BACKGROUND: Sedentary behaviors are associated with poor health outcomes in the general population, but their clinical impact on adult survivors of childhood acute lymphoblastic leukemia (ALL) has not been characterized to date. In the current study, we described the prevalence of sedentary behaviors in survivors of ALL and examined associations between time spent sedentary and body composition and onset of cardiovascular disease (CVD) risk factors. METHODS: Participants' self-reported screen time (eg, television, computer) and activity as measured by accelerometer were used to determine activity time (sedentary, light activity, and moderate or vigorous physical activity). The percentage of time spent in each activity was compared between 331 survivors of ALL and 330 controls. Associations between time sedentary and body composition were evaluated in survivors using linear regression models. Cox proportional hazard models were used to examine the association between time sedentary at baseline and CVD risk factor onset during follow-up. RESULTS: Survivors spent approximately 65% of their time sedentary, 32% in light activity, and 2% in moderate or vigorous physical activity compared with 67% (P =.04), 30% (P<.01), and 3% (P<.01), respectively, in controls. Among survivors, percentage lean body mass decreased by 1.0% ± 0.4% (P =.01) per 10% increase in time sedentary. Survivors who were sedentary ≥60% per day were found to be at an increased risk of high total cholesterol (hazard ratio, 2.52; 95% confidence interval, 1.12-5.64) and any CVD risk factor (hazard ratio, 1.96; 95% confidence interval, 1.16-3.30). CONCLUSIONS: Sedentary behavior is associated with low lean mass and CVD risk factor development and should be limited in survivors of childhood ALL. Cancer 2018;124:1036-43. © 2017 American Cancer Society.

Howell Carrie R.    Wilson Carmen L.    Ehrhardt Matthew J    Partin Robyn E.    Sue Kaste    Lanctot Jennifer    裴正康     Leslie Robison    Melissa Hudson    Kirsten kimberlie Ness   

Cancer

2018

Chemaitilly Wassim    Zhenghong Li    Krasin Matthew J.    Brooke Russell J.    Wilson Carmen L.    Daniel Green    James Klosky    Barnes Nicole    Clark Karen L.    Farr Jonathan B.    Fernandez-Pineda Israel    Bishop Michael W.    Metzger Monika L.    裴正康     Sue Kaste    Kirsten kimberlie Ness    Deo kumar Srivastava    Leslie Robison    Melissa Hudson    Yasui Yutaka    Charles Sklar   

Obstetrical and Gynecological Survey

2018

Context: Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. Objective: To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes. Design: Cross-sectional. Setting: The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center. Patients: Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. Main Outcome Measure: POI was defined by persistent amenorrhea combined with a folliclestimulating hormone level .30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). Results: The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED 8000 mg/m2. Patients with a body mass index 30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. Conclusion: High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.

Chemaitilly Wassim    Zhenghong Li    Krasin Matthew J.    Brooke Russell J.    Wilson Carmen L.    Daniel Green    James Klosky    Barnes Nicole    Clark Karen L.    Farr Jonathan B.    Fernandez-Pineda Israel    Bishop Michael W.    Metzger Monika L.    裴正康     Sue Kaste    Kirsten kimberlie Ness    Deo kumar Srivastava    Leslie Robison    Melissa Hudson    Yasui Yutaka    Charles Sklar   

Journal of Clinical Endocrinology and Metabolism

2017

STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The inclusion criteria were males, ≤18 years of age, ≤10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/mCED (RR = 2.06, 95% CI, 1.08-3.94) or ≤12 g/mCED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/mCED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/mand an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL.

Daniel Green    Zhu Liang    Wang Mingjuan    Chemaitilly Wassim    Deo kumar Srivastava    Kutteh William H.    Ke Raymond W.    Charles Sklar    裴正康     Larry Kun    Raul corrêa Ribeiro    Leslie Robison    Melissa Hudson   

Human Reproduction

2017

Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for low lean muscle mass and muscle weakness, which may contribute to inactivity and early development of chronic diseases typically seen in older adults. Although increasing protein intake, in combination with resistance training, improves lean muscle mass in other populations, it is not known whether muscular tissue among survivors of ALL, whose impairments are treatment-related, will respond similarly. Objective: The aim of this study was to evaluate associations among dietary protein intake, resistance training, and lean muscle mass in survivors of ALL and age-, sex-, and race-matched controls. Design: This was a cross-sectional study. Methods: Lean muscle mass was determined with dual-energy x-ray absorptiometry, dietary information with 24-hour recalls, and participation in resistance training with a questionnaire. Participants were 365 survivors of ALL (52% male; 87% white; median age=28.5 years, range=23.6 -31.7) and 365 controls with no previous cancer. Results: Compared with controls, survivors of ALL had lower lean muscle mass (55.0 versus 57.2 kg, respectively) and lower percentage of lean muscle mass (68.6% versus 71.4%, respectively) than controls. Similar proportions of survivors (71.1%) and controls (69.7%) met recommended dietary protein intake (0.8 g/kg/d). Survivors (45.4%) were less likely to report resistance training than controls (53.8%). In adjusted models, 1-g higher protein intake per kilogram of body mass per day was associated with a 7.9% increase and resistance training ≥1×wk, with a 2.8% increase in lean muscle mass. Limitations: The cross-sectional study design limits temporal evaluation of the association between protein intake and lean muscle mass. Conclusions: The findings suggest that survivors of childhood ALL with low lean muscle mass may benefit from optimizing dietary protein intake in combination with resistance training. Research is needed to determine whether resistance training with protein supplementation improves lean muscle mass in survivors of childhood ALL.

Boland Alexandra M.    Gibson Todd M.    Lu Lu    Sue Kaste    James Delany    Partin Robyn E.    Lanctot Jennifer    Howell Carrie R.    Nelson Heather H.    Chemaitilly Wassim    裴正康     Leslie Robison    Mulrooney Daniel A.    Melissa Hudson    Kirsten kimberlie Ness   

Physical Therapy

2016

Background Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation. Methods In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195. Findings Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3–59·1] vs 52·2 [50·4–53·9], p=0·020) and initiation (55·5 [52·7–58·3] vs 52·1 [50·4–53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all). Interpretation Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy. Funding National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities.

Cheung Yin Ting    Sabin Noah D.    Reddick Wilburn E.    Bhojwani    Liu    Brinkman Tara M.    Glass John O.    Hwang Scott N    Srivastava DeoKumar    裴正康     Leslie Robison    Melissa Hudson    Krull Kevin R.   

The Lancet Haematology

2016

Background Survivors of childhood acute lymphoblastic leukaemia (ALL) are at risk for neurocognitive deficits that affect development in adolescence and young adulthood, and influence educational attainment and future independence. We examined a large and diverse cohort of survivors to identify risk predictors and modifiers of these outcomes. Methods In this cohort study, cognitive and behaviour symptoms were assessed via a standardised parent questionnaire for 1560 adolescent survivors of ALL diagnosed between 1970 and 1999. Clinically significant symptoms (≥90th percentile) and learning problems were compared between survivors and a sibling cohort. Multivariable regression models were used to examine associations with demographic and treatment characteristics. Models were adjusted for inverse probability of sampling weights to reflect undersampling of ALL survivors in the expansion cohort. In a subset of survivors with longitudinal data (n=925), we examined associations between adolescent symptoms or problems and adult educational attainment. Findings Compared with siblings, survivors treated with chemotherapy only were more likely to demonstrate headstrong behaviour (155 [19%] of 752 survivors vs 88 [14%] of 610 siblings, p=0·010), inattention–hyperactivity (15 [19%] vs 86 [14%], p<0·0001), social withdrawal (142 [18%] vs 75 [12%], p=0·002), and had higher rates of learning problems (191 [28%] vs 76 [14%], p<0·0001). In multivariable models among survivors, increased cumulative dose of intravenous methotrexate (ie, >4·3 g/m) conferred increased risk of inattention–hyperactivity (relative risk [RR] 1·53, 95% CI 1·13–2·08). Adolescent survivors with cognitive or behaviour problems and those with learning problems were less likely to graduate from college as young adults than adolescent survivors without cognitive or behaviour problems. Interpretation Although modern therapy for childhood ALL has eliminated the use of cranial radiation therapy, adolescent survivors treated with chemotherapy only remain at increased risk for cognitive, behaviour, and academic problems that adversely affect adult education outcomes. Funding National Cancer Institute, American Lebanese-Syrian Associated Charities.

Jacola Lisa M.    Edelstein Kim    Liu    裴正康     Hayashi Robert    Kadan-Lottick Nina    Srivastava DeoKumar    Henderson Tara O.    Wendy Leisenring    Leslie Robison    Gregory Armstrong    Krull Kevin R.   

The Lancet Psychiatry

2016

Partnerships between medical institutions in high-income countries (HICs) and low- to mid-income countries (LMICs) have succeeded in initiating and expanding pediatric cancer control efforts. The long-term goal is consistently a sustainable national pediatric cancer program. Here, we review the elements required for successful implementation, development, and long-term sustainability of pediatric cancer programs in LMICs that first arise as partnerships with institutions in HICs. Although plans must be adapted to each country's resources, certain components are unfailingly necessary. First, an essential step is provision of treatment regardless of ability to pay. Second, financial support for program development and long-term sustainability must be sought from sources both international and local, public and private. A local leader, typically a well-trained pediatric oncologist who devotes full-time effort to the project, should direct medical care and collaborate with hospital, governmental, and community leadership and international agencies. Third, nurses must be trained in pediatric cancer care and allowed to practice this specialty full-time. It is also essential to develop a grassroots organization, such as a foundation, dedicated solely to pediatric oncology. Its membersmust be trained and educated to provide pediatric cancer advocacy, fundraising, and (in concert with government) program sustainability. Finally, a project mentor in the HIC is crucial and should explore the possibility of collaborative research in the LMIC, which may offer significant opportunities. Relationships between the partnership's leaders and influential individuals in the community, hospital, grassroots foundation, and government will lay the foundation for productive collaboration and a sustainable pediatric oncology program.

Raul corrêa Ribeiro    Antillon Frederico    Pedrosa Francisco    裴正康    

Journal of Clinical Oncology

2016

In genetic association studies of an ordered categorical phenotype, it is usual to either regroup multiple categories of the phenotype into two categories and then apply the logistic regression (LG), or apply ordered logistic (oLG), or ordered probit (oPRB) regression, which accounts for the ordinal nature of the phenotype. However, they may lose statistical power or may not control type I error due to their model assumption and/or instable parameter estimation algorithm when the genetic variant is rare or sample size is limited. To solve this problem, we propose a set-valued (SV) system model to identify genetic variants associated with an ordinal categorical phenotype. We couple this model with a SV system identification algorithm to identify all the key system parameters. Simulations and two real data analyses show that SV and LG accurately controlled the Type I error rate even at a significance level of 10 but not oLG and oPRB in some cases. LG had significantly less power than the other three methods due to disregarding of the ordinal nature of the phenotype, and SV had similar or greater power than oLG and oPRB. We argue that SV should be employed in genetic association studies for ordered categorical phenotype.

Bi Wenjian    Guolian Kang    Zhao Yanlong    Cui Yuehua    Yan Song    Yun Li    Cheng Cheng    Stanley Pounds    Borowitz Michael J.    Mary Relling    Yang Jun J.    Liu Zhifa    裴正康     Stephen Hunger    Hartford Christine M.    Leung Wing    张纪峰   

Annals of Human Genetics

2015

Background: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Methods: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. Findings: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). Interpretation: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. Funding: US National Institutes of Health and American Lebanese Syrian Associated Charities.

Moriyama Takaya    Metzger Monika L.    Wu Gang    Nishii Rina    Qian Maoxiang    Meenakshi Devidas    Yang Wenjian    Cheng Cheng    Cao Xueyuan    Quinn Emily    Raimondi Susana    Julie Gastier-Foster    Elizabeth Raetz    Larsen Eric    Paul langlie Martin    Bowman W. Paul    Naomi Winick    Komada Yoshihiro    Wang Shuoguo    Edmonson Michael    Xu Heng    Elaine Mardis    Robert Fulton    裴正康     Mullighan Charles    Evans William E.    Zhang Jinghui    Stephen Hunger    Mary Relling    Nichols Kim E.    Loh Mignon L.    Jun Yang   

The Lancet Oncology

2015