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Patients with metastatic breast cancer to the liver are generally considered to have a poor prognosis. The purpose of this study was to identify factors contributing to long term survival in 11 patients who were 35 76 years old at the time of diagnosis with liver metastasis, and survived for 5 years. No patients were treated with a standard systemic chemotherapy alone. All of the 11 patients received OK 432 combined adoptive immunotherapy (OK-AIT), 5 underwent hepatectomy as an additional local therapy, and 2 were additionally treated by hepatic arterial infusion chemotherapy. The liver was the primary and secondary sites of metastasis in 8 and 3 of the 11 patients, respectively. In all of the 128 patients given OK-AIT at 5 years after diagnosis, the 5-year survival rates with primary and secondary liver metastases were 11.8. and 5%, respectively. Hormone receptors (HR) were undetermined in 4 patients, positive in 6, and negative in 1 patient, who was also positive for HER2. To determine the relationships among the prognosis of the liver metastasis, AIT indications, HR, and HER2, we analyzed our 139 liver metastasis patients encountered in 2001 and onwards. Fifty-one patients with primary liver metastasis had a median survival time (MST) of 31 months, and a 5-year survival rate of 25%, indicating an improved prognosis. In particular, a MST of 50 months (n=18) in HR (+), HER2 (-) patients was in sharp contrast to the poor prognosis (a MST of 6 months, n=2) in HR (-) HER2 (-) patients. HER2 (+) patients had a MST of 27 months (n=31). Eighty-eight patients with secondary liver metastasis had a MST of only 11 months and a 5-year survival of only 6%; however, the MST in these patients showed the same tendency as in the primary liver metastasis patients: ER (+) HER2 (-) >HER2 (+) >HR (-) HER2 (-) (17, 13, and 4 months, respectively). The response rates of OK-AIT in the primary and secondary liver metastasis patients were 52 and 34%, respectively, showing no significant difference. However, there was a significant difference in the response rate between the HR (+) and HR (-) patients, at 52 and 12%, respectively (p=0.0041). Of the patients in the past, 18 with primary liver metastasis underwent hepatectomy in combination with OK-AIT. Of these 18 patients, 5 had concurrent metastases to other sites, but achieved a 5-year survival rate of 56%, suggesting that it is incorrect to conclude that patients with liver metastasis have generally a poor prognosis. Key

Sex hormone, an essential hormone in reproduction, acts upon the tissues through binding to its receptors. Thus, the study on the receptors is essential for understanding the reproductive processes, physiologically or pathologically. With the advent of molecular biology, receptorology in our field has rapidly developed. In this lecture, we presented our recent findings on the receptor and its gene expression, together with some brief overview on the development of the receptor study, basically or clinically. I. Basic study. 1) Methology: A specific and highly sensitive quantitative RT-PCR assay for measurement of the steroid hormone receptor (SHR) mRNA was developed. 2) Rat progesterone receptor (PR) cDNA, especially PR-BcDNA, was partially cloned. Using primers designed upon the cloned cDNA, two distinct different promoters was found to exist in PR-A and B gene expression in the rat. 3) Tissue specificity of gene expression of the SHRs in the central and peripheral tissues: The synthesis of the receptor protein was regulated mostly on the level of transcription. In some tissues, however, the receptor synthesis was regulated posttranscriptionally. Gene expression of the SHRs was widely distributed even in non-target tissue, indicating the existence of 'basic action' of SH on the tissues. 4) Primate monkey studies: SHR, especially PR, was localized mostly in the preoptic hypothalamic region and hypophysis in contrast with its wide distribution in the rat brain, suggesting the more limited feedback site of progesterone in women. 5) Brain sex differentiation and acquisition of steroid sensitivity: Region-specific and dynamic appearance of SHRs during peri- and postnatal development seemed to a major determinant of sex differentiation and hormone sensitivity' acquisition in female rats. Based upon analysis of PR-A and B mRNAs, gene expression of PR-B was first 'turn on', followed by PR-B gene expression. Progesterone seemed to be associated with 'termination' of the critical period of sex differentiation in the brain. 6) Thyroid hormone may be a regulator of synthesis and gene expression of the PR in rat cerebral cortex. Arachidonic acid, released from cell membrane, regulated SHRs in a non-competitive way, indicating some 'second messenger' role. Cross-talk might exist between the membrane factor and SHR. 7) Antisense mRNA against GnRHmRNA, SH2RNA, was identified in rat brain. Most interestingly, there was a reciprocal relationship between GnRHmRNA and SH2RNA, suggesting some GnRHmRNA regulatory mechanism other than previously thought. 8) Depression of the GnRH receptor (GnRHR)mRNA level by GnRH agonist indicated another mechanism on down-regulation of GnRHR.(ABSTRACT TRUNCATED AT 400 WORDS)

Human uterine endometrial steroid receptor [estrogen (ER), progestin (PR) and androgen (AR) receptors] in the normal menstrual cycle were determined at the cellular level. Endometria with pathological out-of-phase findings or with hypoplastic uterus were evaluated for the concentration of steroid receptors, for a better understanding of their pathophysiology. ER and PR levels gradually rose toward the early secretory phase, remained at the maximum level during the mid-secretory phase and dropped to the lowest level during the late secretory phase. Especially nuclear PR reached the maximum level during the mid-secretory phase. These results indicate that the endometrial ER and PR, especially the endometrial nuclear PR, is kept in the maximum level at implantation. AR showed only a slight change in a very low level throughout the menstrual cycle. This indicates that androgen may not play so important a role in endometrial physiology. Endometria with out-of-phase or with hypoplastic uterus contained significantly low levels of endometrial ER and PR, while serum hormones levels were normal. This indicates indigenous reduction of ER and PR synthesis in such endometria.

Fibroblasts grown from abdominal and vulvar skin from normal women were tested for their dihydrotestosterone binding activity. Fibroblasts from either source had 8S cytoplasmic dihydrotestosterone receptors as confirmed by sucrose gradient analysis and the concentration of dihydrotestosterone binding sites and the apparent dissociation constant were 21.6 +/- 1.1 fmoles/mg protein and 0.50 +/- 0.028 nM, respectively, for fibroblasts from abdominal skin and 35.9 +/- 1.7 fmoles/mg protein and 0.24 +/- 0.015 nM, respectively, for fibroblasts from vulvar skin. The dihydrotestosterone binding activity was greater in fibroblasts from vulvar skin than from abdominal skin (P less than 0.01). Fibroblasts formed dense monolayers were treated with various concentrations of dihydrotestosterone (10, 100, 1,000 ng/ml) for six days and were assessed for hormone effect. The production of proteins was elevated in fibroblasts from either source with a slightly greater hormonal response occurring in fibroblasts from vulvar skin than from abdominal skin. Collagen production was elevated significantly in fibroblasts from vulvar skin but only marginally in fibroblasts from abdominal skin. The synthesis of DNA was not affected in fibroblasts from either source. These results than response to dihydrotestosterone was greater in fibroblasts with a higher hormone binding activity may reflect the hormone effect being mediated through dihydrotestosterone receptors.

The advance in knowledge of clinical disorders involving calcium and bone diseases has resulted in part from the development of assay procedures for the major vitamin D metabolites, but the values of the same samples measured in different laboratories vary considerably. They suggest that the chromatographic purification involved in these assays seems to be a critical step. In this study, we compared the results of 1,25-dihydroxyvitamin D (1,25(OH)2D) using different chromatographic purification methods: Sephadex LH-20 column chromatographic purification (non-HPLC method) described by Mallon et al. and High Performance Liquid Chromatographic purification (HPLC method) modified by Yamaoka et al. Serum 1,25(OH)2D levels of healthy volunteers before and after oral load of 4 micrograms of 1 alpha-hydroxyvitamin D3 (1 alpha OHD3) were measured by the two different methods mentioned above. A good correlation (r = 0.951, p less than 0.001) was noted in the samples before loading. The mean values of serum 1,25(OH)2D before loading did not differ significantly between HPLC method and non-HPLC method. After loading, however, the mean value of serum 1,25(OH)2D was significantly higher in non-HPLC method (p less than 0.01). The values of 1,25(OH)2D were determined in the serum added 1,25-dihydroxy-24-oxo-vitamin D3 (24-oxo-D3) (0 pg/ml, 200 pg/ml or 2000 pg/ml). In the samples added 2000 pg/ml of 24-oxo-D3, the mean value of 1,25(OH)2D was significantly higher in non-HPLC method (p less than 0.001). The affinity of 24-oxo-D3 for 1,25(OH)2D3 cytosolic receptor was evaluated in chick embryo intestinal mucosa and rachitic chick intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)