Porous orbital implant after enucleation in retinoblastoma patients: indications and complications.

This study aims to identify risk factors associated with complications in retinoblastoma patients following primary and secondary enucleations with porous implant placement. A retrospective case-control study was performed between 2010 and 2015. Data pertaining to subjects' demographics, medical history, clinical, and pathological findings, implant characteristics and complications were collected. The analysis included 103 eyes of 101 patients age 27.8 ± 21.9 months undergoing enucleation for retinoblastoma. Postoperatively, 19/103 (18%) eyes developed exposure, extrusion, or hematoma requiring subsequent surgery. Exposure was the most common postoperative complication (12/19, 63%). Age at enucleation 24 months or younger, Hispanic ethnicity, female gender, and intravenous chemotherapy prior to enucleation were associated with increased odds of implant complications. In contrast, patients who were given intravitreal melphalan (IM), subtenons carboplatin (SC), or external beam radiation therapy (EBRT) did not demonstrate an increased risk of complications. In this cohort of retinoblastoma patients undergoing primary or secondary enucleation with porous implants, implant exposure was the most common postoperative complication. Our findings suggest that female gender, Hispanic ethnicity, age at enucleation 24 months or younger, and intravenous chemotherapy prior to enucleation may increase the risk of complications.

Neighborhood Factors and Urinary Metabolites of Nicotine, Phthalates, and Dichlorobenzene.

BACKGROUND AND OBJECTIVES: Exposures to environmental chemicals are ubiquitous in the US. Little is known about how neighborhood factors contribute to exposures. METHODS: Growing Up Healthy is a prospective cohort study of environmental exposures and growth and development among Hispanic and African American children (n = 506) in New York City. We sought to determine associations between neighborhood-level factors (eg, housing type, school, time spent indoors versus outdoors) and urinary biomarkers of chemical exposures suspected to be associated with these characteristics (cotinine, 2,5-dichlorophenol, and phthalate metabolites) adjusted by age, sex, race, and caregiver education and language. RESULTS: Urinary cotinine concentrations revealed a prevalent exposure to secondhand smoke; children living in public housing had higher concentrations than those in private housing. In homes with 1 smoker versus none, we found significant differences in urinary cotinine concentrations by housing, although not in homes with 2 or more smokers. Children in charter or public schools had higher urinary cotinine concentrations than those in private schools. School type was associated with exposures to both low- and high-molecular-weight phthalates, and concentrations of both exposure biomarkers were higher for children attending public versus private school. 2,5-Dichlorophenol concentrations declined from 2004 to 2007 (P = .038) and were higher among charter school children. CONCLUSIONS: Housing and school type are associated with chemical exposures in this minority, inner city population. Understanding the role of neighborhood on environmental exposures can lead to targeted community-level interventions, with the goal of reducing environmental chemical exposures disproportionately seen in urban minority communities.

Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma.

Importance: Retinoblastoma (Rb) is one of the first tumors to have a known genetic etiology. However, because biopsy of this tumor is contraindicated, it has not been possible to define the effects of secondary genetic changes on the disease course. Objective: To investigate whether the aqueous humor (AH) of Rb eyes has sufficient tumor-derived DNA to perform genetic analysis of the tumor, including DNA copy number alterations. Design, Setting, and Participants: This investigation was a case series study at a tertiary care hospital (Children's Hospital Los Angeles) with a large Rb treatment center. Cell-free DNA (cfDNA) was isolated from 6 AH samples from 3 children with Rb, including 2 after primary enucleation and 1 undergoing multiple intravitreous injections of melphalan for vitreous seeding. Samples were taken between December 2014 and September 2015. Main Outcomes and Measures: Measurable levels of nucleic acids in the AH and identification of tumor-derived DNA copy number variation in the AH. The AH was analyzed for DNA, RNA, and micro-RNA using Qubit high-sensitivity kits. Cell-free DNA was isolated from the AH, and sequencing library protocols were optimized. Shallow whole-genome sequencing was performed on an Illumina platform, followed by genome-wide chromosomal copy number variation profiling to assess the presence of tumor DNA fractions in the AH cfDNA of the 3 patients. One child's cfDNA from the AH and tumor DNA were subjected to Sanger sequencing to isolate the RB1 mutation. Results: Six AH samples were obtained from 3 Rb eyes in 3 children (2 male and 1 female; diagnosed at ages 7, 20, and 28 months). A corroborative pattern between the chromosomal copy number variation profiles of the AH cfDNA and tumor-derived DNA from the enucleated samples was identified. In addition, a nonsense RB1 mutation (Lys→STOP) from 1 child was also identified from the AH samples obtained during intravitreous injection of melphalan, which matched the tumor sample postsecondary enucleation. Sanger sequencing of the AH cfDNA and tumor DNA with polymerase chain reaction primers targeting RB1 gene c.1075A demonstrated this same RB1 mutation. Conclusions and Relevance: In this study evaluating nucleic acids in the AH from Rb eyes undergoing salvage therapy with intravitreous injection of melphalan, the results suggest that the AH can serve as a surrogate tumor biopsy when Rb tumor tissue is not available. This novel method will allow for analyses of tumor-derived DNA in Rb eyes undergoing salvage therapy that have not been enucleated.

Risk of metastasis and orbital recurrence in advanced retinoblastoma eyes treated with systemic chemoreduction versus primary enucleation.

BACKGROUND: The purpose of this study was to evaluate the risk of metastatic disease and orbital recurrence in advanced retinoblastoma treated with systemic chemoreduction versus primary enucleation. METHODS: A retrospective review of patients with Group D/E retinoblastoma was conducted with data collection from 1995 to 2015. Overall, 345 eyes (294 patients) were included (165 Group D and 180 Group E). Primary outcome measures were orbital recurrence and metastatic disease. RESULTS: Of the 345 eyes, 139 were treated with systemic chemoreduction (102 Group D, 37 Group E) and 206 with primary enucleation (63 Group D, 143 Group E). In the chemoreduction group, one patient developed metastasis (0.7%) and one an orbital recurrence (0.7%). In the primary enucleation group, two patients developed metastases (0.9%) and one an orbital recurrence (0.5%). After systemic chemoreduction, 58 of the 139 eyes (30 Group D, 28 Group E) were secondarily enucleated for treatment failure (41.7%). The median time to secondary enucleation from diagnosis was 8.1 months. None of the eyes in the systemic chemoreduction group had high-risk pathologic features. In the primary enucleation group, 56 eyes had high-risk pathology. CONCLUSION: Over a 20-year period, 345 eyes were treated for advanced retinoblastoma at Children's Hospital Los Angeles. Incidence of orbital recurrence and metastatic disease was <1% and did not vary by treatment modality or group classification. None of the eyes enucleated for treatment failure had high-risk pathology, and none of these patients developed metastatic disease. Globe salvage therapy with systemic chemoreduction and subsequent enucleation for poor response does not increase the risk of metastatic disease or orbital recurrence.

Treatment Outcomes of Focal Laser Consolidation during Chemoreduction for Group B Retinoblastoma.

PURPOSE: To evaluate the ocular treatment outcomes of focal laser consolidation during systemic chemoreduction for Group B tumors in the posterior fundus. DESIGN: Single-institution retrospective chart review from 1995 to 2016. PARTICIPANTS: Patients with Group B retinoblastoma with at least 1 tumor in the posterior fundus. METHODS: Evaluation of tumor response to chemotherapy and laser consolidation. OUTCOME MEASURES: Change in the tumor size with treatment, and the association of timing of laser consolidation to the horizontal and vertical diameter of the final chorioretinal scar. RESULTS: Forty Group B eyes (22 right eyes and 18 left eyes) were included in the analysis. Mean age at diagnosis was 6.4 months (range 0-24 months). Of the 40 eyes, 35 were treated with both systemic chemotherapy and laser, 4 with chemotherapy only, and 1 eye with laser without chemotherapy. Mean age at initial laser treatment was 7.7 months (standard deviation 5.9 months) and mean number of laser sessions was 6 (standard deviation 5 sessions). The overall globe salvage rate was 95% (38/40 eyes). Mean horizontal and vertical diameters of the tumors in this group showed statistically significant decreases from diagnosis to all subsequent visits (P = 0.0024). The median percent reductions in the horizontal and vertical diameters of the tumors treated with both chemotherapy and laser from diagnosis to the final visit were 13% and 14%, respectively; the overall scar area showed a 13% decrease. For tumors receiving chemotherapy prior to laser therapy, the median reduction in tumor area was 18% from diagnosis to the final examination. Small tumors were found to have a 52% increase in final scar size from diagnosis, whereas larger tumors demonstrated a 37% decrease. CONCLUSIONS: The overall success in treating Group B tumors with chemotherapy and laser was very favorable when considering scar size and globe salvage rates. The size of the chorioretinal scar at the end of treatment was on average 13% smaller than the original tumor size, with greater reductions being noted when chemotherapy preceded laser treatment and when the tumor size at diagnosis was greater than 4.5 mm. A small subset of perifoveal lesions was treated successfully with chemotherapy, alone without laser consolidation.

Perfluoroalkyl and polyfluoroalkyl substances and indicators of immune function in children aged 12-19 y: National Health and Nutrition Examination Survey.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are immunotoxic in laboratory studies. Human studies of immune effects are inconsistent. Using the US National Health and Nutrition Examination Survey (NHANES), we examined PFAS serum concentration and indicators of prevalent immune function among 12-19-y-old children. METHODS: In this cross-sectional study, we examined PFAS serum concentration in relation to measles, mumps, and rubella antibody concentrations in NHANES 1999-2000 and 2003-2004 (n = 1,191) and to allergic conditions and allergic sensitization in NHANES 2005-2006 (n = 640). RESULTS: In adjusted, survey-weighted models, a doubling of perfluorooctane sulfonate (PFOS) concentration among seropositive children was associated with a 13.3% (95% confidence interval (CI): -19.9, -6.2) decrease in rubella antibody concentration and a 5.9% decrease in mumps antibody concentration (95% CI: -9.9, -1.6). We observed no adverse association between exposure and current allergic conditions, including asthma. Children with higher PFOS concentration were less likely to be sensitized to any allergen (odds ratio (OR): 0.74; 95% CI: 0.58, 0.95). CONCLUSION: Increased exposure to several PFAS was associated with lower levels to mumps and rubella antibody concentrations, especially among seropositive individuals. These lower antibody concentrations may indicate a less robust response to vaccination or greater waning of vaccine-derived immunity over time.

Environmental phenols and pubertal development in girls.

Environmental exposures to many phenols are documented worldwide and exposures can be quite high (>1 µM of urine metabolites). Phenols have a range of hormonal activity, but knowledge of effects on child reproductive development is limited, coming mostly from cross-sectional studies. We undertook a prospective study of pubertal development among 1239 girls recruited at three U.S. sites when they were 6-8 years old and were followed annually for 7 years to determine age at first breast or pubic hair development. Ten phenols were measured in urine collected at enrollment (benzophenone-3, enterolactone, bisphenol A, three parabens (methyl-, ethyl-, propyl-), 2,5-dichlorophenol, triclosan, genistein, daidzein). We used multivariable adjusted Cox proportional hazards ratios (HR (95% confidence intervals)) and Kaplan-Meier survival analyses to estimate relative risk of earlier or later age at puberty associated with phenol exposures. For enterolactone and benzophenone-3, girls experienced breast development 5-6 months later, adjusted HR 0.79 (0.64-0.98) and HR 0.80 (0.65-0.98) respectively for the 5th vs 1st quintiles of urinary biomarkers (µg/g-creatinine). Earlier breast development was seen for triclosan and 2,5-dichlorophenol: 4-9 months sooner for 5th vs 1st quintiles of urinary concentrations (HR 1.17 (0.96-1.43) and HR 1.37 (1.09-1.72), respectively). Association of breast development with enterolactone, but not the other three phenols, was mediated by body size. These phenols may be antiadipogens (benzophenone-3 and enterolactone) or thyroid agonists (triclosan and 2,5-dichlorophenol), and their ubiquity and relatively high levels in children would benefit from further investigation to confirm these findings and to establish whether there are certain windows of susceptibility during which exposure can affect pubertal development.

Surpassing the Target: How a Recruitment Campaign Transformed the Participant Accrual Trajectory in the Epilepsy Phenome/Genome Project.

Participant recruitment challenges pervade the majority of publicly funded clinical trials. However, little is known about methods for enhancing participant accrual. The Epilepsy Phenome/Genome Project (EPGP), a multicenter study funded by the National Institute of Neurological Disorders and Stroke (NINDS), aimed to enroll a total of 5,250 participants to better understand the genetic causes and phenotypic manifestations of epilepsy. However, similar to other trials, EPGP encountered recruitment challenges, and by the end of its first year, net enrollment was only 48% of the target for that time. To address this, EPGP established a National Participant Recruitment Campaign and began implementing and tracking the enrollment outcomes of a variety of proven and relatively novel recruitment methods. At the conclusion of the project, EPGP had successfully enrolled a total of 5,445 participants, thus surpassing its enrollment target. Data pertaining to EPGP's National Participant Recruitment Campaign was analyzed retrospectively, and the results are reported here, so that other multicenter trials may consider these methods in their recruitment planning and potentially avoid the costly repercussions of participant accrual issues.

Systems biology of cancer: a challenging expedition for clinical and quantitative biologists.

A systems-biology approach to complex disease (such as cancer) is now complementing traditional experience-based approaches, which have typically been invasive and expensive. The rapid progress in biomedical knowledge is enabling the targeting of disease with therapies that are precise, proactive, preventive, and personalized. In this paper, we summarize and classify models of systems biology and model checking tools, which have been used to great success in computational biology and related fields. We demonstrate how these models and tools have been used to study some of the twelve biochemical pathways implicated in but not unique to pancreatic cancer, and conclude that the resulting mechanistic models will need to be further enhanced by various abstraction techniques to interpret phenomenological models of cancer progression.

Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004-7.

BACKGROUND: Exposures of children to phthalates, parabens, and bisphenol-A (BPA) are of concern because of their hormonal potential. These agents are found in a wide range of foods and packaging. We investigated whether intake of certain foods predict exposures to these chemicals in young girls. METHODS: Among 1101 girls (6-8 years at enrollment) from the Breast Cancer and Environment Research Program (BCERP) study, we measured urinary exposure biomarkers for phthalates, parabens, and BPA and assessed dietary intake using 24-h recall 2-4 times. We examined the average daily servings of major and minor food groups categorized as 0 to <0.5, 0.5 to <1 and ≥ 1 servings per day. Items included dairy, eggs, fats, fish, fruit, single grains, meat, non-poultry meats, pasta, poultry and vegetables. Covariate-adjusted least squares geometric means and 95% confidence intervals of creatinine-corrected phthalate and phenol metabolite concentrations in urine were calculated in relation to food intake. RESULTS: Grains, flour and dry mixes and total fish consumption were positively associated with BPA and the sum of four di-2-ethylhexylphthalate (DEHP) urinary metabolite concentrations. Non-fresh vegetables and poultry were both positively associated with BPA and paraben urinary concentrations. Fats, oils and poultry consumption were positively associated with BPA. Whole-fat dairy consumption was associated with ΣDEHP. CONCLUSIONS: Some foods may contribute to child exposures to certain chemicals, and this may constitute modifiable means to reduce these environmental exposures.

Asthma and physical activity in multiracial girls from three US sites.

OBJECTIVE: Studies comparing physical activity levels in children with and without asthma have had mixed results. Our objective was to investigate the association between asthma diagnosis and physical activity and to examine differences in these associations by race/ethnicity, weight status and caregiver education. METHODS: We investigated the association between asthma (defined as report of physician-diagnosed asthma with at least one asthma related symptom) and measures of physical and sedentary activity in a study of 6- to 8-year-old girls in the Breast Cancer and the Environment Research Project. We compared reported activity and pedometer measurements among girls with and without asthma, and examined modification of these associations by race/ethnicity, weight status and caregiver education. RESULTS: Girls (n = 1182) were included with 33.5% White, 4.8% Asian, 30.6% non Hispanic Black and 30.7% Hispanic. Asthma was present in 16.2% of girls. Overall, 38% of girls reported no participation in organized recreational activities and 58% had >2 h/day of television, video game and computer time combined. Girls with asthma whose parents were less educated reported fewer pedometer steps and less non-scheduled activity than girls without asthma with similar caregiver education level. Among girls with asthma, those on a controller medication had higher levels of sedentary activity and more structured physical activity but were less likely to report high intensity physical activity. CONCLUSIONS: Among girls whose parents are less educated, girls with asthma may have lower physical activity levels than girls without asthma. Use of a controller medication may be related to physical and sedentary activity.

Associations between neighborhood resources and physical activity in inner-city minority children.

OBJECTIVE: The role of neighborhood physical activity resources on childhood physical activity level is increasingly examined in pediatric obesity research. We describe how availability of physical activity resources varies by individual and block characteristics and then examine its associations with physical activity levels of Latino and black children in East Harlem, New York City. METHODS: Physical activity resource availability by individual and block characteristics were assessed in 324 children. Availability was measured against 4 physical activity measures: average weekly hours of outdoor unscheduled physical activity, average weekly metabolic hours of scheduled physical activity, daily hours of sedentary behavior, and daily steps. RESULTS: Physical activity resource availability differed by race/ethnicity, caregiver education, and income. Presence of one or more playgrounds on a child's block was positively associated with outdoor unscheduled physical activity (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.11-3.43). Presence of an after-school program on a child's block was associated with increased hours of scheduled physical activity (OR = 3.25, 95% CI 1.41-7.50) and decreased sedentary behavior (OR = 3.24, 95% CI 1.30-8.07). The more resources a child had available, the greater the level of outdoor unscheduled physical activity (P for linear trend = .026). CONCLUSIONS: Neighborhood physical activity resource availability differs by demographic factors, potentially placing certain groups at risk for low physical activity level. Availability of select physical activity resources was associated with reported physical activity levels of East Harlem children but not with objective measures of physical activity.

A lysine-rich arabinogalactan protein in Arabidopsis is essential for plant growth and development, including cell division and expansion.

Arabinogalactan proteins (AGPs), a family of hydroxyproline-rich glycoproteins, occur throughout the plant kingdom. The lysine-rich classical AGP subfamily in Arabidopsis consists of three members, AtAGP17, 18 and 19. In this study, AtAGP19 was examined in terms of its gene expression pattern and function. AtAGP19 mRNA was abundant in stems, with moderate levels in flowers and roots and low levels in leaves. AtAGP19 promoter-controlled GUS activity was high in the vasculature of leaves, roots, stems and flowers, as well as styles and siliques. A null T-DNA knockout mutant of AtAGP19 was obtained and compared to wild-type (WT) plants. The atagp19 mutant had: (i) smaller, rounder and flatter rosette leaves, (ii) lighter-green leaves containing less chlorophyll, (iii) delayed growth, (iv) shorter hypocotyls and inflorescence stems, and (v) fewer siliques and less seed production. Several abnormalities in cell size, number, shape and packing were also observed in the mutant. Complementation of this pleiotropic mutant with the WT AtAGP19 gene restored the WT phenotypes and confirmed that AtAGP19 functions in various aspects of plant growth and development, including cell division and expansion, leaf development and reproduction.