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Glover J.,Randall Childrens Hospital | Krailo M.,Childrens Oncology Group | Tello T.,Childrens Oncology Group | Marina N.,Stanford University | And 5 more authors.
Pediatric Blood and Cancer | Year: 2015

Background: Survival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients. Procedure: The biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research. Results: Originally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals. Conclusions: These samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma. © 2014 Wiley Periodicals, Inc. Source

Kolb E.A.,DuPont Company | Gorlick R.,The Childrens Hospital at Montefiore | Maris J.M.,Childrens 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. Source

Mason T.B.A.,Childrens Hospital of Philadelphia | Arens R.,The Childrens Hospital at Montefiore | Sharman J.,Childrens Hospital of Philadelphia | Bintliff-Janisak B.,Childrens Hospital of Philadelphia | And 5 more authors.
Sleep Medicine | Year: 2011

Objective: To analyze sleep in children with Williams Syndrome (WS) compared to normal healthy controls in order to determine whether particular sleep features are characteristic of WS, and to explore associations between disturbed sleep and behavior. Methods: Thirty-five children with genetically-confirmed WS and 35 matched controls underwent overnight polysomnography and performance testing in the Sleep Center at the Children's Hospital of Philadelphia. Parents completed questionnaires regarding the subjects' sleep and behavior. Results: WS subjects had significantly different sleep than controls, with decreased sleep efficiency, increased respiratory-related arousals and increased slow wave sleep on overnight polysomnography. WS subjects were also noted to have more difficulty falling asleep, with greater restlessness and more arousals from sleep than controls. Fifty-two percent of WS subjects had features of attention deficit-hyperactivity disorder. Conclusion: Children with WS had significantly different sleep than controls in our sample. These differences demonstrated in our study may reflect genetic influences on sleep. © 2011 Elsevier B.V. Source

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. Source

Morton C.L.,St Jude Childrens Research Hospital | Maris J.M.,Childrens Hospital of Philadelphia | Keir S.T.,Duke University | Gorlick R.,The Childrens Hospital at Montefiore | And 5 more authors.
Pediatric Blood and Cancer | Year: 2012

Background: Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings. Procedures: Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models). Results: The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine-cediranib combination). The cediranib-cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra-additive with rapamycin in four models, although the effects were not large. Conclusions: Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination. © 2011 Wiley Periodicals, Inc. Source

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