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Cohen B.H.,Northeast Ohio Medical University | Geyer J.R.,Cancer and Blood Disorders Center | Miller D.C.,University of Missouri | Curran J.G.,Phoenix Childrens Hospital | And 10 more authors.
Pediatric Neurology | Year: 2015

Abstract Background The primary goals of the Children's Cancer Group 99703 study were to assess the feasibility and tolerability of - as well as the response rate to - a novel dose-intensive chemotherapy regimen. Methods Between March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide, and cisplatin) administered every 21-28 days. Patients without tumor progression then received three consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue. Results The maximum tolerated dose of thiotepa was 10 mg/kg/day × 2 days per cycle. The toxic mortality rate was zero during induction and 2.6% during consolidation. Centrally evaluated response rates to induction and consolidation in evaluable patients with residual tumor were 73.3% and 66.7%, respectively. Disease progression rates on induction and consolidation were 4%. Five-year event-free survival and overall survival were 43.9 ± 5.2% and 63.6 ± 5% respectively. Gross total resection versus less than gross total resection were the only significant outcome comparisons: 5-year maximum tolerated dose and overall survival of 54.4 ± 7% versus 28.9 ± 7% (P = 0.0065) and 75.9 ± 8% versus 48.7 ± 8% (P = 0.0034), respectively. The 5-year maximum tolerated dose for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5 ± 9.5% versus 30 ± 14.5% (P = 0.007). The 5-year maximum tolerated dose and overall survival for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6 ± 11% versus 50.5 ± 12% (P = 0.038) and 85.7 ± 9.4% versus 60.6 ± 11.6% (P = 0.046), respectively. Conclusions This phase I dose-escalation study of marrow-ablative thiotepa regimen determined a maximum tolerated dose that had acceptable toxicity. Overall survival data justify this strategy for current Children's Oncology Group studies. © 2015 Elsevier Inc. Source

Tanzeem S.,East West University of Bangladesh | Reddick W.E.,St Jude Children Research Hospital | Iftekharuddin K.M.,Old Dominion University
International Journal of Pharmacy and Technology | Year: 2015

The focus of this work was to develop a 3D mapping of brain tumor (glioma) growth based on cell proliferation and diffusion. In this mathematical model, we incorporated high resolution brain tissue maps (white and gray matter) from an anonymized pediatric patient and initialized the model with a single voxel seed point of tumor with a Gaussian distribution. We used this model to investigate the ratio of growth rate to the diffusion coefficient (ρ/D) which determines the proportion of tumor that is detectable. After expansion of the tumor growth model to three dimensions and solving the differential equations for our specific starting conditions, we performed several simulations to assess tumor growth patterns. After observing the performance of the model at varying time points across a one year time frame with different values for ρ/D, we ascertained that the tumor diffused more rapidly than the cell proliferated for a short period of time followed by an exponential growth in detectable tumor size. This growth pattern results in a transition point in the voxel-wise cell count with respect to time when the rate of diffusion and proliferation equilibrate and can in some cases result in the tumor becoming undetectable for a period of time. © 2015, International Journal Of Pharmacy and Technology. All Rights Reserved. Source

Ratanakorn P.,Mahidol University | Wiratsudakul A.,Mahidol University | Wiriyarat W.,Mahidol University | Eiamampai K.,Wildlife and Plant Conservation | And 6 more authors.
PLoS ONE | Year: 2012

Brown-headed gulls (Larus brunnicephalus), winter visitors of Thailand, were tracked by satellite telemetry during 2008-2011 for investigating their roles in the highly pathogenic avian influenza (HPAI) H5N1 virus spread. Eight gulls negative for influenza virus infection were marked with solar-powered satellite platform transmitters at Bang Poo study site in Samut Prakarn province, Thailand; their movements were monitored by the Argos satellite tracking system, and locations were mapped. Five gulls completed their migratory cycles, which spanned 7 countries (China, Bangladesh, India, Myanmar, Thailand, Cambodia, and Vietnam) affected by the HPAI H5N1 virus. Gulls migrated from their breeding grounds in China to stay overwinter in Thailand and Cambodia; while Bangladesh, India, Myanmar, and Vietnam were the places of stopovers during migration. Gulls traveled an average distance of about 2400 km between Thailand and China and spent 1-2 weeks on migration. Although AI surveillance among gulls was conducted at the study site, no AI virus was isolated and no H5N1 viral genome or specific antibody was detected in the 75 gulls tested, but 6.6% of blood samples were positive for pan-influenza A antibody. No AI outbreaks were reported in areas along flyways of gulls in Thailand during the study period. Distance and duration of migration, tolerability of the captive gulls to survive the HPAI H5N1 virus challenge and days at viral shedding after the virus challenging suggested that the Brown-headed gull could be a potential species for AI spread, especially among Southeast Asian countries, the epicenter of H5N1 AI outbreak. © 2012 Ratanakorn et al. Source

Luo M.,Hefei University of Technology | Yan B.,St Jude Children Research Hospital | Yan B.,Shandong University
Tetrahedron Letters | Year: 2010

A series of novel N-metal complexes containing chiral α-ethylphenyl amines was synthesized and they catalyzed asymmetric Henry reactions affording products with high enantioselectivity. © 2010 Elsevier Ltd. All rights reserved. Source

Kahlert U.D.,Johns Hopkins Hospital | Kahlert U.D.,University Medical Center Dusseldorf | Suwala A.K.,University Medical Center Dusseldorf | Koch K.,University Medical Center Dusseldorf | And 5 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2015

Wingless (Wnt) signaling is an important pathway in gliomagenesis and in the growth of stem-like glioma cells. Using immunohistochemistry to assess the translocation of β-catenin protein, we identified intranuclear staining suggesting Wnt pathway activation in 8 of 43 surgical samples (19%) from adult patients with glioblastoma and in 9 of 30 surgical samples (30%) from pediatric patients with glioblastoma. Wnt activity, evidenced by nuclear β-catenin in our cohort and high expression of its target AXIN2 (axis inhibitor protein 2) in published glioma datasets, was associated with shorter patient survival, although this was not statistically significant. We determined the effects of the porcupine inhibitor LGK974 on 3 glioblastoma cell lines with elevated AXIN2 and found that it reduced Wnt pathway activity by 50% or more, as assessed by T-cell factor luciferase reporters. Wnt inhibition led to suppression of growth, proliferation in cultures, and modest induction of cell death. LGK974 reduced NANOG messenger RNA levels and the fraction of cells expressing the stem cell marker CD133 in neurosphere cultures, induced glial differentiation, and suppressed clonogenicity. These data indicate that LGK974 is a promising new agent that can inhibit the canonical Wnt pathway in vitro, slow tumor growth, and deplete stem-like clonogenic cells, thereby providing further support for targeting Wnt in patients with glioblastoma. Copyright © 2015 by the American Association of Neuropathologists, Inc. Source

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