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Recent identification of the neonatal 2nd coronary vascular population (2nd CVP) suggests that a subset of these vessels form de novo and mature in the inner myocardial wall of the postnatal heart. However, the origin of smooth muscle cells (SMCs) in the postnatal 2nd CVP remains undetermined. Using a tamoxifen-inducible Wt1-CreER driver and a Rosa26-RFP reporter line, we traced the lineage of epicardial cells to determine if they contribute to SMCs of the 2nd CVP. Late embryonic and postnatal induction of Wt1-CreER activity demonstrated that at these stages Wt1-labeled epicardium does not significantly migrate into the myocardium to form SMCs. However, following tamoxifen treatment at an early embryonic stage (E10.5), we detected Wt1 descendants (epicardium-derived cells, or EPDCs) in the outer myocardial wall at E17.5. When the 2nd CVP forms and remodels at postnatal stage, these early labeled EDPCs re-migrate deep into the inner myocardial wall and contribute to 2nd CVP-SMCs in the adult heart. Our findings reveal that SMCs in the postnatal 2nd CVP are pre-specified as EPDCs from the earliest wave of epicardial cell migration. Rather than the re-activation and migration of epicardial cells at later stages, these resident EPDCs mobilize and contribute to smooth muscle of the 2nd CVP during postnatal development.

Purpose The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. Methods The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. Results During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged ≥ 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged ≥ 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with ≤ 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). Conclusions In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia.

44. Zhang X, Cook KK, Hilakivi-Clarke L. Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats. Presented at: Annual Meeting of the American Association of Cancer Research (abstract 904). April 19, 2015. http://www. abstractsonline.com/Plan/ViewAbstract.aspx?mID1⁄43682& sKey1⁄45c372efb-ca04-41ea-8c64-852c1ea4d8bf&cKey1⁄4 4b9b4b58-c9eb-40eb-9ac8-8f6d479ab8a9&mKey1⁄4 19573a54-ae8f-4e00-9c23-bd6d62268424. Accessed June 5, 2015.

The authors conducted a retrospective cohort study of female patients diagnosed with breast cancer (BRCA), evaluating the risk of new-onset depression associated with tamoxifen treatment among those with estrogen receptor-positive (ER + ) tumors, versus estrogen receptor-negative (ER–) tumors, who were not receiving tamoxifen. A total cohort of 2,943 patients was identified. The hazard-ratio for new-onset depression in the tamoxifen group was nonsignificant. A post-hoc analysis revealed that chemotherapy and ER + status were significantly and independently associated with an increased risk for developing depression.

Individual women differ with respect to their sensitivity to estrogen and serum levels of sex hormone-binding globulin (SHBG) may reflect the individual response. We found a significant correlation between estrogen receptor (ER) concentrations in breast cancer tissue and SHBG levels during tamoxifen treatment. Estrogen sensitivity may be a general characteristic common to various organs and different between individual women.

Endometrial cancer is the most common gynecological malignancy and accounts for 6% of all cancers in women. An increased incidence has also been found in association with tamoxifen treatment, as in the case described herein. We present the case of a 54-year-old woman who was treated with tamoxifen for breast cancer. The patient was subsequently diagnosed with endometrial cancer. The clinical course was unfavorable with abdominopelvic disease recurrence.

Between September 1, 1989 and October 31, 1994, 173 postmenopausal breast cancer women on tamoxifen treatment were followed up in the authors' institutions. During this period, 14 (8.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. Eight (57.1%) were found to have adenomyosis, of whom one had a large fundal adenomyotic lump and the other seven patients had two to four small microscopic foci of adenomyosis. In this study, the rate of adenomyosis described among those postmenopausal breast cancer patients treated with tamoxifen is nearly three to four times higher than the rate reported in the literature for pre- and postmenopausal women. There is no previous reported increased incidence of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Thus, it is suggested that the prolonged and unopposed estrogen-like stimulation by tamoxifen may play a causal role rather than be a casual factor in the development of this pathologic entity.

The aim of this study was to assess among a population of women who had taken adjuvant tamoxifen for 5 years, how many were prepared to enter a randomised trial looking at the duration of tamoxifen treatment and what was the preference of those who declined trial entry. There is uncertainty as to the optimum duration of adjuvant tamoxifen and this is the subject of the aTTom (adjuvant Tamoxifen Treatment offer more?) trial in which patients are randomised to continue or stop tamoxifen after 5 years. Patients have been recruited to the aTTom trial in Dundee since 1996 and a record has been kept of all the patients with whom the trial was discussed. Patients who declined trial entry were allowed to choose whether to electively stop or continue tamoxifen. 306 patients were eligible for trial entry of whom 171 (56%) consented to randomisation (82 to continue and 89 to stop). Amongst the 135 (44%) who declined randomisation, 28 (21%) elected to stop tamoxifen treatment, 90 (67%) elected to continue and in 17 (13%) their decision was unclear. These results illustrate that patients eligible for the aTTom trial share our clinical equipoise. A majority (56%) of patients were agreeable to randomisation, but among those who declined, some (67%) preferred to continue, some (21%) to stop tamoxifen. This trial is unusual in that the patients have already experienced the treatment options, so the patients' preferences reflect a truly informed choice.

The insulin-like growth factor (IGF) system is believed to be an important mediator of oestrogen action and may also be involved in mediating and modulating the actions of anti-oestrogens. In circulation, the majority of IGFs are bound to specific IGF binding proteins (IGFBP-1 to 6), which modulate the biological effects of IGFs. Low plasma IGF-I concentrations have been reported in breast cancer patients during tamoxifen treatment. IGFs are also believed to be involved in the regulation of oestrogen-induced cellular proliferation in the normal endometrium.

[1] Florian Jr JA, Eiseman JL, Parker RS. Nonlinear model predictive control for dosing daily anticancer agents: a tamoxifen treatment of breast cancer case study. J. Proc. Control 2006 (submitted). [2] Parker RS, Doyle III FJ, Peppas NA. The intravenous route to blood glucose control. IEEE Eng Med Biol Mag 2001:20;65-73. [3] Reynolds A., Rubin J, Clermont, G, Day J, Vodovotz Y, Bard EG. A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation. J Theor Biol 2006.

One hundred and sixty-eight female Sprague-Dawley rats were divided among 4 groups ( 42 rats/group) and were irradiated with 400 rad [ 137 Cs ] γ rays to the whole body when 59 days old. The estrogen antagonist tamoxifen was injected s.c. daily from 29–89 days of age (Series 1 ) or from 89–149 days of age (Series 2 ), prior to the onset of palpable mammary tumors. Two groups of rats were injected with the diluent and served as controls. All rats were palpated bi-weekly for mammary tumors and killed 37 weeks after γ-irradiation. The number of mammary carcinomas which developed in each group and their significance levels were: series 1 , controls, 31 ; tamoxifen treated, 11, P ; series 2 , controls, 33 ; tamoxifen treated, 17, P . Tamoxifen treatment did not significantly influence the incidence of benign mammary tumors (fibroadenomas) nor the rate of body weight gain. Thus, the effective use of an estrogen antagonist for the prophylaxis of radiogenic mammary carcinomas has been demonstrated in this study.

This study of the effects of long-term tamoxifen administration on semen analysis of oligospermic males confirms the potential therapeutic efficacy in normogonadotrophic oligospermia. 38 out of the 56 patients responded well to long-term treatment with 30 mg tamoxifen daily. According to the nomenclature of Eliasson, 32 patients reached normal sperm density and 16 patients normal sperm motility after tamoxifen treatment. In the group of responders a pregnancy rate of 34% is obtained. As far as the endocrinological parameters are concerned normogonadotrophic patients (responders and non-responders) showed an increase in testosterone, 17beta-estradiol, LH and FSH levels, whereas the levels of prolactin and testosterone/estradiol-binding globulin remained unchanged. No alterations at all were seen with regard to semen volume, during the time of tamoxifen treatment.