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1.  Prevalence of osteonecrosis and associated risk factors in children before allogenic bone marrow transplantation 
Bone marrow transplantation  2010;46(6):813-819.
Osteonecrosis (ON) is a debilitating long-term complication of allogenic bone marrow transplantation (alloBMT) but may begin before alloBMT in some children because of their primary disease treatment. Therefore, to estimate the prevalence and associated risk factors for ON before alloBMT, we conducted a retrospective analysis of magnetic resonance (MR) studies of 118 children who underwent first alloBMT at our institution between December 2000 and September 2007. Of the 118 consecutive patients, 107 (90.7%) underwent prospective MR studies irrespective of symptoms (69 males; median age at alloBMT 12.9 years), and 11 underwent MR studies for symptoms. Amongst the 107 who had prospective imaging, 23 (21.5%) had ON; nearly 50% had at least 30% epiphyseal involvement. Knees were more frequently involved than were hips; severity of ON was greater in hips. ON prevalence before alloBMT was 23.72% when all 118 patients were included in the denominator. Risk factor analysis, limited to MR studies performed irrespective of symptoms, revealed female gender (P = 0.049) and age ≥10 years at the time of MR study (P = 0.03) as significant risk factors and primary diagnosis of lymphoid malignancies and aplastic anemia trended towards significance. ON prior to alloBMT is a common occurrence in children.
doi:10.1038/bmt.2010.210
PMCID: PMC3010322  PMID: 20818446
Osteonecrosis; allogenic bone marrow transplantation; children; females; lymphoid malignancies; aplastic anemia
2.  Allogeneic Bone Marrow Transplantation in First Remission for Children With Ultra-High-Risk Features of Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study Report 
The prognosis for childhood acute lymphoblastic leukemia (ALL) has improved dramatically over the past quarter of a century. Despite improvements in the treatment of childhood ALL, relapse still occurs in 20 to 30% of patients. While many of these relapses occur in the “standard-risk” patients, approximately 10% of these patients present at diagnosis with clinical and biological features that identify them as very high risk of relapse. Children (2 months-21 years) with at least one ultra-high-risk feature (UHRF) of ALL in first remission treated on a frontline Children’s Cancer Group (CCG) ALL study with a matched family allogeneic donor were eligible for study entry onto CCG-1921 and an allogeneic bone marrow transplant (AlloBMT). Each patient received fractionated total body irradiation (1200 cGy) and cyclophosphamide (120 mg/kg) conditioning therapy followed by unmobilized bone marrow from a matched family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporin. Twenty-nine patients with median age of 8.7 years with UHRF ALL in first complete remission (CR1) received an AlloBMT from a family member. The incidence of grade II–IV acute GVHD was 20.7% and the incidence of chronic GVHD was 3.7%. AlloBMT conditioning regimen was well tolerated and only one patient (3%) had treatment-related mortality. Ten patients (35%) died due to progressive disease. The 5-year event free survival (EFS) for all patients was 58.6% and patients without cytogenetic abnormalities had a 5-year EFS of 77.8%. The 5-year EFS for infants and non-infants was 20.0% and 66.7% (log Rank p=0.01), respectively. Patients with Philadelphia chromosome positive ALL had a 5-year EFS of 66.7%. The children with UHRF of ALL may benefit from AlloBMT in CR1, especially patients with primary induction failure and Philadelphia chromosome positive ALL. Randomized prospective cooperative group studies are required to establish the role of allogeneic hematopoietic stem cell transplantation vs intensive chemotherapy in children with UHRF ALL in CR1.
doi:10.1016/j.bbmt.2006.09.013
PMCID: PMC2731715  PMID: 17241927
childhood acute lympoblastic leukemia; stem cell transplant; Philadelphia chromosome positive ALL; infantile ALL; induction failure
3.  Myeloablative Allogeneic Bone Marrow Transplant Using T Cell Depleted Allografts Followed by Post-Transplant GM-CSF in High Risk Myelodysplastic Syndromes 
Leukemia research  2008;32(9):1439-1447.
Allogeneic blood and marrow transplantation (alloBMT) remains the only curative treatment for patients with myelodysplastic syndromes (MDS), but its application has been limited by the older age range of patients with this disease. T cell depletion decreases transplant-related toxicity related to graft-versus-host disease (GVHD), but does not improve overall survival because of increased risk for relapse and graft failure. Myeloid growth factors have been used to speed engraftment following alloBMT, but data suggest that they may also have anti-tumor properties. We treated 43 patients (median age 56) with MDS/AML with high risk features using a myeloablative T cell depleted alloBMT followed by prolonged systemic GM-CSF. The current event-free survival at 1 and 3 years was 47% and 34% respectively with a median follow-up of 22.8 months in surviving patients. The toxicities compared favorably with those seen using reduced intensity conditioning regimens and included grade III/IV GVHD (10%), graft failure (9%), and cumulative treatment related mortality (28%). The cumulative incidence of relapse remained high at 38%; however, 3/10 patients receiving donor lymphocyte infusions achieved durable complete remissions. These results suggest that it is possible to maintain treatment intensity while minimizing toxicity in older, high-risk MDS patients.
doi:10.1016/j.leukres.2007.12.017
PMCID: PMC2719785  PMID: 18261793
allogeneic bone marrow transplantation; t cell depletion; myelodysplastic syndrome; acute myeloid leukemia; GM-CSF
4.  Impact of Disease Risk on Efficacy of Matched Related Bone Marrow Transplantation for Pediatric Acute Myeloid Leukemia: The Children's Oncology Group 
Journal of Clinical Oncology  2008;26(35):5797-5801.
Purpose
There is considerable variation in the use of HLA-matched related bone marrow transplantation (BMT) for the treatment of pediatric patients with newly diagnosed acute myeloid leukemia (AML). Some oncologists have argued that BMT should be offered to most patients in first complete remission (CR). Others have maintained that transplantation in first remission should be reserved for patients with high-risk disease. We performed this study to determine how disease risk influences the efficacy of BMT.
Methods
We combined data from four cooperative group clinical trials: Pediatric Oncology Group 8821, Children's Cancer Group (CCG) 2891, CCG 2961, and Medical Research Council 10. Using cytogenetics and the percentage of marrow blasts after the first course of chemotherapy, patients were stratified into favorable, intermediate, and poor-risk disease groups. Patients who could not be risk classified were analyzed separately. Outcomes for patients assigned to BMT and for patients assigned to chemotherapy alone were compared.
Results
The data set included 1,373 pediatric patients with AML in first CR. In the intermediate-risk group, the estimated disease-free survival at 8 years for patients who did not undergo transplantation was 39% ± 5% (2 SE), whereas it was 58% ± 7% for BMT patients. The estimated overall survival for patients who did not undergo transplantation was 51% ± 5%, whereas it was 62% ± 7% for BMT patients. Both differences were significant (P < .01). There were no significant differences for survival in the other two risk groups or in the non–risk-stratified patients.
Conclusion
Our study indicates that HLA-matched related BMT is an effective treatment for pediatric patients with intermediate-risk AML in first CR.
doi:10.1200/JCO.2007.13.5244
PMCID: PMC2645105  PMID: 18955460
5.  Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia 
Bone marrow transplantation  2004;34(9):799-806.
Summary
Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8–17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n = 12), in untreated first relapse (n = 11) or with refractory disease (n = 35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27–80%), 36% (11–63%) and 9% (2–21%), respectively. Non-relapse mortality estimates were 0%, 27% (0–54%) and 17% (5–30%), and relapse estimates were 42% (14–70%), 36% (8–65%) and 74% (60–89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.
doi:10.1038/sj.bmt.1704689
PMCID: PMC2926343  PMID: 15361903
acute myeloid leukemia; childhood leukemia
6.  The Use of Imatinib Mesylate as a Lifesaving Treatment of Chronic Myeloid Leukemia Relapse after Bone Marrow Transplantation 
Journal of Transplantation  2009;2009:357093.
We describe the response of imatinib as lifesaving treatment of chronic myeloid leukemia (CML) relapse in seven patients who underwent allogeneic bone marrow transplantation (alloBMT) at our institution over a period of 4 years. Retrospective analysis of their medical records revealed that a mean age at transplant was 45.2 years. The median time to diagnosis was 7.4 years after transplant. At relapse, four, two, and one patients were classified as having hematologic, major molecular, and cytogenetic relapse, respectively. At imatinib initiation, five had CML in a chronic phase, while one patient was diagnosed as having accelerated phase and blast crisis. All these patients could be evaluated for the therapeutic efficacy. At a mean of follow-up of 1.9 years of therapy, all evaluable patients achieved major molecular response without compromising safety. Consistent with available data, our results indicate that imatinib is safe and effective treatment option for patients with relapse after BMT.
doi:10.1155/2009/357093
PMCID: PMC2809434  PMID: 20107580
7.  Emotional Functioning and School Contentment in Adolescent Survivors of Acute Myeloid Leukemia, Infratentorial Astrocytoma, and Wilms Tumor 
Purpose: Cancer in childhood may disrupt normal developmental processes and cause psychosocial problems in adolescent survivors of childhood cancers (ACCSs). Previous studies report inconsistent findings. Study aims were to assess subjective well-being (SWB), psychological distress, and school contentment in survivors of three dissimilar childhood cancers. Patients and methods: Nordic patients treated for acute myeloid leukemia (AML), infratentorial astrocytoma (IA), and Wilms tumor (WT) in childhood from 1985 to 2001, aged ≥1 year at diagnosis, and aged 13–18 years at the time of study were eligible for this questionnaire-based survey that included items on SWB, psychological distress, school contentment, self-esteem, and personality traits; 65% (151/231) responded. An age-equivalent group from a Norwegian health survey (n=7910) served as controls. Results: The median age of ACCSs was 16 years; 52% were males. ACCSs reported better SWB (p=0.004) and self-esteem (p<0.001). They had fewer social problems in school (p=0.004) and their school contentment tended to be higher than controls. SWB and school contentment were positively influenced by self-esteem. However, ACCSs reported higher levels of psychological distress (p=0.002), mostly attributable to general worrying. No significant differences in outcomes were found across diagnoses, and time since diagnosis did not significantly affect the results. Conclusion: The overall emotional functioning of ACCSs was good, possibly due to changes in their perception of well-being after having survived a life-threatening disease. However, they seemed more worried than their peers. This may cause an additional strain at a vulnerable period in life.
doi:10.1089/jayao.2011.0019
PMCID: PMC3621515  PMID: 23610734
8.  Recent Decrease in Acute GVHD in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants 
Unrelated donor (URD) BMT is an effective treatment for leukemia in children, but success is limited by graft versus host disease (GVHD) and relapse. In this study we describe the incidence and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMT performed between 1990 and 2003 for treatment of AML, ALL, CML or MDS, using the Center for International Blood & Marrow Transplant Research (CIBMTR) database. Recipients were <18 years of age, and had available high resolution HLA typing for HLA A, B, C and DRB1. Overall, 27% of recipients developed aGVHD grades III-IV and risk was significantly higher in recipients of T-replete compared with T-depleted grafts (OR 3.12, 95%CI 2.02-4.83; p< 0.0001). Acute GVHD significantly reduced risk of relapse in children with ALL (OR 0.34 95% CI 0.13-0.86, p=0.0052) but not AML (OR 0.58, 95% CI 0.22-2.98; p=0.26). Risk of aGVHD was higher in children transplanted in earlier years (1990-1998, n=365) compared to 1999-2003 (OR 1.93 95%CI 1.27-2.91; p=0.002). We conclude that outcomes have changed significantly over time, with reduced risk of aGVHD in more recent transplants.
doi:10.1016/j.bbmt.2008.12.495
PMCID: PMC3365559  PMID: 19203727
9.  Short-Term Bisphosphonate Therapy Could Ameliorate Osteonecrosis: A Complication in Childhood Hematologic Malignancies 
Case Reports in Medicine  2010;2010:206132.
Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture.
doi:10.1155/2010/206132
PMCID: PMC2892653  PMID: 20589085
10.  Partially Mismatched Transplantation and Human Leukocyte Antigen Donor-Specific Antibodies 
The presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA-haploidentical, allogeneic marrow(alloBMT) transplantation. As preexisting sensitization to HLA antigens is not well characterized among candidates for HLA-haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to-strong for results consistent with positive flow cytometric or cytotoxicity crossmatches. We evaluated 296 alloBMT candidates; 111 (37.5%) were female. DSA were detected in 43 (14.5%) candidates, mostly among female candidates (42.9% female versus 12.5% male). Moderate-to-strong DSA strength was more frequently encountered when directed against haploidentical donors as compared with mismatched unrelated donors. DSAwere most commonly detected in female patients directed against their children. Because the presence of DSA has been considered prohibitive for HLA-mismatched alloBMT, we additionally report a desensitization methodology used to reduce DSA to negative or weak levels, ie, levels well below those detectable in a flow cytometric crossmatch. Nine patients without other available donors underwent desensitization. Eight who reduced their DSA to negative or weak levels proceeded to alloBMT and achieved full donor engraftment. These data support routine DSA evaluation in all patients considered for mismatched alloBMT; however, for patients with no other viable options, desensitization to weak or negative DSA levels may afford the opportunity for successful transplantation.
doi:10.1016/j.bbmt.2013.01.016
PMCID: PMC3768172  PMID: 23353119
Donor specific antibodies; Haploidentical allogeneic bone marrow transplantation; Desensitization
11.  Late-Occurring Neurologic Sequelae in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;28(2):324-331.
Purpose
Children with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors.
Patients and Methods
We analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditory-vestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed.
Results
The median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications.
Conclusion
Children treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.
doi:10.1200/JCO.2009.22.5060
PMCID: PMC2815720  PMID: 19917844
12.  Brief report: Pregnant by age 15 years and substance use initiation among US adolescent girls 
Journal of adolescence  2012;35(5):1393-1397.
We examined substance use onset and associations with pregnancy by age 15 years. Participants were girls ages 15 years or younger (weighted n = 8319) from the 1999–2003 Youth Risk Behavior Surveillance System (YRBS). Multivariable logistic regression examined pregnancy as a function of substance use onset (i.e., age 10 years or younger, 11–12, 13–14, and age 15 years) for alcohol, cigarettes and marijuana, controlling for race/ethnicity and metropolitan location. Of girls pregnant by age 15 years (3% of the sample, weighted n = 243), 16% had smoked marijuana by age 10 years and over 20% had smoked cigarettes and initiated alcohol use by age 10 years. In the multivariable analysis, marijuana use by age 14 years and/or cigarette smoking by age 12 years clearly distinguished girls who became pregnant by age 15 years and is perhaps due to a common underlying risk factor.
doi:10.1016/j.adolescence.2012.03.001
PMCID: PMC3432655  PMID: 22560516
Teenage pregnancy; Adolescent risk behaviors; Sexual intercourse; Substance use
13.  Quality of life following bone marrow transplantation: findings from a multicentre study. 
British Journal of Cancer  1995;71(6):1322-1329.
Questionnaires assessing a range of quality of life (QOL) outcomes were completed by 200 adult bone marrow transplant (BMT) recipients from five BMT treatment centres. Respondents had undergone allogeneic (46%) or autologous BMT (54%) for a haematological malignancy and were disease free and at least 12 months post BMT (mean 43 months). Variability in post-BMT QOL was reported with deficits in physical, sexual and occupational functioning particularly likely. Allogeneic recipients reported poorer QOL than autologous recipients. Greater age at BMT, lower level of education and more advanced disease at BMT were consistent risk factors for poorer QOL. Contrary to previous research, evidence for improved functional status with the passage of time post BMT was obtained. Factors generally not associated with post-BMT QOL included disease diagnosis, dose of total body irradiation, presence of chronic graft-versus-host disease (GVHD), type of GVHD prophylaxis and extent of marrow graft match. In conclusion, while many BMT recipients reported normal QOL, the majority indicated that their QOL was compromised relative to premorbid status. Prospective, longitudinal research will be necessary to further identify risk factors for poor post-BMT QOL and identify the temporal trajectory of post-BMT QOL.
PMCID: PMC2033838  PMID: 7779732
14.  Beyond the “Model Minority” Stereotype: Trends in Health Risk Behaviors Among Asian/Pacific Islander High School Students 
Background
Asian/Pacific Islander (API) students have been stereotyped as the “model minority.” The objective of this study was to examine the trends in health risk behaviors among API students who participated in the San Diego City Schools Youth Risk Behavior Survey (YRBS) between 1993 and 2005.
Methods
High school students from the San Diego City School District completed the self-administered YRBS between 1993 and 2005. Among sexually active students, logistic regression for survey data was used to examine trends in health risk behaviors.
Results
From 1993 to 2005, condom use at last sexual intercourse was consistently lower among API students than their cross-ethnic peers. We observed a significant increasing trend in lifetime smoking, drinking, and marijuana use. Parental communications regarding human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) were significantly less frequent and decreased over time.
Conclusions
Our findings challenge the notion of API youth being the “model minority.” API students face unique challenges, including barriers to good communication about sex and lower rates of condom use. School-based prevention programs are needed for API students, including a focus on HIV communication with parents.
doi:10.1111/j.1746-1561.2009.00420.x
PMCID: PMC2818149  PMID: 19630868
Child and adolescent health; risk behaviors; health communication
15.  Health knowledge about symptoms of heart attack and stroke in adult survivors of childhood acute lymphoblastic leukemia 
Annals of epidemiology  2007;17(10):778-781.
Purpose
Children with acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, have a 5-year survival rate of better than 80%. Long-term survivors of childhood ALL, however, carry an elevated risk of early mortality from cardiac events and stroke, and a disproportionately high prevalence of dyslipidemia and obesity, presumably as an adverse effect of treatment.
Methods
As part of a clinical follow-up study of 70 young adult survivors of childhood ALL, we evaluated the degree to which this high risk group differed in knowledge about symptoms of heart attack and stroke from that of a population-based comparison group frequency-matched by age, sex, and body mass index. Questions from the Behavioral Risk Factor Surveillance System were used to assess health knowledge.
Results
Survivors of ALL scored considerably worse on symptom knowledge than did their population counterparts. The strongest association was observed for chest pain as a symptom of a heart attack: ALL survivors were 14-fold more likely than the comparison group to answer the question incorrectly. Seventy-seven percent of survivors failed to identify pain in the jaw, neck or back as a heart attack symptom.
Conclusions
These results indicate an important gap in knowledge, and underscore the need for health education among survivors of childhood leukemia that includes information about symptoms of myocardial infarction and stroke.
doi:10.1016/j.annepidem.2007.05.004
PMCID: PMC2036017  PMID: 17662616
Cancer; myocardial infarction; health education; adverse late effects
16.  Auditory Complications in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Studya 
Pediatric blood & cancer  2011;57(1):126-134.
Background
Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures.
Procedure
The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to ≥ 5 years post diagnosis, and > 5 years post diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure.
Results
Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR=2.3; 95% CI: 1.8–2.8), tinnitus (RR=1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR=4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR=5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR=2.1; 95% CI: 1.3–3.2), tinnitus (RR=2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR=4.1; 95% CI:2.5–6.7)
Conclusions
Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life.
doi:10.1002/pbc.23025
PMCID: PMC3091978  PMID: 21328523
late effects of therapy; radiation therapy
17.  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
18.  Risk of Thyroid Dysfunction and Subsequent Thyroid Cancer Among Survivors of Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2009;53(3):432-437.
Background
To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.
Procedure
Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970–1986, and compared with 3,846 siblings and population rates, respectively.
Results
The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received ≥20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses ≥20 Gy combined with thyroid doses ≥10 Gy were associated with hypothyroidism, whereas pituitary doses ≥20 Gy combined with thyroid doses ≥15 Gy were associated with hyperthyroidism.
Conclusions
The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.
doi:10.1002/pbc.22082
PMCID: PMC2713362  PMID: 19459201
late effects; leukemia; radiation; hypothyroidism; hyperthyroidism; thyroid cancer
19.  Behaviors Associated with Ultraviolet Radiation Exposure in a Cohort of Adult Survivors of Childhood and Adolescent Cancer. A Report from the Childhood Cancer Survivor Study1 
Cancer  2009;115(18 Suppl):4374-4384.
Background
Previous research from the Childhood Cancer Survivor Study (CCSS) has shown that risk of skin cancer is strongly associated with exposure to radiation therapy. The potential role of ultraviolet radiation exposure in survivors has not been described.
Participants Methods
The CCSS is a retrospective cohort study designed to investigate late effects among 5-year survivors of children and adolescents diagnosed with cancer between 1970–1986. Data regarding current sun protection behavior were collected on 9,298 survivors and 2,950 sibling controls. Median age at follow-up was 31 years (range: 17–54).
Results
In this cohort, childhood cancer survivors and siblings showed similar patterns of sunscreen use (67% vs. 66%). Survivors were significantly less likely to report having sunbathed in the previous year (none vs. any in previous year: RR=0.92, 95%CI=0.89–0.95) or use artificial tanning (none vs. any in previous year: RR=0.76, 95%CI=0.70–0.83). Compared to survivors without radiation therapy, survivors with radiation exposure showed increased use of sunscreen (RR=1.06, 95%CI=1.03–1.10), and less sunbathing (none vs. any in previous year; RR=0.89, 95%CI=0.86–0.92) or artificial tanning (none vs. any in previous year; RR=0.62, 95%CI=0.56–0.69). In adjusted multivariable analysis, statistically significant factors for regular sunscreen use in the past summer (vs. never/rarely) in the survivor population were being female, having lighter skin complexions, having previously been examined for skin cancer, and having skin that burned when in the sun unprotected.
Conclusions
Survivors of childhood cancer self-reported lower tanning practices than siblings. However, because of the potential increased risk of skin cancer from therapy-related exposures, future research should be directed at intervention studies to further reduce UV exposures.
doi:10.1002/cncr.24581
PMCID: PMC2778206  PMID: 19731349
Skin cancer; sun protection behaviors; survivor; radiation; siblings
20.  The Costs and Cost-Effectiveness of Allogeneic Peripheral Blood Stem Cell Transplantation versus Bone Marrow Transplantation in Pediatric Patients with Acute Leukemia 
In a retrospective study, we evaluated the cost and cost-effectiveness of allogeneic peripheral blood stem cell transplantation (PBSCT) (n=30) compared with bone marrow transplantation (BMT) (n=110) in children with acute leukemia at 1 year of follow up. Treatment success was defined as disease free survival at one year post transplant. For standard risk disease patients the treatment success rate was 57.1% for PBSCT patients and 80.3% for recipients of BMT (P=NS). The average total cost per treatment success at 1 year in the standard risk disease group was $512,294 for the PBSCT group and $352,885 for the BMT group (P=NS). For patients with high risk disease, the treatment success rate was 18.8% for PBSCT patients and 23.5% for BMT (P=NS). The cumulative average cost for patients in the BMT group was $457,078 compared to $377,316 for PBSCT (P=NS). Point estimates of the incremental cost-effectiveness ratio (ICER) indicate that allogeneic transplantation of bone marrow grafts is dominant over PBSCT for its lower costs and higher effectiveness in patients with standard risk disease (ICER = −$687,108; 95% CI = $2.4 million to dominated). For patients with high risk disease, BMT was more effective and more costly and the ICER was $1.69 million (95% CI = $29.7 million to dominated) per additional treatment success. The comparative economic evaluation provides support for BMT for standard risk patients, but a great degree of uncertainty limits the clear advantage for either treatment option in patients with high risk disease. Further research using larger and randomized controlled trials will be required to confirm the long term cost-effectiveness of each procedure.
doi:10.1016/j.bbmt.2010.03.016
PMCID: PMC2919628  PMID: 20348004
children; acute leukemia; allogeneic stem cell transplantation
21.  Health-Related Quality of Life in Long-Term Survivors of Relapsed Childhood Acute Lymphoblastic Leukemia 
PLoS ONE  2012;7(5):e38015.
Background
Relapses occur in about 20% of children with acute lymphoblastic leukemia (ALL). Approximately one-third of these children can be cured. Their risk for late effects is high because of intensified treatment, but their health-related quality of life (HRQOL) was largely unmeasured. Our aim was to compare HRQOL of ALL survivors with the general population, and of relapsed with non-relapsed ALL survivors.
Methodology/Principal Findings
As part of the Swiss Childhood Cancer Survivor Study (SCCSS) we sent a questionnaire to all ALL survivors in Switzerland who had been diagnosed between 1976–2003 at age <16 years, survived ≥5 years, and were currently aged ≥16 years. HRQOL was assessed with the Short Form-36 (SF-36), which measures four aspects of physical health and four aspects of mental health. A score of 50 corresponded to the mean of a healthy reference population. We analyzed data from 457 ALL survivors (response: 79%). Sixty-one survivors had suffered a relapse. Compared to the general population, ALL survivors reported similar or higher HRQOL scores on all scales. Survivors with a relapse scored lower in general health perceptions (51.6) compared to those without (55.8;p=0.005), but after adjusting for self-reported late effects, this difference disappeared.
Conclusion/Significance
Compared to population norms, ALL survivors reported good HRQOL, even after a relapse. However, relapsed ALL survivors reported poorer general health than non-relapsed. Therefore, we encourage specialists to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects. This will help to improve patients’ HRQOL.
doi:10.1371/journal.pone.0038015
PMCID: PMC3360640  PMID: 22662262
22.  Differential Effects of Radiotherapy on Growth and Endocrine Function Among Acute Leukemia Survivors: A Childhood Cancer Survivor Study Report 
Pediatric blood & cancer  2012;60(1):110-115.
Background
The differential effects of cranial (CRT), spinal (SRT), and total body irradiation (TBI) on growth and endocrine outcomes have rarely been examined in combination among childhood acute leukemia survivors.
Procedure
Self-reported height/weight, hypothyroidism, and pregnancy/live birth were determined among acute lymphoblastic and myeloid leukemia survivors (n=3,467) participating in the Childhood Cancer Survivor Study, an ongoing cohort study of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986.
Results
Compared with no radiotherapy, risk estimates were consistent across outcomes (adult short stature, hypothyroidism, absence of pregnancy/live birth) with CRT treatment associated with 2–3 fold increased risks, TBI associated with 5–10 fold increased risks, and CRT+TBI associated with >10 fold increased risks. Exposure to any SRT further increased risk of these outcomes 2–3 fold. Changes in body composition were more nuanced as CRT only was associated with an increased risk of being overweight/obese (OR 1.6, 95% CI 1.3–1.9) whereas TBI only was associated with an increased risk of being underweight (OR 6.0, 95% CI 2.4–14.9).
Conclusions
Although patients treated with CRT+TBI were at greatest risk for short stature, hypothyroidism, and a reduced likelihood of pregnancy/live birth, those treated with either modality alone had significantly increased risks as well, including altered body composition. Any SRT exposure further increased risk in an independent fashion.
doi:10.1002/pbc.24198
PMCID: PMC3436954  PMID: 22628201
leukemia; childhood; survivor; growth; hypothyroidism; pregnancy
23.  Reduced Cardiorespiratory Fitness in Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2013;60(8):1358-1364.
Background
Adult survivors of childhood acute lymphoblastic leukemia (ALL) are at increased cardiovascular risk. Studies of factors including treatment exposures that may modify risk of low cardiorespiratory fitness in this population have been limited.
Procedure
To assess cardiorespiratory fitness, maximal oxygen uptake (VO2max) was measured in 115 ALL survivors (median age, 23.5 years; range 18–37). We compared VO2max measurements for ALL survivors to those estimated from submaximal testing in a frequency-matched (age, gender, race/ethnicity) 2003–2004 National Health and Nutritional Examination Survey (NHANES) cohort. Multivariable linear regression models were constructed to evaluate the association between therapeutic exposures and outcomes of interest.
Results
Compared to NHANES participants, ALL survivors had a substantially lower VO2max (mean 30.7 vs 39.9 ml/kg/min; adjusted P<0.0001). For any given percent total body fat, ALL survivors had an 8.9 ml/kg/min lower VO2max than NHANES participants. For key treatment exposure groups (cranial radiotherapy [CRT], anthracycline chemotherapy, or neither), ALL survivors had substantially lower VO2max compared with NHANES participants (all comparisons, P<0.001). Almost two-thirds (66.7%) of ALL survivors were classified as low cardiorespiratory fitness compared with 26.3% of NHANES participants (adjusted P<0.0001). In multivariable models including only ALL survivors, treatment exposures were modestly associated with VO2max. Among females, CRT was associated with low VO2max (P=0.02), but anthracycline exposure was not (P=0.58). In contrast, among males, anthracycline exposure ≥100 mg/m2 was associated with low VO2max (P=0.03), but CRT was not (P=0.54).
Conclusion
Adult survivors of childhood ALL have substantially lower levels of cardiorespiratory fitness compared with a similarly aged non-cancer population.
doi:10.1002/pbc.24492
PMCID: PMC3725590  PMID: 23418044
childhood cancer; acute lymphoblastic leukemia; survivor; cardiorespiratory fitness
24.  Congenital Abnormalities and Acute Leukemia among Children with Down Syndrome: A Children’s Oncology Group Study 
Children with Down syndrome, due to their heightened risk of leukemia and increased prevalence of congenital abnormalities, comprise a valuable population in which to study etiology. A Children’s Oncology Group study investigated the causes of childhood leukemia in children with Down syndrome diagnosed at ages 0 to 19 years during the period 1997–2002. Telephone interviews were completed with mothers of 158 cases [n = 97 acute lymphoblastic leukemia (ALL) and n = 61 acute myeloid leukemia (AML)] and 173 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed via unconditional logistic regression to evaluate the association between congenital abnormalities and acute leukemia overall, and ALL and AML analyzed separately. The results do not provide evidence for an association among the index children (ORCombined, 0.74; 95% CI, 0.45–1.23; ORALL, 0.67; 95% CI, 0.38–1.20; ORAML,1.03; 95% CI, 0.49–2.16) or their siblings (ORCombined, 1.23; 95% CI, 0.71–2.13; ORALL, 1.12; 95% CI, 0.60–2.09; ORAML, 1.60; 95% CI, 0.66–3.86), suggesting congenital malformations do not confer additional risk of leukemia beyond the risk attributable to trisomy 21 in this population.
doi:10.1158/1055-9965.EPI-08-0284
PMCID: PMC2610427  PMID: 18829445
25.  Combination of Intra-Bone Marrow–Bone Marrow Transplantation and Subcutaneous Donor Splenocyte Injection Diminishes Risk of Graft-Versus-Host Disease and Enhances Survival Rate 
Stem Cells and Development  2010;20(5):759-768.
The combination of allogeneic bone marrow transplantation (allo-BMT) and donor lymphocyte infusion (DLI) is a useful method for establishing donor chimerism and preventing a relapse of leukemia/lymphoma. However, there is a risk of inducing uncontrollable fatal graft-versus-host disease (GVHD). In fact, allo-BMT plus intravenous (IV)-DLI using donor splenocytes induces fatal GVHD in recipient mice. In this study, we examined the effects of the combination of intra-bone marrow (IBM)-BMT and the subcutaneous injection of donor splenocytes (SC-DLI) on the allo-BMT system. Recipient BALB/c mice were conditioned by sublethal irradiation (5 Gy), followed by IBM-BMT plus IV-DLI or SC-DLI in C57BL/6 mice. The IV-DLI group showed better engraftment of donor hemopoietic cells than the control group (without DLI) but showed fatal GVHD. The SC-DLI group, however, showed good reconstitution and mild GVHD. These results suggest that the combination of SC-DLI and IBM-BMT promotes the reconstitution of hemopoiesis and helps reduce the risk of GVHD.
doi:10.1089/scd.2010.0232
PMCID: PMC3128777  PMID: 20954841

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