Janeway K.A.,Dana Farber Childrens Hospital Cancer Center |
Barkauskas D.A.,University of Southern California |
Krailo M.D.,University of Southern California |
Meyers P.A.,Sloan Kettering Cancer Center |
And 6 more authors.
Cancer | Year: 2012
BACKGROUND: There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. METHODS: Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). RESULTS: A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P =.019) and OS (P =.043). The 10-year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P =.019) and OS (P =.049). CONCLUSIONS: In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation. Cancer 2012. © 2012 American Cancer Society. In children and young adults with osteosarcoma enrolled on North American cooperative group trials, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, a higher incidence of poor histologic response, or metastatic disease at presentation. Copyright © 2012 American Cancer Society.
Friedrich P.,Dana Farber Childrens Hospital Cancer Center |
Ortiz R.,La Mascota Childrens Hospital |
Strait K.,Dana Farber Childrens Hospital Cancer Center |
Fuentes S.,Benjamin Bloom National Childrens Hospital |
And 7 more authors.
Cancer | Year: 2013
Background: Children with cancer in middle-income countries have inferior outcomes compared with similar children in high-income countries. The magnitude and drivers of this survival gap are not well understood. In the current report, the authors sought to describe patterns of clinical presentation, magnitude of treatment abandonment, and survival in children with sarcoma in Central America. METHODS: A retrospective review was conducted of hospital-based registries from national pediatric oncology referral centers. Patients with newly diagnosed osteosarcoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and soft tissue sarcoma (STS) between January 1, 2000 and December 31, 2009 were included. Survival analyses were performed first using standard definitions of overall survival (OS) and event-free survival (EFS) and then with abandonment included as an event (abandonment-sensitive OS and abandonment-sensitive EFS). RESULTS: In total, 785 new cases of pediatric sarcoma were reported (264 diagnoses of osteosarcoma, 175 diagnoses of Ewing sarcoma, 240 diagnoses of RMS, and 106 diagnoses of STS). The rate of metastatic disease at presentation was high (osteosarcoma, 38%; Ewing sarcoma, 39%; RMS, 29%; and STS, 21%). The treatment abandonment rate also was high, particularly among patients with extremity bone sarcomas (osteosarcoma, 30%; Ewing sarcoma, 15%; RMS, 25%; and STS, 15%). Of 559 patients who experienced a first event, 59% had either recurrent or progressive disease. The 4-year OS rate (±standard error) was 40% ± 3%, and the EFS rate was 30% ± 2%; however, these rates decreased further to 31% ± 2% and 24% ± 2%, respectively, when abandonment was taken into account. CONCLUSIONS: The current results indicated that high rates of metastases and treatment abandonment and difficulty with upfront treatment effectiveness are important contributors to the poor survival of children with pediatric sarcomas in Central America. Initiatives for early diagnosis, psychosocial support, quality improvement, and multidisciplinary care are warranted to improve outcomes. © 2012 American Cancer Society.
Heath J.A.,Royal Melbourne Hospital |
Zacharoulis S.,Royal Marsden Hospital |
Kieran M.W.,Dana Farber Childrens Hospital Cancer Center
Asia-Pacific Journal of Clinical Oncology | Year: 2012
Tumors of the central nervous system (CNS) are the most common solid malignancies in childhood and are the leading cause of cancer-related death in this age group. While an ongoing improvement in overall prognosis has been achieved in the last few decades, current therapeutic approaches still confer significant morbidities, especially for the very young. The traditional strategies of surgery, radiotherapy and conventional cytotoxic chemotherapy need to be further refined while newer approaches, including molecularly targeted agents, hold the promise of better responses, improved outcomes and reduced toxicities. This article discusses treatment standards, the focus of current clinical investigations and the future promise of novel, biologically based approaches for the most common pediatric CNS tumors: primitive neuroectodermal tumors including medulloblastomas, ependymomas and astrocytomas (both low-grade and high-grade glioma). © 2012 Wiley Publishing Asia Pty Ltd.
Macdonald T.J.,Emory University |
Vezina G.,George Washington University |
Stewart C.F.,St Jude Childrens Research Hospital |
Turner D.,St Jude Childrens Research Hospital |
And 5 more authors.
Neuro-Oncology | Year: 2013
BackgroundCilengitide, an v integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population.MethodsCilengitide (1800 mg/m2/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1-20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point.ResultsToxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11-114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28-325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively.ConclusionsWe conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded. © 2013 © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: email@example.com.
Wang L.D.,Harvard Stem Cell Institute |
Wang L.D.,Joslin Diabetes Center |
Wang L.D.,Dana Farber Childrens Hospital Cancer Center |
Wagers A.J.,Harvard Stem Cell Institute |
And 2 more authors.
Nature Reviews Molecular Cell Biology | Year: 2011
Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate all mature blood cells. HSC function is tightly controlled to maintain haematopoietic homeostasis, and this regulation relies on specialized cells and factors that constitute the haematopoietic 'niche', or microenvironment. Recent discoveries, aided in part by technological advances in in vivo imaging, have engendered a new appreciation for the dynamic nature of the niche, identifying novel cellular and acellular niche components and uncovering fluctuations in the relative importance of these components over time. These new insights significantly improve our understanding of haematopoiesis and raise fundamental questions about what truly constitutes a stem cell niche. © 2011 Macmillan Publishers Limited. All rights reserved.
Elborai Y.,Dana Farber Childrens Hospital Cancer Center |
Elborai Y.,Cairo University |
Uwumugambi A.,Rwinkwavu District Hospital |
Lehmann L.,Dana Farber Childrens Hospital Cancer Center
Immunotherapy | Year: 2012
Thalassemia is an autosomal recessive disorder associated with defective synthesis of the α-or-chain of hemoglobin. For-thalassemia major patients, therapeutic options are either monthly red cell transfusions and chelation therapy or allogeneic stem cell transplant. Patients undergoing transfusion therapy remain at risk for transmitted infections and iron overload with associated tissue damage. Stem cell transplant is the only curative approach and success is inversely correlated with the degree of iron overload and hepatic damage. Overall outcomes following stem cell transplant with a matched sibling donor are excellent with over 90% of low-risk children becoming transfusion free. Hypertransfusion therapy and aggressive chelation in addition to hydroxyurea, azathioprine and fludarabine is a new approach for high-risk patients to decrease graft rejection by suppressing endogenous erythropoiesis pretransplant. The use of unrelated donors and novel approaches such as gene therapy are under current investigation. © 2012 Future Medicine Ltd.
Adair J.E.,Fred Hutchinson Cancer Research Center |
Beard B.C.,Fred Hutchinson Cancer Research Center |
Beard B.C.,University of Washington |
Trobridge G.D.,Washington State University |
And 7 more authors.
Science Translational Medicine | Year: 2012
Chemotherapy with alkylating agents for treating malignant disease results in myelosuppression that can significantly limit dose escalation and potential clinical efficacy. Gene therapy using mutant methylguanine methyltransferase (P140K) gene-modified hematopoietic stem and progenitor cells may circumvent this problem by abrogating the toxic effects of chemotherapy on hematopoietic cells. However, this approach has not been evaluated clinically. Here, we show efficient polyclonal engraftment of autologous P140K-modified hematopoietic stem and progenitor cells in three patients with glioblastoma. Increases in P140K-modified cells after transplant indicate selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified more than 12,000 unique RISs in the three glioblastoma patients, with multiple clones present in the peripheral blood of each patient throughout multiple chemotherapy cycles. To assess safety, we monitored RIS distribution over the course of chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RISs associated with the intronic coding region of PRDM16 (PR domain-containing 16) or the 3′ untranslated region of HMGA2 (high-mobility group A2) genes with no adverse clinical outcomes. All three patients surpassed the median survival for glioblastoma patients with poor prognosis, with one patient alive and progression-free more than 2 years after diagnosis. Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered.
Rodriguez-Galindo C.,Dana Farber Childrens Hospital Cancer Center |
Rodriguez-Galindo C.,Harvard University |
Friedrich P.,Dana Farber Childrens Hospital Cancer Center |
Friedrich P.,Harvard University |
And 3 more authors.
Current Opinion in Pediatrics | Year: 2013
PURPOSE OF REVIEW: Reduction of child mortality is one of the Millennium Development Goals; as low-income and middle-income countries (LMICs) advance toward the achievement of this goal, initiatives aimed at reducing the burden of noncommunicable diseases, including childhood cancer, need to be developed. RECENT FINDINGS: Approximately 200â€Š000 children and adolescents are diagnosed with cancer every year worldwide; of those, 80% live in LMICs, which account for 90% of the deaths. Lack of quality population-based cancer registries in LMICs limits our knowledge of the epidemiology of pediatric cancer; however, available information showing variations in incidence may indicate unique interactions between environmental and genetic factors that could provide clues to cause. Outcome of children with cancer in LMICs is dictated by late presentation and underdiagnosis, high abandonment rates, high prevalence of malnutrition and other comorbidities, suboptimal supportive and palliative care, and limited access to curative therapies. Initiatives integrating program building with education of healthcare providers and research have proven to be successful in the development of regional capacity. Intensity-graduated treatments adjusted to the local capacity have been developed. SUMMARY: Childhood cancer burden is shifted toward LMICs; global initiatives directed at pediatric cancer care and control are urgently needed. International partnerships facilitating stepwise processes that build capacity while incorporating epidemiology and health services research and implementing intensity-graduated treatments have been shown to be effective. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.
Raabe E.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
Kieran M.W.,Dana Farber Childrens Hospital Cancer Center |
Cohen K.J.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Clinical Cancer Research | Year: 2013
Pediatric low-grade gliomas (pLGG) account for more brain tumors in children than any other histologic subtype. While surgery, chemotherapy and radiation remain the mainstay of upfront treatment, recent advances in molecular interrogation of pLGG have shown a small number of recurring genetic mutations in these tumors that might be exploited therapeutically. Notable findings include abnormalities in the RAS/MAP kinase pathway such as NF-1 loss or BRAF activation and mTOR activation. Recent identification of activating re-arrangements in c-MYB and MYBL1 in pediatric diffuse astrocytoma also provide candidates for therapeutic intervention. Targeting these molecularly identified pathways may allow for improved outcomes for patients as pediatric oncology moves into the era of biology-driven medicine. © 2013 AACR.
Janeway K.A.,Dana Farber Childrens Hospital Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013
The somatic genomic alterations in pediatric cancers to some extent overlap with those seen in adult cancers, but the exact distribution throughout the genome and the types and frequency of alterations differ. The ultimate goal of genomic research in children, as with adults, is translation to the clinic to achieve more accurate diagnosis, more precise risk stratification, and more effective, less toxic therapy. The genomic features of pediatric malignancies and pediatric-specific issues in clinical investigation may make translating genomic discoveries to the clinic more difficult. However, through large-scale molecular profiling of pediatric tumors, continued coordinated efforts to evaluate novel therapies in the pediatric population, thoughtful phase II and III trial design, and continued drug development, genomically based therapies will become more common in the pediatric oncology clinic in the future.