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1/32. leiomyoma of the round ligament in a postmenopausal woman.

    OBJECTIVE: leiomyoma of the round ligament of the uterus is a rare condition. We present the first case of a postmenopausal, previously hysterectomised, woman who received combined hormonal replacement therapy and developed a leiomyoma of the right round ligament. METHOD: In sections of the tumor, immunohistochemical reaction with monoclonal antibodies against smooth muscle actin, desmin, vimentin, estrogen receptor and progesterone receptor was performed. RESULTS: The leiomyoma showed bizarre histologic appearance in absence of mitotic figures and degenerative changes. Leiomyocytes presented a positive immunohistochemical reaction with monoclonal antibodies against smooth muscle actin, desmin vimentin and progesterone receptor in absence of estrogen receptor. CONCLUSION: Progestin as part of a combined hormonal replacement therapy may play an important role in promoting the development of leiomyoma in hormonal responsive tissue of the round ligament in postmenopausal women.
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2/32. The nature of tamoxifen action in the control of female breast cancer.

    tamoxifen, now in use in the breast cancer clinic worldwide, was a study subject of controversy showing an estrogenic property on one occasion and an anti-estrogenic property on another occasion. The outcomes of 4 case-control studies of tamoxifen use were disclosed through 4 publications in 1998. The contents of these reports were intriguing, not only to surgeons of breast cancer clinics, but also to researchers of oncological science in general. The results of 4 research groups, being compatible with each other, were summarized in succession as follows: a) long-term use of tamoxifen reduced the occurrence of estrogen receptor (ER)-positive tumors by 69%, but no difference in the occurrence of ER(-) tumors was seen; b) the incidence of endometrial cancer was increased in the tamoxifen group; c) in women who did not have breast cancer and who had had a hysterectomy, there was no difference of breast cancer occurrence between the placebo- and tamoxifen-arms. Nevertheless, there was a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial; d) there was also no case-control difference of breast cancer occurrence between tamoxifen- and placebo-groups, when tested in a healthy population with a strong family history; e) the beneficial effect of long term use of tamoxifen in patients with early breast cancer, as assessed in terms of recurrence reduction, survival improvement and suppression of a contralateral tumor growth, was restricted to ER( ) patients; f) there was a positive correlation between the duration of tamoxifen use and the occurrence of endometrial cancer. All these observations provide strong support to the concept of the steroid criminal theory of human carcinogenesis in general. On the basis of both tamoxifen data and other information surrounding the hormonal aspect of human carcinogenesis of multiple tumors including breast cancer, we propose that the steroid generating system, as linked to the ever changing environment, plays a cardinal role as the transmitter of steroidal signals that can be taken as a "go" sign by the local oncogene-tumor suppressor gene complex of one target tissue and as a "stop" sign by that of another target tissue. The fitness of the tamoxifen data to the steroid carcinogenesis concept was discussed in the light of experimental pathology of chemical carcinogens, including the mammocarcinogen 7,12-dimethyl-benz(a)anthracene.
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3/32. Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling.

    Oligonucleotide microarrays were used to analyse gene expression profiles in human ZR75-1 breast cancer cells in the presence of 17beta-oestradiol and oestrogen antagonists. Differential gene expression of a number of genes was confirmed by quantitative rna analysis. In addition to known oestrogen-responsive genes, an appreciable number of novel targets were identified, including growth factors and components of the cell cycle, adhesion molecules, enzymes, signalling molecules and transcription factors. The most pronounced oestrogen-sensitive gene was that for the cytochrome P450-IIB enzyme, involved in metabolising steroids and xenobiotics, which was increased 100-fold over a 24 h period. It is a direct target gene for oestrogens, because its expression was increased in the presence of cyclohexamide. In contrast, expression of cytochrome P450-IIB was not detected in human MCF7 breast cancer cells. Expressions of the cationic amino acid transporter E16, gap junction protein and insulin-like growth factor binding protein 4 were also markedly increased by oestrogens, but the kinetics of induction varied according to the target gene. With the exception of the cationic amino acid transporter E16 and the insulin-like growth factor binding protein 4, the expression of the majority of the genes was unaffected by antioestrogen treatment. Further analysis of this set of markers will provide alternative approaches to the investigation of the mitogenicity of oestrogens in breast cancer cells.
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4/32. Expression of glucocorticoid receptor and 11beta hydroxysteroid dehydrogenase in a case of pulmonary epithelioid haemangioendothelioma.

    This report describes a case of pulmonary epithelioid haemangioendothelioma in which the tumour cells expressed the glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase. The patient, a 15 year old girl, who had no other complaints or past illnesses, was found to have an abnormal shadow on a chest roentgenogram obtained at a school medical examination. Multiple nodular shadows in the bilateral lungs were also confirmed by computerised axial tomography scan. A diagnosis of pulmonary epithelioid haemangioendothelioma was made on the basis of lung biopsy specimens. The tumour cells were immunohistochemically positive for factor viii related antigen, CD31, and CD34, but not surfactant apoprotein A. In addition, almost all of the tumour cells showed simultaneous expression of the glucocorticoid receptor and 11beta hydroxysteroid dehydrogenase, suggesting that steroid treatment would be effective.
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5/32. A case of pulmonary metastasis from breast cancer following an 18-year disease-free interval that responded to tamoxifen treatment.

    A 61-year-old woman was admitted to our hospital with an abnormal shadow on chest roentgenogram. She had undergone a radical mastectomy for right breast cancer 18 years previously. Since pleural dissemination was noted at the time of thoracotomy, only tumor biopsy was performed. Although a decisive diagnosis could not be obtained histologically, the tumor resembled breast cancer and the estrogen receptor status was positive. She underwent post-operative chemotherapy and tamoxifen treatment. After tamoxifen treatment, complete response was observed. The patient is now doing well without recurrence about 10 years after thoracotomy. Based on the clinical course, we obtained both a definitive diagnosis and complete remission.
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6/32. The biological basis for the use of an anti-androgen and a 5-alpha-reductase inhibitor in the treatment of recurrent prostate cancer: Case report and review.

    Although many prostate cancer cases relapse to a hormone-insensitive state, endocrine therapy involving androgen depletion by orchiectomy or by treatment with LHRH-analogue as well as blockade of the androgen receptor (AR) with anti-androgens remains a primary treatment option. quality of life (QOL) however, is a prime consideration of men choosing such an approach. In this report we discuss a synergistic combination of 150-mg bicaltumide (Casodex) and 5 mg finasteride (Proscar) in the treatment of a 69-year-old patient with a relapsed (biochemical failure) Gleason score 7 prostate cancer, initially treated with external beam radiation therapy. A successful clinical outcome as evidenced by undetectable serum PSA, bone scan density and overall general well-being was accomplished with minimal side effects. Experiments using an established hormone-dependent prostate cancer cell line (LNCaP) showed that the combination of bicaltumide-finasteride at the same ratio as used clinically, produced synergistic effects on the inhibition of cell proliferation and AR expression/phosphorylation. A more complete inactivation of the AR on this regimen may have had the effect of constraining the ability of the AR to mutate, and/or diminishing the ability of androgen independent clones to evolve. Thus, passage to androgen independence may have been slowed or arrested.
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7/32. Selecting adjuvant endocrine therapy for breast cancer.

    This year alone, more than 215,000 women in the united states will be diagnosed with, and over 40,000 will die from, invasive breast cancer. Recently, mortality from female breast cancer has declined despite an increase in its incidence. This decline corresponds with improved screening for prompt tumor detection, and advances in the treatment of early disease. Of these, endocrine therapy has played a prominent role. For women with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancers, endocrine therapy has proven to be a major component of adjuvant therapy, but it is not effective in women whose breast cancers lack ERs and PRs. The selective estrogen-receptor modulator (SERM) tamoxifen has been well established as safe and effective in the adjuvant care of both pre- and postmenopausal women with hormone-receptor-positive early breast cancer. For premenopausal women, ovarian suppression is an important option to be considered. Additionally, the aromatase inhibitors have recently demonstrated utility in postmenopausal women. The ideal sequencing of treatment with tamoxifen and/or an aromatase inhibitor is the subject of several ongoing studies. Factors involved in selecting an appropriate endocrine regimen have grown considerably over the past decade. It is becoming more important for those caring for women with breast cancer to fully understand the available endocrine treatment options and the prognostic and predictive factors available to help select the most appropriate treatment. The goal of this article is to assist clinicians in making decisions regarding adjuvant hormonal therapy and to provide information regarding available clinical trials. To achieve this, the therapeutic options for hormonal therapy will be reviewed, as will prognostic and predictive factors used in making decisions. Finally, four cases illustrating these difficult decisions will be discussed, with recommendations for treatment.
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8/32. Orbital metastasis from prostate cancer: an atypical case of neuroendocrine dedifferentiation during progression from hormone-sensitive to refractory stage.

    We report a case of orbital metastasis from a neuroendocrine dedifferentiated prostate cancer during progression from hormone-sensitive to hormone refractory stage. A patient receiving androgen deprivation for hormone-sensitive prostate cancer presented with sudden-onset right-sided ptosis and an increasing serum prostate-specific antigen level. Imaging studies revealed a mixed blastic and lytic lesion involving the right orbital wall and the right cavernous sinus. Comparison of the metastatic histology with the original pathology confirmed a histologic change to poorly differentiated prostate adenocarcinoma with neuroendocrine features. Local radiation of the lesion and palliative systemic chemotherapy resulted in marked short-term improvement of all presenting symptoms. Because prostate cancer metastasis involves hematogenous and lymphatic routes, we also evaluated expression of the vascular endothelial growth factor (VEGF) and receptors (VEGFR-1, VEGFR-2, and VEGFR-3) in the metastatic deposit by immunohistochemistry. Strong expression of VEGFR-2 and VEGFR-3 restricted to the malignant epithelium was noted. We recommend a second biopsy of atypical prostate metastasis associated with sudden change to aggressive clinical behavior in order to evaluate for dedifferentiation features before planning appropriate treatment interventions especially in patients who are candidates for systemic chemotherapy.
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9/32. Primary hormone treatment in postmenopausal women with breast cancer.

    Clinical benefits of hormone therapy in patients with hormone-sensitive tumors have been clearly established. Postmenopausal women with positive hormone receptors represent the largest group of patients in whom early stage breast cancer is diagnosed. Third-generation aromatase inhibitors (letrozole, anastrozole, and exemestane) are active and well tolerated in postmenopausal women with hormone-sensitive metastasic or locally advanced breast cancer as first or second line treatment. These are also valuable agents in the neoadjuvant setting in postmenopausal women, and even as single treatment in localized breast tumors in women not amenable to surgery.
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10/32. Combined ovarian ablation and aromatase inhibition as first-line therapy for hormone receptor-positive metastatic breast cancer in premenopausal women: report of three cases.

    aromatase inhibitors have become well established for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for adjuvant hormonal therapy for primary breast cancer. Benefit of aromatase inhibition has not yet been extended to premenopausal women. Ovarian ablation by oophorectomy, ovarian radiation or hormonal suppression is the initial recommended treatment for hormone receptor-positive metastatic breast cancer in premenopausal women. The addition of tamoxifen improves the benefit of ovarian ablation/ovarian suppression. Addition of aromatase inhibitors to luteinizing hormone-releasing hormone analogs has been reported to significantly decrease circulating estrogens and produce tumor responses in only a very small number of patients over the last 15 years. We treated three premenopausal patients with hormone receptor-positive metastatic breast cancer with combined oophorectomy or ovarian irradiation and anastrozole. One patient remained free of progression for 4 years, while the other two remained free of progression for more than 5 and 3 years, respectively. We also note that monthly zoledronic acid for 4 years produced sclerosis of vertebral body metastasis. We conclude that combined ovarian ablation and aromatase inhibition is a feasible treatment modality that deserves more attention and further investigation for hormone receptor-positive metastatic breast cancer in premenopausal women.
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