Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS. METHODS: CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income. RESULTS: Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines. CONCLUSIONS: Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS.

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia.

We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability.

Safe and successful implementation of CPOE for chemotherapy at a children's cancer center.

Computerized prescriber order entry (CPOE) for medications has been implemented in only approximately 1 in 6 United States hospitals, with CPOE for chemotherapy lagging behind that for nonchemotherapy medications. The high risks associated with chemotherapy combined with other aspects of cancer care present unique challenges for the safe and appropriate use of CPOE. This article describes the process for safe and successful implementation of CPOE for chemotherapy at a children's cancer center. A core principle throughout the development and implementation of this system was that it must be as safe (and eventually safer) as existing paper systems and processes. The history of requiring standardized, regimen-specific, preprinted paper order forms served as the foundation for safe implementation of CPOE for chemotherapy. Extensive use of electronic order sets with advanced functionality; formal process redesign and system analysis; automated clinical decision support; and a phased implementation approach were essential strategies for safe implementation of CPOE. With careful planning and adequate resources, CPOE for chemotherapy can be safely implemented.

Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferrioxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO have been utilized in non-compliant patients with heavy iron overload in small case series. PROCEDURE: We review our experience of high dose IV DFO in 27 patients with SCD who had significant iron overload and were noncompliant with subcutaneous (SQ) DFO. All patients were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hr every 2-4 weeks with a mean duration of 19.6 months. RESULTS: We observed a significant decrease in liver iron burden with high dose intermittent IV DFO. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Also there was significant improvement in liver enzymes (ALT, AST) after high dose IV DFO. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. CONCLUSIONS: In our cohort of patients with SCD we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload.

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels.

BACKGROUND: Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion. PROCEDURE: Forty-four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin. RESULTS: Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin >/=2500 ng/ml predicted high liver iron content (>/=7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%. CONCLUSION: We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients.

Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children's Oncology Group study.

BACKGROUND: Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma (ALCL) are rare in young patients. While a high proportion of adults with PTCL have poor risk disease, pediatric PTCL is not well characterized. This study examines the outcome of localized and advanced PTCL in pediatric patients treated in standardized fashion. PROCEDURE: We identified 20 pediatric patients diagnosed with PTCL whose tumor cells did not express CD30 and/or ALK, as determined by immunohistochemistry, between 1992 and 2000 on one of two treatment protocols for localized NHL (POG 9219) or advanced stage large cell lymphoma (POG 9315). All cases were centrally reviewed. RESULTS: The median age was 12.6 (range 0.7-16.9)-9 male and 11 female. Histological subtypes in the WHO Classification included PTCL, unspecified (12), extra-nodal NK/T-cell lymphoma of nasal type (4), subcutaneous panniculitis-like T cell lymphoma (1) and enteropathy-type T-cell lymphoma (1). Two cases exhibited both T-cell and histiocyte markers and were reclassified as histiocytic sarcoma per the WHO, although T-lineage remains possible. Of 10 patients with localized disease, only two relapsed and 9 survive. Of 10 patients with advanced disease, six relapsed and five (50%) survive. CONCLUSIONS: These results suggest that localized PTCL in children and adolescents is frequently cured with modern therapy, but that advanced stage cases may require novel therapy.

Expression of anaplastic lymphoma kinase, tyrosine-phosphorylated STAT3, and associated factors in pediatric anaplastic large cell lymphoma: A report from the children's oncology group.

In anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) activates (phosphorylates) signal transducer and activator of transcription 3 (STAT3) with subsequent cytoplasmic expression, in some cases, of survivin and tissue inhibitor of metalloprotease 1 (TIMP1). These are inhibitors of apoptosis and negative prognostic factors. CD56 is also a negative prognostic marker in ALCL. We assayed 40 cases of predominantly ALK+ pediatric ALCL for pSTAT3, survivin, TIMP1, and CD56 using immunohistochemical analysis. The patients were derived from a Pediatric Oncology Group treatment protocol that showed 72% event-free survival at 4 years for ALCL. The results show that in advanced-stage pediatric ALCL, although most tumors express ALK and a majority show activated STAT3, cytoplasmic localization of survivin and TIMP1 is not frequent, nor is expression of CD56. This may help, in part, explain the relatively good prognosis of pediatric ALCL.

Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial.

PURPOSE: The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkin's lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates. PATIENTS AND METHODS: From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months. RESULTS: The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity. CONCLUSION: The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.

Autologous hematopoietic stem-cell transplantation for children with acute myeloid leukemia in first or second complete remission: a prognostic factor analysis.

PURPOSE: To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was > or = 12 months. RESULTS: Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (> or = 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% CI, 47% to 60%), 23% (95% CI, 10% to 39%), and 60% (95% CI, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children. CONCLUSION: Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.

Results of a randomized phase III trial in children and adolescents with advanced stage diffuse large cell non-Hodgkin's lymphoma: a Pediatric Oncology Group study.

PURPOSE: The Pediatric Oncology Group (POG) adopted a histology-based approach to the management of pediatric non-Hodgkin's lymphomas (NHL) utilizing the National Cancer Institute Working Formulation for Clinical Usage. Patients with diffuse large cell lymphoma (DLCL) were treated on a separate protocol from small cell diffuse undifferentiated or lymphoblastic lymphomas. This study assessed the overall and event free survival of children with DLCL and determined the effects of cyclophosphamide upon these end-points in a prospective randomized trial. PATIENTS AND METHODS: One hundred and twenty eligible stage III or IV NHL patients with the confirmed diagnosis of diffuse large cell or immunoblastic histology were enrolled on study between October 1986 and November 1991. Patients were randomized to receive or not receive cyclophosphamide: 58 received cyclophosphamide, doxorubicin, vincristine, 6-mercaptopurine (6-MP), and prednisone (ACOP+) and 62 were treated with doxorubicin, vincristine, 6-MP, and prednisone (APO). In both treatment programs methotrexate was substituted when the doxorubicin cumulative dose reached 450 mg/m2. Radiation was administered to bulky disease if progression or no response were observed after induction therapy. Planned duration of therapy was 12 months. RESULTS: The 5-year event free survival (EFS) rates of patients treated with ACOP+ versus APO were 62+/-7 and 72+/-6%, respectively. While there was no statistically significant difference between the two treatment arms (p = 0.28), we can only say that we are 95% confident that the difference in 5-year EFS falls in the wide range from 28% in favor of APO to 8% favoring ACOP+. Marrow suppression was the main toxicity with one fatal infection. There were three other deaths on study due to respiratory failure in patients with mediastinal masses. Only one patient experienced cardiotoxicity requiring discontinuation of doxorubicin. Ten patients received radiation therapy to achieve remission. CONCLUSION: The efficacy of elimination of cyclophosphamide from the treatment program of children and adolescents with advanced stage diffuse large cell lymphoma was inconclusive as to its effect on EFS. Furthermore, the majority of the patients (92%) did not require any radiation therapy to bulky disease indicating that the chemotherapy regimens are quite efficient for achievement of complete remission.

Prevalence of the metabolic syndrome among obese adolescents enrolled in a multidisciplinary weight management program: clinical correlates and response to treatment.

OBJECTIVE: The aim of this study was to determine the prevalence of the metabolic syndrome at baseline and after 6 months of lifestyle modification among obese adolescents referred to a multidisciplinary weight management program. METHODS: A total of 165 obese adolescents were evaluated at baseline, and measurements were repeated in 57 subjects who completed 6 months of the program. Metabolic syndrome was defined as having three or more of the following: a body mass index (BMI) >97(th) percentile, hypertension, low high-density lipoprotein cholesterol (HDL-C), hypertriglyceridemia, and impaired fasting glucose (IFG). RESULTS: The prevalence of a BMI >97(th) percentile, hypertension, hypertriglyceridemia, low HDL-C, and IFG was 92.7, 54.5, 29.1, 26.7, and 2.4%, respectively. The prevalence of the metabolic syndrome at baseline was 30.3%. After 6 months of lifestyle modification, BMI z scores, percent body fat, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline; however, there was no significant change in the number of subjects demonstrating >or=three criteria of the metabolic syndrome. CONCLUSIONS: Approximately one third of the study subjects met the criteria of the metabolic syndrome, emphasizing the growing concern for the future development of premature cardiovascular disease in this high-risk population. Our data suggest that new strategies for lifestyle modification may be needed to improve cardiovascular risk factors significantly among adolescents with obesity.

Evaluation of a 6-month multi-disciplinary healthy weight management program targeting urban, overweight adolescents: effects on physical fitness, physical activity, and blood lipid profiles.

This study evaluated preliminary physical fitness, physical activity, and blood lipid profile data obtained from overweight adolescents upon enrolling in a healthy weight management program and following 6 months of program participation. One hundred and sixty-eight participants (13.4+/-1.8 years, 37.9+/-8.3 kg/m(2), 59.5% female and 76.2% African-American) enrolled in the program. The intervention addressed factors related to nutrition, physical activity, and other behaviors related to weight management. Sixty-four participants (38.1%) completed 6 months of program participation. While there was no significant reduction in body mass or body mass index (BMI), BMI z-score was reduced by 1.2% (p < 0.05), cardiorespiratory fitness was increased by 10.8% (p = 0.001), body fat percentage was reduced by 2.6% (p = 0.001), total cholesterol was reduced by 7.2% (p < 0.001), and low density lipoprotein (LDL-C) was reduced by 8.4% (p < 0.001) at 6 months. Continued development and evaluation of programs designed to prevent and treat child and adolescent overweight is warranted to address this major public health issue.

Gender, ethnicity, psychosocial factors, and quality of life among severely overweight, treatment-seeking adolescents.

OBJECTIVE: To examine gender and ethnic differences in psychosocial functioning among 100 (78% African American and 59% girls) treatment-seeking overweight 11- to 18-year-old adolescents. Self-esteem was examined as a potential mediator of the association between weight-related teasing and quality of life (QOL). METHODS: Adolescents completed measures evaluating self-esteem, dietary habits, teasing, and QOL. RESULTS: Few racial or gender differences were found. Mean QOL was similar to that reported in another study examining treatment-seeking overweight adolescents and substantially lower than what has been reported for non-treatment-seeking overweight adolescents. Self-esteem partially mediated the association between teasing and QOL. CONCLUSIONS: Severely overweight adolescents of both genders and diverse ethnicities face significant stigmatization and manifest poor overall psychosocial functioning, which is negatively associated with QOL. Furthermore, self-esteem appears to partially mediate the negative relationship between teasing and QOL.

An assay for human hematopoietic stem cells based on transplantation into nonobese diabetic recombination activating gene-null perforin-null mice.

Abstract Nonobese diabetic recombination activating gene-null perforin-null (NOD- Rag1 null Prf1 null ) mice, which totally lack mature T and B cells and natural killer cell cytotoxic function, survive longer and are easier to breed than NOD-severe combined immunodeficiency ( scid ) or NOD- scid /beta 2 -microglobulin null mice. We have tested the use of NOD- Rag1 null Prf1 null mice as recipients in a long-term xenograft assay for human hematopoietic stem cells (HSCs) by adopting Yoder and colleagues' method of conditioned newborn mice, with minor modifications. Pregnant NOD- Rag1 null Prf1 null dams were treated with busulfan 22.5 mg/kg. On the day of delivery, the busulfan-exposed pups underwent transplantation with 4 to 5 million T cell--depleted human cord blood mononuclear cells via the facial vein. At 2 months after transplantation, all 11 transplanted mice showed human hematopoietic engraftment in the peripheral blood. At 6 months after transplantation, human cells were detected in 5 mice, which showed higher than 0.9% human cell engraftment at 2 months. The mean percentage of human CD45 + cells in the bone marrow of engrafted mice was 43.9% +/- 36.5% (range, 2.0%-79.9%). Next, we tested the usefulness of conditioned newborn NOD- Rag1 null Prf1 null mice for applications to characterize the dye efflux capability and phenotypic features of human HSCs. Given that cord blood HSCs have the ability to efflux rhodamine 123 (Rho), we attempted transplantations of sorted cells that retained a low level (Rho low ) or high level (Rho high ) of Rho. Six-month engraftment was found only with the Rho low cells, which contained high percentages of CD34 + CD38 - cells and side population cells with Hoechst 33324 efflux activity. These observations suggest that Rho low cells are highly enriched for primitive hematopoietic cells. Accordingly, conditioned newborn NOD- Rag1 null Prf1 null mice provide a desirable model for an assay of long-term transplantable human HSCs.

Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events.

We conducted a retrospective study to determine whether the presence of moyamoya collaterals influenced the risk of recurrence of cerebrovascular events (CVEs: stroke or transient ischemic attack) in patients with sickle cell disease placed on chronic transfusions after a stroke. Forty-three patients with homozygous sickle cell anemia (HbSS) and 1 with HbSO(Arab) (16 females, 28 males) who had suffered strokes while under the age of 18 were studied. All patients had been on transfusions aimed at maintaining the sickle hemoglobin (HbS) level below 30%. They were followed for a mean of 6.6 years (2.2 to 20.4 years). The presence of collaterals was diagnosed based on either magnetic resonance angiography or conventional angiography. Eighteen (41%) of the 44 patients suffered recurrent CVEs. Nineteen (43%) (6 females, 13 males) patients had moyamoya collaterals. Eleven (58%) of these 19 experienced 21 total recurrent CVEs, including 4 strokes in 4 patients (21%). In comparison, 7 (28%) of 25 patients without moyamoya collaterals experienced 9 recurrent CVEs (P <.05) with only 1 recurrent stroke (4%). Moyamoya patients were also more likely to have 2 recurrent CVEs (42% vs 8%, P <.05) as well as poorer neuropsychological testing results. A proportional hazards regression analysis indicated that patients with moyamoya were more than twice as likely to incur a subsequent CVE (hazard ratio, 2.40; 95% confidence interval, 0.85, 6.75). We conclude that up to 41% of patients with sickle cell disease experience recurrent CVEs after an initial stroke despite chronic transfusions and that the risk of recurrence is significantly higher for those who have moyamoya collaterals.