Understanding the confluence of injury and obesity in a Grade 2 obesity and above population.

OBJECTIVE: Obesity and injury are major inter-related public health challenges. The objective of this study was to explore the perceptions of injury in people with severe obesity. METHODS: A cross-sectional design was employed to capture injury perception and lifestyle habits via questionnaires. Weight (kg) and height (m) were measured by clinicians for patients attending a weight loss group program. Univariate, chi-square, ANOVA and ordinal regression analyses were undertaken. RESULTS: There were 292 participants (67.1% female), mean age 49.3 years and Body Mass Index 47.2 kg/m2 (range 30.7-91.9 kg/m2). Concern about having an injury was found in 83%, and 74.2% thought that weight would increase the likelihood of injury. A greater concern of being injured at baseline was associated with less weight loss at eight weeks (F=3.567; p=0.03). Depression, anxiety and sleepiness score were higher in those who reported greater 'Concern about having an injury'. CONCLUSIONS: People with obesity fear injury and falling, which limits their willingness to exercise. Anxiety symptoms appear to exacerbate this connection. IMPLICATIONS FOR PUBLIC HEALTH: In individuals with obesity, anxiety, sleepiness and depression are associated with a fear of being injured. Addressing fear and reducing anxiety may decrease barriers to participating in physical activity.

Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9-28-112 µg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063.

Association between Obesity and Omega-3 Status in Healthy Young Women.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential for healthy development and protect against metabolic disease. However, individuals with obesity may be pre-disposed to experiencing lower n-3 PUFA status than normal-weight individuals. This cross-sectional study examined the relationship between the omega-3 index (O3I), body mass index (BMI) and dietary intake in healthy young women (n = 300; age = 18-35 y), a group not previously focused on. Intake was adjusted for energy using the residuals method, and associations were explored using independent t-tests and Pearson's correlations. Participants with obesity were found to have significantly lower O3I than normal-weight participants (p < 0.0001); however, no significant differences were observed in mean n-3 PUFA intakes. Even so, energy-adjusted intakes of n-3 PUFAs, with the exception of alpha-linolenic acid, were significantly correlated with O3I. This study demonstrates that O3I is influenced by both BMI and diet in young women; however the relationship between these two variables may be complex. Current intakes of n-3 PUFA observed in young women may not be effective in achieving target O3I levels in those with obesity, and further research is needed to find effective ways of improving n-3 PUFA status in a group already at increased risk of metabolic disease.

Omega-3 polyunsaturated fatty acids status and cognitive function in young women.

BACKGROUND: Research indicates that low omega-3 polyunsaturated fatty acid (n-3 PUFA) may be associated with decreased cognitive function. This study examined the association between n-3 PUFA status and cognitive function in young Australian women. METHODS: This was a secondary outcome analysis of a cross-sectional study that recruited 300 healthy women (18-35 y) of normal weight (NW: BMI 18.5-24.9 kg/m2) or obese weight (OB: BMI ≥30.0 kg/m2). Participants completed a computer-based cognition testing battery (IntegNeuro™) evaluating the domains of impulsivity, attention, information processing, memory and executive function. The Omega-3 Index (O3I) was used to determine n-3 PUFA status (percentage of EPA (20:5n-3) plus DHA (22:6n3) in the red cell membrane) and the participants were divided into O3I tertile groups: T1 < 5.47%, T2 = 5.47-6.75%, T3 > 6.75%. Potential confounding factors of BMI, inflammatory status (C-reactive Protein), physical activity (total MET-min/wk), alpha1-acid glycoprotein, serum ferritin and hemoglobin, were assessed. Data reported as z-scores (mean ± SD), analyses via ANOVA and ANCOVA. RESULTS: Two hundred ninety-nine women (26.9 ± 5.4 y) completed the study (O3I data, n = 288). The ANOVA showed no overall group differences but a significant group × cognition domain interaction (p < 0.01). Post hoc tests showed that participants in the low O3I tertile group scored significantly lower on attention than the middle group (p = 0.01; ES = 0.45 [0.15-0.74]), while the difference with the high group was borderline significant (p = 0.052; ES = 0.38 [0.09-0.68]). After confounder adjustments, the low group had lower attention scores than both the middle (p = 0.01) and high (p = 0.048) groups. These findings were supported by univariate analyses which found significant group differences for the attention domain only (p = 0.004). CONCLUSIONS: Cognitive function in the attention domain was lower in women with lower O3I, but still within normal range. This reduced but normal level of cognition potentially provides a lower baseline from which cognition would decline with age. Further investigation of individuals with low n-3 PUFA status is warranted.

Transplantation in adults with relapsed/refractory acute lymphoblastic leukemia who are treated with blinatumomab from a phase 3 study.

BACKGROUND: Blinatumomab, a bispecific T-cell-engaging (BiTE®) immuno-oncology therapy, demonstrated superior overall survival versus standard-of-care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL) in the phase 3 TOWER study. Herein, the authors reported clinical features and outcomes for those patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with blinatumomab. METHODS: In the TOWER study, adults with R/R ALL were randomized 2:1 to receive blinatumomab or SOC. Study treatment consisted of 2 cycles of induction with blinatumomab or SOC followed by consolidation and maintenance therapy. At any time after the first cycle, patients who were eligible for HSCT could proceed to HSCT. RESULTS: Of the 97 patients who underwent HSCT during the study, baseline characteristics generally were comparable and donor types were similar between the patients treated with blinatumomab (65 patients) and those receiving SOC (32 patients). There was no evidence to suggest that the survival benefit of HSCT differed between the patients treated with blinatumomab and those receiving SOC (P = .68). On the basis of descriptive statistics, a survival benefit of HSCT versus no HSCT was not observed in patients who achieved complete remission with full, partial, or incomplete hematologic recovery with blinatumomab (odds ratio, 1.17; 95% CI, 0.54-2.53). The best outcomes were achieved in patients with no prior salvage therapy and with minimal residual disease response to blinatumomab regardless of on-study HSCT status. CONCLUSIONS: Survival was found to be driven by response to study treatment and by salvage status regardless of on-study HSCT status. These data should be interpreted with caution because the current study was not designed to prospectively assess survival outcomes associated with HSCT after blinatumomab. LAY SUMMARY: Evidence before this study: Blinatumomab is associated with superior morphologic and molecular response rates and superior overall outcome when compared with standard of care chemotherapy in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Added value of this study: The best outcomes with blinatumomab were observed in patients who achieved minimal residual disease remission in first salvage treatment regardless of subsequent allogeneic stem cell transplantation (HSCT). Implications of all the available evidence: Patients achieving CR/CRh/CRi following blinatumomab can have a durable response with or without HSCT.

Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE®) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph-) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph- R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

Association between Haem and Non-Haem Iron Intake and Serum Ferritin in Healthy Young Women.

Iron is an essential micronutrient for human health and inadequate intake may result in iron deficiency (ID) or iron deficiency anaemia (IDA). Unlike other recent studies investigating iron status in young women, this cross-sectional study analysed dietary intake and biochemical data from healthy young (18-35 years) women (n = 299) to determine the association between both haem iron (HI) and non-haem iron (NHI) intakes and serum ferritin (SF). Dietary restraint and possible inflammation secondary to obesity were also measured and accounted for, and energy intake was adjusted for using the residuals method. Independent samples t-tests and chi-squared tests were performed, and factors found to be significantly different between iron replete (IR) and ID/IDA participants were analysed using general linear modelling. ID/IDA participants consumed significantly lower total energy than iron replete (IR) (p = 0.003). Lower energy intake was also associated with higher levels of dietary restraint (p = 0.001). Both HI and NHI were positively associated with SF with HI was found to be a stronger predictor (ß = 0.128, p = 0.009) than NHI (ß = 0.037, p = 0.028). The study demonstrates that intake of both HI and NHI, as well as adequate dietary energy, are associated with normal iron status levels in young women, and that restrained eaters may be at greater risk of low iron status.

Iron Deficiency Anemia, Not Iron Deficiency, Is Associated with Reduced Attention in Healthy Young Women.

Women of reproductive age are at increased risk for iron deficiency (ID) and iron deficiency anemia (IDA), with both implicated in decreased cognitive function (CF). Obesity may complicate this association via inflammatory-mediated ferritin elevation. This cross-sectional study examined the association between hematological iron status (iron replete (IR), ID or IDA) and CF in healthy, young (18-35 years) women of normal-weight (NW: BMI 18.5-24.9 kg/m²) or obese-weight (OB: BMI >30 kg/m²). Participants completed a validated, computer-based cognition assessment evaluating impulsivity, attention, information processing, memory and executive function; CF reported as z-scores (mean ± SD). Iron status and CF were compared between groups via ANOVA, with adjustment for potential confounders (BMI, physical activity, C-reactive protein) via ANCOVA. A total of 157 NW and 142 OB women (25.8 ± 5.1 years) participated. Prevalence of ID and IDA were 14% and 6% respectively, with no significant difference between NW and OB groups. Women with IDA scored significantly lower on attention (although within normal range; ±1 z-score), compared to ID (IDA: -0.75 ± 1.89; ID: 0.53 ± 1.37; p = 0.004) but not IR (0.03 ± 1.33, p = 0.21) groups; there were no significant differences between ID and IR groups (p = 0.34). Adjustment for confounders did not significantly alter these results. In conclusion, women with IDA showed significantly reduced attention compared to women with ID.

Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective.

OBJECTIVE: To evaluate the cost-effectiveness of blinatumomab (Blincyto) vs standard of care (SOC) chemotherapy in adults with relapsed or refractory (R/R) Philadelphia-chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL) based on the results of the phase 3 TOWER study from a US healthcare payer perspective. METHODS: The Blincyto Global Economic Model (B-GEM), a partitioned survival model, was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs SOC. Response rates, event-free survival (EFS), overall survival (OS), numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from TOWER. EFS and OS were estimated by fitting parametric survival distributions to failure-time data from TOWER. Utility values were based on EORTC-8D derived from EORTC QLQ-C30 assessments in TOWER. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% per year. RESULTS: The B-GEM projected blinatumomab to yield 1.92 additional life years and 1.64 additional quality-adjusted life years (QALYs) compared with SOC at an incremental cost of $180,642. The ICER for blinatumomab vs SOC was estimated to be $110,108/QALY gained in the base case. Cost-effectiveness was sensitive to the number and cost of inpatient days for administration of blinatumomab and SOC, and was more favorable in the sub-group of patients who had received no prior salvage therapy. At an ICER threshold of $150,000/QALY gained, the probability that blinatumomab is cost-effective was estimated to be 74%. LIMITATIONS: The study does not explicitly consider the impact of adverse events of the treatment; no adjustments for long-term transplant rates were made. CONCLUSIONS: Compared with SOC, blinatumomab is a cost-effective treatment option for adults with R/R Ph - B-precursor ALL from the US healthcare perspective at an ICER threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its incremental survival and health-related quality-of-life (HRQoL) benefit over SOC.

Relationship between Obesity and Cognitive Function in Young Women: The Food, Mood and Mind Study.

Limited research addresses links between obesity and cognitive function in young adults. Objective. To investigate the relationship between obesity and cognitive function in young women. Methods. This cross-sectional study recruited healthy, young (18-35 y) women of normal (NW: BMI = 18.5-24.9 kg·m-2) or obese (OB: BMI ≥ 30.0 kg·m-2) weight. Participants completed a validated, computer-based cognitive testing battery evaluating impulsivity, attention, information processing, memory, and executive function. Questionnaires on depression and physical activity and a fasting blood sample for C-reactive protein and the Omega-3 Index were also collected. Cognition data are presented as z-scores (mean ± SD), and group comparisons were assessed via ANOVA. Potential confounding from questionnaire and blood variables were evaluated using ANCOVA. Results. 299 women (NW: n = 157; OB: n = 142) aged 25.8 ± 5.1 y were enrolled. Cognition scores were within normal range (±1 z-score), but OB had lower attention (NW: 0.31 ± 1.38; OB: -0.25 ± 1.39; ES: 0.41, CI: 0.17-0.64; p < 0.001) and higher impulsivity (NW: 0.36 ± 1.14; OB: -0.07 ± 1.07; ES: 0.39, CI: 0.15-0.62; p=0.033). Confounder adjustment had minimal impact on results. Conclusion. The OB group had normal but significantly lower performance on attention and were more impulsive compared to NW participants. This may indicate early cognitive decline, but longitudinal research confirming these findings is warranted.

Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG.

IDH1 SNP rs11554137 was recently reported in association with poor prognosis in normal karyotype adult acute myeloid leukemia (AML). We aimed to determine the prevalence, clinical associations, and prognostic significance of SNP rs11554137 in unselected pediatric and adult AML patients. Diagnostic marrow specimens from 527 AML patients treated on the pediatric trial Children's Oncology Group-AAML03P1 (N = 253) or adult SWOG trials (N = 274) were analyzed for the presence of the SNP. SNP rs11554137 was present in 11% of all patients. SNP status had no prognostic impact on survival in pediatric patients. In adult AML, overall survival for SNP-positive patients was 10% versus 18% for SNP-negative patients (P = .44). Among the 142 adults who achieved complete remission, 5-year relapse-free survival was significantly worse for SNP-positive patients (0% vs 25%, P = .0014). However, among adults with normal cytogenetics, FLT3/ITD was present in 90% of SNP-positive patients versus 59% of SNP-negative patients (P = .0053). In multivariate analysis, adjusting for the effects of age, cytogenetics, and FLT3/ITD, the independent prognostic effect of SNP positivity was not statistically significant (hazard ratio = 1.72, P = .18). The clinical profile of SNP-positive patients suggests that SNP rs11554137 may have biologic effects that bear further investigation. The clinical trials in this study are registered at http://www.clinicaltrials.gov as #NCT000707174 and #NCT00899171.

WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the children's oncology group.

PURPOSE: To analyze the prevalence and clinical implications of Wilms' tumor 1 (WT1) single nucleotide polymorphism (SNP) rs16754 in the context of other prognostic markers in pediatric acute myeloid leukemia (AML). PATIENTS AND METHODS: Available diagnostic marrow specimens (n = 790) from 1,328 patients enrolled in three consecutive Children's Cancer Group/Children's Oncology Group trials were analyzed for the presence of SNP rs16754. SNP status was correlated with disease characteristics, WT1 expression level, and clinical outcome. RESULTS: SNP rs16754 was present in 229 (29%) of 790 patients. The SNP was significantly more common in Asian and Hispanic patients and less common in white patients (P < .001). SNP rs16754 was also less common in patients with inv(16) (P = .043) and more common in patients with -5/del(5q) (P = .047). WT1 expression levels were significantly higher in patients with rs16754 or with WT1 mutations compared with WT1 wild-type patients (P = .021). Five-year overall survival (OS) for patients with and without the SNP was 60% and 50%, respectively (P = .031). Prognostic assessment by risk group demonstrated that in patients with low-risk disease, OS for those with and without SNP rs16754 was 90% versus 64% (P < .001) with a corresponding disease-free survival of 72% versus 53% (P = .041). CONCLUSION: The presence of SNP rs16754 was an independent predictor of improved OS; outcome differences were most pronounced in the low-risk subgroup. The high prevalence of WT1 SNP rs16754, and its correlation with improved outcome, identifies WT1 SNP rs16754 as a potentially important molecular marker of prognosis in pediatric AML.

Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy.

We evaluated the efficacy and safety of romiplostim, a thrombopoietin mimetic, in patients with low- or intermediate-risk myelodysplastic syndromes (MDS) receiving azacitidine therapy. Forty patients with low- or intermediate-risk MDS were stratified by baseline platelet counts (< 50 vs ≥ 50 × 10(9)/L) and randomized to romiplostim 500 µg or 750 µg or placebo subcutaneously once weekly during 4 cycles of azacitidine. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined by grade 3 or 4 thrombocytopenia starting on day 15 of the first cycle or platelet transfusion at any time during the 4-cycle treatment period. No formal hypothesis testing was planned. The incidence of clinically significant thrombocytopenic events in patients receiving romiplostim 500 µg, romiplostim 750 µg, or placebo was 62%, 71%, and 85%, respectively. The incidence of platelet transfusions was 46%, 36%, and 69%, respectively. These differences were not statistically significant with the small numbers in each group. Romiplostim 750 µg significantly raised median platelet counts during cycle 3 on day 1 (P = .0373) and at the nadir (P = .0035) compared with placebo. Grade 3 rash and arthralgia each were reported in 1 romiplostim-treated patient (4%). This study suggests romiplostim may provide clinical benefits in MDS patients during azacitidine therapy.

Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.

Recent studies of WT1 mutations in acute myeloid leukemia (AML) mostly report an association with unfavorable clinical outcome. We screened 842 patients treated on 3 consecutive pediatric AML trials for WT1 zinc-finger mutations. Eighty-five mutations were detected in 70 of 842 patients (8.3%). Mutations occurred predominantly in exon 7 (n = 74) but were also found in exons 8 (n = 5) and 9 (n = 6). Normal karyotype was observed in 35.3% of WT1(mut) patients, whereas 27.5% WT1(mut) patients harbored favorable risk cytogenetics. Patients with or without mutations had similar rates of complete remission after one course of induction chemotherapy. Overall survival (OS) for patients with WT1 mutations was 41% versus 54% for those without mutations (P = .016). Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (28% vs 42%; P = .01). However, FLT3/ITD was present in 36% of the WT1(mut) cohort; WT1(mut) patients without FLT3/ITD had similar OS (56% vs 56%, respectively; P = .8) and EFS (35% and 44%, respectively; P = .34) to patients who were wild type for both mutations. In current risk stratification schemes incorporating cytogenetics and FLT3/ITD status, the presence of WT1 mutations has no independent prognostic significance in predicting outcome in pediatric AML. The clinical trials are registered at www.clinicaltrials.gov as #NCT00002798 and #NCT00070174.

High expression of the very late antigen-4 integrin independently predicts reduced risk of relapse and improved outcome in pediatric acute myeloid leukemia: a report from the children's oncology group.

PURPOSE: To evaluate the prognostic significance of the integrin cell adhesion molecule very late antigen-4 (VLA-4) in acute myeloid leukemia (AML). PATIENTS AND METHODS: We prospectively quantified VLA-4 expression in 216 patients enrolled onto COG-AAML03P1 by flow cytometry and correlated expression levels with disease characteristics and clinical outcome. RESULTS: VLA-4 mean fluorescence intensity (MFI) varied 35-fold (range, 30 to 1,110; median, 219.5). High VLA-4 expression (> median MFI), compared with low expression, was associated with younger age (7.1 v 12.1 years, respectively; P < .001), lower FLT3 internal tandem duplication prevalence (4% v 21%, respectively; P < .001), and higher likelihood of extramedullary disease (16% v 5%, respectively; P = .013). In low- and high-expression groups, rates of remission (89% v 80%, respectively; P = .137) and minimal residual disease (29% v 25%, respectively; P = .700) were similar. Patients with low VLA-4 expression, compared with high expression, had a higher relapse rate (RR; 44% +/- 10% v 24% +/- 9%, respectively; P = .011) and lower disease-free survival (DFS; 48% +/- 11% v 67% +/- 10%, respectively; P = .023) after 3 years. Multivariate analyses showed that low VLA-4 expression was an independent adverse prognostic factor for DFS (hazard ratio [HR] = 1.98; P = .038) and RR (HR = 2.77; P = .009). Subgroup analyses indicated that the prognostic role of VLA-4 expression was most prominent in patients with standard-risk AML, in whom low VLA-4 expression was associated with inferior DFS (34% +/- 16% v 69% +/- 14% for high expression; P = .011) and higher RR (61% +/- 16% v 26% +/- 14% for high expression; P = .009). A similar trend was seen in low-risk but not high-risk patients. CONCLUSION: High VLA-4 expression is associated with better clinical outcome in pediatric AML and is an independent predictor of relapse that may refine our abilities to stratify patients without identifiable cytogenetic or molecular risk factors.

Prospective monitoring for invasive aspergillosis using galactomannan and polymerase chain reaction in high risk pediatric patients.

BACKGROUND: The diagnosis of invasive aspergillus remains a challenge in the care of high-risk patients. Outcomes are improved when invasive aspergillus is diagnosed early, prompting the initiation of appropriate antifungal therapy. We evaluated the utility of prospective monitoring for invasive aspergillosis (IA) using biomarkers such as serum galactomannan (GM) and/or blood polymerase chain reaction (PCR) in high-risk pediatric patients. METHODS: Patients with high-risk leukemia (HRL) or allogenic hematopoietic cell transplant (HCT) recipients were prospectively monitored twice weekly for IA using GM and PCR for Aspergillus species. RESULTS: Sixty-eight patients had collected >or=2 specimens. The 1086 specimens were collected; 627 from HRL (58%) and 459 (42%) from HCT recipients. Median specimens/patient was 11.0 (2 to 58), and median follow-up/patient was 98.5 days (14 to 437). Fifty-six percent of samples were obtained from patients receiving mold-active agents; 32% HRL and 89% HCT. There were no proven, 3 probable, and 20 possible episodes of IA. Thirteen specimens (1.2%) from 4 patients (5%) were GM+. None were positive by PCR. CONCLUSIONS: The prospective use of GM and PCR in this high-risk pediatric population did not identify cases of proven IA. A high false positive rate was not detected. It is speculated that changes in clinical practice, such as early use of empiric and/or prophylactic mold-active agent and frequent imaging studies have impacted the epidemiology of IA. In a population with low incidence of IA, the use of these assays as a screening device on blood may not further enhance current outcomes.

Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.

CEBPA mutations have been associated with improved outcome in adult acute myeloid leukemia (AML). We evaluated the prevalence and prognostic significance of CEBPA mutations in 847 children with AML treated on 3 consecutive pediatric trials. Two types of CEBPA mutations-N-terminal truncating mutations and in-frame bZip-domain mutations-were detected in 38 (4.5%) of 847 patients tested; 31 (82%) of 38 patients with mutations harbored both mutation types. Mutation status was correlated with laboratory and clinical characteristics and clinical outcome. CEBPA mutations were significantly more common in older patients, patients with FAB M1 or M2, and patients with normal karyotype. Mutations did not occur in patients with either favorable or unfavorable cytogenetics. Actuarial event-free survival at 5 years was 70% versus 38% (P = .015) with a cumulative incidence of relapse from complete remission of 13% versus 44% (P = .007) for those with and without CEBPA mutations. The presence of CEBPA mutations was an independent prognostic factor for improved outcome (HR = 0.24, P = .047). As CEBPA mutations are associated with lower relapse rate and improved survival, CEBPA mutation analysis needs to be incorporated into initial screening for risk identification and therapy allocation at diagnosis.

Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Longer and more intensive postinduction intensification (PII) improved the outcome of children and adolescents with "higher risk" acute lymphoblastic leukemia (ALL) and a slow marrow response to induction therapy. In the Children's Cancer Group study (CCG-1961), we tested longer versus more intensive PII, using a 2 x 2 factorial design for children with higher risk ALL and a rapid marrow response to induction therapy. Between November 1996 and May 2002, 2078 children and adolescents with newly diagnosed ALL (1 to 9 years old with white blood count 50 000/mm3 or more, or 10 years of age or older with any white blood count) were enrolled. After induction, 1299 patients with marrow blasts less than or equal to 25% on day 7 of induction (rapid early responders) were randomized to standard or longer duration (n = 651 + 648) and standard or increased intensity (n = 649 + 650) PII. Stronger intensity PII improved event-free survival (81% vs 72%, P < .001) and survival (89% vs 83%, P = .003) at 5 years. Differences were most apparent after 2 years from diagnosis. Longer duration PII provided no benefit. Stronger intensity but not prolonged duration PII improved outcome for patients with higher-risk ALL. This study is registered at http://clinicaltrials.gov as NCT00002812.

Phase 2 study of docetaxel in the treatment of childhood refractory acute leukemias: a Children's Oncology Group report.

BACKGROUND: To determine the response rate and toxicity of docetaxel when administered as a 60 mg/m(2) dose by 1 hr intravenous (IV) infusion weekly x 3 weeks in children with relapsed acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). PROCEDURE: Patients who were under the age of 22-year-old at the time of the original ALL or AML diagnosis and in a second relapse were accrued from August 2002 to May 2005 for this Children's Oncology Group (COG) phase 2 study (ADVL0023). Ten patients with ALL and two patients with AML were enrolled. RESULTS: There were no complete or partial responses observed. The most common grade 3 or 4 toxicities were hematologic followed by febrile neutropenia. One patient developed a dose limiting elevation in serum bilirubin, but no other significant hepatotoxicity was observed. CONCLUSIONS: Docetaxel was not effective therapy for children with relapsed ALL at the dose and schedule tested.

Leukemias and lymphomas: treatment and prophylaxis of the central nervous system.

Central nervous system (CNS)-directed therapy is required for many acute leukemia patients and for nearly all aggressive or high-grade non-Hodgkin's lymphoma patients as part of an overall chemotherapy plan for disease eradication. The CNS therapy decisions differ for overt disease treatment versus prophylactic treatment and take into consideration the type of leukemia or lymphoma, the age of the patient, and other prognostic factors. A variety of CNS-directed therapies are used for prevention or treatment of CNS disease in acute leukemias or aggressive lymphomas: intrathecal medications (cytosine arabinoside, methotrexate, or both in combination with hydrocortisone) with or without cranial or craniospinal irradiation, intrathecal medication only with intensive systemic chemotherapy, or high-dose chemotherapy specifically chosen for CNS penetrance. Any type of CNS-directed therapy, whether intrathecal chemotherapy, high-dose systemic chemotherapy, or irradiation, may cause acute or delayed (late) toxicity. Ongoing clinical trial research aims to reduce the risk of toxicity from CNS-directed therapy while preserving or improving treatment efficacy.