Does tantalum exhibit any intrinsic antimicrobial or antibiofilm properties?

AIMS: Tantalum (Ta) trabecular metal components are increasingly used to reconstruct major bone defects in revision arthroplasty surgery. It is known that some metals such as silver have antibacterial properties. Recent reports have raised the question regarding whether Ta components are protective against infection in revision surgery. This laboratory study aimed to establish whether Ta has intrinsic antibacterial properties against planktonic bacteria, or the ability to inhibit biofilm formation. MATERIALS AND METHODS: Equal-sized pieces of Ta and titanium (Ti) acetabular components were sterilised and incubated with a low dose inoculum of either Staphylococcus (S.) aureus or S. epidermidis for 24 hours. After serial dilution, colony forming units (cfu) were quantified on Mueller-Hinton agar plates. In order to establish whether biofilms formed to a greater extent on one material than the other, these Ta and Ti pieces were then washed twice, sonicated and washed again to remove loosely adhered planktonic bacteria. They were then re-incubated for 24 hours prior to quantifying the number of cfu. All experiments were performed in triplicate. RESULTS: More than 1x108 cfu/ml were observed in both the Ta and Ti experiments. After washing and sonication, more than 2x107 cfu/ml were observed for both Ta and Ti groups. The results were the same for both S. aureus and S. epidermidis. CONCLUSION: Compared with Ti controls, Ta did not demonstrate any intrinsic antibacterial activity or ability to inhibit biofilm formation. Hence, intrinsic antimicrobial properties of Ta do not account for the previously observed reduction in the frequency of subsequent infections when Ta was used in revision procedures. Cite this article: Bone Joint J 2017;99-B:1153-6.

Molecular diversity of the methanotrophic bacteria communities associated with disused tin-mining ponds in Kampar, Perak, Malaysia.

In a previous study, notable differences of several physicochemical properties, as well as the community structure of ammonia oxidizing bacteria as judged by 16S rRNA gene analysis, were observed among several disused tin-mining ponds located in the town of Kampar, Malaysia. These variations were associated with the presence of aquatic vegetation as well as past secondary activities that occurred at the ponds. Here, methane oxidizing bacteria (MOB), which are direct participants in the nutrient cycles of aquatic environments and biological indicators of environmental variations, have been characterised via analysis of pmoA functional genes in the same environments. The MOB communities associated with disused tin-mining ponds that were exposed to varying secondary activities were examined in comparison to those in ponds that were left to nature. Comparing the sequence and phylogenetic analysis of the pmoA clone libraries at the different ponds (idle, lotus-cultivated and post-aquaculture), we found pmoA genes indicating the presence of type I and type II MOB at all study sites, but type Ib sequences affiliated with the Methylococcus/Methylocaldum lineage were most ubiquitous (46.7 % of clones). Based on rarefaction analysis and diversity indices, the disused mining pond with lotus culture was observed to harbor the highest richness of MOB. However, varying secondary activity or sample type did not show a strong variation in community patterns as compared to the ammonia oxidizers in our previous study.

Molecular diversity of the ammonia-oxidizing bacteria community in disused tin-mining ponds located within Kampar, Perak, Malaysia.

Disused tin-mining ponds make up a significant amount of water bodies in Malaysia particularly at the Kinta Valley in the state of Perak where tin-mining activities were the most extensive, and these abundantly available water sources are widely used in the field of aquaculture and agriculture. However, the natural ecology and physicochemical conditions of these ponds, many of which have been altered due to secondary post-mining activities, remains to be explored. As ammonia-oxidizing bacteria (AOB) are directly related to the nutrient cycles of aquatic environments and are useful bioindicators of environmental variations, the focus of this study was to identify AOBs associated with disused tin-mining ponds that have a history of different secondary activities in comparison to ponds which were left untouched and remained as part of the landscape. The 16S rDNA gene was used to detect AOBs in the sediment and water sampled from the three types of disused mining ponds, namely ponds without secondary activity, ponds that were used for lotus cultivation and post-aquaculture ponds. When the varying pond types were compared with the sequence and phylogenetic analysis of the AOB clone libraries, both Nitrosomonas and Nitrosospira-like AOB were detected though Nitrosospira spp. was seen to be the most ubiquitous AOB as it was present in all ponds types. However, AOBs were not detected in the sediments of idle ponds. Based on rarefaction analysis and diversity indices, the disused mining pond with lotus culture indicated the highest richness of AOBs. Canonical correspondence analysis indicated that among the physicochemical properties of the pond sites, TAN and nitrite were shown to be the main factors that influenced the community structure of AOBs in these disused tin-mining ponds.

Critical research needs for managing coral reef marine protected areas: perspectives of academics and managers.

Marine protected areas (MPAs) are a primary policy instrument for managing and protecting coral reefs. Successful MPAs ultimately depend on knowledge-based decision making, where scientific research is integrated into management actions. Fourteen coral reef MPA managers and sixteen academics from eleven research, state and federal government institutions each outlined at least five pertinent research needs for improving the management of MPAs situated in Australian coral reefs. From this list of 173 key questions, we asked members of each group to rank questions in order of urgency, redundancy and importance, which allowed us to explore the extent of perceptional mismatch and overlap among the two groups. Our results suggest the mismatch among MPA managers and academics is small, with no significant difference among the groups in terms of their respective research interests, or the type of questions they pose. However, managers prioritised spatial management and monitoring as research themes, whilst academics identified climate change, resilience, spatial management, fishing and connectivity as the most important topics. Ranking of the posed questions by the two groups was also similar, although managers were less confident about the achievability of the posed research questions and whether questions represented a knowledge gap. We conclude that improved collaboration and knowledge transfer among management and academic groups can be used to achieve similar objectives and enhance the knowledge-based management of MPAs.

Microbiological characterization in children with aggressive periodontitis.

UNLABELLED: The objective of this study was to characterize the subgingival microbiota of African-American children with Localized Aggressive Periodontitis (LAP). Fifty-one children were included. Subgingival plaque samples were taken from diseased (DD) and healthy sites (DH) in LAP and from healthy sites in HS and HC and analyzed by 16S rRNA-based microarrays. Aggregatibacter actinomycetemcomitans (Aa) was the only species found to be both more prevalent (OR = 8.3, p = 0.0025) and abundant (p < 0.01) in DD. Filifactor alocis (Fa) was also found to be more prevalent in DD (OR 2.31, CI 1.06-5.01, p = 0.03). Most prevalent species in healthy sites were Selenomonas spp, Veillonella spp, Streptococcus spp, Bergeyella sp, and Kingella oralis. Overall, Streptococcus spp, Campylobacter gracilis, Capnocytophaga granulosa, Haemophilus parainfluenzae, and Lautropia mirabilis were most abundant in healthy children, while Aa, Fa, Tannerella sp, Solobacterium moorei, Parvimonas micra, and Capnocytophaga sp were most abundant in LAP. Based on a comprehensive analysis with 16S rRNA-based microarrays, Aa was strongly associated and site-specific in LAP. In contrast, other species were found to be associated with healthy sites and individuals (ClinicalTrials.gov number CT01330719). ABBREVIATIONS: healthy site in healthy sibling (HS); healthy site in healthy control child (HC).

Spatial patterns and recruitment processes of coral assemblages among contrasting environmental conditions in the southwestern lagoon of New Caledonia.

We investigated the spatial distribution of adult and juvenile coral assemblages in the southwestern lagoon of New Caledonia, from disturbed fringing reefs within bays, to oceanic barrier reefs. Generic richness, abundance, and percent cover were highly variable at this scale, but no clear cross-shelf gradient was found. Rather, community composition was more related to reef biotopes. Correlations and canonical correspondence analyses revealed that composition and abundance of coral assemblages were related to substrate types (cover of turf algae and cover of encrusting coralline algae), but not to water quality or metal concentrations in sediments. We found a strong relationship between juvenile and adult distribution for all dominant genera, which suggests that recruitment processes are also a major factor structuring these populations. The densities of juveniles and their proportion in the coral assemblages were relatively low, which implies that replenishment capacities and potential for recovery are probably limited for these reefs.

Development of a sublethal test to determine the effects of copper and lead on scleractinian coral larvae.

A new sublethal toxicity test was developed in this study to measure the effect of copper and lead on the motility of coral larvae. Larval motility was significantly affected by copper and lead doses immediately after dosing. The copper EC50 values for motility of Goniastrea aspera brain coral larvae (12 h, 21 microg/L; 24 h, 16 microg/L; 48 h, 22 microg/L) were much lower than the copper LC50 values for G. aspera larval survival (6 h, 260 microg/L, and 24 h, 121 microg/L, for 5-day-old larvae and 6 h, 248 microg/L, and 24 h, 136.64 microg/L, for 6-day-old larvae) during the early part of the experiments. However, at later times, the LC50 values (48 h, 40 microg/L, for 5-day-old larvae and 48- h, 87 microg/L, for 6-day-old larvae) were similar to the EC50 values for larval motility. The lead 72-h EC50 value for G. aspera larval motility (2900 microg/L) was much lower than the lead 72-h LC50 value for larval survival (9890 microg/L). The results show that larval motility can be a useful parameter to measure in order to determine the sublethal effects of trace metals on coral larvae.

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.

The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia.

PURPOSE: The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs. METHODS: Using a crossover study design, we compared the pharmacokinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients. RESULTS: The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P= 0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 microM. CONCLUSIONS: Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.

Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia or non-Hodgkin lymphoma.

The purpose of this study was to determine the frequency with which magnetic resonance (MR) imaging detects avascular necrosis of the bone (AVNB) in children with acute lymphoblastic leukemia (ALL) or advanced-stage non-Hodgkin lymphoma (NHL) who receive prednisone during remission induction, reinduction, and maintenance chemotherapy; to assess the clinical significance of these findings; and to identify factors predictive of AVNB. We prospectively obtained MR imaging of the hips and knees of 116 children who had completed at least 1 year of treatment for ALL or advanced-stage NHL on identical prednisone-containing regimens between December 1991 and October 1994. MR imaging findings of AVNB were compared with clinical outcomes, and the effect of therapeutic and patient factors on the frequency of AVNB was analyzed. The MR imaging findings of 17 of the 116 participating patients were consistent with AVNB. The most common clinical manifestation was joint pain (11 patients). Only one patient had progressive joint deterioration that necessitated surgical replacement. Only age 10 years or more at the time of the primary diagnosis was significantly associated with the development of AVNB (P = 0.004). MR imaging showed changes consistent with AVNB in approximately 15% of this patient population. However, most patients in this study who had MR imaging signs of AVNB did not experience progressive joint destruction, even with continued prednisone therapy. Therefore, the clinical usefulness of MR imaging as a screening tool for AVNB in this set of patients remains uncertain.

Acute lymphoblastic leukemia in a developing country: preliminary results of a nonrandomized clinical trial in El Salvador.

PURPOSE: To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. PATIENTS AND METHODS: Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Children's Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index < 1.16, age 12 months or younger, white blood cell count > or = 50 x 10(9)/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range I d-17 yrs), median leukocyte count was 15 (range 1-766) x 10(9)/L, and sex distribution was equal. RESULTS: Immunophenotypes were early beta-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was > or = 1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate +/- 1 standard error was 48 +/- 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 +/- 7% (n = 121) and 69 +/- 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 +/- 8% and 75 +/- 14%, respectively. CONCLUSIONS: These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.

Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia.

The effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P =.026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 +/- 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1. 36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.

Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia.

CONTEXT: Patients with thrombocytopenia are at risk for spontaneous or procedure-related hemorrhage. Whether such patients can safely undergo lumbar puncture (LP) without prophylactic platelet transfusion is unknown. OBJECTIVE: To determine whether an association exists between thrombocytopenia and LP complications among children with acute lymphoblastic leukemia. DESIGN, SETTING, AND PATIENTS: Retrospective review of the records of 958 consecutive children (median age, 5.5 years) with newly diagnosed acute lymphoblastic leukemia who were treated at a pediatric cancer center between February 1984 and July 1998. INTERVENTIONS: All patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy. MAIN OUTCOME MEASURE: Serious complications of LP occurring during the remission induction and consolidation treatment periods (when thrombocytopenia is likely to occur), defined as any neurologic, infectious, or hemorrhagic problems related to the procedure, reported by platelet count at the time of the procedure. RESULTS: Of the 5223 LPs evaluated, 29 were performed at platelet counts of 10 x 10(9)/L or less, 170 at platelet counts of 11 to 20 x 10(9)/L, and 742 at platelet counts of 21 to 50 x 10(9)/L. No serious complications were encountered, regardless of the platelet count. The 95% confidence interval for the proportion of serious complications in the 199 patients with platelet counts of 20 x 10(9)/L or less was 0% to 1.75% and that for the 941 patients with platelet counts of 50 x 10(9)/L or less was 0% to 0.37%. CONCLUSIONS: In our study of children undergoing remission induction or consolidation therapy for acute lymphoblastic leukemia, serious complications of LP were not observed, regardless of platelet count. Prophylactic platelet transfusion is not necessary in children with platelet counts higher than 10 x 10(9)/L. Due to the small number of patients in our study with platelet counts of 10 x 10(9)/L or less, conclusions cannot yet be drawn for such patients. JAMA. 2000;284:2222-2224.

Human cytochrome P450 maximal activities in pediatric versus adult liver.

Drug clearance is often higher in children than in adults, particularly when normalized to body weight. We previously showed that liver volume normalized to body weight was inversely related to age, but that the systemic clearance of a nonspecific cytochrome P450 (CYP) substrate (antipyrine) was higher in young children compared with adults even when normalized per liver volume. Our purpose herein was to evaluate whether P450 catalytic activities, expressed as maximal catalytic rates per milligram of microsomal protein, differed in up to 37 normal livers from subjects <10 (range 0.5-9 years of age), >10 but <60 years of age (range 10-59 years), and >60 year (range 63-93 years of age). There were no age-related differences in the oxidation of ethoxyresorufin (P =.83) (CYP1A2), ethoxycoumarin (P =.52) (CYP2E1 and other P450s), teniposide (P =. 58), midazolam (P =.47) (CYP3A4/3A5), or paclitaxel (P =.24) (at the 17alpha position, CYP2C8). Tolbutamide hydroxylation tended to be lower in children versus adults (P =.047) (CYP2C9), but did not reach statistical significance after correcting for multiple comparisons. No relationship was found to exist between age and microsomal recovery (P =.98); thus, recovery did not account for the lack of age-related differences in catalytic activity. We conclude that increased intrinsic cytochrome P450 activity is unlikely to account for increased clearance of most P450 drug substrates in children.

Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia.

PURPOSE: Development of antibodies and hypersensitivity to asparaginase are common and may attenuate asparaginase effect. Our aim was to determine the relationship between antiasparaginase antibodies or hypersensitivity reactions and event-free survival (EFS). PATIENTS AND METHODS: One hundred fifty-four children with acute lymphoblastic leukemia received Escherichia coli asparaginase 10,000 IU/m(2) intramuscularly three times weekly for nine doses during multiagent induction and reinduction phases and for seven monthly doses during continuation treatment. Erwinia asparaginase was used in case of clinical hypersensitivity to E coli but not for subclinical development of antibodies. Plasma antiasparaginase antibody concentrations were measured on day 29 of induction in 152 patients. RESULTS: Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase. Of the 98 patients who had no detectable antibodies, 18 (18.4%) had allergic reactions. Patients with antibodies were more likely to have a reaction than those without antibodies (P <.001). Among the 50 patients who experienced allergic reactions (including two for whom antibodies were not measured), 36 (72.0%) were subsequently given Erwinia asparaginase; seven (19.4%) reacted to this preparation. EFS did not differ among patients who did and did not have antibodies (P =.54), with 4-year EFS (+/- 1 SE) of 83% +/- 6% and 76% +/- 5%, respectively. Similarly, EFS did not differ among patients who did and did not develop allergic reactions (P =.68), with 4-year estimates of 82% +/- 6% and 78% +/- 5%, respectively. CONCLUSION: In this setting, in which most patients with allergy were switched to another preparation, there was no adverse prognostic impact of clinical or subclinical allergy to asparaginase.

Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia.

PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase. PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing. RESULTS: The percentage of patients with undetectable (< 0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5 days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70 micromol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003). CONCLUSION: CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.

Sex differences in prognosis for children with acute lymphoblastic leukemia.

PURPOSE: Whether recent improvements in the treatment of childhood acute lymphoblastic leukemia (ALL) have nullified the adverse prognosis associated with male sex remains unclear. Therefore, we analyzed the survival experience and presenting clinical and laboratory features of boys and girls with newly diagnosed ALL who were treated at our institution over the past three decades. PATIENTS AND METHODS: One thousand one hundred fifty-one boys and 904 girls were treated in 13 consecutive Total Therapy studies between 1962 and 1994. An overview analysis was used to investigate the impact of sex on overall and event-free survival, both for the entire cohort and for subgroups defined by treatment era and blast-cell immunophenotype. Stratified analyses were performed to adjust for treatment protocol and known risk factors, and in the modern treatment era, for protocol, immunophenotype, and the DNA content of leukemic cells (ie, DNA index). The pharmacokinetics of methotrexate, teniposide, and cytarabine, as well as the thiopurine methyltransferase activity of erythrocytes, were compared between boys and girls treated on a single protocol. RESULTS: Compared with girls, boys were more likely to have T-cell ALL (20.9% v 10.7%, P < .001) and seemed less likely to have a favorable DNA index (17.8% v 25.1%, P = .072). There were no other statistically significant differences between the two sexes with respect to presenting features, including leukemic-cell genetic abnormalities, nor were there significant sex differences in the pharmacokinetics of methotrexate, teniposide, or cytarabine or in erythrocyte thiopurine methyltransferase activity. Girls clearly fared better than boys (P < .001) on protocols used during the early era of treatment (10-year event-free survival +/- 1 SE, 43.1%+/-2.1% v 31.5%+/-1.7%). Although prognosis improved for both sexes in the modern era, the difference in outcome between girls and boys persisted (P = .025) (10-year event-free survival, 73.4%+/-3.7% v 63.5%+/-4.0%). However, stratification of modern-era patients by protocol, immunophenotype, and DNA index mitigated statistical evidence of a sex difference in overall survival (P = .263) and event-free survival (P = .124). CONCLUSION: Although boys and girls alike have benefited from improvements in ALL therapy, these gains have not completely eliminated the sex difference in prognosis that has persisted since the early 1960s. The apparent difference in outcome is partially explained by differences between boys and girls in the distributions of ALL immunophenotype and DNA index.

Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia.

The purpose of this study was to determine the incidence of and pharmacokinetic parameters associated with the development of transient encephalopathy following the administration of high-dose methotrexate and intrathecal chemotherapy in children with acute lymphoblastic leukemia (ALL). Two hundred and fifty-nine children with newly diagnosed ALL treated on one of two consecutive trials were analyzed. Presenting features in patients who developed transient encephalopathy were compared with those of patients who did not experience this event. For each patient who developed transient encephalopathy, methotrexate pharmacokinetic parameters were compared with those of matched controls. The cumulative incidence of acute encephalopathy was 3% (SE 1%) at 1 year and was associated with age greater than or equal to 10 years at diagnosis. Pharmacokinetic data did not differ between patients who developed transient encephalopathy and those who did not. The majority of patients had no long-term sequelae and were able to receive further courses of methotrexate without modification. Transient focal neurologic deficits occur in about 3% of children with ALL following the administration of intravenous and intrathecal methotrexate. These events cannot be predicted by pharmacokinetic parameters Of methotrexate disposition. However, these events are generally benign, suggesting that patients who experience acute encephalopathy should continue to receive this important chemotherapeutic agent.