The Childrens Hospital at Montefiore

Borough of Bronx, NY, United States

The Childrens Hospital at Montefiore

Borough of Bronx, NY, United States
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Maxwell R.R.,The Childrens Hospital At Montefiore | Cole P.D.,The Childrens Hospital At Montefiore | Cole P.D.,Yeshiva University
Current Hematologic Malignancy Reports | Year: 2017

Purpose of Review: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Recent Findings: Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. Summary: We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs. © 2017 Springer Science+Business Media New York


Villegas S.C.,Long Island University | Villegas S.C.,The Childrens Hospital at Montefiore | Breitzka R.L.,Children's Medical Center Dallas
Clinical Therapeutics | Year: 2012

Background: Head lice infestations are responsible for social and economic distress. Despite a reported increase in resistance, permethrin 1% is still the first-line treatment of head lice. Alternative topical pediculicidal agents include malathion and benzyl alcohol, but resistance is of growing concern. In 2011, a new pediculicide, spinosad, was introduced. Objective: Our aim was to review the clinical pharmacology, efficacy, tolerability, and current place in therapy of spinosad for the treatment of head lice. Methods: Pertinent articles and abstracts were identified through searches of MEDLINE/Ebsco and MEDLINE/Ovid from 1948 to September 2011 and International Pharmaceutical Abstracts from 1966 to September 2011. Results: Two reports described 3 trials of spinosad used for the treatment of head lice. One study (n = 120) demonstrated efficacy of both spinosad 0.5% and spinosad 1% compared with placebo, with 82.5% and 86.1% of patients free of live lice 14 days after treatment, respectively, compared with 25.6% in the placebo group (. P < 0.001 for each treatment). The difference between the spinosad 0.5% and 1% treatment groups was not significant. Two trials (n = 1038) comparing spinosad 0.9% with permethrin 1% reported greater efficacy for spinosad with absence of live lice 14 days after 1 or 2 treatments for 84.6% and 86.7%, respectively, of primary cases compared with 44.9% and 42.9% with permethrin (. P < 0.001 for both studies). The most common reported adverse events were eye and scalp irritation, but they were not statistically significant (. P = 0.329 and . P = 0.395, respectively). Only application-site erythema reactions showed statistical significance, with 6.8% in the permethrin group versus 3.1% in the spinosad group (. P = 0.007). Conclusions: Although limited, the available literature suggests that spinosad is an effective and well-tolerated agent for the treatment of head lice. In a time of increasing resistance, spinosad has demonstrated superior performance compared with permethrin. A review of the literature did not identify any studies comparing spinosad to benzyl alcohol 5% or malathion 0.5%. © 2012 Elsevier HS Journals, Inc.


Gorlick R.,The Childrens Hospital at Montefiore | Kolb E.A.,DuPont Company | Keir S.T.,Duke University | Maris J.M.,Children's Hospital of Philadelphia | And 8 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: Volasertib (BI 6727) is a potent inhibitor of Pololike kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP. Procedures: Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels administered IV at a dose of 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. Results: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts. Conclusions: Volasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied. © 2013 Wiley Periodicals, Inc.


Fornari E.D.,The Childrens Hospital At Montefiore
Journal of Pediatric Orthopaedics | Year: 2016

BACKGROUND:: The Pediatric Orthopedic Society of North America (POSNA)-Children’s Orthopedics in Underserved Regions (COUR) International Scholar Program was initiated in 2007 to provide educational opportunities for emerging leaders who treat children with orthopaedic conditions in resource-challenged environments worldwide. Financial support is available each year for 4 to 6 orthopaedic surgeons to attend either the POSNA Annual Meeting or the International Pediatric Orthopedic Symposium. The scholars are also encouraged to visit selected centers for observerships during their trip. Since 2007 there have been 41 international scholars who have participated in the program. We wished to assess the impact of the program and to obtain feedback to improve the experience for future participants. METHODS:: A 23-question web-based survey was created and sent to 38 past scholars from 22 countries who have participated in the program by July 2013. The responses were gathered online and the data were analyzed for the 24 (62%) respondents from 18 countries who completed the survey. RESULTS:: Of the respondents, 16/24 (66%) reported that their current practice is comprised of at least 75% pediatrics. Twelve of 24 (52%) were fellowship trained in pediatric orthopaedics, typically outside of North America. All scholars found the meeting they attended to be very useful and have subsequently made changes to their clinical practice. Nineteen of 24 (82%) did a premeeting or postmeeting observership. Twenty-two of 24 (92%) participants have remained in contact with POSNA members they met at the meeting, with 86% of respondents stating that they have subsequently consulted POSNA members on management of patients. Sixty-two percent of the scholars had a POSNA member visit them following the scholarship and 29% have since returned to visit POSNA members for further clinical observerships. Twenty-one of 24 (91%) have had the opportunity to share the knowledge they gained with others in their region through lectures, surgical demonstrations, and/or clinical training. A common response from the scholars was that the scholarship program was a truly transformative life experience that provided them with an opportunity to receive the highest quality of professional education. The main challenges that these scholars report are lack of available fellowship/subspecialty training in their region, patients’ inability to pay, and excessive physician workload. All of the respondents expressed interest in arranging a POSNA cosponsored regional meeting. CONCLUSIONS:: Since 2007, the POSNA-COUR international scholar program has been a fruitful resource for orthopaedists practicing in resource-challenged environments worldwide. It has provided unique training for the scholars and has further enabled them to teach others in their region. The program has thus far succeeded in fostering lasting relationships that have led to continued educational exchanges. LEVEL OF EVIDENCE:: Level IV—case series. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Sterba Y.,The Childrens Hospital At Montefiore | Ilowite N.,The Childrens Hospital At Montefiore
Current Rheumatology Reports | Year: 2016

The past two decades have brought immense satisfaction to pediatric rheumatologists and families of children with rheumatologic diseases. We have been able to better classify, recognize, and diagnose rheumatologic diseases, but most importantly, the discovery of biologic therapies and their efficacy and relative safety in treating multiple rheumatologic conditions, improving quality of life for the patients we care for. We will review the advances of the past two decades and discuss potential areas for new discoveries. © 2016, Springer Science+Business Media New York.


Statter M.B.,The Childrens Hospital at Montefiore
Seminars in Pediatric Surgery | Year: 2013

The cultural, ethnic, religious, socioeconomic, and educational diversity of the patient population and the expanded surgical options provided by innovation and technology can pose significant ethical challenges. The questions confronting pediatric surgeons and their patients' families have greater complexity, and both the pediatric surgeon and the family perceive increasing vulnerability and uncertainty. The analysis and management of ethical issues in pediatric surgery cannot simply be extrapolated from the approach applied to adult cases. By reviewing the history of the events that contributed to the creation and utilization of hospital ethics committees and examining the role of the ethics consultant in the context of pediatric surgical care, practitioners and trainees will be better able to address these multifaceted situations. © 2013 Elsevier Inc.


Orrock J.E.,The Childrens Hospital At Montefiore | Ilowite N.T.,The Childrens Hospital At Montefiore
Expert Review of Clinical Pharmacology | Year: 2016

Introduction: Canakinumab, a fully human monoclonal antibody against interleukin-1β, is a relatively new medication approved for treatment of systemic juvenile idiopathic arthritis (SJIA). Here, we review data supporting use of canakinumab for patients with active SJIA, as compared to other available biologic medications. Areas covered: This article provides an overview of chemistry of canakinumab as well as the phase II and phase III trials that led to approval for treatment of active SJIA. To undertake this review, the authors performed literature search using Pubmed, with keywords ‘canakinumab,’ ‘biologic,’ ‘anti-IL-1B,’ and ‘systemic juvenile idiopathic arthritis,’ focusing on publications within the last 5 years. Expert commentary: Canakinumab has shown efficacy in treatment of SJIA with active systemic features including fever. There is no evidence to suggest increased risk of macrophage activation syndrome. Its use in the treatment of chronic arthritis without active systemic features has not been approved and warrants further study. © 2016 Informa UK Limited, trading as Taylor & Francis Group.


Kolb E.A.,DuPont Company | Gorlick R.,The Childrens Hospital at Montefiore | Maris J.M.,Children's Hospital of Philadelphia | Keir S.T.,Duke University | And 5 more authors.
Pediatric Blood and Cancer | Year: 2012

Background: IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. Procedures: IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone. Results: Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. Conclusions: The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective. © 2011 Wiley Periodicals, Inc.


Joseph S.P.,The Childrens Hospital at Montefiore
Journal of health care for the poor and underserved | Year: 2010

Nativity status seems to have a protective effect on asthma. However, there is little information in the literature on the effect of nativity status on asthma for non-Hispanic Black and White children and adolescents. This study investigates the association between nativity status and self-reported asthma in U.S. children and adolescents under 21 years of age after controlling for selected characteristics including education and income. Logistic regression was conducted using SUDAAN to estimate odds ratios from data of the National Health and Nutrition Examination Survey 1999-2004. The prevalence of asthma for U.S. children and adolescents is 14.5%, with U.S.-born exhibiting a higher prevalence (15.1%) than foreign-born (7.3%, p<.0001). In the fully-adjusted analysis, foreign-born children and adolescents were almost twice less likely than U.S.-born counterparts to report asthma. This association differs by race/ethnicity, with the lowest odds being observed in Whites (OR: 0.29, 95% CI: 0.10-0.86), followed by Mexican Americans (OR: 0.38; 95% CI: 0.25-0.56) and Blacks (OR: 0.52; 95% CI: 0.29-0.94). Moreover, this association varies by education: Foreign-born children of survey respondents who had at least a high school education were more than twice less likely than their U.S.-born counterparts to have asthma. The findings of this study underscore the importance of inquiring about nativity status when studying asthma among U.S. children and adolescents.


Kolb E.A.,DuPont Company | Gorlick R.,The Childrens Hospital at Montefiore | Billups C.A.,St Jude Childrens Research Hospital | Hawthorne T.,Celldex Therapeutics, Inc. | And 3 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. Procedures: Glembatumumab vedotin was administered intravenously at a dose of 2.5mg/kg using a weekly×3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. Results: Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P<0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. Conclusions: Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels. © 2014 Wiley Periodicals, Inc.

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