Novel HMGA2-YAP1 fusion gene in aggressive angiomyxoma

We describe a case of a 44-year-old woman with locally advanced aggressive angiomyxoma with a novel translocation high-mobility group AT-hook 2–yes-associated protein 1 (HMGA2-YAP1) fusion, implying a t(11;12)(q22.1;q14.3) translocation. She was started on gonadotropin-releasing hormone agonist injection and an aromatase inhibitor for persistent disease, which responded to treatment; she was subsequently treated with radiation before a more definitive operation was conducted. This case report indicates that HGMA2-YAP1–translocated aggressive angiomyxoma is responsive to oestrogen antagonism and hopefully will allow for the development of diagnostics useful for this rare but often morbid neoplasm. This case also highlights the importance of appropriate workup of a soft tissue mass.

AGONIST AND ANTAGONIST ACTIVITY OF EN-CLOMIPHENE UPON OESTROGEN-MEDIATED EVENTS IN THE UTERUS, PITUITARY GLAND AND BRAIN OF THE RAT

The oestrogen agonist and antagonist activity of a single dose of en-clomiphene (0·5–50 mg/kg) was studied in peripheral and brain tissue in the 3 week ovariectomized rat. 17β-Oestradiol benzoate (100 pg/kg) or vehicle was injected 24 h after en-clomiphene administration and data collected at 72 h. En-clomiphene produced a dose-related (agonist) fall in body weight and food intake. Agonist action was not observed upon sexual receptivity and prolactin secretion; oestrogen antagonism of these parameters was only seen at the higher doses. The effects of en-clomiphene upon serum LH and FSH were complex, both agonist and antagonist activity being demonstrated in the absence and presence of oestrogen. En-clomiphene was uterotrophic at all doses tested; however, oestrogen antagonism was only seen at the higher doses. Inhibition of the accumulation of uterine luminal fluid at the higher doses of en-clomiphene was a sensitive index of oestrogen antagonism. The results are discussed in relation to previous studies of the effects of enclomiphene on oestrogen receptors. With the exception of the antagonism of oestrogen-induced sexual receptivity no correlation could be made between biological activity and the status of oestrogen receptors in tissue.

THE LIMITATIONS OF USING MOUSE UTERINE WEIGHT AS AN ASSAY OF OESTROGEN ANTAGONISM

ABSTRACT Oestrogen antagonists were tested by subcutaneous injection for their ability to reduce the weight of uteri of ovariectomized mice continuously stimulated by drinking a solution of oestrone. Only a limited weight reduction was achieved, even with high doses or repeated injections of the antagonists. This limitation could not be accounted for by the uterotrophic action of the antagonists themselves. The narrow range of weight reduction, together with the variability of the animals, made assays of relative activity unsatisfactory.

STRUCTURE-ACTIVITY RELATIONSHIPS OF ANTI-OESTROGENS WITH REGARD TO INTERACTION WITH 17β-OESTRADIOL IN THE MOUSE UTERUS AND VAGINA

ABSTRACT Anti-oestrogenic substances have been studied systematically in order to get some guides about structure - activity relationships. The substances were tested in the mouse a) for uterotrophic and anti-uterotrophic activities and b) for their capacity to inhibit the uptake of 17β-oestradiol by the uterus and vagina in vitro. A few such in vitro experiments were also carried out in the rat. Only MER-25 was completely devoid of any oestrogenic activity and was able to suppress oestrogenic stimulation completely. U-11,100A and CN-55,945 were partial agonists producing less than total oestrogen antagonism. MRL-37, DMS, meso-butoestrol, oestriol and ent-17β-oestradiol were impeded oestrogens, i. e., produced dose-response curves with shallow slopes. These compounds, except oestriol which was inactive, were weakly anti-uterotrophic. Cis- and trans-clomiphene, ICI-47,699 and ICI-46,474 which are also cis/trans isomers, WSM-4613 and U-11,555A showed no sign of anti-oestrogenic activity. All the tested substances suppressed the binding of 17β-oestradiol to the mouse uterus and vagina. The impeded oestrogens were generally very potent. However, their inhibitory action was of short duration since they were easily washed out. The remaining compounds (dialkylamino-alkyl-ether derivatives) were generally very firmly bound to the target tissues, the binding being even firmer than that of the oestrogens 17β-oestradiol or meso-hexoestrol. Possible mechanisms of actions of the two kinds of anti-oestrogens are presented. A model explaining the impeded uterotrophic response is also given.

EFFECTS OF CLOMIPHENE ON OESTRADIOL ALTERATIONS IN THYROXINE AND CORTISOL TRANSPORT IN MAN

ABSTRACT Clomiphene, the ovulation stimulating agent, may act via 1) direct oestrogen-like action, 2) oestrogen antagonism, and/or 3) other mechanisms. The indirect effects of clomiphene alone and together with oestradiol were studied in an oestrogen sensitive system, i. e. the binding affinities of transcorten and thyroxine binding globulin for cortisol and thyroxine. In 7 normal males after treatment with 0.2 mg oestradiol alone for 7 days their mean triiodothyronine (T3) resin uptake ratios fell from 1.05 to 0.90 while their mean plasma cortisol rose to 25.9 from 14.2 mg/100 ml. Two weeks later, the administration of 100 mg of clomiphene alone daily to 10 subjects had no effect on either T3 resin uptakes or cortisol. The addition of 0.2 mg of oestradiol to the continuing clomiphene regimen in 7 subjects resulted in 0.94 mean T3 resin uptake and a mean cortisol concentration of 22.3 mg/100 ml. Changes were not significant compared to oestrogen alone (P < 0.20), but were different from control (P < 0.03), and clomiphene alone (P < 0.02). Since the T3 resin uptake and cortisol concentrations reflect plasma binding, these data suggest that clomiphene may not exert a major influence in this oestrogen sensitive system in man, and do not support the hypothesis that clomiphene acts solely to compete for tissue oestrogen receptor sites in man.