One‐ and two‐stage design proposals for a phase II trial comparing three active treatments with control using an ordered categorical endpoint

Phase II clinical trials are performed to investigate whether a novel treatment shows sufficient promise of efficacy to justify its evaluation in a subsequent definitive phase III trial, and they are often also used to select the dose to take forward. In this paper we discuss different design proposals for a phase II trial in which three active treatment doses and a placebo control are to be compared in terms of a single‐ordered categorical endpoint. The sample size requirements for one‐stage and two‐stage designs are derived, based on an approach similar to that of Dunnett. Detailed computations are prepared for an illustrative example concerning a study in stroke. Allowance for early stopping for futility is made. Simulations are used to verify that the specified type I error and power requirements are valid, despite certain approximations used in the derivation of sample size. The advantages and disadvantages of the different designs are discussed, and the scope for extending the approach to different forms of endpoint is considered. Copyright © 2008 John Wiley & Sons, Ltd.     

Results of gastrojejunal anastomotic technique designed to reduce stricture

BackgroundThe incidence of strictures developing after gastrojejunostomy has been reported to range from 3% to 31%. We found an unacceptably high stricture rate (13%) using a 21-mm circular stapler. Attempts to use the 25-mm circular stapler were frustrated by disparities between the size of the instrument and the patient's anatomy. We, therefore, modified the technique to accomplish the anastomosis with the linear stapler and hand sewing (LSA) at community hospitals in Southern California.MethodsA total of 124 anastomoses were accomplished with the circular stapler (CSA) followed by 100 anastomoses using the LSA technique. Drains were used routinely with the CSA technique but were used only selectively with the LSA technique. Stricture was defined as that requiring endoscopic dilation for symptoms. Leaks were confirmed radiologically or surgically, and bleeding was defined as the need for transfusion. Our analysis used the Student t test and Fisher's exact test, with P <.05 considered statistically significant.ResultsNo patient died. The LSA technique was faster and resulted in significantly fewer postoperative strictures and complications compared with the CSA technique.ConclusionThe results of our study have shown that the LSA technique, as described, is preferable to the CSA technique.     

Histopathological characterisation of effects of the mouse Pax6 missense mutation on eye development

Mutations in PAX6/Pax6 lead to a variety of ocular anomalies in humans and mice. The aim of the study was to characterise the ocular abnormalities caused by the missense Pax6^Leca4 mutation and compare them to published observations on Pax6 alleles that are functionally equivalent to Pax6⁻ null alleles (such as Pax6^Sey and Pax6^Sey-Neu) and human inherited eye diseases. Ocular features of homozygous Pax6^Leca4/Leca4 and heterozygous Pax6^Leca4/+ embryos at E12.5-E18.5, heterozygous Pax6^Leca4/+ young mice at P18 and heterozygous Pax6^Leca4/+ adults at 12 weeks were analysed histologically with their wild-type Pax6^+/+ littermates. Homozygous Pax6^Leca4/Leca4 fetuses died perinatally with no eyes although an optic cup rudiment with pigmented cells developed. Pax6^Leca4/+ mice were microphthalmic and a range of other severe ocular phenotypes affected both the anterior and the posterior segments. In contrast to Pax6^+/−, the Pax6^Leca4/+ eyes had no goblet cells in the corneal epithelium, the iris was not hypoplastic and there was no lens-corneal epithelial plug. However, microphthalmia was more severe, corneal vascularisation occurred earlier (during fetal stages), pigmented cells were present in the vitreous and corneal stroma and the ciliary body was malformed or abnormal. These results show that, although Pax6^Leca4/+ lacked some eye abnormalities commonly seen in Pax6^Sey/+ and Pax6^Sey-Neu/+ eyes, in most respects their eyes were more severely affected. These differences probably reflect both differences between the Pax6^Leca4 and the Pax6^Sey-Neu mutations and differences in modifier gene expression in different genetic backgrounds. The presence of pigmented cells in the cornea is a novel observation. Some Pax6^Leca4/+ ocular abnormalities were similar to those present in human Peters' anomaly and persistent hyperplastic primary vitreous (PHPV) so Pax6^Leca4/+ mice provide a useful model for some inherited eye diseases.     

Linear and angular measurements of computer-generated models: are they accurate, valid, and reliable?

INTRODUCTION: Traditional advanced imaging modalities such as CT and MRI are limited in their ability to perform accurate linear distance and angular measurements regardless of anatomical orientation. The construction of 3D models has been used to perform anthropometric analyses as well as in the reconstruction of rapid prototypes. We hypothesized that such measurements would be precise to within 2 mm or 2 degrees of measurements performed with a coordinate measurement machine (CMM). We also hypothesized that there would be a high degree of interobserver reliability with these measurements. MATERIALS AND METHODS: Multiple aluminum screws were implanted in various positions in three foam pelvises which were subsequently scanned by CT and rendered as 3D models using a commercially available software package (Mimics). Linear and angular measurements were performed using a CMM machine, the software package, and a dial caliper or goniometer. The deviation of the measurements from the CMM data was compared using ANOVA. The interobserver reliability of both the manual and computer-generated measurements was calculated. RESULTS: The mean difference between the CMM distances and those measured manually and with the software was 2.12 +/- 1.20 mm and 1.57 +/- 1.05 mm, respectively. The mean difference between the CMM angular measurements and the angular measurements performed manually and with the software was 4.07 +/- 4.70 degrees and 1.62 +/- 1.32 degrees, respectively. In all cases, the manual measurements were significantly less accurate (p < 0.0001) and there was a high degree of interobserver reliability. CONCLUSIONS: Computer-generated measurements taken from three-dimensionally reconstructed models are more accurate than manual measurements and are within 2 mm and 2 degrees of measurements performed with a CMM. These measurements have high interobserver reliability.     

The relationship between interstitial cystitis and endometriosis in patients with chronic pelvic pain.

OBJECTIVE: This study was designed to determine the relationship between interstitial cystitis (IC), endometriosis (endo), and chronic pelvic pain (CPP) in individuals in whom nongynecological and nonurological problems had been previously ruled out. METHODS: A prospective study of 162 consecutive women with a complaint of chronic pelvic pain seen in the clinic was performed between August 2002 and December 2005. These patients underwent a workup to exclude other causes of pelvic pain, had PUF (Pain Urgency and Frequency) questionnaires filled out, and underwent a laparoscopy and a cystoscopy with hydrodistention. Pain levels were determined, and treatment was reviewed and enumerated. Results were obtained and quantified. RESULTS: In this study, 123 (76%) patients were diagnosed with active endometriosis, 133 (82%) were diagnosed with interstitial cystitis, and 107 (66%) had both disease entities simultaneously. Thirteen (8%) patients were diagnosed with pathologies unrelated to endometriosis and interstitial cystitis. Pain levels were seen to decrease at 6 months in all groups of patients with the exception of those patients with endometriosis only. CONCLUSION: CPP is a difficult, taxing, and frustrating concern for many women in the United States. These individuals have traditionally been difficult to treat. A large number of women with CPP in our patient population have been shown to have endometriosis, interstitial cystitis, or both. Therefore, a workup for premenopausal individuals with CPP involves obtaining a history that keys into possible nongynecologic causes of pain, a complete accounting of urinary problems, and a thorough history of gynecological problems. A physical examination with a comprehensive history should be performed, and the investigation may include the possibility of a simultaneous laparoscopy and cystoscopy if warranted. These procedures can serve as both a means for diagnosis and treatment of these problems when encountered.