A successful system of scientific data audits for clinical trials. A report from the Cancer and Leukemia Group B

OBJECTIVE: To report on data collected during on-site audits of source documents in the Cancer and Leukemia Group B (CALGB). DESIGN: A retrospective review of audit reports in four audit cycles. SETTING: A cooperative group of institutions conducting clinical trials in cancer treatment. PARTICIPANTS: Patients taking part in clinical trials at collaborating CALGB institutions, members of the CALGB Data Audit Committee, and group chairmen of CALGB. MAIN OUTCOME MEASURE: The results of 691 institutional audits conducted by the CALGB in 1982 through 1992 with comparisons of main CALGB institutions vs affiliates. RESULTS: In four full reviews of all participating institutions in the CALGB, 3787 patients have had their on-site medical records compared with data submitted to the CALGB Data Management Center. Compliance with federal regulations for oversight by an institutional review board improved from a deficiency rate of 28.0% among the main institutions and 49.6% of the affiliate institutions in the first audit cycle to respective figures of 13.3% and 28.2% in the fourth cycle. Consent form deficiencies also dropped overall from 18.5% in the first cycle to 3.9% in the fourth. Patient eligibility was verified by auditors in 94.5%, and assessment of tumor changes in response to treatment was verified in 96.4% in the fourth cycle; both figures were only slightly lower in the first cycle. Two instances of scientific impropriety were discovered for a rate of only 0.28% of all audits. Both occurred prior to 1984, and none have occurred since. Major protocol deviations in drug dosing have held steady at about 11% over four audit cycles. Over the 11-year period of audits, three main institutions and 96 affiliate institutions have discontinued CALGB membership due solely, or at least partly, to unfavorable audit results. CONCLUSION: Scientific improprieties have occurred very rarely in clinical trials conducted by the CALGB. Protocol compliance in assessing patient eligibility and tumor responses has been high. Attention to administrative matters of consent forms, institutional review board approval, and ancillary data submission has measurably improved in the CALGB, which is at least partly due to the pressure from this on-site peer review of investigator performance.     

Evidence that guanylate cyclase is involved in modulating the resting tension and neurally-induced contraction of the guinea pig tracheal muscle

Electrical field stimulation of guinea-pig tracheal muscle strips produced a frequency-dependent biphasic response consisting of an initial cholinergic contraction followed by relaxation. Both phases of the response were of neural origin. In the presence of methylene blue, a guanylate cyclase inhibitor, the resting tension and the contraction were increased, but the accompanying relaxation was inhibited. However, in the presence of sodium nitroprusside, a guanylate cyclase activator, the resting tension was reduced and the contraction was inhibited, but the relaxation was prolonged and increased. Similarly, in the presence of either 3-isobutyl-1-methylxanthine, which promotes cyclic guanosine monophosphate (cGMP) accumulation, or 8-bromo-cGMP, an analogue of cGMP, the resting tension was reduced and the contraction was inhibited but the relaxation was prolonged and increased. From these results, it is concluded that guanylate cyclase is involved in modulating the resting tension and the neurally-induced contraction of guinea-pig tracheal muscle.     

Identification of a domain in the beta subunit of the type I interferon (IFN) receptor that exhibits a negative regulatory effect in the growth inhibitory action of type I IFNs

Expression of human alpha and long form of the beta (betaL) subunits of type I interferon receptor (IFN-R) in mouse cells is sufficient to activate the Jak-Stat pathway and to elicit an antiviral state in response to human IFNalpha2 and IFNbeta. We demonstrate herein, however, that these cells respond to the antiproliferative effects of murine IFNalphabeta but not human type I IFNs. These results suggest that an unknown species-specific component is required for the antiproliferative effect of human type I IFNs. The absence of this component can be complemented by expressing the human betaL chain truncated at amino acid 346. Thus, the distal region of betaL appears to function as a negative regulator of the growth inhibitory effects of type I IFNs. Further studies looking for possible targets of the betaL regulatory domain demonstrated that this region associates with a tyrosine phosphatase. These results suggest that a protein associated with the negative regulatory domain of betaL, likely a tyrosine phosphatase, plays a role in regulating the growth inhibitory effects of human type I IFNs.     

Interaction of 4-aminobutyrate-transaminase from swine kidneys with 5'- and 6'-methyl derivatives of pyridoxal-5'-phosphate

The study of interaction of 4-aminobutyrate transaminase with 5'- 6'-methyl derivates of PLP demonstrated that only the former was capable of forming a catalytically active holoenzyme possessing 0.37 activity of the native holoenzyme and a low affinity substrates. This compound interacts with the apoenzyme at a slower rate than does PLP; it has a reduced affinity towards apotransaminase (Km = 1.10(-4) M) and is replaced from the active site by native coenzyme. The other analog of pyridoxal-5'-phosphate forms a catalytically inactive complex with the apoenzyme; the other analog is not replaced from the active center by native coenzyme and non-competitively inhibits the reconstruction of apotransaminase (Ki = 2.10(-5) M).     

Enhancement of progesterone receptor levels by interferons in AE-7 endometrial cancer cells

BACKGROUND: Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells and to sensitize them to antiproliferative hormones. Endometrial cancer cells with high progesterone receptor (PR) level respond better to progesterone therapy than cells with either low or absent PR level. The effect of four different interferons (alpha and beta, both natural [n] and recombinant [r]) on cell proliferation and steroid receptor levels was investigated in the PR positive AE-7 human endometrial cancer cell line over a period of 12 days. METHODS: Cells were exposed to 10,100 and 1000 IU/ml of each IFN either for 3 days or continuously for 12 days. Hormone receptors were determined by the monoclonal enzyme immunoassay. Chemosensitivity was evaluated with the adenosine triphosphate-cell viability assay. RESULTS: AE-7 has a low level of estrogen receptors, which was not significantly affected by IFN exposure. The four IFN showed significantly enhanced PR levels over 12 days in both the 3-day and continuous-exposure experiments. No significant difference of PR enhancement was observed between 3 days and continuous exposure to IFN. This increase of receptors did not appear to be dose related. IFN enhanced PR level to a maximum level of about two times control cells. IFN did not produce significant cytotoxicity. Antiproliferative activity was observed with nIFN beta and rIFN beta at 1000 IU/ml dose in continuous-exposure experiments, which showed survival values of 79% and 69% respectively, compared with control at day 12. CONCLUSIONS: These preliminary data on PR expression modulation support other studies, which have shown that IFN modulate hormone receptor expression and, therefore, may play a role in the treatment of endometrial cancer.     

Percutaneous transluminal balloon aortic and mitral valvuloplasty in 27 patients treated at Hermann Hospital

Percutaneous aortic and mitral valvuloplasty are recognized as alternative interventions in cases of severe symptomatic aortic and mitral stenosis. We described the acute hemodynamic results, immediate clinical outcomes, and complications in 27 patients treated consecutively at Hermann Hospital with either percutaneous balloon aortic or mitral valvuloplasty. We review the possible mechanisms of action of balloon valvulotomy and the current indications for either procedure. Balloon aortic valvuloplasty is indicated in elderly patients with severe aortic stenosis in whom open-heart surgery is contraindicated or carries excessive mortality. All patients with symptomatic mitral stenosis are potential candidates for balloon mitral valvulotomy. In centers with an experienced interventional team in transseptal catheterization and an active surgical program, balloon valvulotomy is the initial procedure of choice for significant mitral stenosis with mobile leaflets and minimal chordal thickening.     

Converting text into speech in real time with microcomputers

Speech synthesizers have led to the evolution of many talking machines, which are now being used as automated text readers for the blind, communication aids for the nonvocal, and as a means of transmitting information from a database to remote locations. Where machine operators are fully using their eyes and hands to perform delicate operations, synthetic speech has proved invaluable in providing feedback from the machine to the operator. In this paper, the design method of a modest system for automatic translation of unlimited-vocabulary English text to synthetic speech is described in detail, as well as suggestions on possible applications of the system.     

Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients

The effects and plasma concentrations of different doses of propranolol and metoprolol were studied in 34 hyperthyroid patients. The initial daily doses were propranolol 160 mg or metoprolol 200 mg. If the resting heart rate remained above 75 beats per min after treatment for 4-7 days, the dose was increased and the patient re-examined after a further 4-7 days. Propranolol (n = 17) caused a reduced heart rate, a decrease in serum 3,3',5-triiodothyronine (T3) and an increase in serum 3,3',5'-triiodothyronine (reverse T3, rT3). In 10 patients, there was no change in T3 or rT3 until the daily dose of propranolol had been increased to 240 or 320 mg. The plasma level of propranolol was significantly correlated with the decrease in T3 and the increase in rT3. Metoprolol (n = 17) caused a reduction in heart rate similar to that following propranolol. However, serum T3 was only slightly reduced even after an increase in dose to 300 or 400 mg, and serum rT3 was not altered. Metoprolol concentrations were not significantly correlated with the fall in T3. It appears that the influence of beta-blockers on T4 conversion is of little importance for the clinical improvement in hyperthyroid patients, and rather it is a consequence of beta 1-adrenergic blockade interfering with the effect of T3. In addition, the findings support the assumption that therapeutic failure with beta-blockers in hyperthyroidism may be due to suboptimal treatment, and that individualized dosage is necessary.