Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice.

Human prostate cancer displays a high degree of variability in its rate of spread, which could be due largely to differences in the invasive potential of the tumor cells. The degradation of the basal lamina and stromal extracellular matrix is mediated in part by the secretion of matrix metalloproteinases (MMPs). Matrilysin (PUMP-1, MMP-7) and gelatinase A (M(r) 72,000 type IV collagenase, MMP-2) have been shown to be overexpressed in prostate carcinoma. We have expressed the single MMP matrilysin in the tumorigenic but nonmetastatic human prostate tumor cell line DU-145 to determine if matrilysin has a functional role in prostate tumor cell invasion. DU-145 cells expressing matrilysin were significantly more invasive than vector-only transfected cell lines as assayed by a severe combined immunodeficient mouse model of tumor cell invasion. Vector-only transfected DU-145 cells injected i.p. into severe combined immunodeficient mice invaded the diaphragm in only 1 of 9 mice (11%), whereas matrilysin-transfected DU-145 cells invaded the diaphragm in 12 of 18 mice (66%). The difference between the controls and matrilysin-transfected cells was statistically significant (P < 0.006). These results suggest a functional role for matrilysin in the initial invasion of prostate cancer through the epithelial basal lamina and into the surrounding stroma.

v-jun oncogene suppresses both phorbol ester-induced cell invasion and stromelysin gene expression in a mouse papilloma cell line.

The viral jun (v-jun) oncogene encodes a transcription factor that can participate in the transactivation of genes through the AP-1 complex. Evidence indicates that the ability of v-jun to transform cells and stimulate transcription depends on the cell type. We have asked whether expression of the v-jun gene in benign tumor forming mouse keratinocytes that already express an activated c-rasHa oncogene would cause malignant progression. Our results showed that the v-jun transfection did not result in malignant progression; instead, we made the unexpected observation that the ability of these cells to invade reconstituted basement membrane matrix (in vitro) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, was suppressed. This phenomenon could, in part, be explained by the suppression of the induction by phorbol ester of expression of the metalloproteinase, stromelysin (transin). Of interest was the finding that 12-O-tetradecanoylphorbol-13-acetate induction of other cellular genes known to be regulated by AP-1 was not inhibited in the benign tumor cells expressing v-jun.

Statistical methods to improve the precision of the treadmill exercise test.

OBJECTIVES: The study systematically compared different measures of ST segment depression from the treadmill exercise test. BACKGROUND: The value of the treadmill exercise test for objectively measuring treatment effects is limited by random error in the measurement of ST depression and may be biased by regression to the mean or by the decision to terminate the test. METHODS: Treadmill exercise was performed in 21 subjects with ischemic heart disease 1 h after isosorbide dinitrate 10 mg or placebo in a double-blind randomized crossover study. A 12-lead electrocardiogram (ECG) was recorded every 30 s during and at peak exercise. The relative sample size needed to detect the nitrate effect was compared for different summary measures of ST depression. RESULTS: The ST depression measured from a single unmatched lead at longest equivalent sub-maximal exercise needed the lowest sample size to detect the nitrate effect in paired comparisons (p = 0.000006). Averaging over multiple leads or times did not improve detection of the nitrate effect. The rate of increase in ST depression (in mm/min) calculated by linear regression needed a similar sample size (x1.32, 95% CI 0.62 to 2.58). A larger sample size was needed for ST depression at peak exercise (x2.9, CI 1.3, 11.1) and exercise duration (x4.5, CI 1.5, 38). Time to 1-mm ST depression was the least efficient measurement (relative sample size x15.5, CI 1.6, >1,000). Comparison of matched leads resulted in >2-fold differences in estimates of the nitrate effect because of bias from regression to the mean. CONCLUSIONS: Maximal ST depression at longest equivalent sub-maximal exercise and the maximal rate of increase in ST depression had less bias and random variation than did other commonly used measures. The rate of increase in ST depression is preferred because it can be calculated in either paired or unpaired studies.

Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings.

BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.

Interstitial irradiation versus interstitial thermoradiotherapy for supratentorial malignant gliomas: a comparative survival analysis.

PURPOSE: To compare the survival of two groups of patients with supratentorial malignant gliomas who were treated on two sequential protocols with either interstitial thermoradiotherapy or with interstitial irradiation without hyperthermia. METHODS AND MATERIALS: Between 1988-1992, patients with anaplastic astrocytoma or glioblastoma multiforme were treated at the University of Arizona on a Phase I/II protocol of interstitial thermoradiotherapy with ferro-magnetic seeds. The treatment protocol consisted of debulking surgery, a course of external beam radiotherapy and hyperthermia given immediately before and after brachytherapy. The survival of patients so treated was compared with that of a similar group of patients treated with interstitial brachytherapy alone at the Barrows Neurological Institute between 1982-1990. RESULTS: Twenty-five patients with primary tumors treated at the time of initial presentation with thermoradiotherapy were compared with a control group of 37 patients treated with interstitial brachytherapy alone. All primary patients were followed for a minimum of 34 months post implant. Multivariate analysis based on proportional hazards models showed that hyperthermia (p = 0.027), patient age (p < or = 0.00001) and histology (anaplastic astrocytoma vs. glioblastoma multiforme, p = 0.0017) were the only factors significantly associated with survival in this data set. From the fitted model, the hazard of dying when treated with hyperthermia was .53 times (95% confidence intervals 0.29-0.94) than that of the control group. In addition, we treated a small group of patients with recurrent tumors (13 with brachytherapy alone, and eight with thermoradiotherapy) and found no survival difference (p = 0.62). CONCLUSION: Within the constraints of the selection factors and the different treatment parameters used in these studies, we conclude that an interstitial thermoradiotherapy boost confers a statistically significant survival benefit to patients with primary high grade gliomas when compared to interstitial brachytherapy alone.

Clinical hyperthermia with a new device: the current sheet applicator.

PURPOSE: The current sheet applicator (CSA) is a newly developed microwave hyperthermia device. Advantages over commercial microwave applicators include its small size and high ratio of heating area to physical aperture area. These physical characteristics make the CSA excellent for heating constricted areas and allow the use of arrays of CSAs over large surfaces. This study examines the clinical efficacy of the CSA for heating superficial malignant tumors. METHODS AND MATERIALS: From December 1989 through October 1991, 19 patients with recurrent or metastatic superficial malignant tumors were treated once or twice weekly to 30 hyperthermia fields using one to four CSAs. Each field received from one to four hyperthermia treatments for a total of 74 treatments. The treatment objective was to elevate the tumor temperature to a minimum of 42.5 degrees C for 30 min (2 patients) or 60 min (17 patients). Intratumor temperatures were measured with percutaneous fiberoptic thermometry probes. All patients received concurrent fractionated radiation therapy with total dose ranging from 20 to 65 Gy (median 46 Gy). Seventeen of the 30 fields had been previously irradiated to a median dose of 50 Gy. RESULTS: Mean values for the maximum temperature, average temperature, and minimum temperature were 43.6 degrees C +/- 1.0, 42.2 degrees C +/- 1.4, and 41.0 degrees C +/- 1.5, respectively. Mean values for T50 and T90 were 42.2 degrees C +/- 1.1 and 41.0 degrees C +/- 1.3, respectively. The overall response rate for all assessable fields was 96%. Only Only three responding tumors have progressed with a median follow-up period of 6 months. Treatment related morbidity was generally mild and self-limited. CONCLUSION: The CSA is a promising new microwave hyperthermia device capable of heating superficial tumors to therapeutic temperatures. When used in combination with radiotherapy, response rates are excellent without excessive toxicity.

Interstitial thermoradiotherapy: thermal dosimetry and clinical results.

From August 1977 to August 1986, 72 patients with advanced primary or recurrent cancers were treated using interstitial thermoradiotherapy. Sites treated included the pelvis in 49 patients, the head and neck in 15, and other sites in six. Median tumor volume was 52 cm3, and all but nine patients had received prior irradiation. In 69 patients, hollow stainless steel catheters were implanted and used as electrodes with a 0.5 MHz radiofrequency (RF) generator, whereas in three patients, standard plastic Henschke tubes were used with a commercially available interstitial microwave (MW) system operating at 915 MHz. Most patients were heated intraoperatively for 30 minutes, aiming for a minimum measured intratumoral temperature (Tmin) of 42 degrees C. The implant was occasionally preceded by external irradiation, and after hyperthermia, the catheters were afterloaded with 192Ir for brachytherapy. Tmin exceeded 42 degrees, 42.5 degrees, 43 degrees, and 44 degrees in 25, 16, 12, and 3, respectively, of 70 patients with temperature data available, and the probability of successful heating was independent of tumor volume or site. Twenty-five of 69 (36%) evaluable patients achieved a complete response (CR). Probability of CR demonstrated a significant univariate dependence upon Tmin, radiation dose, site treated, and tumor volume, but multivariate analysis showed only three significant predictor variables: tumor volume, radiation dose, and Tmin. The probability of a CR ranged from 95% for patients with small tumors receiving high doses of radiation and adequate heat, to 5% for patients with large tumors receiving low radiation doses and less than adequate heat. Of 25 patients with CR, 10 relapsed; median response duration was less than 18 months, depended marginally upon disease site, and was independent of Tmin, radiation dose, and tumor volume. Seventeen patients sustained a complication, of which nine were severe enough to require hospitalization or surgery. All severe complications occurred in patients with pelvic tumors. The probability of a complication of any severity had a significant univariate association with maximum intratumoral temperature (Tmax) and tumor size. We conclude that interstitial thermoradiotherapy offers the promise of heating large tumors in locations where externally applied hyperthermia has not been successful.

Pterygium treated with excision and postoperative beta irradiation.

A retrospective study was done of 338 patients with pterygia treated between October 1974 and May 1990. These patients resided in the desert of the southwestern United States, where the hot, dry, dusty climate is thought to predispose to pterygium formation and subsequent recurrence. The pterygia were excised, and the administration of beta irradiation was initiated within 24 hr of surgery. Sixteen percent of the pterygia were recurrent. Ninety-five percent of the beta irradiation prescriptions consisted of 3 weekly 800 cGy fractions. For patients with a minimum of 6 months follow-up, the crude local control rate was 225/258 (88%). The Kaplan-Meier estimate of the 5-year local control rate was 84% (95% confidence interval: 79-89%). Ten of 33 recurrences were diagnosed within 6 months, and 32/33 recurrences were diagnosed within 5 years of treatment. Previously untreated pterygia were controlled more easily than were recurrent pterygia (p = 0.005). In 86% of the cases, patients judged the cosmetic results to be satisfactory. No severe complications developed. This study and others, when compared with studies involving excision alone, suggest that postoperative beta irradiation reduces the likelihood for pterygium recurrence. When the beta irradiation is fractionated, satisfactory cosmetic results can be achieved with low morbidity.

Treatment of malignant gliomas with interstitial irradiation and hyperthermia.

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.

Interstitial thermoradiotherapy with ferromagnetic implants for locally advanced and recurrent neoplasms.

PURPOSE: The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation. METHODS AND MATERIALS: Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions. RESULTS: The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity. CONCLUSION: These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.

Recurrent basal cell carcinoma treated with radiation therapy.

A retrospective study was performed of 61 recurrent basal cell carcinomas treated with radiation therapy between 1974 and 1990 at the University of Arizona College of Medicine or at Southwestern Radiation Oncology, Tucson, Arizona. The median length of follow-up was 57 months. Applying the American Joint Committee on Cancer staging system to these recurrent tumors, 36 were stage I, 19 were stage II, five were stage III, and one was stage IV. Kaplan-Meier methods were used to estimate the 5-year complete remission rates. The Mantel-Haenszel Test and the Cox Proportional Hazards Model were used to determine if tumor size, stage, histologic subtype, anatomic site, age, sex, dose, number of radiation therapy treatments, length of time over which the radiation therapy was administered, or type of radiation beam used (orthovoltage x-rays vs megavoltage electrons) affected the 5-year complete remission rates. Only tumor size and stage had a statistically significant effect on the complete remission rates. The Kaplan-Meier estimates of the 5-year complete remission rates for 0.5- to 1.0-cm tumors vs tumors larger than 1.0 cm were 96% (95% confidence interval, 88% to 100%) and 81% (95% confidence interval, 64% to 99%), respectively. The Kaplan-Meier estimates of the 5-year complete remission rates for stage I/II tumors vs stage III/IV tumors were 93% (95% confidence interval, 85% to 100%) and 42% (95% confidence interval, 8% to 84%), respectively. Functional and cosmetic results were frequently good to excellent at 5 years. Soft-tissue necrosis developed in two of 61 cases, and was successfully managed in both. This article, combined with a review of the literature, suggests that radiation therapy is an effective method of treating recurrent basal cell carcinomas.

A comparison of survival between radiosurgery and stereotactic implants for malignant astrocytomas.

The purpose of this paper is to compare the survival of three groups of patients with high grade supratentorial gliomas who were treated on three sequential protocols with surgical resection, external beam fractionated radiotherapy and a boost to the residual contrasting enhancing mass by either interstitial brachytherapy (IB, n = 33), by interstitial thermoradiotherapy (IT, n = 25) or by stereotactic radiosurgery (SRS, n = 19). The primary aim of this study was to evaluate the role of different boosting techniques in the initial management of primary brain tumors. External beam radiotherapy doses were escalated from one study to the next so that the median doses given to the IB, the IT, and the SRS groups were 41.4 Gy, 48.4 Gy, and 59.4 Gy, respectively. The median dose of interstitial irradiation or stereotactic radiosurgery, were 40 Gy, 32.2 Gy and 10 Gy, respectively, for the same groups. Follow-up was such that all living patients had been followed for a minimum of 30, 27, 4 months in the IB, IT, and SRS groups, respectively; hence, twelve-month survival was 52% (95% CI: 34%-69%), 80% (95% CI: 64%-96%), and 51% (95% CI: 24%-78%) in the same respective groups. Using a multivariate Cox proportional hazards model, treatment with IT conferred a survival advantage over IB (p = 0.029). Furthermore, survival of patients treated with SRS did not significantly differ from that of patients treated with an implant with or without hyperthermia.(ABSTRACT TRUNCATED AT 250 WORDS)

Weighing evidence: quantitative measures of the importance of bitemark evidence.

Quantitative measures of the importance of evidence such as the "likelihood ratio" have become increasingly popular in the courtroom. These measures have been used by expert witnesses formally to describe their certainty about a piece of evidence. These measures are commonly interpreted as the amount by which the evidence should revise the opinion of guilt, and thereby summarize the importance of a particular piece of evidence. Unlike DNA evidence, quantitative measures have not been widely used by forensic dentists to describe their certainty when testifying about bitemark evidence. There is, however, no inherent reason why they should not be used to evaluate bitemarks. The purpose of this paper is to describe the likelihood ratio as it might be applied to bitemark evidence. We use a simple bitemark example to define the likelihood ratio, its application, and interpretation. In particular we describe how the jury interprets the likelihood ratio from a Bayesian perspective when evaluating the impact of the evidence on the odds that the accused is guilty. We describe how the dentist would calculate the likelihood ratio based on frequentist interpretations. We also illustrate some of the limitations of the likelihood ratio, and show how those limitations apply to bitemark evidence. We conclude that the quality of bitemark evidence cannot be adequately summarized by the likelihood ratio, and argue that its application in this setting may be more misleading than helpful.

Estrogen or raloxifene during postmenopausal weight loss: adiposity and cardiometabolic outcomes.

OBJECTIVE: Estrogen-based hormone therapy (HT) attenuates abdominal fat gain after menopause, but whether HT improves abdominal fat loss during weight loss is unknown. It was hypothesized that HT or a selective estrogen receptor modulator (raloxifene) would augment reductions in abdominal visceral fat during weight loss when compared to placebo, potentially increasing improvements in glucose tolerance and lipid profile. METHODS: Healthy postmenopausal women (n = 119; age 50-70 yr) underwent a 6-month weight-loss (primarily exercise) intervention with randomization to raloxifene (60 mg/d), HT (conjugated estrogens, 0.625 mg/d), or placebo. Outcomes were change in total and abdominal (visceral and subcutaneous) fat mass, lipid profile, and fasting and post-challenge glucose and insulin. RESULTS: Neither HT nor raloxifene augmented loss of total or abdominal fat mass during exercise-induced weight loss when compared with placebo. Weight loss-induced improvements in risk factors were similar among the three groups, except for a greater reduction in fasted glucose in the HT group (difference in change [95%CI] from placebo; -0.40 [-0.76, -0.05]) and greater reductions in LDL (-0.36 [-0.63, -0.09]) and increases in HDL (0.15 [0.07, 0.24]) in both treatment groups. CONCLUSIONS: Postmenopausal HT and raloxifene did not increase abdominal fat loss during weight loss, but did improve some cardiometabolic outcomes.

Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

A unifying family of group sequential test designs.

Currently, the design of group sequential clinical trials requires choosing among several distinct design categories, design scales, and strategies for determining stopping rules. This approach can limit the design selection process so that clinical issues are not fully addressed. This paper describes a family of designs that unifies previous approaches and allows continuous movement among the previous categories. This unified approach facilitates the process of tailoring the design to address important clinical issues. The unified family of designs is constructed from a generalization of a four-boundary group sequential design in which the shape and location of each boundary can be independently specified. Methods for implementing the design using error-spending functions are described. Examples illustrating the use of the design family are also presented.

A computationally simpler algorithm for the UMVUE of a normal mean following a group sequential trial.

When using data collected in a group sequential clinical trial, the sample mean is no longer the uniform minimum variance unbiased estimator (UMVUE) of the mean of a normal distribution. Emerson (1993, Computers and Biomedical Research, 26, 68-73) described an algorithm for computing the UMVUE in this setting. This algorithm, although computationally expensive, used only the basic software necessary for deriving group sequential boundaries. In this paper, we present an improved algorithm that results in greatly decreased computation times.

Basal cell carcinoma treated with radiation therapy.

Between 1974 and 1989, 85 patients with 115 biopsy-proven basal cell carcinomas were treated with radiation therapy at the University Medical Center in Tucson. Either orthovoltage or megavoltage photons were used to deliver doses ranging from 2000 cGy in a single treatment to 7300 cGy in 35 fractions over 62 days. The median length of follow-up was 40 months. Kaplan-Meier estimates of the 5-year local control rates are presented by American Joint Committee on Cancer stage. The difference between the local control rates for both previously untreated and recurrent Stage I and II carcinomas (95% at 5 years) and Stage III and IV carcinomas (56% at 5 years) was statistically significant (P = 0.0001, by Mantel-Haensel test). Although recurrent basal cell carcinomas generally have a worse prognosis, the Kaplan-Meier estimate of the 5-year local control rate for recurrent Stage I and II carcinomas treated with radiation therapy was 95%. These results, along with a review of the literature, suggest two points: (1) high cure rates can be obtained when Stage I and II basal cell carcinomas are treated with radiation therapy and (2) radiation therapy is a relatively effective method for treating recurrent basal cell carcinomas, with cure rates surpassed only by Mohs micrographic surgery.