Secrecy for data monitoring committees: inferior ethics, bad policy.
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Advisory Committees↗
Biomedical subjects
R J Wells
Publications and source records attributed to R J Wells.
Gas chromatographic determination of residues of thyreostatic drugs in bovine muscle tissue using combined resin mediated methylation and extraction.
A method is described for the assay of residues of the thyreostatic substances 2-thiouracil, 6-methyl-2-thiouracil, 5- and 6-propyl-2-thiouracils and 6-phenyl-2-thiouracil in beef muscle at levels of quantitation down to 25 microg/kg for thiouracil and 15 microg/kg for substituted thiouracils. Analytes are extracted from the muscle matrix with acetonitrile and methylated by absorption onto a macroporous anion exchange resin followed by treatment with methyl iodide in acetonitrile at room temperature. Supercritical carbon dioxide is also a suitable derivatization solvent. Determination is carried out using gas chromatography with mass spectrometric detection. The methyl ester of 2,4,5-trichlorophenoxyacetic acid serves as an internal standard while 5-methyl-2-thiouracil is a suitable surrogate. 5-Ethyl-2-thiouracil is added to minimise losses of the analytes during the analysis. The method exhibits a linear range of 25-625 microg/kg for the substituted thiouracils and 50-1250 microg/kg for 2-thiouracil. Recovery of the analytes ranges from 50% for 6-phenyl-2-thiouracil to 90% for 2-thiouracil with coefficients of variation of less than 10%.
Animals↗
Gas chromatographic determination of organic acids from fruit juices by combined resin mediated methylation and extraction in supercritical carbon dioxide.
A procedure in which anionic analytes, trapped on ion exchange resin, are simultaneously methylated and released using methyl iodide in either supercritical carbon dioxide or acetonitrile has been extended to polyfunctional organic acids. The combined SFE methylation of fruit juice acids trapped onto ion exchange resin proceeds in good yield producing the methyl esters of fumaric, succinic, malic, tartaric, isocitric and citric acids which are readily separated by GC. Using this procedure low concentrations of one acid can be detected and quantitated in the presence of very high concentrations of another. This new method detects tartaric acid at levels of 10 ppm in juices containing 10,000 ppm citric acid. Quantitation was performed either by using GC-FID with triethyl citrate or diethyl tartrate as internal standards or with the element specific calibration capability of the GC-AED. A simple new technique for the determination of citric/isocitric acid ratio is now available. Also, in contrast to HPLC methods, the identity of an analyte is readily confirmed by GC-MS.
Beverages↗
In situ derivatisation and extraction of volatile fatty acids entrapped on anion-exchange resin from aqueous solutions and urine as a test matrix using pentafluorobenzyl bromide in supercritical carbon dioxide.
The simultaneous extraction and derivatisation of anion-exchange resin-trapped volatile fatty acids (C2-C5) as their pentafluorobenzyl esters has successfully been performed under CO2 supercritical fluid extraction conditions. Volatile fatty acid standards of acetic, propionic and n-butyric acids (at 20 and 100 ppm) as their ester derivatives were recovered at 78.0-101.5% (C.V. 3.5-7.5%, n=6 and 7). Likewise, acrylic acid recoveries were 57.0-61.0% (C.V. 5.5-5.6%, n=6 and 7). This methodology was applied to the quantitation of acetic, propionic, n-butyric and n-valeric acids in spiked urine as a test matrix. Initial clean-up of phosphate and sulfate in the urine was required prior to anion-exchange application and this was achieved by barium salt precipitation. Recoveries ranged from 36 to 66.5% (C.V. 5.9-14.4%, n=9 and 6).
Anion Exchange Resins↗
High-dose cytosine arabinoside and etoposide: an effective regimen without anthracyclines for refractory childhood acute non-lymphocytic leukemia.
The purpose of this report is to describe the tolerability and activity of the combination of high-dose cytosine arabinoside (Ara-C) given at the maximum tolerated dose of 36 g/m2, together with high doses of etoposide in relapsed and refractory childhood acute leukemias. Eighteen children with relapsed or refractory acute leukemia were treated with Ara-C 3 g/m2 every 12 h on days 1-6, followed by etoposide 400 mg/m2 on days 7-9 (HDAC/VP-16). Eight children with refractory disease received HDAC/VP-16 as salvage induction therapy after failing conventional induction regimens; four of five refractory ANLL patients (80%) had a complete response (CR) after HDAC/VP-16 therapy. Ten patients received HDAC/VP-16 as post-remission intensification therapy; five patients (four ANLL, one relapsed ALL) remain in second CR at 56, 26, 9, 5 and 2 months. Toxicities were primarily hematologic and dermatologic. Seven patients (39%) developed bacterial or fungal infections; four patients developed grade 3 or 4 acral erythema. No patient died of therapy-related toxicity. The combination of 36 g/m2 cytosine arabinoside and 1200 mg/m2 etoposide is an effective regimen for children with relapsed or refractory acute nonlymphocytic leukemia, with tolerable toxicities; the absence of anthracyclines makes this regimen suitable for patients who have previously received maximal doses of anthracyclines or who have evidence of cardiac dysfunction. Further evaluation of this regimen in acute nonlymphocytic leukemia is presently being investigated.
Acute Disease↗
Identification of fish species using random amplified polymorphic DNA (RAPD).
The random amplified polymorphic DNA (RAPD) method was investigated as a potential fish species identification method. One hundred and sixteen specimens from eight species of fish were analysed. The eight species tested were barramundi, Nile perch, john dory, mirror dory, silver dory, spikey oreo, warty oreo and smooth oreo. The predominant species tested was barramundi; 80 specimens of this species were analysed. Of these samples, 42 had been individually verified by independent sources. The RAPD profiles generated were consistent within this group. The remaining samples were retail purchased and consisted of 24 imports and eight local whole small barramundi and six fillets. All of the whole barramundi, including the imported fish, generated profiles which agreed with the verified samples. Four of the six fillets purchased did not match the typical barramundi profile, three profiles, however, were consistent with those generated for Nile perch. Species-specific profiles were also generated for the other seven species analysed by RAPD. One john dory, from five fillets tested, did not comply with the six authenticated sample. All of the RAPD profiles were resolved by agarose gel electrophoresis. Forty nine RAPD profiles including those that did not match were also confirmed by native polyacrylamide gel electrophoresis (PAGE) on a DNA sequencer.
Animals↗
Determination of morphine and related alkaloids in crude morphine, poppy straw and opium preparations by micellar electrokinetic capillary chromatography.
A rapid method for the determination of morphine and related alkaloids in crude morphine, poppy straw and opium preparations by micellar electrokinetic capillary chromatography (MEKC) has been developed. Morphine, codeine, thebaine, oripavine, papaverine, narcotine, narceine, cryptopine and salutaridine were separated in less than 10 min using a 70 cm x 50 microm I.D. uncoated fused-silica capillary column with a buffer consisting of 10% dimethylformamide, 90% 0.05 M cetyltrimethylammonium bromide, 0.01 M potassium dihydrogen orthophosphate, 0.01 M sodium tetraborate, pH 8.6. An applied voltage of -25 kV and a temperature of 28 degrees C gave the best separation of the alkaloids. Pholcodine was used as the internal standard. The compounds were detected by UV at 254 nm. The levels of morphine and related alkaloids determined by MEKC were in good agreement with those determined by high-performance liquid-chromatography (HPLC). The coefficients of variation for area calculation (%C.V.) for multiple sample and standard injections by MEKC were slightly greater than for HPLC but were still acceptable (morphine content of poppy straw: %C.V. MEKC 1.7%, %C.V. HPLC 0.3%).
Chromatography↗
Determination of a cardiac antiarrhythmic, tricyclic antipsychotics and antidepressants in human and animal urine by micellar electrokinetic capillary chromatography using a bile salt.
A micellar electrokinetic capillary chromatographic method based on the use of sodium taurodeoxycholate has been developed to detect and quantitate of 26 tricyclic drugs. Detection limits in urine down to 4 ng/ml have been obtained. The method uses a simple liquid-liquid extraction and recovery of analytes followed by ultraviolet detection.
Animals↗
New agents for treatment of children with acute myelogenous leukemia.
Over the past 15 years, daunorubicin, cytosine arabinoside and, to a lesser extent, 6-thioguanine and etoposide have become the standard agents used to treat patients with acute myelogenous leukemia (AML). These agents have been used in various combinations and schedules with only small improvements in overall outcome because few other agents with promise were available. This situation has changed over the past few years so that today there are a number of new agents that have the potential to supplement or replace the standard drugs. Idarubicin, mitoxantrone, amsacrine, homoharringtonine, 2-chlorodeoxyadenosine, fludarabine, carboplatin, retinoids, colony stimulating factors, and interleukin-2 are discussed.
Antineoplastic Agents↗
Phase II window therapy.
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Antineoplastic Combined Chemotherapy Protocols↗
Generic consent for genetic screening.
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Genetic Testing↗
The determination of cocaine and related substances by micellar electrokinetic capillary chromatography.
A quantitative method for the determination of cocaine and related substances by micellar electrokinetic capillary chromatography (MECC) is described. Quantitative results obtained for both monitor materials and a number of actual drug seizures by this new capillary electrophoretic method are comparable to a gas chromatography (GC) run in parallel, both in the values and coefficient of variation achieved. The advantages of this new method include minimal use of solvents, the ability to readily automate the procedure and the ability to quantitate illicit heroin seizures under the same conditions with the exception of detector wavelength alteration. The method has proved rugged and reliable for both heroin and cocaine in a number of inter-laboratory proficiency studies.
Buffers↗
Cytosine arabinoside and mitoxantrone treatment of relapsed or refractory childhood leukemia: initial response and relationship to multidrug resistance gene 1.
The objective of this study was to determine the response rate and toxicity of high-dose cytosine arabinoside (AC) and mitoxantrone (M) in relapsed or refractory childhood acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) and to correlate response with the expression of the multidrug resistance gene 1 (mdr1). Twenty-nine patients were treated with AC 1.0 g/m2 infused over 2 h every 12 h for eight doses (days 1-4) and M 12 mg/m2 infused over 1 h (days 3-6). Mdr1 expression was determined by a polymerase chain reaction (pcr) assay. Ten of 15 patients (67%) with AML obtained a complete remission (CR) of 3 to 30+ months duration. Eight of 14 (57%) ALL patients obtained a CR of 1 to 23+ months duration. The major toxicities were hematopoietic and infectious. Seventy-nine per cent of patients developed a documented infection during induction. Mdr1 did not correlate with a lower induction rate. This AC/M regimen is active in childhood AML and ALL.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Risk factors for recurrent fever after the discontinuation of empiric antibiotic therapy for fever and neutropenia in pediatric patients with a malignancy or hematologic condition.
We studied episodes of fever and neutropenia in children and adolescents without documented infections to determine the risk of recurrent fever after early discontinuation of empiric antibiotic therapy; 213 episodes occurred in 106 patients. All patients received empiric antibiotic therapy after cultures were obtained. Antibiotic therapy was discontinued if no infection was found, culture results were negative for 48 hours, and the patient was afebrile for 24 hours. In 83 episodes without documented infection, antibiotic therapy was stopped with absolute neutrophil counts < 0.5 x 10(9)/L (< 500/mm3); 50 episodes occurred in patients with solid tumors, leukemia in remission, and other hematologic conditions (group 1), and 33 in patients with active leukemia (group 2). Fever recurred before neutropenia resolved in 6% of group 1 and 45% of group 2 episodes; five patients in group 2 had documented infection. Recurrent fever risk correlated with absolute neutrophil count and monocyte count at the time antibiotic therapy was stopped, in both groups, as did increasing absolute neutrophil count and increasing leukocyte count in group 2. We conclude that discontinuing antibiotic therapy is safe in febrile episodes without documented infections before neutropenia resolves in patients with high potential for bone marrow recovery. The risk of recurrent fever and infection is significant for patients with neutropenia and poor marrow recovery potential.
Adolescent↗
Inhibitory effects of enrichment media on the Accuprobe test for Listeria monocytogenes.
During an evaluation of the Accuprobe kit for the detection of Listeria monocytogenes, some of the enrichment media used were found to interfere with the test. Microscopic examination during the lysis step of the test revealed that media containing high salt greatly reduced or prevented cell lysis. This prevented the probe from binding to the cellular RNA, resulting in false-negative results.
Bacteriological Techniques↗
Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study.
PURPOSE: The objectives of this study were to determine if the addition of etoposide, thioguanine, and dexamethasone to daunorubicin and cytarabine (five-drug regimen) during induction would improve remission induction rates and survival of children with acute myeloid leukemia (AML) when compared with the standard regimen of cytarabine and daunorubicin (7 + 3) and whether allogeneic bone marrow transplantation (BMT) or intensive chemotherapy consolidation with or without maintenance would give a superior outcome. PATIENTS AND METHODS: A total of 591 assessable children with AML entered Childrens Cancer Group (CCG) trial 213 between January 1986 and February 1989. The status of patients as of September 1, 1992 forms the basis of this report. The results were compared with previous AML studies. RESULTS: The projected survival rate of all patients at 5 years is 39% (event-free survival [EFS] rate, 31%), which is superior to that of the prior CCG study (P = .01). The induction rate was 79% for 7 + 3 and 76% for the five-drug regimen (not significant). Comparisons of BMT to chemotherapy favored BMT, but these differences do not always reach statistical significance (eg, 5-year disease-free survival [DFS] rate, 46% v 38% [P = .06] with donor available and 54% v 37% [P = .002] if treated according to protocol intent). No benefit for maintenance therapy was found and, in some comparisons, it was inferior to discontinuation of therapy (5-year survival rate, 46% v 68%, P < .01). CONCLUSION: The 5-year EFS rate of patients with AML is 31% and has improved. The five-drug induction regimen is no better than standard induction, BMT appears superior to chemotherapy, and maintenance therapy was not beneficial.
Adolescent↗
Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.
The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.
Adolescent↗
Growth patterns of human neuroblastoma xenografts and their relationship to treatment outcome.
BACKGROUND: Several investigators have reported the ability to establish xenografts in nude mice from children with neuroblastomas, but a correlation of prognosis with this establishment and the growth patterns of the neuroblastomas has not been reported. METHODS: Tumor specimens from 58 children with neuroblastomas were heterotransplanted into BALB/c nude mice. In 34 patients, heterotransplantation was done before therapy; in 24 patients, tumors were obtained after at least one course of chemotherapy or radiation therapy. The histology, cytogenetics, and growth characteristics of serial passages of the xenografts were studied. RESULTS: The engraftment rate was 34%. Neuroblastomas with diploid chromosome numbers did not engraft. Chromosomal abnormalities involving 1p were seen in more than 50% of the xenografts. Cytogenetic features were retained between original tumors and resultant xenografts. Xenografts could be established only from tumors with unfavorable histology, as defined by Shimada classification criteria. The histology of each xenograft line was strikingly similar, and each was highly undifferentiated. Engraftment rates, doubling times, and lag times did not vary appreciably between xenografts established from treated tumors compared with xenografts established from untreated tumors. There was no correlation between doubling or lag times and prognosis. Patients whose tumors engrafted had only a 5% 3-year survival rate. CONCLUSIONS: From these results, it appears that successful engraftment is the most important prognostic indicator for patients with neuroblastomas. Because of the commonality of the histologic features and the stability of the tumor clones from patients before and after heterotransplantation, these xenografts may be useful as an in vivo model for studying drug resistance and for designing treatment regimens.
Animals↗