A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers

While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant (‘Faslodex’) is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect. This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 μg day−1. Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women

Tamoxifen-associated vasculitis in a breast cancer patient

BACKGROUND: Estrogen plays a critical role in breast cancer. Thereafter, endocrine therapy is a standard of care in patients with breast carcinoma, expressing ER or PR. CASE PRESENTATION: Herein we report the case of a 53-year old patient, who developed cholestasis and vasculitis during the treatment with tamoxifen. This toxicity was reversable after the removal of the drug. Thereafter she continued adjuvant treatment for breast carcinoma with anastrazole. Since tamoxifen has been widely indicated for patients with breast carcinoma, we did a literature review, looking for other cases with this type of toxicity. CONCLUSION: This case is the third with vasculitis informed in the literature, but the first one that additionally developed cholestasis and arthritis. Although it is rare, we discuss the indication of this drug in the actual era, where aromatase inhibitors offer a better security profile

Emerging breast cancer epidemic: evidence from Africa

Cancer is an increasingly important public health problem in developing countries, including Africa [1]. As public and professional awareness of the cancer problem has grown, so has interest in the pattern of disease presentation, its epidemiology and treatment outcome. To date, however, there has been limited research about breast cancer in Africa. In the absence of systematic population-based cancer registration, most information has come from small clinical and pathology case series and the bias inherent in these types of studies has influenced current understanding of the pattern and characteristics of breast cancer in Africa. In this communication, we review the evidence for an emerging epidemic of breast cancer in Africa, its risk factors and likely future course. We conclude that, despite limited data, rising incidence of breast cancer is being driven by increasing life expectancy, improved control of infectious diseases, and changing lifestyle, diet, physical activity and obstetric practices. We also review current beliefs about hormone receptor subtypes of breast cancer in Africa and suggest that this is probably not systematically different from the pattern in other populations after adjusting for factors such as age and that the reported differences are related to poor tissue handling and laboratory processing practices

Determinants of a healthy lifestyle and use of preventive screening in Canada

BACKGROUND: This study explores the associations between individual characteristics such as income and education with health behaviours and utilization of preventive screening. METHODS: Data from the Canadian National Population Health Survey (NPHS) 1998–9 were used. Independent variables were income, education, age, sex, marital status, body mass index, urban/rural residence and access to a regular physician. Dependent variables included smoking, excessive alcohol use, physical activity, blood pressure checks, mammography in past year and Pap smear in past 3 years. Logistic regression models were developed for each dependent variable. RESULTS: 13,756 persons 20 years of age and older completed the health portion of the NPHS. In general, higher levels of income were associated with healthier behaviours, as were higher levels of education, although there were exceptions to both. The results for age and gender also varied depending on the outcome. The presence of a regular medical doctor was associated with increased rates of all preventive screening and reduced rates of smoking. CONCLUSION: These results expand upon previous data suggesting that socioeconomic disparities in healthy behaviours and health promotion continue to exist despite equal access to medical screening within the Canadian healthcare context. Knowledge, resources and the presence of a regular medical doctor are important factors associated with identified differences

Myocardial infarction risk and tamoxifen therapy for breast cancer

Tamoxifen prevents recurrence after breast cancer and breast cancer among high-risk women, and may prevent myocardial infarction (MI). To assess the impact of tamoxifen on MI risk, we conducted a case–control study of first MI after breast cancer nested among women diagnosed with breast cancer, while enrolled in a health maintenance organisation from 1980 to 2000. We obtained information on breast cancer treatment and MI risk factors through medical record reviews and interviews. Data were analysed using conditional logistic regression. Of 11 045 women with breast cancer, 134 met MI criteria and were matched to two MI-free control subjects on year of birth and breast cancer diagnosis. After adjusting for smoking, hypertension and diabetes, tamoxifen was unassociated with MI (odds ratio (OR)=1.2, 95% confidence interval (CI)=0.7–1.9). Duration, cumulative dose and recency of use were not associated with MI. Radiation therapy was associated with MI (OR=2.0, 95% CI=1.1–3.5), an association that varied slightly but not statistically significantly by tamoxifen use (radiation with tamoxifen, OR=2.0, 95% CI=0.9–4.4; radiation without tamoxifen, OR=2.9, 95% CI=1.2–7.5). Tamoxifen treatment for breast cancer does not appear to increase or decrease MI risk, although radiation therapy appears to increase MI risk

Large scale patterns in vertical distribution and behavior of mesopelagic scattering layers

Recent studies suggest that previous estimates of mesopelagic biomasses are severely biased, with the new, higher estimates underlining the need to unveil behaviourally mediated coupling between shallow and deep ocean habitats. We analysed vertical distribution and diel vertical migration (DVM) of mesopelagic acoustic scattering layers (SLs) recorded at 38 kHz across oceanographic regimes encountered during the circumglobal Malaspina expedition. Mesopelagic SLs were observed in all areas covered, but vertical distributions and DVM patterns varied markedly. The distribution of mesopelagic backscatter was deepest in the southern Indian Ocean (weighted mean daytime depth: WMD 590 m) and shallowest at the oxygen minimum zone in the eastern Pacific (WMD 350 m). DVM was evident in all areas covered, on average ~50% of mesopelagic backscatter made daily excursions from mesopelagic depths to shallow waters. There were marked differences in migrating proportions between the regions, ranging from ~20% in the Indian Ocean to ~90% in the Eastern Pacific. Overall the data suggest strong spatial gradients in mesopelagic DVM patterns, with implied ecological and biogeochemical consequences. Our results suggest that parts of this spatial variability can be explained by horizontal patterns in physical-chemical properties of water masses, such as oxygen, temperature and turbidity.En prensa2,927

Interspecific Variation in Life History Relates to Antipredator Decisions by Marine Mesopredators on Temperate Reefs

As upper-level predatory fishes become overfished, mesopredators rise to become the new ‘top’ predators of over-exploited marine communities. To gain insight into ensuing mechanisms that might alter indirect species interactions, we examined how behavioural responses to an upper-level predatory fish might differ between mesopredator species with different life histories. In rocky reefs of the northeast Pacific Ocean, adult lingcod (Ophiodon elongatus) are upper-level predators that use a sit-and-wait hunting mode. Reef mesopredators that are prey to adult lingcod include kelp greenling (Hexagrammos decagrammus), younger lingcod, copper rockfish (Sebastes caurinus) and quillback rockfish (S. maliger). Across these mesopredators species, longevity and age at maturity increases and, consequently, the annual proportion of lifetime reproductive output decreases in the order just listed. Therefore, we hypothesized that the level of risk taken to acquire resources would vary interspecifically in that same order. During field experiments we manipulated predation risk with a model adult lingcod and used fixed video cameras to quantify interactions between mesopredators and tethered prey (Pandalus shrimps). We predicted that the probabilities of inspecting and attacking tethered prey would rank from highest to lowest and the timing of these behaviours would rank from earliest to latest as follows: kelp greenling, lingcod, copper rockfish, and quillback rockfish. We also predicted that responses to the model lingcod, such as avoidance of interactions with tethered prey, would rank from weakest to strongest in the same order. Results were consistent with our predictions suggesting that, despite occupying similar trophic levels, longer-lived mesopredators with late maturity have stronger antipredator responses and therefore experience lower foraging rates in the presence of predators than mesopredators with faster life histories. The corollary is that the fishery removal of top predators, which relaxes predation risk, could potentially lead to stronger increases in foraging rates for mesopredators with slower life histories

Borrelia Burgdorferi Induces a Type I Interferon Response During Early Stages of Disseminated Infection in Mice

BACKGROUND: Lyme borrelia genotypes differ in their capacity to cause disseminated disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia burgdorferi strains with different capacities for causing disseminated disease in the blood of C3H/HeJ mice during early infection. RESULTS: B. burgdorferi B515, a clinical isolate that causes disseminated infection in mice, differentially regulated 236 transcripts (P \u3c 0.05 by ANOVA, with fold change of at least 2). The 216 significantly induced transcripts included interferon (IFN)-responsive genes and genes involved in immunity and inflammation. In contrast, B. burgdorferi B331, a clinical isolate that causes transient skin infection but does not disseminate in C3H/HeJ mice, stimulated changes in only a few genes (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by quantitative RT-PCR in mouse skin biopsies collected from the site of infection 24 h after inoculation with B. burgdorferi. The mean values for transcripts of Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2 were found to be significantly increased in B. burgdorferi strain B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B. burgdorferi strain B331 or B31-4, a mutant that is unable to disseminate. CONCLUSIONS: These results establish a positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction in a murine model of Lyme disease

Alterations in the insulin-like growth factor system during treatment with diethylstilboestrol in patients with metastatic breast cancer

Alterations in the insulin-like growth factor (IGF)-system were evaluated in 16 patients treated with diethylstilboestrol 5 mg 3 times daily. Fasting blood samples were obtained before treatment and after 2 weeks, 1 month and/or 2–3 months on therapy. Insulin-like growth factor (IGF)-I, IGF-II, free IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3 were measured by radioimmuno-/immunoradiometric-assays. All samples were subjected to Western ligand blotting as well as immunoblotting for IGFBP-3. We observed a significant decrease (percentage of pretreatment levels with 95 confidence intervals of the mean) in IGF-I [2 weeks 63% (49–79); 1 month 56% (44–73); 2–3 months 66% (53–82)], IGF-II [2 weeks 67% (56–80); 1 month 60% (52–68); 2–3 months 64% (55–75)], free IGF-I [2 weeks 29% (19–42); 1 month 25% (18–36); 2–3 months 31% (21–46)], IGFBP-2 [2 weeks 53% (18–156); 1 month 69% (61–78); 2–3 months 66% (57–78)], IGFBP-3 [2 weeks 74% (63–85); 1 month 69% (62–76); 2–3 months 71% (63–80)], as well as IGFBP-3 protease activity [2 weeks 71% (54–95); 1 month 78% (64–94); 2–3 months 71% (54–93)]. Contrary, the plasma levels (percentage of pretreatment levels with 95 confidence intervals of the mean) of IGFBP-1 [2 weeks 250% (127–495); 1 month 173% (138–542); 2–3 months 273% (146–510)] and IGFBP-4 [2 weeks 146% (112–192); 1 month 140% (116–169); 2–3 months 150% (114–198)] increased significantly. While this study confirms previous observations during treatment with oral oestrogens in substitution doses, the reduction in plasma IGF-II, free IGF-I, IGFBP-2 and -3 are all novel findings. A profound decrease in free IGF-I suggests a reduced bioavailability of IGFs from plasma to the tissues. These observations may be of significance to understand the mechanisms of the antitumour effect of diethylstilboestrol in pharmacological doses. © 2001 Cancer Research Campaign http://www.bjcancer.co