Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors

BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.     

Ureteral stricture formation after removal of impacted calculi

PURPOSE: We retrospectively evaluated the records of 21 patients a mean of 46.1 years old with ureteral stones that had been impacted for greater than 2 months to determine predisposing factors for stricture formation. MATERIALS AND METHODS: Between January 1993 and September 1996, 21 patients were referred for ureteral stones that had remained unchanged in location for at least 2 months. In 11 patients previous attempts at stone removal had failed. Each patient underwent successful stone extraction by retrograde or percutaneous antegrade ureteroscopy, or laparoscopic or open ureterolithotomy. Outcome was determined by reviewing the clinical records and radiographic studies, including excretory urography and nephrostography. RESULTS: Average duration of stone impaction before definitive treatment was 8.8 months (range 2 to 48) and mean stone size was 10.3 mm. (range 1 to 30). All stones were calcium based. There were 3 proximal, 8 mid and 10 distal ureteral calculi. At a mean followup of 7 months ureteral strictures developed in 5 patients (24%) at the previous stone site. Mean duration of stone impaction was 11 months (range 5 to 17) in patients with stricture versus 8.2 months (range 2 to 48) in those with no stricture. Four of the 5 strictures occurred in patients who had had iatrogenic ureteral perforation during previous unsuccessful attempts at stone removal. CONCLUSIONS: Ureteral stone impaction more than 2 months in duration is associated with a 24% incidence of stricture formation. Ureteral perforation at the site of the stone was identified as the primary risk factor for stricture formation in these cases.     

Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade

Caveolin-1 is a principal component of caveolae membranes in vivo. Caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). However, it remains unknown whether downregulation of caveolin-1 is sufficient to mediate cell transformation or tumorigenicity. Here, we employ an antisense approach to derive stable NIH 3T3 cell lines that express dramatically reduced levels of caveolin-1 but contain normal amounts of caveolin-2. NIH 3T3 cells harboring antisense caveolin-1 exhibit anchorage-independent growth, form tumors in immunodeficient mice and show hyperactivation of the p42/44 MAP kinase cascade. Importantly, transformation induced by caveolin-1 downregulation is reversed when caveolin-1 protein levels are restored to normal by loss of the caveolin-1 antisense vector. In addition, we show that in normal NIH 3T3 cells, caveolin-1 expression levels are tightly regulated by specific growth factor stimuli and cell density. Our results suggest that upregulation of caveolin-1 may be important in mediating contact inhibition and negatively regulating the activation state of the p42/44 MAP kinase cascade.     

The detection of recurrent sarcoidosis by FDG-PET in a lung transplant recipient

PURPOSE: While advanced cardiac life support (ACLS) training is widely available, it is not mandatory for all anaesthetists. We hypothesised that adherence to ACLS guidelines during resuscitation of ventricular fibrillation (VFib) as assessed in a simulator environment would be poor by anaesthetists not trained in ACLS compared with those who had received training. METHODS: With approval by the ethics review board, 89 subjects participated in the study. The simulation system consisted of a computer controlled mannequin with lifelike qualities set in a mock operating room. Each subject was given a test scenario that contained several standard anaesthetic problems. A VFib cardiac arrest occurred after approximately one hour into the simulation. A perfect score (score = A) defined complete compliance with the ACLS guidelines, whereas minor deviations (score = B) included changes in energy levels, drug doses or treatment order. The failure to discontinue the anaesthetic, defibrillate or administer epinephrine were considered major deviations (score = C). RESULTS: Eight subjects followed the ACLS guidelines (9%, score = A), while 27 subjects showed minor (30%, score = B) and 54 subjects major deviations (61%, score = C). Sixty-two of the 89 participants (70%) had taken the ACLS course and achieved higher scores than did anaesthetists without such training (P < 0.05). Forty-two participants (47%) did not discontinue the anaesthetic, 10 (11%) never gave epinephrine and 5 (6%) never used the defibrillator. CONCLUSION: Adherence to ACLS guidelines was poor. A greater proportion of subjects without previous ACLS training had deviations from protocol than did subjects who had received training. We need to consider ways to ensure that anaesthetists obtain and retain resuscitation skills according to ACLS guidelines.     

Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression

A simple gas chromatographic system suitable for determining volatile organic compounds from C2 to C7 in air is described. It consists of a capillary cold trap filled with graphitic carbon, a thermodesorbing device, a capillary gas chromatograph equipped with an alumina column and a flame ionization detector. Dry, as well as humid, air samples can be analysed with our system. Up to 2-1 samples of air can be enriched on our trapping device by using Nafion membranes for removing water. Direct analysis of air samples is possible by enriching 250 ml on the carbon trap. The recovery, sensitivity and linearity of our system have been checked with standard mixtures and real samples. The performances have been compared with those afforded by a commercially available instrument exploiting a different enrichment procedure. The results obtained show that our analyser can be successfully applied to determinations of C2 to C7 hydrocarbons present in air samples at levels of 0.01 ppb (v/v).