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author:("Bhatia, smith")
1.  Children’s Oncology Group’s 2013 Blueprint for Research: Survivorship and Outcomes 
Pediatric blood & cancer  2012;60(6):1063-1068.
Improvements in the treatment of childhood cancer have resulted in over 360,000 survivors of childhood cancer in the U.S.. There is now a heightened recognition of the need to reduce treatment-related sequelae and optimize the quality of life of children treated for cancer. Survivorship studies conducted in the cooperative group setting have provided us with important information on long-term intellectual function, organ toxicity, reproductive outcomes, second cancers, late mortality, and disparities in outcomes. Ongoing health education initiatives have helped standardize the follow-up care for childhood cancer survivors and facilitate the early transfer of health-related information to patients, families, and healthcare providers.
doi:10.1002/pbc.24422
PMCID: PMC3799776  PMID: 23255494
Children’s Oncology Group; Survivorship and Outcomes; Late Effects; Health-related Disparities; Long Term Follow-up Guidelines
2.  A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group 
Pediatric blood & cancer  2012;60(4):10.1002/pbc.24445.
Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010 the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence-based methods we provide a framework for the harmonization of guidelines for the long-term follow-up of childhood and young adult cancer survivors.
doi:10.1002/pbc.24445
PMCID: PMC3819170  PMID: 23281199
Guidelines; Late effects; Childhood and young adult cancer survivors; Collaboration
3.  Granulocytes Affect Double-Strand Break Repair Assays in Primary Human Lymphocytes 
PLoS ONE  2014;9(3):e93185.
Patients who develop therapy-related myelodysplasia/acute myeloid leukemia after autologous-hematopoietic stem cell (aHCT) transplant show lower expression levels of DNA repair genes in their pre-aHCT CD34+ cells. To investigate whether this leads to functional differences in DNA repair abilities measurable in patients, we adapted two plasmid-based host-cell reactivation assays for use in primary lymphocytes. Prior to applying these assays to patients who underwent aHCT, we wanted first to verify whether sample preparation affected repair measurements, as patient samples were simply depleted of erythrocytes (with hetastarch) prior to freezing, which is not the classical way to prepare lymphocytes prior to DNA repair experiments (with a density gradient). We show here that lymphocytes from healthy donors freshly prepared with hetastarch show systematically a higher level of double-strand break repair as compared to when prepared with a density gradient, but that most of this difference disappears after samples were frozen. Several observations points to granulocytes as the source for this effect of sample preparation on repair: 1) removal of granulocytes makes the effect disappear, 2) DSB repair measurements for the same individual correlate to the percentage of granulocytes in the sample and 3) nucleofection in presence of granulocytes increases the level of reactive oxygen species (ROS) in neighboring lymphocytes in a dose-dependent manner (R2 of 0.95). These results indicate that co-purified granulocytes, possibly through the release of ROS at time of transfection, can lead to an enhanced repair in lymphocytes that obfuscates any evaluation of inter individual differences in repair as measured by host-cell reactivation. As a result, hetastarch-prepared samples are likely unsuitable for the assessment of DSB repair in primary cells with that type of assay. Granulocyte contamination that exists after a density gradient preparation, although much more limited, could have similar effects, but might be circumvented by freezing cells prior to analysis.
doi:10.1371/journal.pone.0093185
PMCID: PMC3965556  PMID: 24667872
4.  Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma 
Recent studies demonstrate an increased risk of second primary malignancies (SPM) in multiple myeloma (MM) patients on maintenance lenalidomide following autologous stem cell transplantation (ASCT). There may be other risk factors driving SPM post-ASCT in MM, so we explored this possibility through analysis of our large transplant database in conjunction with our long-term followup program. We conducted a retrospective cohort study of 841 consecutive MM patients who underwent ASCT from 1989–2009 at City of Hope, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during and after ASCT. Median length of follow-up for the entire cohort was 3.4 years (range 0.3–19.9). Sixty cases with seventy SPM were identified. The overall cumulative incidence of SPM was 7.4% at five years and 15.9% at ten years if non-melanoma skin cancers (NMSCs) were included, and 5.3% at 5 years and 11.2% at 10 years if NMSCs were excluded. Multivariate analysis of the entire cohort revealed association of both older age (≥55yrs) (RR 2.3 p<0.004) and race (non-Hispanic white) (RR 2.4 p=0.01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend towards increased risk (OR=3.5, p=0.15); however, not enough patients were treated with lenalidomide to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables, but was accompanied with loss of statistical significance. This large single-institution analysis identified race and older age to be associated with increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that may not be restricted to lenalidomide.
doi:10.1016/j.bbmt.2012.09.023
PMCID: PMC3553262  PMID: 23073267
second primary malignancy; transplantation; myeloma
5.  Leveraging Epidemiology and Clinical Studies of Cancer Outcomes: Recommendations and Opportunities for Translational Research 
As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled “Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities” on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival.
doi:10.1093/jnci/djs473
PMCID: PMC3545903  PMID: 23197494
6.  Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms 
Cancer research  2012;72(24):6425-6434.
Second malignant neoplasms (SMNs) are therapy-induced malignancies and a growing problem in cancer survivors, particularly survivors of childhood cancers. The lack of experimental models of SMNs has limited understanding of their pathogenesis. It is currently not possible to predict or prevent this devastating late complication. Individuals with Neurofibromatosis I (NF1) are at increased risk of developing therapy-induced cancers for unclear reasons. To model SMNs, we replicated clinical radiotherapy and delivered fractionated abdominal irradiation to Nf1+/− and wildtype mice. Similar to irradiated cancer survivors, irradiated wildtype and Nf1+/− mice developed diverse in-field malignancies. In Nf1+/− mice, fractionated irradiation promoted both classical NF1-associated malignancies and malignancies unassociated with the NF1 syndrome but typical of SMNs. Nf1 heterozygosity potentiated the mutagenic effects of irradiation, as evidenced by the significantly reduced survival after irradiation and tumor development that was often characterized by synchronous primary tumors. Interestingly, diverse radiation-induced tumors arising in wildtype and Nf1+/− mice shared a genetic signature characterized by monoallelic loss of Nf1 and the adjacent Trp53 allele. These findings implicate Nf1 loss as mediating tumorigenesis in a broad range of cell types and organs extending beyond the classical NF1 tumor histologies. Examining clinical SMN samples, we found LOH of NF1 in SMNs from non-NF1 patients. Nf1 heterozygosity confers broad susceptibility to genotoxin-induced tumorigenesis and this paradigm serves as an experimental platform for future studies of SMNs.
doi:10.1158/0008-5472.CAN-12-1728
PMCID: PMC3787120  PMID: 23071067
Neurofibromatosis I; radiation; abdominal; sarcomas; carcinomas; genetic
7.  Yield of Screening for Long-Term Complications Using the Children's Oncology Group Long-Term Follow-Up Guidelines 
Journal of Clinical Oncology  2012;30(35):4401-4408.
Purpose
The Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines use consensus-based recommendations for exposure-driven, risk-based screening for early detection of long-term complications in childhood cancer survivors. However, the yield from these recommendations is not known.
Methods
Survivors underwent COG-LTFU Guideline–directed screening. Yield was classified as negligible/negative (< 1%), intermediate (≥ 1% to < 10%), or high (≥ 10%). For long-term complications with high yield, logistic regression was used to identify subgroups more likely to screen positive.
Results
Over the course of 1,188 clinic visits, 370 childhood cancer survivors (53% male; 47% Hispanic; 69% leukemia/lymphoma survivors; median age at diagnosis, 11.1 years [range, 0.3 to 21.9 years]; time from diagnosis, 10.5 years [range, 5 to 55.8 years]) underwent 4,992 screening tests. High-yield tests included thyroid function (hypothyroidism, 10.1%), audiometry (hearing loss, 22.6%), dual-energy x-ray absorptiometry scans (low bone mineral density [BMD], 23.2%), serum ferritin (iron overload, 24.0%), and pulmonary function testing/chest x-ray (pulmonary dysfunction, 84.1%). Regression analysis failed to identify subgroups more likely to result in high screening yield, with the exception of low BMD (2.5-fold increased risk for males [P = .04]; 3.3-fold increased risk for nonobese survivors [P = .01]). Screening tests with negligible/negative (< 1%) yield included complete blood counts (therapy-related leukemia), dipstick urinalysis for proteinuria and serum blood urea nitrogen/creatinine (glomerular defects), microscopic urinalysis for hematuria (hemorrhagic cystitis, bladder cancer), ECG (anthracycline-related conduction disorder), and hepatitis B and HIV serology.
Conclusion
Screening tests with a high yield are appropriate for risk groups targeted for screening by the COG-LTFU Guidelines. Elimination of screening tests with negligible/negative yield should be given consideration.
doi:10.1200/JCO.2012.43.4951
PMCID: PMC3515770  PMID: 23091100
8.  Long-term Complications of Therapeutic Exposures in Childhood: Lessons Learned From Childhood Cancer Survivors 
Pediatrics  2012;130(6):1141-1143.
doi:10.1542/peds.2012-2884
PMCID: PMC3507259  PMID: 23166341
childhood; cancer survivors; treatment-related complications; chronic health conditions
9.  Cross-Cultural Adaptation of the Korean Version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form 
Journal of Korean Medical Science  2013;28(12):1788-1795.
We verified the reliability and validity of the Korean version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors.
doi:10.3346/jkms.2013.28.12.1788
PMCID: PMC3857376  PMID: 24339710
Quality of Life; Questionnaires; Validation Studies; Child Psychology; Neoplasms; Survivors
10.  Functional status and health-related quality of life among allogeneic transplant patients at hospital discharge: a comparison of sociodemographic, disease, and treatment characteristics 
Purpose
The purpose of this paper is to report the findings of a study of hematopoietic cell transplant patients, describing the needs of allogeneic transplant patients at the time of discharge in regard to their functional status, quality of life (QOL), and caregiver information and comparing these needs across a number of sociodemographic, disease, and treatment characteristics. The findings of this study are part of a larger mixed-methods study, representing one data time point of the larger study.
Methods
This paper will discuss the baseline data collected at the time of discharge for 282 allogeneic transplant patients, which include sociodemographic data combined with disease, treatment, functional status, and QOL data to present a comprehensive portrait of the transplant patient at discharge.
Results
Mean age was 48 years, males represented 52%, and 22% of the patients were Hispanic. The majority of the patients had acute leukemia (55%), were diagnosed within the last 3 years, and had matched unrelated (52%) transplants. The time from transplant to discharge averaged 30 days. Mean scores for QOL (scale = 1–10, with 10 = best QOL) included a low score of 5.7 for both psychological and social well-being, 6.3 for overall QOL, and 7.1 for both physical and spiritual well-being. Males had significantly higher QOL than females, as did non-Hispanics. Patients with Hodgkin’s disease had significantly lower overall QOL scores.
Conclusions
Our results highlight the physical, psychological, social, and spiritual challenges which present for patients and their caregivers at the time of hospital discharge following allogeneic transplant.
doi:10.1007/s00520-012-1389-8
PMCID: PMC3393810  PMID: 22318502
Allogeneic transplant; Discharge status; Quality of life
11.  Conditional Survival and Cause-specific Mortality after Autologous Hematopoietic Cell Transplantation for Hematological Malignancies 
Leukemia  2012;27(5):1139-1145.
The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but is not known for aHCT populations. We determined disease-, and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies; and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 and 50% at 10 years from aHCT. On the other hand, 5-year relative survival was 70%, 75%, 81%, and 88% after having survived 1, 2, 5, and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95%CI=13.1–14.8). The risk of death approached that of the general population for 10-year survivors (SMR=1.4, 95%CI=0.9–1.9), with the exception of female Hodgkin lymphoma patients transplanted before 1995 at age 40 years or younger (SMR=6.0, 95%CI=1.9–14.0). Among those who had survived 10 years, non-relapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.
doi:10.1038/leu.2012.311
PMCID: PMC3776451  PMID: 23183426
conditional survival; autologous HCT; cause-specific mortality
12.  Evaluation of Polymorphisms in EWSR1 and Risk of Ewing Sarcoma: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;59(1):52-56.
Background
Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology.
Procedure
Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests.
Results
One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79 – 21.7; p = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%.
Conclusions
Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be a Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.
doi:10.1002/pbc.23263
PMCID: PMC3204324  PMID: 21793187
Ewing sarcoma; EWSR1; single nucleotide polymorphism; genetic epidemiology
13.  Nonadherence to Oral Mercaptopurine and Risk of Relapse in Hispanic and Non-Hispanic White Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2012;30(17):2094-2101.
Purpose
Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.
Patients and Methods
A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed.
Results
After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites.
Conclusion
Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence—an observation currently under investigation.
doi:10.1200/JCO.2011.38.9924
PMCID: PMC3601449  PMID: 22564992
14.  Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2011;30(13):1415-1421.
Purpose
Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors.
Patients and Methods
One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques.
Results
A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status.
Conclusion
This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
doi:10.1200/JCO.2011.34.8987
PMCID: PMC3383117  PMID: 22124095
15.  NCI, NHLBI/PBMTC First International Consensus Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: The Need for Pediatric Specific Long Term Follow-up Guidelines 
Existing standards for screening and management of late effects occurring in children who have undergone hematopoietic cell transplantation (HCT) include recommendations from pediatric cancer networks and consensus guidelines from adult-oriented transplantation societies applicable to all recipients of HCT. While these approaches have significant merit, they are not pediatric-HCT focused and they do not address post-HCT challenges faced by children with complex non-malignant disorders. In this article we discuss the strengths and weaknesses of current published recommendations and conclude that pediatric-specific guidelines for post-HCT screening and management would be beneficial to the long-term health of these patients and would promote late-effects research in this field. Our panel of late effects experts also provides recommendations for follow up and therapy of selected post-HCT organ and endocrine complications in pediatric patients.
doi:10.1016/j.bbmt.2012.01.003
PMCID: PMC3281504  PMID: 22248713
16.  Subsequent Malignant Neoplasms after Hematopoietic Cell Transplantation 
Biology of Blood and Marrow Transplantation  2012;18(1 Suppl):S139-S150.
doi:10.1016/j.bbmt.2011.10.005
PMCID: PMC3260455  PMID: 22226098
17.  Altered Hematopoietic Cell Gene Expression Precedes Development of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia and Identifies Patients at Risk 
Cancer cell  2011;20(5):591-605.
SUMMARY
Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a major complication of cancer treatment. We compared gene expression in CD34+ cells from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for lymphoma with controls who did not develop t-MDS/AML. We observed altered gene expression related to mitochondrial function, metabolism, and hematopoietic regulation in pre-aHCT samples from patients who subsequently developed t-MDS/AML. Progression to overt t-MDS/AML was associated with additional alterations in cell-cycle regulatory genes. An optimal 38-gene PBSC classifier accurately distinguished patients who did or did not develop t-MDS/AML in an independent group of patients. We conclude that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and accurately identify patients at risk for this complication.
doi:10.1016/j.ccr.2011.09.011
PMCID: PMC3220884  PMID: 22094254
19.  NCI, NHLBI First International Consensus Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Etiology and Pathogenesis of Late Effects after HCT performed in Childhood – Methodological Challenges 
Hematopoietic cell transplantation (HCT) is now a curative option for certain categories of patients with hematological malignancies and other life-threatening illnesses. Technical and supportive care has resulted in survival rates that exceed 70% for those who survive the first two years after HSCT. However, long-term survivors carry a high burden of morbidity, including endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies. Understanding the etiologic pathways that lead to specific post-HCT morbidities is critical to developing targeted prevention and intervention strategies. Understanding the molecular underpinnings associated with graft vs. host disease (GvHD), organ toxicity, relapse, opportunistic infection and other long-term complications now recognized as health care concerns will have significant impact on translational research aimed at developing novel targeted therapies for controlling chronic GvHD, facilitating tolerance and immune reconstitution, reducing risk of relapse and secondary malignancies, minimizing chronic metabolic disorders and improving quality of life. However, several methodological challenges exist in achieving these goals; these issues are discussed in detail in this article.
doi:10.1016/j.bbmt.2011.07.005
PMCID: PMC3177028  PMID: 21763253
20.  Role of Genetic Susceptibility in Development of Treatment-related Adverse Outcomes in Cancer Survivors 
Clear and unambiguous associations have been established between therapeutic exposures and specific complications. However, considerable inter-individual variability is observed in the risk of developing an outcome for a given therapeutic exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the inter-individual variability. This article provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related complications. Relatively common outcomes with strong associations with therapeutic exposures, including cardiomyopathy, obesity, osteonecrosis, ototoxicity, and subsequent malignancies are discussed here. In order to develop a deeper understanding of the molecular underpinnings of therapy-related complications, comprehensive and near-complete collection of clinically-annotated samples is critical. Methodological issues such as study design, definition of the endpoints or phenotypes, identification of appropriate and adequately sized study population together with a reliable plan for collecting and maintaining high quality DNA, and selection of an appropriate approach or platform for genotyping are also discussed. Understanding the etiopathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life.
doi:10.1158/1055-9965.EPI-11-0659
PMCID: PMC3191885  PMID: 21980013
21.  Health Behaviors and Cancer Screening Practices in Long-term Survivors of Hematopoietic Cell Transplantation (HCT): A Report from the Bone Marrow Transplant Survivor Study (BMTSS) 
Bone Marrow Transplantation  2011;47(2):283-290.
Patients undergoing HCT are at increased risk of chronic health conditions, including second malignant neoplasms and cardiovascular disease. Little is known about health behaviors and cancer screening practices among HCT survivors that could moderate the risk of these conditions. The BMTSS examined health behaviors and cancer screening practices in individuals who underwent HCT between 1976 and 1998, and survived 2+ years. Health behavior was deemed high-risk if an individual was a current smoker and if they reported risky alcohol intake (≥4 drinks/day [males], ≥ 3 drinks/day [females]) on days of alcohol consumption. Cancer screening assessment was per American Cancer Society recommendations. There were 1040 survivors: 42.7% underwent allogeneic HCT; 43.8% were female; median time from HCT: 7.4 years (range 2.0–27.7 years). Median age at study participation: 43.8 years (range 18.3–73.0 years). Multivariate regression analysis revealed younger age (<35 years) at study participation (Odds Ratio [OR]=4.7; p<0.01) and lower education (
doi:10.1038/bmt.2011.60
PMCID: PMC3134636  PMID: 21423125
Journal of Clinical Oncology  2011;29(22):3056-3064.
Purpose
Childhood cancer survivors experience an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN (SN1) remain at risk to develop multiple SNs. Because SNs are a common cause of late morbidity and mortality, characterization of rates of multiple SNs is needed.
Patients and Methods
In a total of 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, analyses were carried out among 1,382 survivors with an SN1. Cumulative incidence of second subsequent neoplasm (SN2), either malignant or benign, was calculated.
Results
A total of 1,382 survivors (9.6%) developed SN1, of whom 386 (27.9%) developed SN2. Of those with SN2, 153 (39.6%) developed more than two SNs. Cumulative incidence of SN2 was 46.9% (95% CI, 41.6% to 52.2%) at 20 years after SN1. The cumulative incidence of SN2 among radiation-exposed survivors was 41.3% (95% CI, 37.2% to 45.4%) at 15 years compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation. Radiation-exposed survivors who developed an SN1 of nonmelanoma skin cancer (NMSC) had a cumulative incidence of subsequent malignant neoplasm (SMN; ie, malignancies excluding NMSC) of 20.3% (95% CI, 13.0% to 27.6%) at 15 years compared with only 10.7% (95% CI, 7.2% to 14.2%) for those who were exposed to radiation and whose SN1 was an invasive SMN (excluding NMSC).
Conclusion
Multiple SNs are common among aging survivors of childhood cancer. SN1 of NMSC identifies a population at high risk for invasive SMN. Survivors not exposed to radiation who develop multiple SNs represent a population of interest for studying genetic susceptibility to neoplasia.
doi:10.1200/JCO.2011.34.6585
PMCID: PMC3157966  PMID: 21709189
Journal of Proteome Research  2011;10(6):2873-2881.
Hematopoietic stem cell transplantation is the oldest and successful form of stem cell therapy. High dose therapy (HDT) followed by hematopoietic stem cell transplantation allows physicians to administer increased amounts of chemotherapy and/or radiation while minimizing negative side effects such as damage to blood-producing bone marrow cells. Although HDT is successful in treating a wide range of cancers, it leads to lethal therapy-related myelodysplasia syndrome or acute myeloid leukemia (t-MDS/AML) in 5–10% of patients undergoing autologous hematopoietic cell transplantation for Hodgkin lymphoma and non-Hodgkin lymphoma. In this study, we carried out metabolomic analysis of peripheral blood stem cell samples collected in a cohort of patients before hematopoietic cell transplantation in order to gain insights into the molecular and cellular pathogenesis of t-MDS. Nonparametric tests and multivariate analyses were used to compare the metabolite concentrations in samples from patients that developed t-MDS within 5 years of transplantation and the patients that did not. The results suggest that the development of t-MDS is associated with dysfunctions in cellular metabolic pathways. The top canonical pathways suggested by the metabolomic analysis include alanine and aspartate metabolism, glyoxylate and dicarboxylate metabolism, phenylalanine metabolism, citrate acid cycle, and aminoacyl-t-RNA biosynthesis. Dysfunctions in these pathways indicate mitochondrial dysfunction that would result in decreased ability to detoxify reactive oxygen species generated by chemo and radiation therapy, therefore leading to cancer causing mutations. These observations suggest predisposing factors for the development of t-MDS.
doi:10.1021/pr200200y
PMCID: PMC3390255  PMID: 21510650
NMR; metabolomics; peripheral blood stem cells; leukemia
Children and adolescents with acute lymphoblastic leukemia (A.L.L.) receive treatment that relies on daily self- or parent/caregiver-administered oral chemotherapy for approximately two years. Despite the fact that pediatric A.L.L. is uniformly fatal without adequate treatment, non-adherence to oral chemotherapy has been observed in up to one-third of patients. Little is known about the reasons for non-adherence in these patients. This study employed Straussian grounded theory methodology to develop and validate a model to explain the process of adherence to oral chemotherapy in children and adolescents with A.L.L. Thirty-eight semi-structured interviews (with 17 patients and 21 parents/caregivers) and four focused group discussions were conducted. Three stages were identified in the process of adherence: (1) Recognizing the Threat, (2) Taking Control, and (3) Managing for the Duration. Doing Our Part was identified as the core theme explaining the process of adherence, and involves the parent (or patient) taking responsibility for assuring that medications are taken as prescribed. Understanding the association between taking oral chemotherapy and control/cure of leukemia (Making the Connection) appeared to mediate adherence behaviors.
doi:10.1177/1043454211409582
PMCID: PMC3131415  PMID: 21653911
pediatric acute lymphoblastic leukemia; oral chemotherapy; adherence; grounded theory
Pediatric blood & cancer  2011;56(6):994-1002.
Disparities in cancer burden by race/ethnicity have been reported, primarily in adults with cancer. However, there appear to be gaps in the pediatric oncology literature with regards to a comprehensive overview on this topic. Extant literature is used to highlight the results of studies focusing on racial and ethnic disparities in outcome observed in selected childhood cancers. A comprehensive approach is utilized to understand possible underlying causes of disparities in cancer outcomes, and to highlight the gaps that currently exist. This review helps define areas of future research that could help develop targeted, disease-specific approaches to eliminate the disparities.
doi:10.1002/pbc.23078
PMCID: PMC3369622  PMID: 21328525
Childhood Cancer; Health Disparities; Survival; Survivorship

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