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author:("Bhatia, smith")
1.  Ototoxicity in Children With High-Risk Neuroblastoma: Prevalence, Risk Factors, and Concordance of Grading Scales—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(6):527-534.
Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study.
Patients and Methods
Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m2; exposure one) or after cisplatin (400 mg/m2) plus carboplatin (1,700 mg/m2; exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]).
Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection.
Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.
PMCID: PMC3918536  PMID: 24419114
2.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine if less telomere content was associated with treatment-related second malignant neoplasms (SMNs) in childhood cancer survivors.
Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at time of sample collection, years of follow up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content (TC) as a continuous variable to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
There was an inverse relationship between TC and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single copy gene ratio (95% CI, 0.09–1.02, p=0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR 0.04, 95% CI, 0.00–0.55, p=0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
3.  Recommendations for Breast Cancer Surveillance for Female Childhood, Adolescent and Young Adult Cancer Survivors Treated with Chest Radiation: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group 
The Lancet. Oncology  2013;14(13):e621-e629.
Female childhood, adolescent and young adult (CAYA) cancer survivors treated with radiation to fields that include breast tissue (chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these survivors receive optimum care, and thereby reduce the detrimental consequences of cancer treatment. However, surveillance recommendations vary among the existing long-term follow-up guidelines. This guideline provides international harmonized breast cancer surveillance recommendations for female CAYA cancer survivors treated with chest radiation prior to age 30 years. We applied evidence-based methods to develop the international harmonized recommendations. The recommendations were formulated by an international multidisciplinary guideline panel and categorized according to a 4-level colour grading schema adapted from existing level of evidence criteria. The harmonized breast cancer surveillance recommendations are based on a transparent process and are intended to be scientifically rigorous, positively influence health outcomes, and facilitate care for CAYA cancer survivors.
PMCID: PMC4257601  PMID: 24275135
4.  Therapy-related myelodysplasia and acute myeloid leukemia 
Seminars in oncology  2013;40(6):10.1053/j.seminoncol.2013.09.013.
Therapy-related leukemia (t-MDS/AML) is a well known complication of conventional chemoradiotherapy used to treat a variety of primary malignancies including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancer. The median time to development of t-MDS/AML is 3 to 5 years, with the risk decreasing markedly after the first decade. t-MDS/AML is the major cause of non-relapse mortality after autologous hematopoietic cell transplantation (HCT) for HL or NHL. The magnitude of risk of t-MDS/AML is higher, and the latency is shorter after HCT, compared to conventional therapy. Two types of t-MDS/AML are recognized depending on the causative therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type. Interindividual variability in the risk for development of t-MDS/AML suggests a role for genetic variation in susceptibility to genotoxic exposures. Treatment of t-MDS/AML with conventional therapy is associated with a uniformly poor prognosis, with a median survival of 6 months. Because of the poor response to conventional chemotherapy, allogeneic HCT is recommended. Current research is focused on developing risk prediction and risk reduction strategies.
PMCID: PMC3867743  PMID: 24331189
5.  Neurocognitive and Behavioral Outcomes in Latino Childhood Cancer Survivors 
Pediatric blood & cancer  2013;60(10):1696-1702.
Children with brain tumors and leukemia are at risk for neurocognitive and behavioral late effects due to central nervous system-directed therapies. Few studies have examined these outcomes in ethnic minority samples, despite speculation that socio-demographic factors may increase vulnerability for adverse neurobehavioral outcomes. We evaluated the neurocognitive and behavioral outcomes and their impact on the health-related quality of life in survivors of childhood cancer drawn from Latino families in the Los Angeles region.
Using culturally-relevant recruitment strategies, 73 predominantly Spanish-speaking parents of pediatric brain tumor or leukemia survivors completed standardized questionnaires, including the Conners Parent-Report and the Bidimensional Acculturation Scales. Clinical and socio-demographic factors influencing the development of neurocognitive and behavioral dysfunction were examined.
Approximately 50% of the children placed at or above the “elevated” level for difficulties with attention, school-based learning, and peer relations. Younger age at diagnosis significantly predicted dysfunction in inattention, learning problems, and hyperactivity/impulsivity. Children whose parents were less adherent to the non-Hispanic white culture were more likely to have problems with peer relations and executive functioning. HRQL was significantly lower in survivors with neurocognitive and behavioral dysfunction relative to those with normal range scores on the Conners scale.
In addition to the child’s age at diagnosis, acculturation appears to predict select neurocognitive and behavioral outcomes in this socio-demographically homogeneous sample of Latino families. Further research is needed to understand the interaction of ethnic and cultural factors with therapeutic exposures in determining the adverse neurobehavioral outcomes, so as to optimally design interventions.
PMCID: PMC3776597  PMID: 23733619
childhood cancer; neurocognitive; late effects; Latino; health disparities
6.  Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure in Survivors of Haematopoietic Cell Transplantation 
British journal of haematology  2013;163(2):205-213.
Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.
PMCID: PMC3795883  PMID: 23927520
Anthracyclines; congestive heart failure; genetic susceptibility; haematopoietic cell transplantation; late effects
7.  Burden of morbidity in 10+ year survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study 
Long-term morbidity after hematopoietic cell transplantation (HCT) is unknown. The risk of physical and psychological health in 324 patients who had survived 10 or more years after HCT, and a sibling comparison group (n=309) was evaluated. Using the CTCAE v3.0, the 15-year cumulative incidence of severe/life-threatening/fatal conditions was 41% (95%CI, 34–48%). HCT survivors were 5.7 times as likely to develop a severe/life-threatening condition (p<0.001), and 2.7 times as likely to report somatic distress (p<0.001) compared with siblings. Compared with allogeneic HCT recipients with no chronic GvHD, those with active chronic GvHD were at a 1.8-fold higher risk of severe/life-threatening health conditions (p=0.006), and 4.5-fold higher risk of somatic distress (p=0.04); allogeneic HCT recipients with resolved chronic GvHD were not at increased risk of morbidity compared with those with no chronic GvHD. Only 27% of the HCT survivors returned to the transplant center for their cancer-related care. The burden of long-term physical and emotional morbidity borne by survivors remains substantial, even beyond 10 years after HCT; however, specialized healthcare is underutilized. Patients, families and healthcare providers need to be made aware of the high burden, such that they can plan for post-HCT care, even many years after HCT.
PMCID: PMC3691346  PMID: 23583827
8.  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.
PMCID: PMC3799776  PMID: 23255494
Children’s Oncology Group; Survivorship and Outcomes; Late Effects; Health-related Disparities; Long Term Follow-up Guidelines
9.  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.
PMCID: PMC3819170  PMID: 23281199
Guidelines; Late effects; Childhood and young adult cancer survivors; Collaboration
10.  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.
PMCID: PMC3965556  PMID: 24667872
11.  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.
PMCID: PMC3553262  PMID: 23073267
second primary malignancy; transplantation; myeloma
12.  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.
PMCID: PMC3545903  PMID: 23197494
13.  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.
PMCID: PMC3787120  PMID: 23071067
Neurofibromatosis I; radiation; abdominal; sarcomas; carcinomas; genetic
14.  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.
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.
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.
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.
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.
PMCID: PMC3515770  PMID: 23091100
15.  Long-term Complications of Therapeutic Exposures in Childhood: Lessons Learned From Childhood Cancer Survivors 
Pediatrics  2012;130(6):1141-1143.
PMCID: PMC3507259  PMID: 23166341
childhood; cancer survivors; treatment-related complications; chronic health conditions
16.  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.
PMCID: PMC3857376  PMID: 24339710
Quality of Life; Questionnaires; Validation Studies; Child Psychology; Neoplasms; Survivors
17.  Functional status and health-related quality of life among allogeneic transplant patients at hospital discharge: a comparison of sociodemographic, disease, and treatment characteristics 
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.
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.
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.
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.
PMCID: PMC3393810  PMID: 22318502
Allogeneic transplant; Discharge status; Quality of life
18.  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.
PMCID: PMC3776451  PMID: 23183426
conditional survival; autologous HCT; cause-specific mortality
19.  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.
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.
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.
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%.
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.
PMCID: PMC3204324  PMID: 21793187
Ewing sarcoma; EWSR1; single nucleotide polymorphism; genetic epidemiology
20.  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.
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.
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.
Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence—an observation currently under investigation.
PMCID: PMC3601449  PMID: 22564992
21.  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.
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.
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.
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.
PMCID: PMC3383117  PMID: 22124095
22.  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.
PMCID: PMC3281504  PMID: 22248713
23.  Subsequent Malignant Neoplasms after Hematopoietic Cell Transplantation 
Biology of Blood and Marrow Transplantation  2012;18(1 Suppl):S139-S150.
PMCID: PMC3260455  PMID: 22226098
24.  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.
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.
PMCID: PMC3220884  PMID: 22094254

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