Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different ...weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PI
) that maximized discrimination of the predictive model. Patients with higher PI
have higher predicted relapse risk. The PI
reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PI
identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PI
identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PI
identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PI
can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.
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 > or =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.
Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated ...pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.
Objective: To determine the frequency of underlying bleeding disorders in adolescents with menorrhagia. Study design: We retrospectively reviewed the charts of all girls, aged 10 to 19 years, who ...presented to our children’s hospital for inpatient or outpatient evaluation of menorrhagia between January 1990 and November 1998. Results: At presentation, 9 of the 71 girls (13%) had thrombocytopenia (platelet count <150,000/μL; range, 5000-106,000/μL). The most common causes for thrombocytopenia were immune thrombocytopenic purpura (n = 5) and myelosuppression caused by chemotherapy (n = 2). Of 14 girls who underwent a more detailed hemostatic evaluation, 8 were given a diagnosis of a hereditary coagulation disorder: 6 had platelet function defects and 2 had type 1 von Willebrand disease. Excessive menstrual bleeding commonly results in anemia. One half of the total group had anemia (hemoglobin <12.0 g/dL). Seven girls (10%) had potentially life-threatening anemia (hemoglobin <5.0 g/dL). Conclusions: Acquired and congenital bleeding disorders are common causes of menorrhagia in adolescent girls. Severe anemia is a frequent complication of menorrhagia. We recommend that adolescents without thrombocytopenia who present with menorrhagia receive a comprehensive hemostatic evaluation, including testing for von Willebrand disease and platelet function defects. (J Pediatr 2001;138:856-61)
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP‐binding cassette (ABC) transporter that functions as a chloride channel. Nucleotide‐binding domain 1 (NBD1), one of two ABC ...domains in CFTR, also contains sites for the predominant CF‐causing mutation and, potentially, for regulatory phosphorylation. We have determined crystal structures for mouse NBD1 in unliganded, ADP‐ and ATP‐bound states, with and without phosphorylation. This NBD1 differs from typical ABC domains in having added regulatory segments, a foreshortened subdomain interconnection, and an unusual nucleotide conformation. Moreover, isolated NBD1 has undetectable ATPase activity and its structure is essentially the same independent of ligand state. Phe508, which is commonly deleted in CF, is exposed at a putative NBD1‐transmembrane interface. Our results are consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an NBD1–NBD2 nucleotide sandwich that forms upon displacement of NBD1 regulatory segments.
Patients with out-of-hospital respiratory distress who received treatment from emergency medical services personnel with advanced-life-support training had a lower in-hospital mortality than those ...who received treatment from providers without this training. The difference may be in part attributable to advanced-life-support interventions. Whether the data are sufficient to justify broad implementation of such training is unclear.
Patients with out-of-hospital respiratory distress who received treatment from emergency medical services personnel with advanced-life-support training had a lower in-hospital mortality than those who received treatment from providers without this training.
Each year, emergency medical services (EMS) personnel in the United States transport 2 million patients with respiratory distress to hospitals by ambulance. Respiratory distress is the second most common symptom of adults transported by ambulance and is associated with a relatively high overall mortality before hospital discharge of 18%.
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Among the most common causes of respiratory distress in this setting are congestive heart failure, pneumonia, chronic obstructive pulmonary disease, and asthma.
In many cities in the United States and Canada, out-of-hospital care for critically ill and injured patients is provided by paramedics who are trained in advanced-life-support measures. Advanced . . .
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.
Although numerous somatic mutations that contribute to the pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been identified, no specific cytogenetic or molecular abnormalities are ...known to be consistently associated with relapse. The p16(INK4A) (p16), which encodes for both p16(INK4A) and p19(ARF) proteins, and p15(INK4B) (p15) genes are inactivated by homozygous deletion and/or p15 promoter hypermethylation in a significant proportion of cases of childhood ALL at the time of initial diagnosis. To determine whether alterations in these genes play a role in disease progression, we analyzed a panel of 18 matched specimen pairs collected from children with ALL at the time of initial diagnosis and first bone marrow relapse for homozygous p16 and/or p15 deletions or p15 promoter hypermethylation. Four sample pairs contained homozygous p16 and p15 deletions at both diagnosis and relapse. Among the 14 pairs that were p16/p15 germline at diagnosis, three ALLs developed homozygous deletions of both p16 and p15, and two developed homozygous p16 deletions and retained p15 germline status at relapse. In two patients, p15 promoter hypermethylation developed in the interval between initial diagnosis and relapse. In total, homozygous p16 deletions were present in nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases at relapse. These findings indicate that loss of function of proteins encoded by p16 and/or p15 plays an important role in the biology of relapsed childhood ALL, and is associated with disease progression in a subset of cases.
ATP-binding cassette (ABC) proteins transport a diverse collection of substrates. It is presumed that these proteins couple
ATP hydrolysis to substrate transport, yet ATPase activity has been ...demonstrated for only a few. To provide direct evidence
for such activity in Ste6p, the yeast ABC protein required for the export of a-factor mating pheromone, we established conditions
for purification of Ste6p in biochemical quantities from both yeast and Sf9 insect cells. The basal ATPase activity of purified
and reconstituted Ste6p ( V
max = 18 nmol/mg/min; K
m for MgATP = 0.2 m m ) compares favorably with several other ABC proteins and was inhibited by orthovanadate in a profile diagnostic of ABC transporters
(apparent K
I = 12 μ m ). Modest stimulation (â¼40%) was observed upon the addition of a-factor either synthetic or in native form. We also used an
8-azido- α- 32 PATP binding and vanadate-trapping assay to examine the behavior of wild-type Ste6p and two different double mutants (G392V/G1087V
and G509D/G1193D) shown previously to be mating-deficient in vivo . Both mutants displayed a diminished ability to hydrolyze ATP, with the latter uncoupled from pheromone transport. We conclude
that Ste6p catalyzes ATP hydrolysis coupled to a-factor transport, which in turn promotes mating.
Motivation: The DeCyder software (GE Healthcare) is the current state-of-the-art commercial product for the analysis of two-dimensional difference gel electrophoresis (2D DIGE) experiments. Analyses ...complementing DeCyder are suggested by incorporating recent advances from the microarray data analysis literature. A case study on the effect of smallpox vaccination is used to compare the results obtained from DeCyder with the results obtained by applying moderated t-tests adjusted for multiple comparisons to DeCyder output data that was additionally normalized. Results: Application of the more stringent statistical tests applied to the normalized 2D DIGE data decreased the number of potentially differentially expressed proteins from the number obtained from DeCyder and increased the confidence in detecting differential expression in human clinical studies. Availability: The marray and limma packages used here are available from http://www.bioconductor.org/ Contact: fodor1@llnl.gov
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