Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial

Context  Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. Objective  To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. Design, Setting, and Patients  The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19 747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. Intervention  Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. Main Outcome Measures  Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. Results  There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. Conclusions  Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. Trial Registration  clinicaltrials.gov Identifier: NCT00003906      

Phase 2 trial of Allovectin-7 in advanced metastatic melanoma

Treatment of metastatic melanoma with chemotherapeutic regimens has led to disappointing response rates, duration of response and no appreciable impact on survival. Intralesional injection of a low dose of an HLA-B7/beta2 microglobulin plasmid formulated with cationic lipids (Allovectin-7 is a registered trademark of Vical, Incorporated, San Diego, California, USA) has been shown previously to be safe and well tolerated. A phase 2, open-label study was performed at 16 centers in the United States. Seventy-seven patients were treated with 10 mug intralesional Allovectin-7 weekly for 6 weeks and clinical response to treatment were evaluated by World Health Organization criteria. Minimal adverse events were associated with the Allovectin-7 injections. Seven patients (9.1%) had complete or partial response with 4.8 months median duration of response. Allovectin-7 was shown to be safe and exhibit biological activity at this dose. Its safety profile may enable Allovectin-7 to be used at higher doses, which may provide greater clinical activity.     

Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity

Defective expression of HLA class I molecules is common in tumor cells and may allow escape from CTL-mediated immunity. We here investigate alterations in expression of HLA class I and their underlying molecular mechanisms in ovarian cancer patients. The HLA class I and HLA-A2 expression levels on noncultured tumor cells of 12 patients diagnosed with ovarian carcinoma were investigated by flow cytometry. Molecular analyses of antigen-processing machinery (APM) components were done in metastatic cancer cells, and the HLA genotype was determined in both these and the primary tumor. HER-2/neu-specific immunity was evaluated by enzyme-linked immunospot assays. The metastatic tumor cells from all patients expressed low levels of HLA class I surface antigens. In six of nine HLA-A2+ patients, HLA-A2 expression was heterogeneous with a subpopulation of tumor cells exhibiting decreased or absent HLA-A2 expression. One patient-derived tumor cell line completely lacked HLA-A2 but exhibited constitutive expression of APM components and high HLA class I expression that was further inducible by IFN-gamma treatment. Genotyping showed a haplotype loss in the metastatic tumor cells, whereas tumor tissue microdissected from the primary tumor exhibited an intact HLA gene complex. Interestingly, HLA-A2-restricted HER-2/neu-specific T-cell responses were evident among the lymphocytes of this patient. Abnormalities in HLA class I antigen expression are common features during the progression of ovarian cancer, and haplotype loss was, for the first time, described as an underlying mechanism.     

The joint effect of smoking and AIB1 on breast cancer risk in BRCA1 mutation carriers

Women with BRCA1 mutations are at an elevated risk for breast cancer. AIB1 (NCOA3/SRC3) genotype and smoking may alter this risk. We examined the differences in breast cancer risk by AIB1 polyglutamine repeat polymorphism and pre-diagnosis smoking habits for BRCA1 mutation carriers to determine if there was an interaction between smoking and AIB1 genotype. Multivariate Cox proportional hazards regression was used with 316 female BRCA1 mutation carriers to model breast cancer risk. Ever having smoked was associated with a decreased breast cancer risk [Hazard Ratio (HR) = 0.63, 95% CI, 0.47-0.87]. A dose-response relationship between number of pack-years smoked and breast cancer risk was also found for women who smoked <20 pack years of cigarettes (HR = 0.72, 95% CI, 0.52-1.00) and for women who smoked >/=20 pack years (HR = 0.41, 95% CI, 0.23-0.71; P for trend = 0.0007). Women with a 28 repeat allele for AIB1 had a significantly reduced risk of breast cancer (HR = 0.72, 95% CI, 0.51-1.00). Women who smoked >/=20 pack-years with a 28 repeat allele had an even greater reduced risk of breast cancer (HR = 0.19, 95% CI, 0.07-0.54) compared to women who were never smokers with no 28 allele. Since AIB1 appears to modulate the effect of endogenous hormones via the estrogen receptor, and smoking affects circulating hormone levels, these results support evidence that steroid hormones play an important role in breast carcinogenesis in BRCA1 mutation carriers, and suggest mechanisms for developing novel cancer prevention strategies for BRCA1 mutation carriers.     

Anterior release of the elbow for extension loss

BACKGROUND: There are many causes of elbow contracture. When nonoperative techniques fail to increase the arc of motion of the elbow, surgical intervention may be indicated. The purpose of this study was to report the outcomes of surgical correction, predominantly with an anterior release, of elbow flexion contractures. In addition, we evaluated the efficacy of continuous passive motion in the immediate postoperative period. METHODS: We retrospectively reviewed the outcomes of 106 consecutive patients who had undergone anterior elbow release for the treatment of a flexion contracture between July 1975 and June 2001. Twenty-nine patients were excluded because they had been followed for less than twelve months, leaving a study group of seventy-seven patients. Postoperatively, fifty-four of the seventy-seven patients were treated with continuous passive motion and the other twenty-three patients were treated with extension splinting. The average duration of follow-up was thirty-three months. The average patient age was thirty-four years. The results were evaluated on the basis of both preoperative and postoperative radiographs as well as clinical measurements of elbow motion, all performed by the same examiner using the same large (47-cm-long) goniometer. RESULTS: The mean preoperative extension in the seventy-seven patients was 52 degrees, which decreased to 20 degrees postoperatively. The mean flexion increased from 111 degrees preoperatively to 117 degrees postoperatively, and the mean total arc of motion increased from 59 degrees to 97 degrees. The total arc of motion in the patients treated with continuous passive motion increased 45 degrees, compared with an increase of 26 degrees in those treated with extension splinting. There were eleven complications in ten patients. The majority were traction neuropathies. There were two infections (one superficial and one deep), both of which resolved following treatment. CONCLUSIONS: Release of a pathologically thickened anterior elbow capsule through a predominantly anterior approach to correct diminished elbow extension is a safe and effective technique. Furthermore, compared with splinting in extension alone, the utilization of continuous passive motion during the postoperative period increases the total arc of motion.     

Reducing hospital morbidity and mortality following esophagectomy

Background

Esophagogastrectomy (EG) is a formidable operation with significant morbidity and mortality rates. Risk factor analyses have been performed, but few studies have produced strategies that have improved operative results. This study was performed in order to identify prognostic variables that might be used to develop a strategy for optimizing outcomes after EG.

Methods

The records of all patients (n = 379) who underwent EG patients at a tertiary medical center between 1996 and 2002 were retrospectively reviewed. Thirty-day morbidity and mortality were determined, and multivariable logistical regression analysis assessed the effect of preoperative and postoperative variables on early mortality.

Results

Operations included Ivor Lewis (n = 179), transhiatal (n = 130), and other approaches (n = 70). Operative mortality was 5.8%; 64% experienced complications, including respiratory complications (28.5%), anastamotic strictures (25%), and leak (14%). Increasing age, anastomotic leak, Charlson comorbidity index 3, worse swallowing scores, and pneumonia were associated with increased risk of mortality by univariate analysis. However, only age (p = 0.002) and pneumonia (p = 0.0008) were independently associated with mortality by multivariable analysis. Pneumonia was associated with a 20% incidence of death. Patients with pneumonia had significantly worse deglutition and anastomotic integrity on barium esophagogram compared with patients without pneumonia (p < 0.001, Mann-Whitney rank sum test).

Conclusions

Morbidity and mortality of EG are significant, but most complications, including anastomotic leak, are not independent predictors of mortality. The most important complication after EG is pneumonia. Strategies to decrease postoperative mortality should include careful assessment of swallowing abnormalities and predisposition to aspiration by cineradiography or fiberoptic endoscopy. After EG, acceptable pharyngeal function and airway protection should be verified before resuming oral intake.     

Development of physician leadership competencies: perceptions of physician leaders, physician educators and medical students

Research regarding the development of healthcare leadership competencies is widely available. However, minimal research has been published regarding the development of physician leadership competencies, despite growing recognition in recent years of the important need for effective physician leadership. Usingdata from an electronically distributed, self-administered survey, the authors examined the perceptions held by 110 physician leaders, physician educators, and medical students regarding the extent to which nine competencies are important for effective physician leadership, ten activities are indicative of physician leadership, and seven methods are effective for the development of physician leadership competencies. Results indicated that "interpersonal and communication skills" and "professional ethics and social responsibility" are perceived as the most important competencies for effective physician leadership. Furthermore, respondents believe "influencing peers to adopt new approaches in medicine" and "administrative responsibility in a healthcare organization" are the activities most indicative of effective physician leadership. Finally, respondents perceive"coaching or mentoring from an experienced leader" and "on-job experience (e.g., a management position)" as the most effective methods for developing physician leadership competencies. The implications of these findings for the education and development of physician leaders are discussed.