Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00).

BACKGROUND: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing after aromatase inhibitor (AI) treatment. PATIENTS AND METHODS: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n=70) with AI-responsive disease and group B (n=20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (+/-3) days. RESULTS: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease [SD] for >or=24 weeks) in 28% (90% confidence interval [CI] 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B. CONCLUSIONS: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.

Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

Marker-independent identification of glioma-initiating cells.

Tumor-initiating cells with stem cell properties are believed to sustain the growth of gliomas, but proposed markers such as CD133 cannot be used to identify these cells with sufficient specificity. We report an alternative isolation method purely based on phenotypic qualities of glioma-initiating cells (GICs), avoiding the use of molecular markers. We exploited intrinsic autofluorescence properties and a distinctive morphology to isolate a subpopulation of cells (FL1(+)) from human glioma or glioma cultures. FL1(+) cells are capable of self-renewal in vitro, tumorigenesis in vivo and preferentially express stem cell genes. The FL1(+) phenotype did not correlate with the expression of proposed GIC markers. Our data propose an alternative approach to investigate tumor-initiating potential in gliomas and to advance the development of new therapies and diagnostics.

Self-deception as affective coping. An empirical perspective on philosophical issues.

In the philosophical literature, self-deception is mainly approached through the analysis of paradoxes. Yet, it is agreed that self-deception is motivated by protection from distress. In this paper, we argue, with the help of findings from cognitive neuroscience and psychology, that self-deception is a type of affective coping. First, we criticize the main solutions to the paradoxes of self-deception. We then present a new approach to self-deception. Self-deception, we argue, involves three appraisals of the distressing evidence: (a) appraisal of the strength of evidence as uncertain, (b) low coping potential and (c) negative anticipation along the lines of Damasio's somatic marker hypothesis. At the same time, desire impacts the treatment of flattering evidence via dopamine. Our main proposal is that self-deception involves emotional mechanisms provoking a preference for immediate reward despite possible long-term negative repercussions. In the last part, we use this emotional model to revisit the philosophical paradoxes.

Same Performance Changes after Live High-Train Low in Normobaric vs. Hypobaric Hypoxia.

PURPOSE: We investigated the changes in physiological and performance parameters after a Live High-Train Low (LHTL) altitude camp in normobaric (NH) or hypobaric hypoxia (HH) to reproduce the actual training practices of endurance athletes using a crossover-designed study. METHODS: Well-trained triathletes (n = 16) were split into two groups and completed two 18-day LTHL camps during which they trained at 1100-1200 m and lived at 2250 m (P i O2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg) under NH (hypoxic chamber; FiO2 18.05 ± 0.03%) or HH (real altitude; barometric pressure 580.2 ± 2.9 mmHg) conditions. The subjects completed the NH and HH camps with a 1-year washout period. Measurements and protocol were identical for both phases of the crossover study. Oxygen saturation (S p O2) was constantly recorded nightly. P i O2 and training loads were matched daily. Blood samples and VO2max were measured before (Pre-) and 1 day after (Post-1) LHTL. A 3-km running-test was performed near sea level before and 1, 7, and 21 days after training camps. RESULTS: Total hypoxic exposure was lower for NH than for HH during LHTL (230 vs. 310 h; P < 0.001). Nocturnal S p O2 was higher in NH than in HH (92.4 ± 1.2 vs. 91.3 ± 1.0%, P < 0.001). VO2max increased to the same extent for NH and HH (4.9 ± 5.6 vs. 3.2 ± 5.1%). No difference was found in hematological parameters. The 3-km run time was significantly faster in both conditions 21 days after LHTL (4.5 ± 5.0 vs. 6.2 ± 6.4% for NH and HH), and no difference between conditions was found at any time. CONCLUSION: Increases in VO2max and performance enhancement were similar between NH and HH conditions.