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.

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.

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).

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.

The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control.

Exhaled nitric oxide (eNO) levels are increased in untreated or unstable asthma and measurements can be made easily. Our aim was to assess the usefulness of eNO for diagnosing and predicting loss of control (LOC) in asthma following steroid withdrawal. Comparisons were made against sputum eosinophils and airway hyperresponsiveness (AHR) to hypertonic saline (4.5%). Seventy-eight patients with mild/moderate asthma had their inhaled steroid therapy withdrawn until LOC occurred or for a maximum of 6 wk. Sixty (77.9%) developed LOC. There were highly significant correlations between the changes in eNO and symptoms (p < 0.0001), FEV(1) (p < 0.002), sputum eosinophils (p < 0.0002), and saline PD(15) (p < 0.0002), and there were significant differences between LOC and no LOC groups. Both single measurements and changes of eNO (10 ppb, 15 ppb, or an increase of > 60% over baseline) had positive predictive values that ranged from 80 to 90% for predicting and diagnosing LOC. These values were similar to those obtained using sputum eosinophils and saline PD(15) measurements. We conclude that eNO measurements are as useful as induced sputum analysis and AHR in assessing airway inflammation, with the advantage that they are easy to perform.

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.

Collateral recruitment and "warm-up" after first exercise in ischemic heart disease.

BACKGROUND: Proposed mechanisms for "warm-up" after angina on first exercise include ischemic preconditioning and collateral recruitment. The aim of this study was to determine whether patients with ischemic heart disease and well-developed coronary collateral vessels have a greater warm-up response than those with no visible collateral vessels. METHODS AND RESULTS: Fifteen patients with a total coronary occlusion and collateral vessels and 18 patients with a single coronary artery stenosis and no angiographically visible collateral vessels were studied. Warm-up was measured as the difference in ST depression on the second compared with the first of 2 sequential treadmill exercise tests separated by 10 minutes of rest. There was a trend for the duration of second exercise to increase more in patients with occlusion than in those with stenosis (+1.3 vs +0.54 minutes, respectively, P =.087). In both groups, ST depression was less on second exercise than on first exercise. The size of this decrease was greater in the occlusion group than in the stenosis group. ST depression at equivalent submaximal exercise decreased by 0.52 vs 0.19 mm, respectively (P =.049). The rate of increase in ST depression during exercise decreased by 1.08 versus 0. 55 mm/min, respectively (P =.034). These differences were less after adjustment for ST depression on first exercise (P =.11 and P =.063, respectively). CONCLUSIONS: The trend for a greater decrease in ST depression on second compared with first exercise in the patients with total coronary occlusion suggests that an increase in collateral flow is a mechanism for warm-up after first exercise in ischemic heart disease.

Relation between duration and intensity of first exercise and "warm up" in ischaemic heart disease.

OBJECTIVE: To determine the importance of the duration and intensity of "warm up" exercise for reducing ischaemia during second exercise in patients with exertional angina. DESIGN: Randomised crossover comparison of three warm up exercise protocols. PATIENTS: 18 subjects with stable ischaemic heart disease and > 0.1 mV ST segment depression on treadmill exercise testing. INTERVENTIONS: The warm up protocols were 20 minutes of slow exercise at 2.7 km/h, symptom limited graded exercise for a mean of 7.4 (range 5.0 to 10.5) minutes, and three minutes of symptom limited fast exercise of similar maximum intensity. MAIN OUTCOME MEASURES: ST segment depression during graded treadmill exercise undertaken 10 minutes after each warm up protocol or no warm up exercise. RESULTS: Compared with exercise with no warm up, the duration of graded exercise after earlier slow warm up increased by 4.9% (95% confidence interval (CI), -3.3% to 13.7%), after graded warm up by 10.3% (95% CI, 5.6% to 15.2%), and after fast warm up by 16% (95% CI, 6.2% to 26.7%). ST segment depression at equivalent submaximal exercise decreased after slow warm up by 27% (95% CI, 5% to 44%), after graded warm up by 31% (95% CI, 17% to 44%), and after fast warm up by 47% (95% CI, 27% to 61%). Compared with slow warm up exercise, the more intense graded and fast warm up protocols significantly increased the duration of second exercise (p = 0.0072) and reduced both peak ST depression (p = 0.0026) and the rate of increase of ST depression (p = 0.0069). CONCLUSIONS: In patients with exertional angina the size of the warm up response is related to the maximum intensity rather than the duration of first exercise.

Otago glaucoma surgery outcome study: long-term results of trabeculectomy--1976 to 1995.

OBJECTIVE: To provide data on the long-term results of trabeculectomy performed in the province of Otago, New Zealand. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: A total of 289 eyes of 193 patients (excluding 4 eyes lost to follow-up soon after operation); all trabeculectomies performed for the first time on cases of primary glaucoma from 1976 through 1995. INTERVENTION: Standard Cairns trabeculectomy. MAIN OUTCOME MEASURES: Intraocular pressure, visual acuity, visual field damage. RESULTS: Trabeculectomy was effective in controlling intraocular pressure at a level of 21 mmHg or less, with probabilities of 0.93 (95% confidence interval [CI], 0.90-0.97), 0.87 (95% CI, 0.82-0.93), and 0.85 (95% CI, 0.77-0.92) at 5, 10, and 15 years, respectively, after surgery. The mean visual acuity improved from 20/60 to 20/40 immediately after trabeculectomy but then declined steadily over the postoperative years. The decline in visual acuity led to blindness in 47 eyes. The Kaplan-Meier estimated probability of retaining useful vision (visual acuity > 20/400 and visual field > 5 degrees radius) in the overall group was 0.87 (95% CI, 0.79-0.91), 0.72 (95% CI, 0.60-0.79), and 0.6 (95% CI, 0.43-0.69) at 5, 10, and 15 years, respectively, after surgery. Those eyes that had good preoperative visual acuity (visual acuity > or = 20/30) had a significantly better chance of retaining useful vision (P = 0.02). CONCLUSIONS: The intraocular pressure was well controlled by trabeculectomy, but a steady long-term decline in visual acuity and visual field occurred, decreasing the probability of an eye retaining useful vision up to the time of death to approximately 0.6.

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.

Hemostatic markers in acute ischemic stroke. Association with stroke type, severity, and outcome.

BACKGROUND AND PURPOSE: Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality. METHODS: We measured fibrinopeptide A, cross-linked D-dimer, and beta-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model. RESULTS: The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and beta-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality. CONCLUSIONS: Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Cerebral bloodflow in and around spontaneous malignant gliomas.

Knowledge of the cerebral bloodflow (CBF) in and around malignant gliomas is of crucial importance in developing strategies for hyperthermia-, radiation-, and chemo-therapy of these difficult to cure lesions. To gather data regarding this important physiological variable, the perfusion distributions of 26 patients who had either a glioblastoma multiforme or an anaplastic astrocytoma were determined using stable xenon computed tomography (XeCT). Perfusion values were determined for each of the following anatomical regions: low density tumour core, the enhancing active ring of the tumour, the low density peripheral region of edema, an ipsilateral region of normal brain adjacent to the tumour, and a region of remote normal tissue on the contralateral side of the brain. A multiple regression analysis of the logs of the CBF values was used to analyse: (1) the differences in blood perfusion between the anatomical regions; and (2) the association of blood perfusion with various patient and tumour characteristics. Statistically significant differences in perfusion values were found between all of the anatomically outlined regions with the exceptions that the active tumour and edematous regions do not differ significantly from the ipsilateral normal brain tissue. The ipsilateral normal brain tissue adjacent to the tumour was found to have a relative perfusion (relative to the contra-lateral normal brain tissue perfusion) of 0.84, the edematous tissue had a relative perfusion of 0.52, the active tumour 0.78, and the core 0.39. Significant blood flow was present in the low density tumour core, contradicting the frequent assumption that there is zero or minimal blood flow in such regions. Multiple regression analysis was used to look for other variables that might be associated with blood flow after adjusting for the differences between anatomical regions. This analysis found a significant negative correlation between tumour blood-flow and tumour volume. It also estimated that blood flow in GMB tumours was approximately 67% of that in lower grade tumours. Variables that were found not to be significantly correlated with blood flow were: patient sex, multiple lobe involvement, hemisphere involved, treatment status (initial vs recurrent disease), Karnofsky performance status, age and, lobe involved.

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 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.

Immunohistochemical analysis of cathepsin D in prostate carcinoma.

Cathepsin D is a carboxyl protease that has been implicated as an important factor in tumor cell invasion. Sixty-nine cases of primary adenocarcinoma of the prostate were studied by the indirect immunoperoxidase method using a primary monoclonal anti-cathepsin D antibody. Immunoreactivity was graded from 0 (negative) to 4+ (intense reaction). The normal tubuloalveolar glands were, in general, negative. However, nine cases revealed focal staining of nonneoplastic luminal cells. Basal cells were negative except in areas of basal-cell hyperplasia, which were intensely positive. Thirty-nine of 78 carcinoma samples revealed 2+ or greater positive punctate lysosomal staining. In the 39 positive-stained cases, the reactivity was diffuse in three and focal in the remainder. The percentage of carcinoma cases whose worst lesions stained 2+ or greater showed a nonsignificant (P = 0.055) relation to Gleason grade but a significant (P = 0.031) relationship to pathologic stage. Thus, cathepsin D may prove to be a useful marker of prostate cancer progression.

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.

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)