Prognostic factors of patients with yolk sac tumors of the ovary.

OBJECTIVE: Our purpose was to evaluate the prognostic factors in yolk sac tumors of the ovary. STUDY DESIGN: We performed a retrospective review of 47 patients with yolk sac tumors of the ovary from 1979 to 1997. RESULTS: Twenty-two patients had pure yolk sac tumors and 25 had germ cell tumors with yolk sac tissue as a component of the disease. The 5-year survival rate in stages I, II, III, and IV was 95%, 75%, 30%, and 25%, respectively. Patients with stage I disease had a more favorable prognosis than those with stage III and IV disease (P <.001). All patients who did not respond to chemotherapy died of this disease within 36 months of the first treatment. Chemotherapy regimens that included cisplatin gave better results than those without cisplatin (P <.05). The difference in prognosis was significant in cases in which the size of residual tumor was <2 cm in diameter (P <.01) and in cases in which ascites was either absent or <100 mL in volume (P <.05). Coexistence of other components of ovarian germ cell tumors in histologic specimens, preoperative serum alpha-fetoprotein level, fertility-sparing surgery, dissection of intrapelvic nodes, and p53 status had no significant correlation with the prognosis in this study. CONCLUSIONS: Staging and tumor-reductive surgery strongly affected the prognosis of this disease. Tumor-reductive surgery is advisable when ascites is minimal. Cisplatin-based chemotherapy after surgery was superior to chemotherapy without cisplatin; however, p53 status seemed to have no impact on chemosensitivity in yolk sac tumors of the ovary.

Color-coding reveals tandem repeats in the Escherichia coli genome.

Genomic DNA contains a wide variety of repetitive sequences. In Escherichia coli, there have been several classes of repetitive sequences reported, some of which cluster as tandem repeats. We propose a novel method for analyzing symbolic sequences by two-dimensional pattern formation with color-coding. We applied this method for searching tandem repeats in the E. coli genome and found approximately 50 repeats with periods longer than 30 bases. The longest repeat has a period of 1267 bases.

Preeclampsia with fetal death in a patient with schistosomiasis japonica.

A case of preeclampsia with fetal death at 32 weeks' gestation is reported. Liver examination of the patient revealed network patterns on ultrasonography and linear calcifications on unenhanced CT scans in the liver. These findings are typical of those of chronic schistosomal infection. Indeed, liver biopsy specimens showed eggs of schistosoma japonicum. We diagnosed her case as preeclampsia with liver cirrhosis due to chronic schistosomiasis japonica. Schistosomal placentitis may have been present and may have contributed to preeclampsia and fetal death.

The different stimulatory effect of normal tissues on the secretion of matrix metalloproteinases and their inhibitors by human ovarian cancer cells.

To investigate the influence of normal tissues on secretion of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by ovarian cancer cells, conditioned medium of several normal human tissues (peritoneum, myometrium, and ovary) was added to ovarian cancer cells (NOM1). MMPs were detected by zymography and TIMP-1 levels were assayed by ELISA. The MMP-9 level was significantly higher in peritoneal conditioned medium than in myometrial and ovarian conditioned medium, but the TIMP-1 level was the lowest. Addition of conditioned medium from these normal tissues to NOM1 cells increased the levels of MMPs and TIMP-1 in NOM1 conditioned medium. Peritoneal conditioned medium induced the highest MMP-9 level in NOM1 conditioned medium, while TIMP-1 was the lowest. Conditioned medium from the normal tissues also significantly increased invading cell numbers, with peritoneal conditioned medium being the most potent. These results showed that secretion of MMPs and TIMP-1 is regulated by normal tissues and peritoneum provides the best conditions for ovarian cancer cell invasion.

A newly synthesized bifunctional inhibitor, CKA1083, enhances adriamycin activity against human ovarian carcinoma cells.

BACKGROUND: A newly synthesized drug, CKA1083 ((S)-N-[2-(4-benzyloxy-carbonylpiperazinyl)-1-(P-methoxybenzyl) ethyl]-N-methyl-N(5-isoquinolinesulfonamide)), has the same glutathione-S-transferase (GST)-binding site structure as W-77, a bifunctional inhibitor that enhances the cytotoxicity of Adriamycin for human ovarian carcinoma cells. We examined the effects of CKA1083 on the cytotoxicity of Adriamycin and the resistance of human ovarian carcinoma cells to this drug. MATERIALS AND METHODS: We used GST-pi transfected cells and Adriamycin-sensitive or -resistant cells of human ovarian carcinoma. GST-pi activity, the intracellular Adriamycin content, and the cytotoxicity of Adriamycin in these cell lines in the presence or absence of CKA1083 were measured and compared to the findings obtained with W-77 or verapamil. RESULTS: CKA1083 inhibited GST-pi activity in an uncompetitive manner and more strongly than W-77. It enhanced the cytotoxicity of Adriamycin for GST-pi transfected cells by about 3-times. Further, CKA1083 increased the intracellular Adriamycin content about 3-fold in two Adriamycin-resistant cell lines (NOS2AR and NOS3AR). CKA1083 (10 microM) reduced the IC50 of Adriamycin to 1/38 in NOS2AR cells and 1/21 in NOS3AR cells, and overcame Adriamycin resistance more effectively than both W-77 and verapamil. CONCLUSIONS: CKA1083 enhanced the antitumor effect of Adriamycin more than W-77 by inhibiting both GST activity and P-glycoprotein.

Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma.

High levels of IL-6 have been observed in ascitic fluid in patients with ovarian cancer. In this study, we examined the effects of IL-6 on in vitro invasiveness of human ovarian cancer cells. Human ovarian cancer cells, NOM1 and SKOV, were used. Cell attachment to Matrigel, migration, and invasion were examined with or without IL-6. Zymography was performed to analyze gelatinase production by these cells. NOM1 cell attachment was increased by IL-6 (0 to 10 ng/ml). In a migration assay, IL-6 ranging from 0 to 10 ng/ml showed chemotactic and/or chemokinetic activities for the two cell lines. The invasiveness of these cells was significantly enhanced by IL-6 at the above concentrations. However, IL-6 did not modulate the production of either MMPs or TIMPs. IL-6 affects cell invasion through its effects on attachment and migration in human ovarian cancer cells. IL-6 might thus contribute to the progression of this disease.

Clinical value of CA125, CA19-9, CEA, CA72-4, and TPA in borderline ovarian tumor.

Five tumor markers were analyzed clinically in 101 patients with borderline ovarian tumors who were treated by the Tokai Ovarian Tumor Study Group, an association comprising Nagoya University and its affiliated hospital, between January 1986 and December 1994. The positive rate of CA125 was 68.2% in serous tumor and 51.9% in mucinous tumor. The positive rate of CA19-9 was 51.5% in serous tumor and 44.7% in mucinous tumor. The positive rates and mean serum levels of CA125 in serous and mucinous tumor by stage had rising tendencies with an increase in each stage. The mean serum levels of CA19-9 in serous and mucinous tumor by stage had rising tendencies with an increase in each stage. CA125 and CA19-9 were useful for screening of borderline ovarian tumors. The positive rates of CEA and TPA in mucinous tumor were 32.5 and 27.3%, respectively, although none of the patients with serous tumor were positive in CEA and TPA. The positive rates and mean serum levels of CEA in mucinous tumor by stage had rising tendencies with an increase in each stage. The positive rate of CA72-4 was significantly lower than that of CA125 (P < 0.05).

Effect of KN-62, Ca2+/calmodulin-dependent protein kinase II inhibitor, on adriamycin resistance of human ovarian cancer cells.

We examined effects of an isoquinolinesulfonamide derivative, KN-62, on human ovarian cancer cells, NOS3AR, that are resistant to Adriamycin (ADR). MTT assay revealed that 10 microM KN-62 overcame the resistance. KN-62 had little effect on GST activity. In studies on the intracellular accumulation of ADR, KN-62 increased the ADR contents in the resistant cells close to the level seen in the sensitive cells. These results suggest that the reversal of the resistance against ADR in ovarian cancer cells by KN-62 is mainly due to higher accumulation of ADR in NOS3AR cells. Furthermore, we detected Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in NOS3AR cells since KN-62 is a specific inhibitor of the kinase. In this paper, we discussed on modulation of ADR-resistance by KN-62.

Gonadoblastoma with dysgerminoma in one ovary and gonadoblastoma with dysgerminoma and yolk sac tumor in the contralateral ovary in a girl with 46XX karyotype.

A case of gonadoblastoma with dysgerminoma in the left ovary and gonadoblastoma with dysgerminoma and yolk sac tumor in the right of a 10-year-old girl is reported. Her karyotype was 46XX, normal female type. A case of a gonadoblastoma without a Y chromosome is very rare. Furthermore, the prognosis for gonadoblastoma accompanied by germ cell tumors other than dysgerminoma was very poor in the past, but the patient remains well 25 months after the first operation.

S100 beta is a target protein of neurocalcin delta, an abundant isoform in glial cells.

To clarify the function of neurocalcin delta, an isoform found abundantly in glial cells, we attempted to find its target proteins by using neurocalcin delta-affinity chromatography and the 125I-neurocalcin delta gel-overlay method. The 10, 14, 27, 36 and 50 kDa bands found on SDS/PAGE bound to 125I-neurocalcin delta, and 10, 11, 19, 24, 26, 50 and 70 kDa proteins were eluted from a neurocalcin delta-affinity column in a Ca(2+)-dependent manner. Sequence analysis of proteolytic peptides revealed the following identities: S100 beta (10 kDa), S100 alpha (11 kDa), myelin basic protein (19 kDa), glyceraldehyde-3-phosphate dehydrogenase (36 kDa) and tubulin beta-chain (50 kDa). A zero-length cross-linking study indicated that 1 mol of S100 beta bound to 1 mol of neurocalcin delta. With the gel-overlay method, purified S100 beta protein and calcyclin bound to 125I-neurocalcin delta whereas calgizarrin and calvasculin, other members of the S100 family, did not. These findings suggest that S100 beta is one of the target proteins of neurocalcin delta, and the neurocalcin delta-S100 beta complex may be involved in Ca(2+)-signalling in the glial cell.

A follow-up study of patients with cervical cancer after resection, with special emphasis on the incidence of second primary cancers.

The causes of death in long-term survivors after resection of cervical cancer were investigated in a follow-up study of 375 women, focusing especially on the postoperative development of second primary cancers. The 5- and 10-year overall survival rates were 75.0 and 66.0%, respectively, in cases that showed frank invasion, 94.7 and 92.8%, respectively, in those showing microinvasion, and 96.2 and 96.2% respectively, in those showing carcinoma in situ. Multivariate analysis identified patient age and cancer stage at the time of diagnosis as separate factors prognostic for overall survival. During the observation period, 10 patients developed a second primary cancer, but no significantly elevated risk of developing a second primary cancer was demonstrated. However, during the same period, 20 patients also died of noncancerous disease, 9 of this number succumbing to acute myocardial infarction and/or heart failure. These results suggest that patients with cervical cancer may not have an increased risk of developing second primary cancer. It is felt that continued follow-up of long-term cervical cancer survivors should be pursued in order to prevent or arrest the development of noncancerous disease and/or second primary cancer, so that increased prolongation of survival can be achieved.

Establishment and characterization of acquired resistance to platinum anticancer drugs in human ovarian carcinoma cells.

To investigate differences in resistance to cis-diamminedichloroplatinum(II) (CDDP) and diammine (1,1-cyclobutanecarboxylato)platinum(II) (CBDCA), and their newly developed derivative, ((-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)platinum (II) (DWA2114R), four types of resistant cell lines were established from a parental cell line (NOS2) of a serous cystadenocarcinoma of the ovary. The cross-resistance of CDDP-resistant cells (NOS2CR1 and NOS2CR2) to DWA2114R was slight (only 25% of the resistance to CDDP), and no cross-resistance was observed to anticancer drugs other than the CDDP derivative, except to camptothecin (CPT-11) in the case of NOS2CR2 cells. The cross-resistance of CBDCA-resistant cells (NOS2CBR) to DWA2114R was slight (only about 1/3 of the resistance to CBDCA), and no cross-resistance was observed among anticancer drugs other than the CDDP derivative. On the other hand, DWA2114R-resistant cells (NOS2DR) showed a high cross-resistance to CDDP, CBDCA, etoposide (VP-16), and CPT-11. Intracellular accumulations of CDDP and CBDCA were markedly reduced in NOS2CR1, NOS2CR2, and NOS2CBR cells compared to those in NOS2 cells, but were reduced only slightly in NOS2DR cells. Intracellular accumulation of DWA2114R was reduced somewhat in the four types of resistant cells. Glutathione S-transferase activity was not increased in any of the four types of resistant cells, and intracellular GSH concentration was increased only in NOS2CR2 cells (by 2.6 fold). From these results, we consider that the resistance mechanisms against CDDP and CDBCA are similar, and reduction of intracellular drug accumulations is a significant factor. Resistance to DWA2114R differed from resistance to CDDP and CBDCA in both cross-resistance spectrum and resistance mechanism, indicating that reduction in intracellular drug accumulation is not the major resistance mechanism.

[Immunohistochemical study on the MHC class I antigen expression on squamous cell carcinoma of the uterine cervix].

Immunohistological analysis was performed to detect MHC Class I antigen expression on uterine cervical squamous cell carcinomas of 23 patients using a monoclonal antibody (W6/32) to recognize a monomorphic determinant of HLA-ABC and an antibody (MA2.2) to react only with cells typed as HLA-A2. The results were as follows. 1. In 2 of 23 cases examined, cancer cells lacked reactivity with W6/32, although normal epithelial cells and connective stromal cells surrounding cancer nests were clearly positive for the antibody in all cases. 2. Of the remaining 21 cases, fourteen cases were judged to be HLA-A2 positive, based on the obvious staining of the stromal cells with MA2.2. Of these 14 only 5 carcinomas were positive for HLA-A2, and the cancer cells in the other 9 cases failed to bind MA2.2. These data suggest that in most clinically diagnosed patients, cancer cells do not have their own MHC Class I products on their cell surfaces phenotypically, and this unique property may be related to the biological characteristic that permits cancer cells to survive and proliferate unrestrictedly in vivo, mainly escaping from the immune-surveillance system under cytotoxic T lymphocytes (CTLs), which need to recognize not only cancer-specific (associated) antigen(s) but also the self-MHC Class I products to kill the cancer cells efficiently.

Species difference of 5-lipoxygenase derived from polymorphonuclear leukocytes on sensitivity to drugs.

Effects of 12 compounds including 5-lipoxygenase (5-LO) inhibitors and antiallergic drugs on the activity of 5-LO from the polymorphonuclear leukocytes (PMN) of guinea pigs, rats, rabbits, monkeys and humans were examined. The 5-LO activity was inhibited by the drugs according to the following orders of efficacy: Guinea pig 5-LO, 5-HDHDMF greater than TZI-2721 greater than NDGA greater than AA861 greater than FPL55712 greater than isoproterenol; rat 5-LO, 5-HDHDMF greater than AA861 greater than TZI-2721 greater than NDGA greater than FPL55712 greater than KP-136 greater than MCI-826 greater than benoxaprofen; and rabbit 5-LO, 5-HDHDMF greater than TZI-2721 greater than NDGA greater than AA861 greater than FPL55712 greater than KP-136 greater than MCI-826. The 5-LO activity from the rhesus monkey was dose-dependently inhibited by only 3 compounds, 5-HDHDMF greater than NDGA greater than TZI-2721, in this order, but the other compounds, except for AA861, did not show any effect on this activity. In humans, 5-LO activity was inhibited in the following order: TZI-2721 greater than 5-HDHDMF greater than NDGA greater than AA861 greater than FPL55712. From these results, it was strongly suggested that there is a species difference of this enzyme in its sensitivity to drugs.

[New trends in trophoblastic disease].

In Japan, population-based trophoblastic disease registries were set up in the 1974s by the Registration Committee for Trophoblastic Disease (Japan Society of Obstet. & Gynecol.). The results indicate the following. 1. The incidence rates for trophoblastic disease show that the incidence of hydatidiform mole has been decreasing year by year from 10.2 to 5.9 throughout the observation period 1979-1986. But the incidence for hydatidiform mole per 1,000 pregnancies was from 1.83 to 1.91, and that per 1,000 deliveries was also from 2.84 to 2.93 throughout the observation period. The incidence of choriocarcinoma has also been decreasing year by year from 0.31 to 0.13 throughout the observation period. The frequency of choriocarcinoma after hydatidiform mole with complete remission was 0.32% (4/1, 171), but that after hydatidiform mole with no remission was 3.08% (4/130). The high risk groups for choriocarcinoma were hydatidiform mole over 40 years old, metastatic mole, and invasive mole. Five-year survival rate of choriocarcinoma with no metastatic foci was 100%, and that of metastatic choriocarcinoma was 59.2%. For cases treated with surgery combined with chemotherapy, 80.0 per cent of the cases survived 5 years compared with 71.4 per cent of the cases treated with chemotherapy alone and 67.7 per cent of the cases treated with surgery alone. The mortality for choriocarcinoma per 100,000 female population has been decreasing year by year from 0.123 to 0.065 throughout the observation period.