outcomes were analyzed. RESULTS: Vitreoretinal complications in eyes with Boston keratoprosthesis included retroprosthetic membranes (n = 11), retinal detachment (n = 6), endophthalmitis (n = 4), epiretinal membrane (n = 4), vitreous hemorrhage (n = 2), and choroidal detachment (n = 1). Twenty of 23 eyes (87%) underwent surgical intervention. Retinal reattachment was achieved in 5 eyes (83%) with significant visual improvement in 3 (50%). Mean preoperative visual acuity improved from 1.84 ± 0.89 logMAR to 1.5 ± 0.87 logMAR (P = 0.01) at the last follow-up. Mean 1.4 surgical procedures were performed per eye. Mean follow-up was 28 months (median: 28 months, range: 5-57 months). CONCLUSION: Retroprosthetic membrane and retinal detachment are most common vitreoretinal complications in eyes with Boston keratoprosthesis. Vitreoretinal complications can be managed by appropriate intervention in such eyes with encouraging anatomical and functional results.

Global gene deregulations in FASN silenced retinoblastoma cancer cells: molecular and clinico-pathological correlations.

Activation of fatty acid synthase (FASN) enzyme in the de novo lipogenic pathway has been reported in various cancers including retinoblastoma (RB), a pediatric ocular cancer. The present study investigates lipogenesis-dependent survival of RB cancer cells and the associated molecular pathways in FASN silenced RB cells. The siRNA-mediated FASN gene knockdown in RB cancer cells (Y79, WERI RB1) repressed FASN mRNA and protein expressions, and decreased cancer cell viability. Global gene expression microarray analysis was performed in optimized FASN siRNA transfected and untransfected RB cells. Deregulation of various downstream cell signaling pathways such as EGFR (n = 55 genes), TGF-beta (n = 45 genes), cell cycle (n = 41 genes), MAPK (n = 39 genes), lipid metabolism (n = 23 genes), apoptosis (n = 21 genes), GPCR signaling (n = 21 genes), and oxidative phosporylation (n = 18 genes) were observed. The qRT-PCR validation in FASN knockdown RB cells revealed up-regulation of ANXA1, DAPK2, and down-regulation of SKP2, SREBP1c, RXRA, ACACB, FASN, HMGCR, USP2a genes that favored the anti-cancer effect of lipogenic inhibition in RB. The expression of these genes in primary RB tumor tissues were correlated with FASN expression, based on their clinico-pathological features. The differential phosphorylation status of the various PI3K/AKT pathway proteins (by western analysis) indicated that the FASN gene silencing indeed mediated apoptosis in RB cells through the PI3K/AKT pathway. Scratch assay clearly revealed that FASN silencing reduced the invading property of RB cancer cells. Dependence of RB cancer cells on lipid metabolism for survival and progression is implicated. Thus targeting FASN is a promising strategy in RB therapy.

Primary transpupillary thermotherapy for choroidal melanoma in 391 cases: importance of risk factors in tumor control.

PURPOSE: To report the long-term outcome of primary transpupillary thermotherapy (TTT) for choroidal melanoma. DESIGN: Retrospective review of medical records. PARTICIPANTS: We included 391 patients with choroidal melanoma treated between 1995 and 2012 at the Oncology Service, Wills Eye Hospital, Philadelphia. METHODS: We delivered TTT with an infrared diode laser. MAIN OUTCOME MEASURES: Local tumor recurrence, Snellen visual acuity after TTT, and distant metastasis. RESULTS: Of 391 patients, 311 (80%) were treated from 1995 to 2000 and 80 (20%) from 2001 to 2012. Tumors in the 2001 to 2012 group were ultrasonographically thinner (2.2 vs. 2.7 mm), more distant from the optic disc (3.2 vs. 2.5 mm) and foveola (4.0 vs. 2.0 mm), were less often located in the macular area (14% vs. 40%), and had lower rates of acoustic hollowness on B-scan ultrasonography (63% vs. 84%), subretinal fluid (58% vs. 90%), and orange pigment (50% vs. 70%). Kaplan-Meier estimates for tumor recurrence in the 1995 to 2000 group were 29% at 5 years and 42% at 10 years, whereas estimates for tumor recurrence in the 2001-2012 group were 11% at 5 years and 15% at 10 years. Of 108 recurrent tumors 20 were controlled with additional TTT and 62 required plaque radiation (n=60) or proton beam radiation (n=2), with enucleation necessary in 26 patients. Tumor recurrence correlated with the number of high-risk tumor features: 10-year recurrence was 18% in those with 1 or 2 risk factors, 35% in those with 3 to 5 factors, and 55% in those with 6 or 7 factors. On multivariate analysis, features predictive of tumor recurrence were presence of symptoms (P<0.001), shorter distance between the tumor and the optic disc (P=0.026), subretinal fluid (P=0.035), thickness of residual tumor scar (P<0.001), and elevation of residual tumor scar (P<0.001). The only factor predictive of extraocular tumor extension was intraocular tumor recurrence after TTT treated with additional TTT (P=0.007). Presence of orange pigment before TTT (P=0.019), tumor recurrence (P=0.002), and extraocular tumor extension (P=0.017) were predictive of distant metastasis. CONCLUSION: This study shows a direct correlation between a larger number of high-risk tumor features and higher rates of tumor recurrence after primary TTT of (small) choroidal melanoma. We advise that, when possible, small choroidal melanomas with multiple risk factors be treated with methods other than TTT.

Bone augmentation of the osteo-odonto alveolar lamina in MOOKP--will it delay laminar resorption?

PURPOSE: We aimed to describe a new technique and analyse the early outcomes of augmenting the canine tooth using a mandibular bone graft in an attempt to delay or retard the process of laminar resorption following the modified osteo odonto keratoprosthesis (MOOKP) procedure. DESIGN: This was a retrospective case series. PATIENTS AND METHODS: Eyes that underwent the bone augmentation procedure between December 2012 and February 2014 were retrospectively analysed. The procedure, performed by the oromaxillofacial surgeon, involved securing a mandibular bone graft beneath the periosteum on the labial aspect of the canine tooth chosen to be harvested for the MOOKP procedure. This procedure was performed simultaneously with the Stage 1 A of the MOOKP. Three months later, the tooth was harvested and fashioned into the osteo-odonto alveolar lamina similar to the method described in the Rome-Vienna Protocol. RESULTS: The bone augmentation procedure was performed in 11 eyes (five SJS/ six chemical injuries). The mean follow-up after Stage 2 of MOOKP procedure in these eyes was 7.45 months (2 to 20 months). Complications noted were peripheral laminar exposure (three eyes-SJS) and bone graft exposure and necrosis in the mouth (nine-SJS). No evidence of clinical laminar resorption was noted in any of the eyes. CONCLUSION: Laminar resorption in MOOKP can lead to vision and globe threatening complications due to the consequent cylinder instability and chances of extrusion. Augmenting the bone on the labial aspect of the canine tooth might have a role to play in delaying or preventing laminar resorption.

The scope of artificial intelligence in retinopathy of prematurity (ROP) management.

Artificial Intelligence (AI) is a revolutionary technology that has the potential to develop into a widely implemented system that could reduce the dependence on qualified professionals/experts for screening the large at-risk population, especially in the Indian scenario. Deep learning involves learning without being explicitly told what to focus on and utilizes several layers of artificial neural networks (ANNs) to create a robust algorithm that is capable of high-complexity tasks. Convolutional neural networks (CNNs) are a subset of ANNs that are particularly useful for image processing as well as cognitive tasks. Training of these algorithms involves inputting raw human-labeled data, which are then processed through the algorithm's multiple layers and allow CNN to develop their own learning of image features. AI systems must be validated using different population datasets since the performance of the AI system would vary according to the population. Indian datasets have been used in AI-based risk model that could predict whether an infant would develop treatment-requiring retinopathy of prematurity (ROP). AI also served as an epidemiological tool by objectively showing that a higher ROP severity was in Neonatal intensive care units (NICUs) that did not have the resources to monitor and titrate oxygen. There are rising concerns about the medicolegal aspect of AI implementation as well as discussion on the possibilities of catastrophic life-threatening diseases like retinoblastoma and lipemia retinalis being missed by AI. Computer-based systems have the advantage over humans in not being susceptible to biases or fatigue. This is especially relevant in a country like India with an increased rate of ROP and a preexisting strained doctor-to-preterm child ratio. Many AI algorithms can perform in a way comparable to or exceeding human experts, and this opens possibilities for future large-scale prospective studies.

Posterior segment manifestations of Takayasu arteritis: A narrative review.

Ocular symptoms can be the presenting manifestation of Takayasu arteritis (TA) or could be indicative of disease reactivation. A review of published literature related to posterior segment manifestations of TA by using the keywords "Takayasu arteritis," "ophthalmic manifestations," "retina," "retinopathy," "ocular," "optic nerve," and "optic neuropathy" was performed. In total, 62 case reports and 12 case series were included. The majority of the articles were from Asia (n = 47, 64%). Females outnumbered males in the ratio of 7:1. The mean age of patients was 33 years (range: 8-78 years, SD: 13.5 years). In 58% (n = 41 out of 71) cases, ocular symptoms were the presenting manifestation of the underlying disease. Hypotensive retinopathy was found in 70% of eyes, and hypertensive retinopathy was found in 27%. The mean presenting visual acuity (VA) was +1.03 logMAR (range: -0.12 to 3, SD: 1.07), and at the final follow-up was +1.02 logMAR (range: -0.12 to 3, SD 1.17). VA improved in 34% (n = 29/86), remained stable in 45% (39/86), and worsened in 21% (18/86). The mean follow-up was 9 months (range: 0.5-204, SD: 16 months).