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Poplack D.G.,Texas Childrens Cancer Center | Fordis M.,Center for Collaborative and Interactive Technologies | Landier W.,City of Hope | Bhatia S.,City of Hope | And 2 more authors.
Nature Reviews Clinical Oncology | Year: 2014

Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed. © 2014 Macmillan Publishers Limited. All rights reserved.


Bender J.G.,Columbia University | Blaney S.M.,Texas Childrens Cancer Center | Borinstein S.,Childrens Hospital at Vanderbilt | Reid J.M.,Mayo Medical School | And 8 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. ©2012 AACR.


Mukherjee M.,Texas Childrens Cancer Center | Ge G.,Texas Childrens Cancer Center | Zhang N.,Texas Childrens Cancer Center | Edwards D.G.,Baylor College of Medicine | And 5 more authors.
Oncogene | Year: 2013

Separase, a protease encoded by the ESPL1 gene, cleaves the chromosomal cohesin during mitosis. Separase protein and transcripts are overexpressed in a wide range of human cancers. To investigate the physiological consequence of Separase overexpression in animals, we have generated a transgenic MMTV-Espl1 mouse model that overexpresses Separase protein in the mammary glands. MMTV-Espl1 mice in a C57BL/6 genetic background develop aggressive, highly aneuploid and estrogen receptor alpha-positive (ERα+) mammary adenocarcinomas with an 80% penetrance. The mammary tumors caused by overexpression of Separase, alone or combined with p53 heterozygosity, in mammary epithelium mimic several aspects of the most aggressive forms of human breast cancer, including high levels of genetic instability, cell cycle defects, poor differentiation, distant metastasis and metaplasia. Histopathologically, MMTV-Espl1 tumors are highly heterogeneous showing features of both luminal as well as basal subtypes of breast cancers, with aggressive disease phenotype. In addition to aneuploidy, Separase overexpression results in chromosomal instability (CIN) including premature chromatid separation (PCS), lagging chromosomes, anaphase bridges, micronuclei, centrosome amplification, multinucleated cells, gradual accumulation of DNA damage and progressive loss of tumor suppressors p53 and cadherin gene loci. These results suggest that Separase-overexpressing mammary cells are not only susceptible to chromosomal missegregation-induced aneuploidy but also other genetic instabilities including DNA damage and loss of key tumor suppressor gene loci, which in combination can initiate tumorigenesis and disease progression.Oncogene advance online publication, 25 November 2013; doi:10.1038/onc.2013.493.


Widemann B.C.,NCI Inc | Kim A.,NCI Inc | Kim A.,Childrens National Medical Center | Fox E.,Children's Hospital of Philadelphia | And 9 more authors.
Clinical Cancer Research | Year: 2012

Purpose: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias. Experimental Design: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1. Results: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m 2/dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%. Conclusions: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. ©2012 AACR.


Smith A.R.,University of Minnesota | Majhail N.S.,University of Minnesota | MacMillan M.L.,University of Minnesota | DeFor T.E.,University of Minnesota | And 4 more authors.
Blood | Year: 2011

Quantifying the risk of hematopoietic cell transplantation (HCT)-related mortality for pediatric patients is challenging. The HCT-specific comorbidity index (HCT-CI) has been confirmed as a useful tool in adults, but has not yet been validated in children. We conducted a retrospective cohort study of 252 pediatric patients undergoing their first allogeneic HCT between January 2008 and May 2009. Pretransplantation comorbidities were scored prospectively using the HCT-CI. Median age at transplantation was 6 years (range, 0.1-20) and median follow-up was 343 days (range, 110-624). HCT-CI scores were distributed as follows: 0, n = 139; 1-2, n = 52; and 3+, n = 61. The 1-year cumulative incidence of nonrelapse mortality (NRM) increased (10%, 14%, and 28%, respectively; P < .01) and overall survival (OS) decreased (88%, 67%, and 62%, respectively; P < .01) with increasing HCT-CI score. Multivariate analysis showed that compared with score 0, those with scores of 1-2 and 3+ had relative risks of NRM of 1.5 (95% confidence interval, 0.5-4.3, P = .48) and 4.5 (95% confidence interval, 1.7-12.1, P < .01), respectively. These results indicate that the HCT-CI score predicts NRM and OS in pediatric patients undergoing HCT and is a useful tool to assess risk, guide counseling in the pretransplantation setting, and devise innovative therapies for the highest risk groups. © 2011 by The American Society of Hematology.


Berres M.-L.,Mount Sinai School of Medicine | Berres M.-L.,Tisch Cancer Institute | Berres M.-L.,Immunology Institute | Allen C.E.,Texas Childrens Cancer Center | And 4 more authors.
Advances in Immunology | Year: 2013

Histiocytic disorders represent a group of complex pathologies characterized by the accumulation of histiocytes, an old term for tissue-resident macrophages and dendritic cells. Langerhans cell histiocytosis is the most frequent of histiocytosis in humans and has been thought to arise from the abnormal accumulation of epidermal dendritic cells called Langerhans cells. In this chapter, we discuss the origin and differentiation of Langerhans cells and dendritic cells and present accumulated evidence that suggests that Langerhans cell histiocytosis does not result from abnormal Langerhans cell homeostasis but rather is a consequence of misguided differentiation programs of myeloid dendritic cell precursors. We propose reclassification of Langerhans cell histiocytosis, juvenile xanthogranuloma, and Erdheim-Chester disease as inflammatory myeloid neoplasias. © 2013 Elsevier Inc.


Qi L.,Soochow University of China | Qi L.,Texas Childrens Cancer Center | Zhang X.-D.,Soochow University of China | Zhang X.-D.,University of Texas M. D. Anderson Cancer Center
Acta Biochimica et Biophysica Sinica | Year: 2014

Mutant N-terminal huntingtin (Htt) protein resulting from Huntington's disease (HD) with expanded polyglutamine accumulates and forms aggregates in vulnerable neurons. Both ubiquitin proteasomal and autophagic pathways contribute to the degradation of mutant Htt. Here, we focus on the involvement of chaperone-mediated autophagy (CMA), a selective form of autophagy in the clearance of Htt. Selective catabolism in CMA is conferred by the presence of a KFERQ-like targeting motif in the substrates, by which molecular chaperones recognize the hydrophobic surfaces of the misfolded substrates, and transfer them to the lysosomal membrane protein type-2A, LAMP-2A. The substrates are taken into the lysosomes through LAMP-2A and are rapidly degraded by the lysosomal enzymes. Taken together, we summarize the recent evidence to elucidate that Htt is also a potential substrate of CMA. We propose that the manipulation of CMA could be a therapeutic strategy for HD.©The Author 2013.


Berres M.-L.,Mount Sinai School of Medicine | Berres M.-L.,RWTH Aachen | Merad M.,Mount Sinai School of Medicine | Allen C.E.,Texas Childrens Cancer Center | Allen C.E.,Baylor College of Medicine
British Journal of Haematology | Year: 2015

Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A+/CD207+ mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells. © 2014 John Wiley & Sons Ltd.


Despotovic J.M.,Texas Childrens Cancer Center | Neunert C.E.,Texas Childrens Cancer Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

A 5-year-old boy presents with platelet count of 2×10(9)/L and clinical and laboratory evidence of immune thrombocytopenia. He has epistaxis and oral mucosal bleeding. Complete blood count reveals isolated thrombocytopenia without any decline in hemoglobin and he is Rh+. You are asked if anti-D immunoglobulin is an appropriate initial therapy for this child given the 2010 Food and Drug Administration "black-box" warning.


Kamdar K.Y.,Methodist Hospital | Kamdar K.Y.,Texas Childrens Cancer Center | Rooney C.M.,Methodist Hospital | Heslop H.E.,Methodist Hospital
Current Opinion in Organ Transplantation | Year: 2011

Purpose of review: Despite contemporary immunosuppressive regimens, posttransplant lymphoproliferative disease (PTLD) remains a major complication after liver transplantation. This review highlights advances in the understanding of the pathophysiology, diagnosis, and management of PTLD in liver transplant recipients. Recent findings: The spectrum of PTLD after liver transplant ranges from polymorphic lymphoproliferation to high-grade monoclonal lymphoma and is usually related to outgrowth of lymphocytes infected with Epstein-Barr virus (EBV). Risk factors for PTLD include EBV-seronegativity of the recipient, young age, intensity of immunosuppression, and the first year posttransplant. Measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD although the specificity for PTLD is only about 50% (specificity for EBV is ∼100%). In patients diagnosed with PTLD, management options include reduction of immunosuppression, rituximab, combination chemotherapy, and adoptive immunotherapy. Outcomes have improved because rituximab has been incorporated into treatment regimens, and immunotherapy approaches show promise. Summary: PTLD is a significant complication after liver transplantation, particularly in children. Advances in early detection approaches have aided in the diagnosis and management of PTLD, but further research to identify better predictive biomarkers is needed to improve risk-based treatment strategies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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