The effect of pilot balloon design on estimation of safe tracheal tube cuff pressure.

We studied the effect of pilot balloon design on the ability of experienced anaesthetists to assess and inflate tracheal tube cuffs to safe pressures. A model trachea was designed, incorporating a degree of compliance and an air leak, to evaluate six different pilot balloons grafted onto identical tracheal tubes. Pilot balloons were inflated to one of four pressures and anaesthetists were asked to estimate whether the pressure was acceptable, too low or too high. Anaesthetists were then asked to inflate the cuff of each tube. Overall, 103 (42.9%) of anaesthetists' assessments of tracheal tube cuff pressures were correct (33% correct would be expected by chance, p = 0.002). Pressures generated by anaesthetists inflating tracheal tube cuffs were very variable. Median (IQR [range]) pressures for each pilot balloon ranged from 29 (17-43 [9-56]) cmH(2)O to 74 (49-114 [4-140]) cmH(2)O (p < 0.001). The design of the pilot balloon significantly affects anaesthetists' ability to inflate tracheal tube cuffs to safe pressures.

Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group.

From 1984 to 2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. Ten-year event-free survival (EFS) for patients >12 months of age with B-precursor ALL on acute leukemia in children 14, 15 and 16 series were 66.7+/-1.2%, 68.1+/-1.4% and 73.2+/-2.1%, respectively. Intermediate dose methotrexate (ID MTX; 1 g/m(2)) improved outcomes for standard risk patients (10-year EFS 77.5+/-2.7% vs 66.3+/-3.1% for oral MTX). Neither MTX intensification (2.5 g/m(2)) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m(2)) failed to improve outcomes for either group. Ten-year EFS for patients with T-cell ALL, POG 8704 and 9404 were 49.1+/-3.1% and 72.2+/-4.7%, respectively. Intensive asparaginase (10-year EFS 61.8 vs 42.7%) and high-dose MTX (5 g/m(2)) (10-year EFS 78.0 vs 65.8%) improved outcomes. There was a non-significant improvement in EFS for infants (10-year EFS 17.7+/-7.2-31.9+/-8.3%). Prognostic indicators for B-precursor ALL were age and WBC at diagnosis, gender, central nervous system disease, DNA index and cytogenetic abnormalities. Only gender was prognostic in T-cell ALL. In infants, WBC and MLL translocation were linked to inferior outcome.

Microanalysis of amoxicillin, flucloxacillin, and rifampicin in neonatal plasma.

Simple and rapid reversed-phase high-performance liquid chromatographic assays with ultraviolet detection have been developed and validated for the determination of amoxicillin, flucloxacillin and rifampicin in neonatal plasma. Plasma samples were either precipitated with perchloric acid (amoxicillin) or methanol (rifampicin) or extracted with methylene chloride (flucloxacillin). Precision coefficients of variation and inaccuracy were less than 15% for all three assays. Only small sample volumes (20-40 microL) were required, making the assays suitable for therapeutic drug monitoring and pharmacokinetic studies in preterm and term neonates. The assays have successfully been applied to analysis of amoxicillin, flucloxacillin and rifampicin in previously published pharmacokinetic studies in neonates.

Amoxicillin pharmacokinetics in (preterm) infants aged 10 to 52 days: effect of postnatal age.

The pharmacokinetic parameters of amoxicillin were determined in 32 newborn infants aged 10 to 52 days (mean postnatal age, 24.7 +/- 12.4 days) to improve amoxicillin dosing in this age group. Amoxicillin plasma concentrations were determined using reversed-phase high-performance liquid chromatography in surplus plasma samples from routine gentamicin assays. Amoxicillin pharmacokinetic parameters (mean +/- SD) were as follows: first-order elimination constant (K(el)) = 0.27 +/- 0.10 h(-1), volume of distribution corrected for body weight (V/W) = 0.66 +/- 0.27 L/kg, total body clearance corrected for body weight (CL/W) = 0.18 +/- 0.10 Lkg(-1)h(-1), and elimination half-life (t(1/2)) = 3.0 +/- 1.3 hours. Amoxicillin body clearance was approximately twofold greater in our patients compared with published values in younger neonates (mean postnatal age, 0.76 +/- 1.57 days). Simulation studies using the observed amoxicillin pharmacokinetic data suggest an amoxicillin dose of 40 mg/kg administered every 8 hours in infants older than 9 days postnatal age, independent of gestational age and postconceptional age, to achieve satisfactory target plasma amoxicillin concentrations less than 140 mg/L and time above minimum inhibitory concentration of at least 40%. Prospective evaluation of this suggested new dosage regimen is necessary before implementation in the care of ill neonates.

Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Perforin plays a key role in the cytotoxicity of natural killer and cytotoxic T cells. Genetic mutations in the perforin gene (PRF1) give rise to approximately 30% cases of familial hemophagocytic lymphohistiocytosis. A frequent polymorphism, A91V (C to T transition at position 272), may impair processing of perforin protein to the active form, and has been suggested to increase susceptibility to childhood acute lymphoblastic leukemia (ALL). To investigate the role of A91V in ALL, we genotyped 2272 children with de novo ALL registered on the Pediatric Oncology Group ALL Classification study P9900 and 655 normal controls. Allele frequencies in the controls showed a very low frequency of the variant allele in blacks, 0.7% compared to 4% in white controls. In light of this, analysis was restricted to a comparison of white cases and controls only. Overall genotype frequencies were similar in white ALL cases and normal white controls (P=0.58), indicating that in contrast to the previous report, A91V polymorphism is not associated with increased risk of childhood ALL. PRF1 A91V frequency was significantly increased in children with BCR-ABL positive ALL (24 vs 8.5%; P=0.0048); however, this observation includes a relatively small number of cases and needs further exploration.

High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative.

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.

Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome.

Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph+ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or >50 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P=0.124) and disease-free survival (P=0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

Consensus statements from the Second International Lung Cancer Molecular Biomarkers Workshop: a European strategy for developing lung cancer molecular diagnostics in high risk populations.

The Second Molecular Biomarkers Workshop was held at the Roy Castle International Centre for Lung Cancer Research in Liverpool, in June 2001 and it brought together experts in the clinical, epidemiological and molecular-pathology of lung cancer from Europe and the USA, to address issues surrounding the development of a European strategy for early lung cancer detection. The 2001 Workshop Breakout Groups concentrated on the current challenges in the early detection of lung cancer which need to be addressed in the light of the recent surge in interest in many countries for mounting new clinical trials to evaluate the utility of Spiral CT in early lung cancer detection. If population-based trials of CT screening are mounted it will also be a favorable clinical environment in which to evaluate efficiently recent advances in molecular screening and genotyping. The Workshop focused specifically on: a) clinical and molecular biomarkers, b) sputum as an early detection and diagnostic tool, c) validation of molecular markers prior to their use in early detection trials and d) ethical issues that have to be considered in early lung cancer detection trials. A distillation of the Workshop discussions is given in this article.

Bone marrow stroma-supported culture of T-lineage acute lymphoblastic leukemic cells predicts treatment outcome in children: a Pediatric Oncology Group study.

Significant predictors of treatment outcome are poorly defined for patients with T-lineage acute lymphoblastic leukemia (T-ALL). A high WBC at diagnosis, which has traditionally been a predictor of poor response in T-ALL, has considerably weakened prognostic significance in the face of modern, more intensive chemotherapy. To test the hypothesis that bone marrow stroma-supported leukemic cell recovery might identify children at high risk for relapse, we measured the ex vivo recovery of T-ALL lymphoblasts from 29 newly diagnosed patients using a stromal cell co-culture assay. In all cases the T-ALL lymphoblasts showed an increase in recovery of T-ALL cells (RTC), ranging from 4 to 343%, in comparison to samples maintained without stroma. Since we were blinded to patient outcome in this case-control study, we then correlated patient outcome with RTC. The RTC for 18 patients in complete continuous remission (CCR) for greater than 4 years was stochastically larger than for the 11 patients who eventually relapsed (P = 0.011, by the two-sided Wilcoxon test). Furthermore, 100% of patients with an RTC of more than 26% had a CCR greater than 4 years while 78% of the patients with an RTC of less than 25% relapsed within 4 years. This is the first report to show that higher lymphoblast recovery may predict a more favorable outcome for children with T-ALL. A prospective study is needed to test whether stroma-supported leukemic cell recovery might serve as a basis for assigning risk-adjusted therapy.

Thioredoxin expression in primary T-cell acute lymphoblastic leukemia and its therapeutic implication.

Increased expression of intracellular thioredoxin has been implicated in the inhibition of apoptosis and in a decrease in the sensitivity of the malignancies to drug-induced apoptosis. In the present studies, we analyzed expression of thioredoxin in samples from 28 children with T-cell acute lymphoblastic leukemia and analyzed their sensitivity toward inhibition of thioredoxin expression. Thioredoxin was expressed in variable amounts. Higher expression was associated with higher WBC counts. Exogenously added thioredoxin stimulated proliferation of clonogenic cells among the T-cell acute lymphoblastic leukemia samples expressing relatively lower levels of intracellular thioredoxin, whereas there was no effect on the clonogenic cells expressing high levels of thioredoxin. In addition, there was differential sensitivity of the leukemia clonogenic cells toward 1-methylpropyl 2-imidazolyl disulfide, an inhibitor of thioredoxin expression, as compared with normal hematopoietic progenitors. This suggests the possibility of using this approach for treatment. Because overexpression of thioredoxin is associated with resistance to many anticancer drugs, the inhibition of thioredoxin expression may overcome this drug resistance and probably sensitize leukemia cells to other chemotherapeutic agents.

Knee surgery assistance: patient model construction, motion simulation, and biomechanical visualization.

We present a new system that integrates computer graphics, physics-based modeling, and interactive visualization to assist knee study and surgical operation. First, we discuss generating patient-specific three-dimensional (3-D) knee models from patient's magnetic resonant images (MRIs). The 3-D model is obtained by deforming a reference model to match the MRI dataset. Second, we present simulating knee motion that visualizes patient-specific motion data on the patient-specific knee model. Third, we introduce visualizing biomechanical information on a patient-specific model. The focus is on visualizing contact area, contact forces, and menisci deformation. Traditional methods have difficulty in visualizing knee contact area without using invasive methods. The approach presented here provides an alternative of visualizing the knee contact area and forces without any risk to the patient. Finally, a virtual surgery can be performed. The constructed 3-D knee model is the basis of motion simulation, biomechanical visualization, and virtual surgery. Knee motion simulation determines the knee rotation angles as well as knee contact points. These parameters are used to solve the biomechanical model. Our results integrate 3-D construction, motion simulation, and biomechanical visualization into one system. Overall, the methodologies here are useful elements for future virtual medical systems where all the components of visualization, automated model generation, and surgery simulation come together.

Toward developing a genome-wide microsatellite marker set for linkage analysis in the rhesus macaque (Macaca mulatta): identification of 76 polymorphic markers.

Linkage analysis can be problematic in humans because of the lack of large, multigenerational pedigrees and the difficulties in obtaining phenotypic data on all family members. In contrast, large, captive colonies of rhesus macaque are a potentially valuable resource for linkage studies because detailed phenotypic and genealogical data are kept, inbreeding is avoided, and DNA samples can usually be obtained. Microsatellite marker sets for genome-wide screening are available in a number of species, but not for the rhesus macaque. We tested primers to 400 human microsatellite markers from a genome-wide mapping set using DNA from nine unrelated female rhesus macaques. We found that 76 (19%) of the primers amplified a polymorphic product using the standard protocols for human DNA. The average heterozygosity of the markers in humans was 0.80, compared to 0.65 in the rhesus macaques. This study provides preliminary data, which could be used toward the development of a linkage mapping set in this species. There would be a need, however, to confirm the Mendelian inheritance of the markers.

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial.

A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6 % (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.

Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia.

The downstream effects of p15 and p16 gene deletions and loss of transcripts on dihydrofolate reductase (DHFR) were examined in 63 B-precursor (BP) acute lymphoblastic leukaemia (ALL) samples. p15 and/or p16 gene deletions were seen in 6% and 8%, respectively, of BP-ALL samples; however, losses of p15 and/or p16 transcripts were seen in 26 out of 63 (41%) samples. Loss of p15 transcripts (36.5%) exceeded that for p16 (17.5%). For the 26 BP-ALLs that lacked p15 and/or p16 transcripts, only six (23%) exhibited low levels of DHFR by flow cytometry assay with Pt430, a fluorescent anti-folate. Conversely, 18 out of 37 (49%) BP-ALL samples with intact p15 and/or p16 genes and transcripts showed low levels of DHFR (P = 0.04). In p15- and p16-null K562 cells transfected with a tetracycline-inducible p15 cDNA construct, induction of p15 transcripts and protein was accompanied by decreased growth rates, decreased S-phase fraction, decreased retinoblastoma protein phosphorylation, and markedly reduced levels of DHFR transcripts and protein. Collectively, our results suggest that losses of p15 and/or p16 gene expression result in elevated levels of DHFR in BP-ALL in children. However, additional downstream factors undoubtedly also contribute to elevated levels of this enzyme target.

In vitro sensitivity of T-cell lymphoblastic leukemia to UCN-01 (7-hydroxystaurosporine) is dependent on p16 protein status: a Pediatric Oncology Group study.

p16 regulates the cell cycle pathway by inhibiting the cyclin Ds-cyclin-dependent kinase (CDK) 4/6-mediated phosphorylation of retinoblastoma protein (pRb). Previously, we reported that most primary T-cell acute lymphoblastic leukemia (T-ALL) harbored p16 inactivation and hyperphosphorylated pRb without cyclin Ds or CDK4/6 alterations. Therefore, inhibiting CDK4/6 may be an ideal therapeutic approach for p16 (-) T-ALL. UCN-01 (7-hydroxystaurosporine) is a potent antitumor agent that exerts its effects through the inhibition of CDKs. We now report that p16 protein expression status of T-ALL cells influences their sensitivity to UCN-01. In 36 primary T-ALL cells, the IC50s of UCN-01 in the 27 p16 (-) cells (43+/-52 nM) was significantly lower than that in the 9 p16 (+) cells (258+/-260 nM). Our results suggest that agents like UCN-01 may be useful as a p16-selective therapy for T-ALL.

Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group Study.

Between May 1987 and January 1991, 1354 patients, 1-21 years old, with standard or poor prognosis B-lineage acute lymphocytic leukemia were treated on the Pediatric Oncology Group Study 8602. One thousand three hundred and twenty-three patients entered remission and 1051 patients were randomized on day 43 to an intensification regimen containing L-asparaginase and intermediate-dose methotrexate (regimen B) or cytarabine and intermediate dose methotrexate (regimen C). After completion of intensification at week 25, all patients received the same maintenance therapy until 3 years from diagnosis. Overall 5-year continuous complete remission (CCR) for regimen B was 72+/-2% (s.e.) and for regimen C, 73+/-2% (P = 0.72 by log-rank analysis). Significant differences between treatments for CCR, testicular, CNS relapses overall or with regard to phenotype (pre-B vs early pre-B), gender, or race were not detected. During intensification, regimen C had significantly more bacterial infections (P = 0.05) and days spent in the hospital (P < 0.001) compared with regimen B, while regimen B had significantly more allergic reactions (P < 0.0001). No significant differences in CCR were noted between patients with pre-B and early pre-B ALL (P = 0.22 stratified by risk group and treatment). This study was unable to detect statistical difference between asparaginase (regimen B) and cytarabine (regimen C) during the intensification phase of therapy in children with B-lineage acute lymphocytic leukemia.

Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T-cell acute lymphoblastic leukemia.

p16/p15 regulate the cell cycle pathway by inhibiting the cyclin Ds-CDK4/6 mediated phosphorylation of pRb. We reported previously that in T-cell acute lymphoblastic leukemia (T-ALL), p16 and p15 were frequently (approximately 70%) inactivated at the DNA level by deletion, mutation, or hypermethylation. Therefore, we hypothesize that inactivation of the cell cycle regulatory pathway may be essential in the pathogenesis of T-ALL, and that the remaining T-ALL with a wild-type p16/p15 gene likely harbor inactivation of these genes at RNA or protein levels. Alternatively, the downstream components of the pathway including CDK4/6, cyclin Ds, and pRb may be deregulated. In 124 primary T-ALLs, we found inactivation of the p16 and p15 genes at the DNA level in 79 (64%) and 64 (52%) samples, respectively. Only 9 of the 45 samples with wild-type p16 expressed p16 protein, whereas the remaining 36 lacked p16 expression at the RNA or protein level. In the 60 samples with an intact p15 gene, only 2 expressed p15 mRNA, and the only one analyzed lacked p15 protein. Overall, the abrogation rates for p16 and p15 at DNA/RNA/protein levels were 93% (115 of 124) and 99% (123 of 124), respectively. Although no alterations were evident in cyclin Ds or CDK4/6, pRb was hyperphosphorylated in the majority of samples investigated. These findings strongly support that both p16 and p15 are specific targets in the deregulation of the cell cycle pathway in T-ALL and that the inactivation of these genes is most likely essential in the pathogenesis of this disease.

Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report.

Contemporary chemotherapy has significantly improved event-free survival among patients with T cell-lineage acute lymphoblastic leukemia (T-ALL). Unlike B-precursor ALL, most investigators are still using cranial radiation (CRT) and are hesitant to rely solely on intrathecal therapy for T-ALL. In this study we assessed the effects of CRT upon event-free survival and central nervous system (CNS) relapses in a cohort of children with high risk features of T cell leukemia. In a series of six consecutive studies (1987-1995) patients were non-randomly assigned their CNS prophylaxis per individual protocol. These protocols were based on POG 8704 which relied on rotating drug combinations (cytarabine/cyclophosphamide, teniposide/Ara-C, and vincristine/doxorubicin/6-MP/prednisone) postinduction. Modifications such as high-dose cytarabine, intermediate-dose methotrexate, and the addition of G-CSF, were designed to give higher CNS drug levels (decreasing the need for CRT), to eliminate epidophyllotoxin (decreasing the risk of secondary leukemia), and to reduce therapy-related neutropenia (pilot studies POG 9086, 9295, 9296, 9297, 9398). All patients included in this analysis qualified for POG high risk criteria, WBC >50000/mm3 and/or CNS leukemia. Patients without CNS involvement received 16 doses of age-adjusted triple intra-thecal therapy (TIT = hydrocortisone, MTX, and cytarabine) whereas patients with CNS disease received three more doses of TIT during induction and consolidation. Patients who received CRT were treated with 2400 cGy (POG 8704) or 1800 cGy (POG 9086 and 9295). CNS therapy included CRT in 144 patients while the remaining 78 patients received no radiation by original protocol design. There were 155 males and 57 females with a median age of 8.2 years. The median WBC for the CRT+ and CRT- patients were 186000/mm3 and 200000/mm3, respectively. CNS involvement at diagnosis was seen in 16% of the CRT+ and 23% of the CRT- groups. The complete continuous remission rate (CCR) was not significantly different for the irradiated vs. non-irradiated groups (P = 0.46). The 3-year event-free survival was 65% (s.e. 6%) and 63% (s.e. 4%) for the non-irradiated vs. the radiated group. However, the 3-year CNS relapse rate was significantly higher amongst patients who did not receive CRT; 18% (s.e. 5%) vs. 7% (s.e. 3%) in the irradiated group (P = 0.012). Our analysis in a non-randomized setting, suggests that CRT did not significantly correlate with event-free survival but omitting it had an adverse effect on the CNS involvement at the time of relapse.

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 > 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.