POWER OF LOGRANK TEST AND COX REGRESSION MODEL IN CLINICAL TRIALS WITH HETEROGENEOUS SAMPLES

This paper evaluates the loss of power of the simple and stratified logrank tests due to heterogeneity of patients in clinical trials and proposes a flexible and efficient method of estimating treatment effects adjusting for prognostic factors. The results of the paper are based on the analyses of survival data from a large clinical trial which includes more than 6000 cancer patients. Major findings from the simulation study on power are: (i) for a heterogeneous sample, such as advanced cancer patients, a simple logrank test can yield misleading results and should not be used; (ii) the stratified logrank test may suffer some power loss when many prognostic factors need to be considered and the number of patients within stratum is small. To address the problems due to heterogeneity, the Cox regression method with a special hazard model is recommended. We illustrate the method using data from a gastric cancer clinical trial. © 1997 by John Wiley & Sons, Ltd.     

PREDICTION OF THE THERAPEUTIC DOSE FOR BENZODIAZEPINE ANXIOLYTICS BASED ON RECEPTOR OCCUPANCY THEORY

Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (K_d), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the K_d values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r >0·77). In contrast, a good log-linearity (r =0·96) was observed in the correlation between their K_d values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52·3±3·2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory. ©1997 by John Wiley & Sons, Ltd.     

CLINICOPATHOLOGICAL,IMMUNOLOGICAL AND GENETIC STUDIES OF CD30+ ANAPLASTIC LARGE CELL LYMPHOMA OF B-CELL TYPE; ASSOCIATION WITH EPSTEIN–BARR VIRUS IN A JAPANESE POPULATION

The clinicopathological features, the immunophenotype, and the presence of Epstein–Barr virus (EBV)-associated genomes and gene products were examined in 17 cases of CD30⁺ anaplastic large cell lymphoma (ALCL) of B-cell type. Microscopically, the 17 cases were divided into ten cases of the monomorphic type and seven cases of the pleomorphic type. EBV was detected in 6 of 17 cases (38 per cent) by RNA in situ hybridization (ISH) with EBV-encoded RNA (EBER1). EBER1⁺ cases consisted of two cases (20 per cent) of the monomorphic type and four cases (57 per cent) of the pleomorphic type. The five EBER1⁺ cases showed clonality of the EBV genome by Southern blotting, consistent with the presence of EBV in a monoclonal proliferation. The EBV-encoded latent membrane protein 1 (LMP1) was found in all six EBER1⁺ cases and EBV-encoded nuclear antigen 2 (EBNA2) was present in two cases by immunohistochemistry. No expression of LMP1 or EBNA2 was observed in the EBER1⁻ cases. The EBER1⁺ cases had a tendency for a more favourable prognosis than the EBER1⁻ cases. It is concluded that EBV has an association with CD30⁺ ALCL of B-cell type in the Japanese population studied, and especially with the large pleomorphic type. EBV infection may play a pathoaetiological role and may influence clinical behaviour.     

Involucrin expression in skin appendage tumours

The expression of involucrin was examined in 23 skin tumours of hair follicle origin, 17 tumours of sweat gland origin and three tumours of unknown origin, using an immunoperoxidase technique. All tumours from the hair follicle showed a positive reaction for involucrin. In particular keratoacanthoma and the squamous eddies in various tumours stained strongly. Trichofolliculoma, trichilemmoma and pilomatrixoma exhibited characteristic staining patterns which resembled those in the normal hair follicle. On the other hand the majority of the tumours of sweat gland origin did not stain, with restricted positive reactions in areas showing lumen formation or squamous metaplasia. In contrast to the lack of staining in syringoma, a positive reaction was observed in desmoplastic trichoepithelioma, which is histologically similar to syringoma. Clear cell acanthoma, the origin of which is still controversial, showed a staining pattern which indicated that its origin may not be in the sweat gland. These results suggest that testing for involucrin in skin appendage tumours may be very useful for understanding the kinetics of maturation as well as in determining the origin of the tumours.     

Ventricular Late Potential in Patients with Apparently Normal Electrocardiogram; Predictor of Brugada Syndrome

Backgrounds: Brugada syndrome can be overlooked due to its dynamic change in its electrocardiogram (ECG) manifestation. We hypothesized that positive ventricular late potential (VLP) in patients with nonspecific ECG would predict the inducible coved ST elevation (type‐1 Brugada ECG) and the patients at high risk. Methods: Thirty‐four patients of nonspecific ECG without structural heart disease were eligible for this study. All patients were referred for evaluation of syncopal episodes and/or cardiac arrest and/or frequent episodes of ventricular premature contractions. We assessed the correlation between baseline VLP and the alteration to a drug‐induced type‐1 Brugada ECG, and also evaluated the diagnostic accuracy of positive VLP in normal ECG subjects for the appearance of a drug‐induced type‐1 Brugada ECG. Results: Twenty‐one patients presented positive VLP and 13 patients showed negative VLP. Parameters of VLP (fQRSd, RMS₄₀, LAS₄₀) presented significant correlation with the alteration to a type‐1 ECG by pilsicainide. VLP demonstrated high sensitivity and negative predictive value for the prediction of type‐1 Brugada ECG. Furthermore, in their follow‐up, at least two cases of ventricular fibrillation were recognized in 21 of positive VLP patients with apparently normal ECGs. Conclusions: VLP in apparently normal ECG can predict the alteration to a drug‐induced type‐1 Brugada ECG and unmask the patients at risk. (PACE 2010; 33:266–273)     

A Japanese boy with Young-Simpson syndrome

In 1987 Young and Simpson reported a child with hypothyroidism, a congenital heart disease, severe mental retardation and striking facial dysmorphism, including microcephaly, blepharophimosis, bulbous nose, thin lip, low-set ears and micrognathia. This study presents an 8-month-old boy with virtually identical features to those in Young and Simpson's original case. The patient is a sporadic case and his parents are unrelated and phenotypically normal, hence the family data corresponds to any mode of inheritance. This is the first male case reported in the world and the first in Orientals.