Publications by authors named "Amanda Termuhlen"

53 Publications

Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

Lancet Oncol 2019 10 27;20(10):1420-1431. Epub 2019 Aug 27.

Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA. Electronic address:

Background: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures.

Methods: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation.

Findings: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung.

Interpretation: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure.

Funding: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.
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http://dx.doi.org/10.1016/S1470-2045(19)30418-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871649PMC
October 2019

IRF4 translocation status in pediatric follicular and diffuse large B-cell lymphoma patients enrolled in Children's Oncology Group trials.

Pediatr Blood Cancer 2019 08 22;66(8):e27770. Epub 2019 Apr 22.

Department of Pathology, University of Utah, Salt Lake City, Utah.

Large B-cell lymphoma with IRF4 rearrangement is a provisional entity in the 2017 World Health Organization classification. In order to characterize these lymphomas in children from the United States, IRF4 FISH and immunohistochemical stains were performed on 32 follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) from Children's Oncology Group studies. Two DLBCLs (6%) had IRF4 rearrangements, one involving the ileocecal valve and another involving the tonsil and cerebrospinal fluid. Both cases had strong, diffuse IRF4/MUM1 immunohistochemical staining, which may be a pathologic clue to the diagnosis. Reclassification of these cases may have prognostic and therapeutic implications.
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http://dx.doi.org/10.1002/pbc.27770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941672PMC
August 2019

Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma.

Br J Haematol 2019 06 6;185(6):1055-1070. Epub 2019 Jan 6.

Department of Pediatrics, New York Medical College, Valhalla, NY, USA.

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.
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http://dx.doi.org/10.1111/bjh.15753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555680PMC
June 2019

Pre-irradiation intensive induction and marrow-ablative consolidation chemotherapy in young children with newly diagnosed high-grade brainstem gliomas: report of the "head-start" I and II clinical trials.

J Neurooncol 2018 Dec 3;140(3):717-725. Epub 2018 Nov 3.

Division of Pediatric Hematology/Oncology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.

Background: The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG.

Methods: Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII). Treatment included Induction with 4-5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation.

Results: We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9-55%) and 38% (95% CI 14-63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression.

Conclusions: Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.
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http://dx.doi.org/10.1007/s11060-018-03003-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536888PMC
December 2018

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Br J Haematol 2017 12 29;179(5):739-747. Epub 2017 Oct 29.

Department of Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.
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http://dx.doi.org/10.1111/bjh.14951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650639PMC
December 2017

Natural killer/T-cell lymphomas in pediatric and adolescent patients.

Clin Adv Hematol Oncol 2017 Mar;15(3):200-209

Keck School of Medicine, University of Southern California in Los Angeles, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.

Natural killer/T-cell (NK/T-cell) lymphomas are rare in children and adolescents and consist predominantly of nasal-type extranodal NK/T-cell lymphomas. More than half of pediatric/adolescent patients with NK/T-cell lymphomas present with localized nasal/sinus involvement, but the disease may involve many organs. NK/T-cell lymphoma cells are cytotoxic and associated with necrosis and angioinvasion; they express CD56, CD2, cytoplasmic CD3 epsilon, and to a variable degree CD30. The cells contain Epstein-Barr virus (EBV)-encoded RNA. Loss of chromosome 6q is frequent, and multiple other genetic changes may occur. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) and other pathways are activated in NK/T-cell lymphoma. Adults with stage I/II disease receive radiation with or without chemotherapy, whereas adults with advanced disease receive multiagent chemotherapy, including asparaginase and drugs not affected by P-glycoprotein-mediated resistance. Outcomes data for pediatric patients come from retrospective reviews and retrospective case series. The overall survival of pediatric patients is 77% for those with stage I/II disease and 36% to 59% for those with advanced disease. Bone marrow transplant (BMT) is used in children, but with little evidence regarding the indications and rationale for type of transplant. BMT achieves better outcomes for adult patients in remission, but with high levels of morbidity and mortality. Improved understanding of the biology of this disease will allow the development of targeted approaches, including JAK/STAT inhibitors, checkpoint inhibitors, anti-CD30 agents, epigenetic modifiers, and reduced-intensity conditioning for BMT, to improve outcomes in pediatric patients.
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March 2017

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

J Clin Oncol 2017 May 24;35(15):1730-1736. Epub 2017 Mar 24.

Wendy Landier, Lindsey Hageman, Yanjun Chen, and Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Nancy Kornegay, William E. Evans, and Mary V. Relling, St. Jude Children's Research Hospital, Memphis, TN; Bruce C. Bostrom, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN; Jacqueline Casillas, David Geffen School of Medicine at University of California Los Angeles, Los Angeles; Leo Mascarenhas and Amanda M. Termuhlen, Children's Hospital Los Angeles, Los Angeles; F. Lennie Wong, City of Hope, Duarte, CA; David S. Dickens, Helen DeVos Children's Hospital at Spectrum Health/Spectrum Health at Butterworth Campus, Grand Rapids, MI; Anne L. Angiolillo, The George Washington School of Medicine, Washington, DC; Glen Lew, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; Kelly W. Maloney, University of Colorado School of Medicine, Aurora, CO; A. Kim Ritchey, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA; and William L. Carroll, Perlmutter Cancer Center, New York University-Langone Medical Center, New York, NY.

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.
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http://dx.doi.org/10.1200/JCO.2016.71.7579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455766PMC
May 2017

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.

Blood 2017 04 2;129(14):1919-1926. Epub 2017 Feb 2.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, = .02; Asian, OR, 3.1, = .02; African American, < .001; paternal education less than college (OR, 1.4, = .05); and 6MP nonadherence (OR, 9.4, < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.
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http://dx.doi.org/10.1182/blood-2016-07-726893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383868PMC
April 2017

Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues.

Pediatr Blood Cancer 2017 Jul 13;64(7). Epub 2016 Dec 13.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Background: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing.

Procedure: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55).

Results: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL.

Conclusions: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases.
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http://dx.doi.org/10.1002/pbc.26363DOI Listing
July 2017

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

Oncotarget 2016 Nov;7(45):72733-72745

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.
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http://dx.doi.org/10.18632/oncotarget.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341940PMC
November 2016

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Blood 2016 Mar 29;127(13):1656-65. Epub 2016 Jan 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.
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http://dx.doi.org/10.1182/blood-2015-10-676924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817309PMC
March 2016

Rare Pediatric Non-Hodgkin Lymphomas: A Report From Children's Oncology Group Study ANHL 04B1.

Pediatr Blood Cancer 2016 May 5;63(5):794-800. Epub 2016 Jan 5.

Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: Non-Hodgkin lymphoma (NHL) is a relatively common malignancy in pediatric patients; however, a small subgroup have unusual lymphoma subtypes for the pediatric population.

Procedure: The Children's Oncology Group Rare and Cutaneous NHL registry's (protocol ANHL 04B1) main objectives were to determine the pathologic, biologic, and clinical features of rare and cutaneous pediatric NHL and establish a bank of centrally reviewed tissue specimens. We report the clinical data, treatment data, and outcome for rare pediatric NHL.

Results: In 101 lymphomas, there is a 97.8% concordance between the reviewing study pathologists and an 87.6% concordance between the central and institutional pathology review. Samples in the specimen bank include primary tumor tissue that is snap frozen, in paraffin blocks, or H&E-stained and unstained paraffin slides as well as blood, serum, and bone marrow. This descriptive analysis shows that children with pediatric follicular lymphoma, mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, primary cutaneous, primary central nervous system lymphoma, and subcutaneous panniculitis-like T-cell lymphomas have 100% survival at a median of 2 years from enrollment. There are early deaths, mostly from progressive disease, in subjects with peripheral T-cell (not otherwise specified), NKT, and hepatosplenic T-cell lymphomas.

Conclusions: This registry provides high-quality biologic specimens with clinical data to investigators working on the biology of these unusual pediatric diseases.
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http://dx.doi.org/10.1002/pbc.25881DOI Listing
May 2016

Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia: A Children's Oncology Group Study.

JAMA Oncol 2015 Jun;1(3):287-95

St Jude Children's Research Hospital, Memphis, Tennessee.

Importance: Variability in prescribed doses of 6-mercaptopurine (6MP) and lack of adherence to a 6MP treatment regimen could result in intra-individual variability in systemic exposure to 6MP (measured as erythrocyte thioguanine nucleotide [TGN] levels) in children with acute lymphoblastic leukemia (ALL). The effect on relapse risk of this variability is unknown.

Objective: To determine the effect of high intra-individual variability of 6MP systemic exposure on relapse risk in children with ALL.

Design, Setting, And Participants: We used a prospective longitudinal design (Children's Oncology Group study [COG-AALL03N1]) to monitor 6MP and disease relapse in 742 children with ALL in ambulatory care settings of 94 participating institutions from May 30, 2005, to September 9, 2011. All participants met the following eligibility criteria: (1) diagnosis of ALL at 21 years or younger; (2) first continuous remission in progress at the time of study entry; (3) receiving self-, parent-, or caregiver-administered oral 6MP during maintenance therapy; and (4) completion of at least 6 months of maintenance therapy at the time of study enrollment. The median patient age at diagnosis was 5 years; 68% were boys; and 43% had National Cancer Institute-based high-risk disease.

Main Outcomes And Measures: Daily 6MP regimen adherence was measured over 68 716 person-days using an electronic system that recorded the date and time of each 6MP bottle opening; adherence rate was defined as the ratio of days that a 6MP bottle was opened to days thata 6MP bottle was prescribed. Average monthly 6MP dose intensity was measured over 120 439 person-days by dividing the number of 6MP doses actually prescribed by the number of planned protocol doses (75 mg/m2/d). Monthly erythrocyte TGN levels (pmol/8 × 108 erythrocytes) were measured over 6 consecutive months per patient (n = 3944 measurements). Using intra-individual coefficients of variation (CV%), patients were classified as having stable (CV% <85th percentile) vs varying (CV% ≥85th percentile) indices. Median follow-up time was 6.7 years from the time of diagnosis.

Results: Adjusting for clinical prognosticators, we found that patients with 6MP nonadherence (mean adherence rate <95%) were at a 2.7-fold increased risk of relapse (95% CI, 1.3-5.6; P = .01) compared with patients with a mean adherence rate of 95% or greater. Among adherers, high intra-individual variability in TGN levels contributed to increased relapse risk (hazard ratio, 4.4; 95% CI, 1.2-15.7; P = .02). Furthermore, adherers with varying TGN levels had varying 6MP dose intensity (odds ratio [OR], 4.5; 95% CI, 1.5-13.4; P = .01) and 6MP drug interruptions (OR, 10.2; 95% CI, 2.2-48.3; P = .003).

Conclusions And Relevance: These findings emphasize the need to maximize 6MP regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.
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http://dx.doi.org/10.1001/jamaoncol.2015.0245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561178PMC
June 2015

The importance of assessing priorities of reproductive health concerns among adolescent and young adult patients with cancer.

Cancer 2015 Aug 5;121(15):2529-36. Epub 2015 Jun 5.

Health Outcomes and Behavior Program, Moffitt Cancer Center, Tampa, Florida.

Visions for the future are a normal developmental process for adolescents and young adults (AYAs) with and without cancer, and these visions often include expectations of sexual and romantic relationships. AYA cancer survivors indicate reproductive health is an issue of great importance and more attention is needed in the health care setting throughout the cancer experience, beginning at diagnosis. Various practice guidelines are predominately focused on fertility; are intended to influence survivorship care plans; and do not encompass the broad scope of reproductive health that includes romantic partnering, friendships, body image, sexuality, sexual identity, fertility, contraception, and more. Although interventions to reduce reproductive health-related sequelae from treatment are best approached as an evolving process, practitioners are not certain of the priorities of these various reproductive health content areas. Strategies incongruent with the reproductive health priorities of AYAs will likely thwart adequate follow-up care and foster feelings of isolation from the treatment team. Research is needed to identify these priorities and ensure discussions of diverse content areas. This review explored various domains of reproductive health and emphasized how understanding the priorities of the AYA cancer cohort will guide future models of care.
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http://dx.doi.org/10.1002/cncr.29466DOI Listing
August 2015

CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells.

Integr Biol (Camb) 2014 Aug;6(8):766-80

Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA.

We report the anti-leukemic potency of a unique biotargeted nanoscale liposomal nanoparticle (LNP) formulation of the spleen tyrosine kinase (SYK) P-site inhibitor C61. C61-loaded LNP were decorated with a murine CD19-specific monoclonal antibody directed against radiation-resistant CD19-receptor positive aggressive B-precursor acute lymphoblastic leukemia (ALL) cells. The biotargeted C61-LNP were more potent than untargeted C61-LNP and consistently caused apoptosis in B-precursor ALL cells. The CD19-directed C61-LNP also destroyed B-precursor ALL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. This unique nanostructural therapeutic modality targeting the SYK-dependent anti-apoptotic blast cell survival machinery shows promise for overcoming the clinical radiochemotherapy resistance of B-precursor ALL cells.
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http://dx.doi.org/10.1039/c4ib00095aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158964PMC
August 2014

Constitutive function of the Ikaros transcription factor in primary leukemia cells from pediatric newly diagnosed high-risk and relapsed B-precursor ALL patients.

PLoS One 2013 20;8(11):e80732. Epub 2013 Nov 20.

Systems Immunobiology Laboratory and Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, United States of America ; Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America ; Developmental Therapeutics Program, USC Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.

We examined the constitutive function of the Ikaros (IK) transcription factor in blast cells from pediatric B-precursor acute lymphoblastic leukemia (BPL) patients using multiple assay platforms and bioinformatics tools. We found no evidence of diminished IK expression or function for primary cells from high-risk BPL patients including a Philadelphia chromosome (Ph)(+) subset. Relapse clones as well as very aggressive in vivo clonogenic leukemic B-cell precursors isolated from spleens of xenografted NOD/SCID mice that developed overt leukemia after inoculation with primary leukemic cells of patients with BPL invariably and abundantly expressed intact IK protein. These results demonstrate that a lost or diminished IK function is not a characteristic feature of leukemic cells in Ph(+) or Ph(-) high-risk BPL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835424PMC
December 2014

Why Healthcare Providers Should Focus on the Fertility of AYA Cancer Survivors: It's Not Too Late!

Front Oncol 2013 Oct 7;3:248. Epub 2013 Oct 7.

Jonathan Jaques Children's Cancer Center, Miller Children's Hospital , Long Beach, CA , USA.

Reproductive health among cancer survivors is an important quality of life issue. Certain cancer therapies have known fertility risks. There is an existing cohort of adolescents and young adults (AYA) cancer survivors that, seen less frequently in clinical care settings than active patients, are likely not having discussions of fertility and other reproductive health issues. A survivor or healthcare provider can easily assume that the window of opportunity for fertility preservation has passed, however emerging research has shown this may not be the case. Recent data demonstrates a close relationship between fertility and other late effects to conclude that ongoing assessment during survivorship is warranted. Some fertility preservation procedures have also been shown to mitigate common late effects. This review explores the link between late effects from treatment and common comorbidities from infertility, which may exacerbate these late effects. This review also highlights the relevance of fertility discussions in the AYA survivorship population.
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http://dx.doi.org/10.3389/fonc.2013.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791875PMC
October 2013

Pitfalls of using administrative data sets to describe clinical outcomes in sickle cell disease.

Pediatr Blood Cancer 2013 Dec 26;60(12):1936-9. Epub 2013 Aug 26.

Division of Hematology Oncology, University of California Irvine, Orange, California.

Background: Administrative data sets are increasingly being used to describe clinical care in sickle cell disease (SCD). We recently used such an administrative database to look at the frequency of acute chest syndrome (ACS) and the use of transfusion to treat this syndrome in California patients from 2005 to 2010. Our results revealed a surprisingly low rate of transfusion for this life-threatening situation.

Procedure: To validate these results, we compared California OSPHD (Office of Statewide Health Planning and Development) administrative data with medical record review of patients diagnosed with ACS identified by two pediatric and one adult hospital databases during 2009-2010.

Results: ACS or a related pulmonary process accounted for one-fifth of the inpatient hospital discharges associated with the diagnosis of SCD between 2005 and 2010. Only 47% of those discharges were associated with a transfusion. However, chart reviews found that hospital databases over-reported visits for ACS. OSHPD underreported transfusions compared to hospital data. The net effect was a markedly higher true rate of transfusion (40.7% vs. 70.2%).

Conclusions: These results point out the difficulties in using this administrative data base to describe clinical care for ACS given the variation in clinician recognition of this entity. OSPHD is widely used to inform health care policy in California and contributes to national databases. Our study suggests that using this administrative database to assess clinical care for SCD may lead to inaccurate assumptions about quality of care for SCD patients in California. Future studies on health services in SCD may require a different methodology.
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http://dx.doi.org/10.1002/pbc.24747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864696PMC
December 2013

SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children.

PLoS One 2013 22;8(8):e72557. Epub 2013 Aug 22.

School of Public Health, University of California, Berkeley, Berkeley, California, USA.

The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749982PMC
June 2014

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group.

Br J Haematol 2013 Sep 24;162(6):792-801. Epub 2013 Jul 24.

Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS-negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose MTX in interim maintenance but no IT-MTX in maintenance (Arm B1). Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5-year event-free survival (EFS) for the four arms: Arm A1, 80% [95% confidence interval (CI) 67-89%] and Arm A2, 81% (95% CI 69-89%); Arm B1, 80% (95% CI 68-88%) and Arm B2, 84% (95% CI 72-91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5-year EFS of 63% (95% CI 29-85%)]. For CNS-negative patients, there was no difference in outcome based on CNS prophylaxis (IT-MTX versus HD-MTX) or with intensification.
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http://dx.doi.org/10.1111/bjh.12460DOI Listing
September 2013

Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia.

Blood 2013 May 8;121(21):4348-54. Epub 2013 Apr 8.

Developmental Therapeutics Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

We report preclinical proof of principle for effective treatment of B-precursor acute lymphoblastic leukemia (ALL) by targeting the spleen tyrosine kinase (SYK)-dependent antiapoptotic blast cell survival machinery with a unique nanoscale pharmaceutical composition. This nanoscale liposomal formulation (NLF) contains the pentapeptide mimic 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C61) as the first and only selective inhibitor of the substrate binding P-site of SYK. The C61 NLF exhibited a very favorable pharmacokinetic and safety profile in mice, induced apoptosis in primary B-precursor ALL blast cells taken directly from patients as well as in vivo clonogenic ALL xenograft cells, destroyed the in vivo clonogenic fraction of ALL blast cells, and, at nontoxic dose levels, exhibited potent in vivo antileukemic activity against patient-derived ALL cells in xenograft models of aggressive B-precursor ALL. Our findings establish SYK as an attractive molecular target for therapy of B-precursor ALL. Further development of the C61 NLF may provide the foundation for therapeutic innovation against therapy-refractory B-precursor ALL.
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http://dx.doi.org/10.1182/blood-2012-11-470633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663427PMC
May 2013

Metabolic syndrome and endocrine dysfunctions after HSCT in children.

Pediatr Transplant 2012 Dec;16(8):872-8

Department of Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH 43205, USA.

MS and endocrine dysfunction(s) are common well-recognized complications after HSCT. We retrospectively analyzed our data on 160 patients with a median age at transplant of five yr (0.3-23), who had been followed for a median of seven yr (range 3-18) at Nationwide Children's Hospital after transplant. Dyslipidemia and MS were seen in 13% and 7.5% patients, respectively, and 58% of these patients were <20 yr of age. Twelve patients met the criteria for diagnosis of MS, but four of these did not meet the International Diabetic Federation or WHO criteria. Variation in the diagnostic criteria for MS leading to underdiagnosis is discussed. Female gonadal failure (27%) and hypothyroidism (21%) were the most common endocrine dysfunctions, followed by short stature and GH deficiency (17%) each. TBI and younger age at HSCT were associated with the highest burden of long-term effects, and female sex was more significantly associated with MS-related dysfunction (p < 0.05). Uniform diagnostic criteria for MS and close follow-up after transplant are important for the early diagnosis and management of these late effects, thereby improving the overall quality of life of these patients.
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http://dx.doi.org/10.1111/petr.12002DOI Listing
December 2012

The need for reproductive and sexual health discussions with adolescent and young adult cancer patients.

Contraception 2013 Aug 4;88(2):215-20. Epub 2012 Oct 4.

Reproductive health consistently ranks as one of the most important issues cited by adolescent and young adult (AYA) cancer survivors. Most literature on AYA cancer populations neglects broader reproductive health issues such as unintended pregnancies, contraception use and sexually transmitted infections, which, for cancer patients and survivors with compromised immune systems, can facilitate a multitude of future health problems. Lack of attention coupled with traditional risk-taking behaviors of AYAs poses a significant health risk to patients and survivors, particularly if fertility status is unknown or inaccurately assessed. AYA oncology patients and survivors are vulnerable to reproductive health complications that should be addressed prior to, during and after treatment; however, there are currently no tracking systems or evidence-based guidelines to discuss this subject with patients and survivors. Further research is needed to identify physician practices, AYA preferences and strategies for communication that can pave the way to establishing guidelines to discuss in oncology settings.
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http://dx.doi.org/10.1016/j.contraception.2012.08.041DOI Listing
August 2013

Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group.

Pediatr Blood Cancer 2012 Dec 5;59(7):1229-33. Epub 2012 Apr 5.

Department of Pediatrics, Keck School of Medicine, University of Southern California 701 E. 28th St, Suite 202, Long Beach, CA 90806, USA.

Background: Localized lymphoblastic lymphoma (LL) is rare in pediatric patients. We report the 5-year event-free survival (EFS) and overall survival (OS) for children and adolescents with localized LL treated on a uniform regimen based on Children's Cancer Group (CCG) leukemia therapy (COG A5971).

Procedure: From June 2000 to October 2005, the study enrolled 60 patients >12 months old with Murphy stages I or II LL. Central review confirmed 56 eligible patients. Treatment consisted of 24 months of CCG BFM without day 28 intrathecal methotrexate in maintenance therapy or prophylactic cranial radiation.

Results: Most patients had pre-B immunophenotype (75%). At a median follow-up of 5.9 years (range 1.4-9.3 years), the 5-year EFS was 90% [95% confidence interval (CI), 78-96%] and the 5-year OS was 96% (95% CI, 84-99%). Stage (I vs. II), immunophenotype, elevated LDH > institutional normal, or primary site did not impact outcome. Five relapses occurred-none in the CNS and none in patients with pre-T lymphoblastic disease. Patients tolerated treatment well with no toxic deaths.

Conclusion: Outcomes of pediatric patients with localized LL treated with 2 years of intensive acute lymphoblastic leukemia (ALL)-type therapy was excellent and is similar to the outcome for standard risk ALL treated less intensively. CNS prophylaxis was adequate with limited intrathecal methotrexate and no radiation. Future studies should identify biologic prognostic factors or biomarkers for pediatric patients with LL, explore less intensive treatment for patients with localized disease, and explore novel immunophenotype directed therapies.
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http://dx.doi.org/10.1002/pbc.24149DOI Listing
December 2012

Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation.

Pediatr Blood Cancer 2012 Oct 29;59(4):762-4. Epub 2012 Feb 29.

Division of Pediatric Hematology/Oncology and BMT, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Anti-seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non-induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT.
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http://dx.doi.org/10.1002/pbc.24126DOI Listing
October 2012

How confident are young adult cancer survivors in managing their survivorship care? A report from the LIVESTRONG™ Survivorship Center of Excellence Network.

J Cancer Surviv 2011 Dec 2;5(4):371-81. Epub 2011 Nov 2.

Department of Pediatrics, Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

Introduction: This study examined the association between sociodemographic, cancer treatment, and care delivery factors on young adult cancer survivors' confidence in managing their survivorship care.

Methods: Survivors aged 18-39 years (n = 376) recruited from the LIVESTRONG™ Survivorship Center of Excellence Network sites completed a survey assessing self-reported receipt of survivorship care planning, expectations of their providers, and confidence in managing their survivorship care. Multivariate logistic regression identified characteristics of those reporting low confidence in managing their survivorship care.

Results: Mean age was 28 years; mean interval from diagnosis was 9 ± 8 years. Seventy-one percent reported currently attending an oncology survivorship clinic. Regarding survivorship care planning, 33% did not have copies of their cancer-related medical records, 48% did not have a treatment summary, and 55% had not received a survivorship care plan. Seventy percent identified the oncologist as the most important health care provider for decisions regarding test and treatment decisions while 10% reported using a "shared-care model" involving both primary care providers and oncologists. Forty-one percent were classified as having low confidence in managing survivorship care. In multivariate analysis, low confidence was associated with non-white ethnicity and lack of a survivorship care plan (both p < 0.05).

Discussion/conclusions: Findings suggest that provision of survivorship care plans for young adult cancer survivors can be used to improve confidence in managing survivorship care, particularly for ethnic minorities.

Implications For Cancer Survivors: Survivors should consider advocating for receipt of a survivorship care plan as it may facilitate confidence as a consumer of survivorship care.
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http://dx.doi.org/10.1007/s11764-011-0199-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229469PMC
December 2011

Bilateral burkitt lymphoma of the ovaries: a report of a case in a child with williams syndrome.

Case Rep Med 2011 26;2011:327263. Epub 2011 May 26.

Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome.
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http://dx.doi.org/10.1155/2011/327263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114539PMC
July 2011

Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study.

Pediatr Blood Cancer 2011 Dec 7;57(7):1210-6. Epub 2011 Mar 7.

Department of Pediatrics, University of Southern California, Miller Children's Hospital, Long Beach, California 90806, USA.

Background: Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year WT survivors in the Childhood Cancer Survivor Study (CCSS).

Procedure: The CCSS, a multi-institutional retrospective cohort study, assessed WT survivors (N = 1,256), diagnosed 1970-1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (N = 4,023).

Results: The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HR) were 2.0, 95% confidence interval (CI) 1.8-2.3 for grades 1-4 and 4.7, 95%CI 3.6-6.1 for grades 3 and 4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (prevalence ratio [PR] 1.7; 95%CI 1.2-2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI 1.9-4.0%) and of mortality was 6.1% (95%CI 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin-HR 6.6; 95%CI 1.6-28.3; doxorubicin ≤ 250 mg/m(2) -HR 13.0; 95%CI 1.9-89.7; doxorubicin >250 mg/m(2) -HR 18.3; 95%CI 3.8-88.2), SMN (standardized incidence ratio [SIR] 9.0; 95%CI 3.9-17.7 with and 4.9; 95%CI 1.8-10.6 without doxorubicin) and death.

Conclusion: Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
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http://dx.doi.org/10.1002/pbc.23090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634648PMC
December 2011

Disseminated Rhizomucor pusillus causing early multiorgan failure during hematopoietic stem cell transplantation for severe aplastic anemia.

J Pediatr Hematol Oncol 2011 Apr;33(3):235-7

Department of Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

Matched sibling donor hematopoietic stem cell transplantation is the standard of care for severe aplastic anemia, with an overall survival of 80% to 90%. Only 60% to 70% of patients respond to treatment with immunosuppressive therapy. The main life threatening complications are infections, graft failure, and graft versus host disease. A 10-year-old patient with severe aplastic anemia underwent matched sibling donor hematopoietic stem cell transplantation, but developed sudden onset of fatal multiorgan failure on day +12. The cause of death was found only after autopsy.
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http://dx.doi.org/10.1097/MPH.0b013e3182050a4fDOI Listing
April 2011

Venous thromboembolism and adolescent and young adult oncology inpatients in US children's hospitals, 2001 to 2008.

J Pediatr 2011 Jul 24;159(1):133-7. Epub 2011 Feb 24.

Center for Innovation in Pediatric Practice, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Objectives: To determine the frequency of venous thromboembolism (VTE) in the adolescent and young adult oncology population and the effects of age and cancer type on VTE, and to characterize adolescent and young adult oncology admissions at US children's hospitals.

Study Design: We extracted data on oncology patients 15 to 24 years of age who were discharged from 35 hospitals in the Pediatric Hospital Information System (PHIS) between 2001 and 2008.

Results: Of 9721 unique patients, VTE occurred in 511 (5.3%). An elevated OR of VTE occurred in patients 18 to 20 and 21 to 24 years of age (OR, 1.65; 95% CI, 1.36-2.00 and OR, 1.67; 95% CI, 1.21-2.32, respectively) compared with that in patients 15 to 17 years old. Patients with leukemia (OR, 5.53; 95% CI, 3.63-8.42) and bone/soft tissue sarcomas (OR, 4.32; 95% CI, 2.80-6.69) had a higher risk of VTE compared with patients with brain tumors. The number of adolescent and young adult oncology admissions to pediatric hospitals increased 31.9%, from 5409 admissions in 2001 to 7134 admissions in 2008.

Conclusions: Adolescent and young adult oncology patients, a growing population at pediatric hospitals, experience VTE as a common complication. Pediatricians should implement adolescent and young adult-specific studies to develop a standardized approach to preventing this adverse event.
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http://dx.doi.org/10.1016/j.jpeds.2011.01.005DOI Listing
July 2011