Correcting overall survival for the impact of crossover via a rank-preserving structural failure time (RPSFT) model in the RECORD-1 trial of everolimus in metastatic renal-cell carcinoma.

Clinical trials in oncology often allow patients randomized to placebo to cross over to the active treatment arm after disease progression, leading to underestimation of the treatment effect on overall survival as per the intention-to-treat analysis. We illustrate the statistical aspects and practical use of the rank-preserving structural failure time (RPSFT) model with the Fleming-Harrington family of tests to estimate the crossover-corrected treatment effect, and to assess its sensitivity to various weighting schemes in the RECORD-1 trial. The results suggest that the benefit demonstrated in progression-free survival is likely to translate into a robust overall survival benefit.

Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study.

BACKGROUND: To identify the most effective of two combinations, irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) and irinotecan/cisplatin, in the treatment of advanced gastric cancer, for investigation in a phase III trial. PATIENTS AND METHODS: Patients were randomized to receive irinotecan [80 mg/m2 intravenously (i.v.)], FA (500 mg/m2 i.v.) and a 22-h infusion of 5-FU (2000 mg/m2 i.v.), weekly for 6 weeks with a 1-week rest, or irinotecan (200 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.), on day 1 for 3 weeks. RESULTS: A total of 115 patients were eligible for analysis in the per-protocol population. The overall response rate in the irinotecan/5-FU/FA arm (n=59) was 42.4%, with a complete response rate of 5.1%. Corresponding figures for the irinotecan/cisplatin arm (n=56) were 32.1% and 1.8%, respectively. The median time to progression was 6.5 months (irinotecan/5-FU/FA) and 4.2 months (irinotecan/cisplatin) (P < 0.0001), with median survival times of 10.7 and 6.9 months, respectively (P=0.0018). The major toxicity was grade 3/4 neutropenia, which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA (65.7% versus 27%). Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA (27.0%) and irinotecan/cisplatin (18.1%). CONCLUSIONS: Both combinations were active, with acceptable safety profiles. Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer.

Effect of reversible hypoperfusion on left ventricular volumes measured with gated SPECT at rest and after adenosine infusion.

BACKGROUND: The aims of this study were to assess the degree of postischemic left ventricular (LV) dilatation after adenosine stress and to determine the extent to which LV volumes measured with gated single photon emission computed tomography (SPECT) correspond to those obtained by echocardiography. METHODS: Eight-frame gated SPECT with a 2-day technetium-99m tetrofosmin acquisition protocol was used. End-diastolic (EDV) and end-systolic (ESV) volumes were measured automatically with the quantitative gated SPECT algorithm. Reversible myocardial hypoperfusion was evaluated with a 16-segment, 4-point perfusion score model. LV volumes at rest were also measured with echocardiography by use of the biplane Simpson rule. RESULTS: Twenty-two patients (group 1) showed normal perfusion and normal LV systolic function, whereas 33 patients (group 2) had evident coronary heart disease with reversible hypoperfusion. Patients in group 2 had greater EDV and ESV than those in group 1 both at rest and poststress. A greater reduction in ESV from poststress to rest was seen in group 2, which resulted in a slight increase in ejection fraction for patients in this group. The change in ESV from poststress to rest was significantly influenced by the degree of reversible hypoperfusion and by the change in heart rate from poststress to rest. We found a good correlation between LV volumes measured with gated SPECT and echocardiography. CONCLUSION: LV volume measurements with quantitative gated SPECT are comparable to those obtained with echocardiography. Patients with ischemic heart disease have greater LV volumes than patients with normal perfusion. Exercise-augmented adenosine infusion in patients with ischemic heart disease affects ESV more than EDV. This response is partly modulated by the degree of reversible hypoperfusion and possibly represents a minor degree of poststress stunning.

Prospective audit of cytomegalovirus-negative blood product utilization in haematology/oncology patients.

The transfusion management of immunocompromised patients often requires special blood product use such as cytomegalovirus (CMV)-negative cellular products, which are more costly than standard blood products and occasionally in short supply. We audited the use of CMV-negative products in haematology/oncology patients to determine the appropriateness of their use. A concurrent-prospective audit was conducted of all orders for CMV-negative packed red blood cell (PRBC) and platelet products in 201 haematology/ oncology patients. Once CMV serostatus was determined, orders for inappropriate CMV-negative units were cancelled, and filled as CMV untested units. During the 21-month period of this audit, the rates of inappropriate transfusions decreased for PRBC from 73.2% to 14.3% (chi2 = 68.4, P<0.001) and for platelets from 68.1% to 10.6% (chi2 = 65.6, P<0.001). The median time to cancellation of inappropriate CMV-negative orders was 11 days. This audit resulted in estimated cost savings of $16500 over the 21-month duration. Inappropriate requests for scarce and expensive blood products are substantially reduced by concurrent-prospective auditing of transfusion practice, in a manner that is both simple and cost effective.

Homogeneous two-site immunometric assay kinetics as a theoretical tool for data analysis.

The easily accessible kinetics of a new homogeneous two-site fluorometric immunoassay for prolactin was studied, in order to determine its usefulness for assay data reduction and optimization. The combined use of a simple descriptive model fitted to experimental data and a mechanistic model to simulate the kinetics revealed that (i) the kinetics curve presented an early inflexion point. Its time of occurrence was constant as long as the antigen concentration was below the smallest antibody concentration and decreased to zero for higher concentrations. It may therefore be used as an indicator of hooked samples. (ii) The kinetics steepest slope was correlated with antigen concentration. Its use as a dose-response curve variable would allow higher concentrations to be assayed than with the classical end-point dose-response curve. The results suggest that control and exploitation of kinetic parameters could help to improve the rapidity, analytical range, and reliability of homogeneous two-site immunometric assays.

Thermodynamic analysis of antigen-antibody binding using biosensor measurements at different temperatures.

The thermodynamic parameters of the interaction between hen egg white lysozyme and Fab D1.3 were determined by measuring the temperature dependence of the ratio of its kinetic association and dissociation rate constants. Biosensor technology (BIAcore 2000) was used to measure the rate constants at temperatures ranging from 5 to 40 degrees C. The value of DeltaG degrees at 25 degrees C (-49 kJ M-1) calculated by this method was very close to that obtained previously from fluorescence quenching measurements (-48.5 kJ M-1). However, the value of DeltaH degrees measured at 25 degrees C by biosensor technology (-35 kJ M-1) was smaller than that determined previously by microcalorimetry (-90 kJ M-1). Another difference was the limited variation of ln K and DeltaG with temperature observed with BIAcore compared to the steady decrease of ln K with temperature found by calorimetry. Our data showed that the binding reaction was driven only by enthalpy below 23 degrees C, by enthalpy and entropy between 23 and 35 degrees C, and only by entropy above 35 degrees C. This suggests, inter alia, that the contribution from the enthalpy of hydration due to the water molecules present at the interface in the lysozyme-antibody complex is progressively eliminated as the temperature increases. Whereas calorimetric data pertain to all the components present in the sample, including solvent molecules, BIAcore measurements monitor only the physical association and dissociation of the two macromolecular species. The difference between the two sets of data may also reflect the complexity of the binding mechanism between lysozyme and Fab D1.3.

Simple relationship between acid dissociation constant and minimal pH for microbial growth in laboratory medium.

A simple relationship was observed in growth medium, between the dissociation constant (via the pKa) of the acid used to control pH and the minimum pH at which Salmonellae and Escherichia coli initiate growth. From this new relationship, a simple method was proposed to predict the minimum growth pH for a given strain and different acid types. This method, illustrated on Listeria monocytogenes, would merely require the knowledge of two minimum pH values, one for a strong acid (e.g. hydrochloric acid) and one for a weak acid (e.g. acetic or propionic acid). From these two values, it seems possible to estimate for a given growth medium, the minimum pH value for any other acid within the defined pKa range.

A descriptive model for the kinetics of a homogeneous fluorometric immunoassay.

A descriptive mathematical model was chosen to fit the antigen-antibody association kinetics of a new homogeneous immunometric assay for prolactin, involving time-resolved fluorescence detection (TRACE technology, Time Resolved Amplified Cryptate Emission). We paid special attention to the methodology and criteria applied, to yield a convenient and statistically valid model, designed to allow potential exploitation of kinetic information in the data processing of the assay. We compared specific parameterizations of an hyperbolic model, the Gompertz, and the monomolecular models on the basis of morphological considerations, a statistical analysis of fit, and an assessment of the parameters estimation quality, over a wide range of antigen concentrations. The monomolecular model gave the best fit, and the most precise and stable estimation of its parameters. The study of parameter properties confirmed this choice.

Comparison of a transfusion preparation of newly formed red cells and standard washed red cell transfusions in patients with homozygous beta-thalassemia.

BACKGROUND: Previous studies of transfusions of newly formed red cells (neocytes) demonstrated modest extensions of transfusion interval in patients with homozygous beta-thalassemia. STUDY DESIGN AND METHODS: The clinical benefits of a new system of neocyte preparation (Neocel, Cutter Biological, Berkeley, CA), reported to combine ease of preparation with reduction in the transfusion requirements of thalassemia patients, were evaluated. Sixteen thalassemic patients who had undergone splenectomy received eight consecutive, standard, automated, washed red cell transfusions (standard transfusions), followed by eight transfusions with the neocyte preparation (neocyte transfusions). In each arm of the study, mean pretransfusion hemoglobin and mean red cell mass transfused were carefully controlled and were similar. RESULTS: A significant (p < 0.0001) extension of transfusion interval was observed in patients receiving neocyte transfusions (mean +/- SD; 38.7 +/- 34 days; range, 35.0-44.5), over that in those receiving standard transfusions (32.9 +/- 2.5 days; range, 29.6-38.5). The mean prolongation of transfusion interval by neocyte transfusion corresponded to a mean reduction of 25 mL in packed red cells transfused per kg of body weight per patient per year and a mean reduction in transfused iron of 15 percent per year per patient. During neocyte transfusions, blood preparation costs were considerably increased and donor exposure was significantly (p < 0.0005) higher than during the standard transfusion period. CONCLUSION: These data demonstrate that extension of the transfusion interval, and reduction in transfused iron, may be achieved in thalassemic patients by use of the Neocel system. These benefits are achieved, however, with substantial increases in donor exposure and in component preparation costs.

Proficiency testing in cytology laboratories in Ontario, Canada: a decade of experience. I. Introduction and description of the testing model.

There are few formally documented proficiency testing programs for cytology laboratories, and those that have been documented are not entirely comparable in format. The first of three papers documenting a mandatory universal proficiency testing program for cytology laboratories in the Province of Ontario, Canada, presents data on the structure and function of the participating laboratories (including a comparison of the data for 1974 and 1980) and on the organization of the testing model (including selection of terminology, construction and use of the survey and assessment of responses). In 1980, of the 463 medical laboratories in Ontario, 91 of 222 hospital laboratories and 65 of 216 nonhospital laboratories were licensed in cytology. In that year, the 156 cytology laboratories processed 1.48 million cytology specimens, 92% of which were gynecologic. Hospital laboratories processed 87.5% of the nongynecologic cytology specimens and 30% of the gynecologic cytology specimens. These proportions have been virtually constant for several years. Between 1974 and 1980, there was a trend in Ontario to fewer laboratories processing less than 5,000 cytology specimens per annum. Subsequent papers in this series describe the results of the initial surveys in this program and a precision study to evaluate the consistency of reporting by individual laboratories.

Proficiency testing in cytology laboratories in Ontario, Canada: a decade of experience. II. Results of initial surveys.

The results of the initial surveys in the cytology proficiency testing of the medical laboratories in the Province of Ontario, Canada, showed a high correlation between the opinions of the testing committee and the participants in the categories of "no abnormal cells," "metaplasia" and forms of "benign atypia." The proportion of times that slides were tested in the categories of dysplasia and malignancy in the surveys increased from 38% by the end of survey 3 to 46% by the end of survey 5. A progressive improvement in the diagnostic accuracy was demonstrated in the categories of malignancy and severe dysplasia while results were more variable in the categories of moderate and mild dysplasia. Several educational activities were initiated following survey 3, including development and circulation of demonstration sets of marked glass slides for repeated circulation to participants as well as copies of a slide/tape presentation describing the program and specific case material.

Proficiency testing in cytology laboratories in Ontario, Canada: a decade of experience. III. A precision study of consistency and reproducibility in cytology reporting.

The Ontario Laboratory Proficiency Testing Program's testing model and the results of early surveys of cytology laboratories have been previously described. To test consistency and accuracy, the same slides from one survey were recirculated to the same laboratory in the next survey. There was no statistical difference in either the accuracy or consistency in reporting by the various categories of personnel. Analysis of the data by category of diagnosis showed the reporting of "no abnormal cells" and "benign atypia" to be slightly more accurate and "moderate dysplasia" and "severe dysplasia" to be slightly less accurate than the reporting in other categories. Consistency in reporting appeared to be slightly less accurate in severe dysplasia than in the other categories. The analysis, which includes the results from all licensed cytology laboratories in Ontario, provides evidence that, in the reporting of cervical cytologic material, it is feasible to differentiate among the various categories within the spectrum of squamous epithelial abnormalities with a general level of accuracy and consistency that, although satisfactory, is not yet ideal.

Proficiency testing in immunohaematology in Ontario, Canada, and in the United Kingdom: a comparative study.

A comparative study of proficiency testing models in immunohaematology has been carried out between the United Kingdom National External Quality Assessment Scheme and the Laboratory Proficiency Testing Program of the Ontario Medical Association, using material supplied by both programmes to laboratories in the United Kingdom and Ontario. The results suggest that the general standard of performance in immunohaematology practice is similar in the two jurisdictions and that, where clear differences are seen, these reflect differences in technique or in educational emphasis.

Sensitivity of routine blood bank methods for the detection of anti-D as determined during proficiency testing.

A proficiency testing program in immunohematology, involving over 240 laboratories, was used to assess the detection of anti-D in six concentrations ranging from 11 to 8,500 ng/mL. Using the indirect antiglobulin test, more than 98% of laboratories reporting detected anti-D at all concentrations. Enzyme and albumin antiglobulin methods as routinely practiced did not clearly increase sensitivity, and the direct agglutination methods used were much less sensitive than indirect antiglobulin methods. If proficiency testing truly reflects performance in practice in Ontario, Canada, the sensitivity of manual indirect antiglobulin methods in routine use for the detection of anti-D appears to meet reasonable expectations of these technics.

Proficiency testing in immunohaematology in Ontario, Canada, 1977-1979.

An analysis of the results of a compulsory proficiency testing programme in immunohaematology is presented. Error rates have been calculated for the determination of ABO and Rh(D) groups, the direct antiglobulin test and antibody detection according to defined criteria. The introduction of proficiency testing has been associated with alterations in error rates for some determinations. An educational programme introduced for laboratories with poor performance has proved effective in improving their results in the proficiency testing programme.