Browsing by Subject "Retinopathy of prematurity"
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Item Choice of Dose Level for a Randomized Clinical Trial of Low-Dose Bevacizumab vs Laser for Type 1 Retinopathy of Prematurity(American Medical Association, 2021) Kraker, Raymond T.; Wallace, David K.; Beck, Roy W.; Saunders, Christina T.; Lorenzi, Elizabeth; Melia, B. Michele; Li, Zhuokai; Ophthalmology, School of MedicineThis study determines which of 8 doses of bevacizumab are effective in treating severe retinopathy of prematurity to carry forward to a large-scale randomized clinical trial.Item Efficacy of supplemental oxygen in reducing the need for laser or intravitreal bevacizumab in preterm infants with stage 2 retinopathy of prematurity(Springer Nature, 2024-05-24) Minturn, Robert; Hartigan, Kelly; Vegunta, Sravanthi; Boente, Charline; Golzarri-Arroyo, Lilian; Hynes, Elizabeth; Laughlin, Elleen; Haider, Kathryn; Kua, Kok Lim; Ophthalmology, School of MedicineBackground: Retinopathy of prematurity (ROP) is a disease that affects preterm infants born younger than 30 weeks of gestation. The pathophysiology of ROP involves an initial vaso-obliterative phase followed by vaso-proliferative phase that leads to disease progression. The use of supplemental oxygen during the vaso-proliferative phase of ROP has been associated with reduced disease progression, but how this impacts the need for ROP treatment is unclear. The goal of this study was to compare the rate of laser or intravitreal bevacizumab after implementation of a new supplemental oxygen therapy protocol in preterm infants with stage 2 ROP. Methods: This is a retrospective chart review of preterm infants diagnosed with stage 2 ROP at Riley Hospital for Children between 1/2017 and 12/2022. Patients diagnosed between 1/2017 and 6/2020 were classified as Cohort A, preprotocol implementation. Patients diagnosed from 8/2020 to 12/2022 were classified as Cohort B, postprotocol implementation. In Cohort A, oxygen saturation was kept at 91-95% through the entire hospitalization. In Cohort B, oxygen saturation was increased to 97-99% as soon as Stage 2 ROP was diagnosed. Statistical analyses were performed using chi-square and Student's T test, followed by multivariate analyses to determine the impact of the oxygen protocol on the need for ROP treatment. Results: A total of 211 patients were diagnosed with stage 2 ROP between 1/2017 and 12/2022. Of those patients, 122 were before protocol implementation therapy (Cohort A), and 89 were after implementation of supplemental oxygen protocol (Cohort B). Gestational age was slightly higher in Cohort B (Cohort A 25.3 ± 1.9, Cohort B 25.8 ± 1.84, p = 0.04). There was no difference in birth weight, NEC, BPD, or survival. Cohort B had lesser need for invasive mechanical ventilation and higher days on CPAP during hospitalization. Notably, Cohort A had 67 (55%) patients treated with laser photocoagulation or intravitreal bevacizumab versus 20 (22%) patients in Cohort B (OR 0.19, 0.08-0.40). Conclusion: The need for laser photocoagulation or intravitreal bevacizumab was significantly decreased in high-risk patients treated with the supplemental oxygen protocol. This result supports the idea that targeted supplemental oxygen therapy to keep saturations between 97 and 99% can reduce disease progression in infants with stage 2 ROP and potentially decrease the burden of additional procedures.Item International Classification of Retinopathy of Prematurity, Third Edition(Elsevier, 2021) Chiang, Michael F.; Quinn, Graham E.; Fielder, Alistair R.; Ostmo, Susan R.; Chan, R. V. Paul; Berrocal, Audina; Binenbaum, Gil; Blair, Michael; Campbell, J. Peter; Capone, Antonio, Jr.; Chen, Yi; Dai, Shuan; Ells, Anna; Fleck, Brian W.; Good, William V.; Hartnett, M. Elizabeth; Holmstrom, Gerd; Kusaka, Shunji; Kychenthal, Andrés; Lepore, Domenico; Lorenz, Birgit; Martinez-Castellanos, Maria Ana; Özdek, Şengül; Ademola-Popoola, Dupe; Reynolds, James D.; Shah, Parag K.; Shapiro, Michael; Stahl, Andreas; Toth, Cynthia; Vinekar, Anand; Visser, Linda; Wallace, David K.; Wu, Wei-Chi; Zhao, Peiquan; Zin, Andrea; Ophthalmology, School of MedicinePurpose: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. Design: Review of evidence-based literature, along with expert consensus opinion. Participants: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. Methods: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. Main outcome measures: Consensus statement. Results: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. Conclusions: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.Item Low- and Very Low-Dose Bevacizumab for Retinopathy of Prematurity: Reactivations, Additional Treatments, and 12-Month Outcomes(Elsevier, 2022) Freedman, Sharon F.; Hercinovic, Amra; Wallace, David K.; Kraker, Raymond T.; Li, Zhuokai; Bhatt, Amit R.; Boente, Charline S.; Crouch, Eric R.; Hubbard, G. Baker; Rogers, David L.; VanderVeen, Deborah; Yang, Michael B.; Cheung, Nathan L.; Cotter, Susan A.; Holmes, Jonathan M.; Pediatric Eye Disease Investigator Group; Ophthalmology, School of MedicinePurpose: Low-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants. Design: Masked, multicenter, dose de-escalation study. Participants: One hundred twenty prematurely born infants with type 1 ROP. Methods: A cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment. Main outcome measures: Reactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age. Results: Sixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants. Conclusions: Retinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.Item Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization(Association for Research in Vision and Ophthalmology, 2018-05-01) Zhang, Hanfang; Hudson, Farlyn Z.; Xu, Zhimin; Tritz, Rebekah; Rojas, Modesto; Patel, Chintan; Haigh, Stephen B.; Bordán, Zsuzsanna; Ingram, David A.; Fulton, David J.; Weintraub, Neal L.; Caldwell, Ruth B.; Stansfield, Brian K.; Medicine, School of MedicinePurpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. Methods: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/-), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. Results: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/- retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/- and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/- retinas. Conclusions: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial.Item Plasma Levels of Bevacizumab and Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity in Infants(American Medical Association, 2022) Hartnett, M. Elizabeth; Wallace, David K.; Dean, Trevano W.; Li, Zhuokai; Boente, Charline S.; Dosunmu, Eniolami O.; Freedman, Sharon F.; Golden, Richard P.; Kong, Lingkun; Prakalapakorn, S. Grace; Repka, Michael X.; Smith, Lois E.; Wang, Haibo; Kraker, Raymond T.; Cotter, Susan A.; Holmes, Jonathan M.; Ophthalmology, School of MedicineImportance: Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. Objective: To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. Design, setting, and participants: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. Interventions: Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. Main outcomes and measures: Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. Results: A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection. Conclusions and relevance: Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.Item Promoting vascular repair in the retina: can stem/progenitor cells help?(Dovepress, 2016-05-26) Phuong Trinh, Thao Le; Calzi, Sergio Li; Shaw, Lynn C.; Yoder, Mervin C.; Grant, Maria B.; Biochemistry and Molecular Biology, School of MedicineSince its first epidemic in the 1940s, retinopathy of prematurity (ROP) has been a challenging illness in neonatology. Higher than physiological oxygen levels impede the development of the immature retinal neuropil and vasculature. Current treatment regimens include cryotherapy, laser photocoagulation, and anti-VEGF agents. Unfortunately, none of these approaches can rescue the normal retinal vasculature, and each has significant safety concerns. The limitations of these approaches have led to new efforts to understand the pathological characteristics in each phase of ROP and to find a safer and more effective therapeutic approach. In the era of stem cell biology and with the need for new treatments for ROP, this review discusses the possible future use of unique populations of proangiogenic cells for therapeutic revascularization of the preterm retina.Item Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants(SpringerNature, 2016-08) Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz III, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.; Department of Pediatrics, IU School of MedicineBACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.