Kelly W. Maloney

Diarrhoea prevention in Bolivia through point-of-use water treatment and safe storage: a promising new strategy

A novel water quality intervention that consists of point-of-use water disinfection, safe storage and community education was field tested in Bolivia. A total of 127 households in two periurban communities were randomized into intervention and control groups, surveyed and the intervention was distributed. Monthly water quality testing and weekly diarrhoea surveillance were conducted. Over a 5-month period, intervention households had 44% fewer diarrhoea episodes than control households (P = 0.002). Infants < 1 year old (P = 0.05) and children 5-14 years old (P = 0.01) in intervention households had significantly less diarrhoea than control children. Campylobacter was less commonly isolated from intervention than control patients (P = 0.02). Stored water in intervention households was less contaminated with Escherichia coli than stored water in control households (P < 0.0001). Intervention households exhibited less E. coli contamination of stored water and less diarrhoea than control households. This promising new strategy may have broad applicability for waterborne disease prevention.

Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994.

This paper presents the long-term results of treatment for children with acute lymphoblastic leukemia (ALL) as conducted by the Pediatric Oncology Group (POG) from 1986 to 1994. The data are presented using standard NCI/Rome risk criteria. The overall event-free survival (EFS) at 5 and 10 years were 70.9% and 67.3% for children with B-precursor ALL, 51.0% and 50.2% for patients with T cell ALL, and 22.4% and 20.9% for infants with ALL. Concomitant biologic studies found that in B-precursor ALL a DNA index (DI) of ⩾1.16 and trisomies of both chromosomes 4 and 10 were good prognostic indicators for patients with B-precursor ALL. The traditional prognostic indicators (age and white count), DI and trisomies did not predict outcome in patients with T cell disease. Infants continued to do poorly overall despite more intensive therapy with rotating pairs of chemotherapy. We recommend continued reporting of study results using common risk criteria in order to facilitate comparisons both within and across study groups.

Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia

The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.

6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<

Intrachromosomal Amplification of Chromosome 21 Is Associated With Inferior Outcomes in Children With Acute Lymphoblastic Leukemia Treated in Contemporary Standard-Risk Children's Oncology Group Studies: A Report From the Children's Oncology Group

50 000: 84.5%, vs ≥

Significant Discrepancies Between Diagnostic and Pathologic Gleason Sums in Prostate Cancer: The Predictive Role of Age and Prostate-Specific Antigen

50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group

PURPOSE Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Childrens Oncology Group (COG) ALL trials. PATIENTS AND METHODS Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS. RESULTS iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age ≥ 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age ≥ 10 years, WBC less than 50,000/μL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD ≥ 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome. CONCLUSION iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols.

TEL-AML1 fusion identifies a subset of children with standard risk acute lymphoblastic leukemia who have an excellent prognosis when treated with therapy that includes a single delayed intensification.

OBJECTIVES To assess the discrepancies between diagnostic and pathologic Gleason sums and the predictive role of age and prostate-specific antigen (PSA) level on Gleason sum discrepancies. METHODS A total of 2963 patients receiving radical prostatectomy at Duke University from 1988 to 2006 were divided into two groups according to year of diagnosis: 1988 to 1999 and 2000 to 2006. The Gleason sum discrepancies were evaluated in the above groups. The predictive roles of diagnostic age (less than 50, 50 to 60, 60.1 to 70, and greater than 70 years), PSA level (less than 10, 10 to 20, and greater than 20 ng/mL), race, body mass index, and prostate weight on the discrepancies were analyzed. RESULTS Overall, 55.8% of diagnostic Gleason sums differed from those on final surgical pathology (58.6% in the 1988 to 1999 and 49.3% in the 2000 to 2006 groups). Diagnostic Gleason sums were undergraded in 41.2% of cases and overgraded in 12.8% of cases. Men older than 60 years were more likely to have their diagnostic Gleason sums undergraded than men younger than 50 (odds ratio in age groups less than 50, 50 to 60, 60.1 to 70, and greater than 70 years: 1.00, 2.30, 4.03, and 3.96, respectively). Biopsy Gleason sums in men with a high PSA level were more likely to be undergraded compared with the PSA group less than 10 ng/mL (odds ratio in PSA groups less than 10, 10 to 20, and greater than 20 ng/mL: 1.00, 2.11, and 3.64, respectively). CONCLUSIONS Significant discrepancies between diagnostic and pathologic Gleason sums remain in recent years. The rate of diagnostic Gleason sum undergrading was 3.2-fold that of overgrading. Advanced age and high PSA level were predictive of diagnostic Gleason sum undergrading, and caution should be exercised when recommending active surveillance in older men.

A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and an inferior outcome. We reviewed data from 2811 children with ALL enrolled in Childrens Oncology Group P9900, which included prospective testing for the major cytogenetic lesions in childhood ALL: ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL translocations and trisomies of chromosomes 4 and 10. Eighty (3%) B-precursor ALL patients had DS. Age, sex, white blood cell count, and risk group were similar between DS-ALL and non-DS-ALL but significantly more patients with DS-ALL were white (91.2% vs 76.4%, P = .001). Children with DS-ALL had lower rates of the favorable cytogenetic lesions ETV6-RUNX1 (2.5% vs 24%, P < .001) and trisomies 4 and 10 (7.7% vs 24%, P < .001). Five-year event-free (EFS) and overall survival (OS) were inferior in children with DS-ALL: 69.9% +/- 8.6% versus 78.1% +/- 1.2% (P = .078), and 85.8% +/- 6.5% versus 90.0% +/- 0.9% (P = .033). However, when children with MLL translocations, BCR-ABL1, ETV6-RUNX1, and trisomies 4 and 10 were excluded, the EFS and OS were similar for children with and without DS (EFS 68.0 %+/- 9.3% vs 70.5% +/- 1.9%, P = .817; and OS 86.7% +/- 6.7% vs 85.4% +/- 1.5%; P = .852), both overall and adjusted for race. DS-ALL displays a unique spectrum of biologic subtypes with different frequencies of sentinel cytogenetic lesions having a large influence on outcome.

Acute leukemias in children with Down syndrome

The Children’s Cancer Group (CCG) found that children with moderate risk acute lymphoblastic leukemia (ALL) had an improved 5-year event-free survival (EFS) rate when treated with therapy that included a doubled delayed intensification (DDI) vs a single DI (SDI) phase. Because of increased toxicity with DDI, it is important to determine whether subgroups of children with ALL can be identified who have excellent outcomes with SDI therapy. TEL-AML1 fusion and hyperdiploid DNA content are present in the leukemic blasts of significant proportions of children with ALL and have been associated with an excellent prognosis. In this study, we retrospectively examined the impact of TEL-AML1 status and ploidy on treatment outcome in a cohort of 75 children with standard risk ALL treated at our institution between 1983 and 1993 with SDI therapy. TEL-AML1 fusion was present in 19/43 (44%) evaluable cases. Fifteen of 56 (27%) evaluable cases were classified as hyperdiploid based on a modal chromosome number of ⩾51 and/or a DNA index of ⩾1.16. The 7-year EFS was 81% for the 19 TEL-AML1-positive patients vs 54% for the 24 TEL-AML1-negative patients (P = 0.0264). In multivariate analyses, TEL-AML1-positive status was associated with a superior EFS (P = 0.02) even when the intial white blood count was included in the model. Overall survival (OS) at 7 years for TEL-AML1-positive patients was 100% vs 83% for TEL-AML1-negative patients (P = 0.0677). There were no differences in 7-year EFS or OS based on ploidy comparisons. These results underscore the need to examine closely the effects of treatment intensification on specific biologically defined subgroups of children with ALL.