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P L Harrison

Publications and source records attributed to P L Harrison.

At least 19 recordsLinked to original sources
PubMed2004

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.

Animals↗
PubMed2003

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.

Adolescent↗
PubMed2001

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.

Adolescent↗
PubMed2001

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.

Adolescent↗
PubMed2000

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.

Adolescent↗
PubMed2000

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.

Adolescent↗
PubMed2000

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.

Adolescent↗
PubMed2000

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.

Adolescent↗
PubMed1999

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.

Adolescent↗
PubMed1999

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.

Adolescent↗
PubMed1998

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.

Adolescent↗
PubMed1997

Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St Jude Total Therapy Study XII.

To determine the frequency and prognostic significance of recently described genetic lesions in pediatric acute lymphoblastic leukemia (ALL), all cases with available leukemic cell samples treated on St Jude Study XII were analyzed by molecular techniques for alterations of the p16, MLL and ETV6 genes. Homozygous p16 deletion was seen in 36 of 155 cases, including 14 of 23 T cell cases, but had no prognostic value. Rearrangement of MLL was seen in nine of 170 cases (5%) and conferred a poor prognosis, with a 5-year EFS estimate of only 11 +/- 7%, compared with 74 +/- 5% for the germline MLL group (P=0.0001). By contrast, rearrangement of ETV6 was found in 35 cases (21%) and was significantly associated with a better outcome (5-year EFS estimates: 87 +/- 7% vs 64 +/- 6%). In a Cox regression model adjusted for age, DNA index, race, leukocyte count, treatment group, and CNS status, ETV6 rearrangement retained independent prognostic significance (two-sided P value 0.012). Thus, in this uniformly treated group of patients, we confirmed the unfavorable prognostic significance of MLL rearrangement and demonstrated the favorable impact of ETV6 rearrangement, suggesting that these factors be added to ALL risk classification schemes.

Carrier Proteins↗
PubMed1997

Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies.

Standard prophylaxis and treatment of malignancy-associated hyperuricemia in the USA has been allopurinol with vigorous hydration, urinary alkalinization and osmotic diuresis. Urate oxidase, the enzyme that converts uric acid to allantoin (a readily excreted metabolite that has 5- to 10-fold higher solubility than uric acid), is an alternative therapy; however, few published findings support this practice. Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both. Their blood levels of uric acid and other indicators of tumor lysis were measured at diagnosis and during treatment and then compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia. Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma. Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels than did the historical controls (median maximal level during treatment, 2.3 vs 3.9 mg/dl, P < 0.001). They also had lower creatinine (0.6 vs 0.7 mg/dl, P = 0.01) and blood urea nitrogen (11 vs 24 mg/dl, P < 0.001) levels. Similar findings were made in the eight cases of B cell ALL or non-Hodgkin lymphoma. None of the patients required dialysis for acute renal failure. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm and hypoxemia. Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy.

Allopurinol↗
PubMed1993

Nucleotide sequence of the histone gene cluster in the coral Acropora formosa (Cnidaria; Scleractinia): features of histone gene structure and organization are common to diploblastic and triploblastic metazoans.

We report the nucleotide sequence of the core histone gene cluster from the Cnidarian Acropora formosa. This is the first histone gene cluster to be sequenced from a diploblastic organism and the predicted amino acid sequences most resemble those of sea urchin equivalents. Each of the Cnidarian histone genes has two conserved regions 3' of the coding sequences and these closely resemble those of the metazoan alpha-class histone genes. In A. formosa the core histone genes are arranged as opposed (H3/H4 and H2A/H2B) pairs, a pattern common to the nondeuterostome metazoa, and tandem repetition is the predominant pattern of organization in the Cnidarian. With the recent identification of several classes of homeobox genes in Cnidarians these features clearly align the Cnidaria with triploblastic metazoans, supporting a monophyletic origin of the metazoa.

Amino Acid Sequence↗
PubMed1993

Post-hospitalization followup appointment-keeping among the medically indigent.

The purpose of this study was to measure followup appointment-keeping in patients discharged from a General Medicine Inpatient Service and to identify possible predictors of compliance. Patients were interviewed on hospital admission and all charts were reviewed on discharge. A subset of patients were interviewed by telephone an average of one month after first followup appointment date. The study was conducted in an urban public teaching hospital with hospital-based and community clinics. A convenience sample of 209 patients were selected from admissions to the General Medicine Inpatient Service over a three month period. Followup appointment-keeping was recorded on all 195 patients discharged alive. Seventy-five percent of patients had no medical insurance, public or private. A compliance rate of 60% (95% confidence interval: 53% to 67%) with first followup appointment was found. Variables associated with compliance and which retained independence on multiple logistic regression analysis, followed by adjusted odds ratios (95% confidence intervals) were: no copayment requirement, odds ratio 3.2 (1.6 to 6.3), single followup appointment 2.9 (1.4 to 5.9), apartment dwelling 3.2 (1.4 to 7.3) and non-primary care clinic appointment 2.3 (1.1 to 4.8). We conclude that health-care-delivery related factors such as no copayment requirements are strongly associated with appointment-keeping in a public hospital population.

Adolescent↗
PubMed1980

Subtest patterns and recategorized groupings of the McCarthy Scales for EMR children.

The profiles of 40 EMR children (aged 6 to 8.5 years) on the McCarthy Scales of Children's Abilities were examined to determine areas of strengths and weaknesses. Subtest profiles were explored, and McCarthy tasks were recategorized in accordance with the approaches of Bannatyne and Sattler to investigate EMR persons' performance. The group showed a strength in memory for common objects and weaknesses in acquired knowledge, numerical reasoning, and conceptual thinking. In addition, the sample's average General Cognitive Index was lower than would be expected for a group of EMR children. Implications of these findings for placement of EMR children were discussed.

Child↗