Takeo Kano

Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases

Twenty‐nine ovarian cancer patients with yolk sac tumors and germ cell tumors with yolk sac tissue as a component of their disease (16 endodermal sinus tumor, 11 mixed germ cell tumors, one embryonal carcinoma, and one polyembryoma) were treated with cytoreductive surgery and combination chemotherapy. Prognostic factors were investigated in this group. Patients with Stage I disease had a more favorable prognosis (P < 0.003) than those with Stages II and IV disease. The difference in prognosis was significant in cases where residual tumor was absent (P < 0.003) and in cases where ascites was either absent or less than 100 ml in volume (P < 0.05). Endodermal sinus tumor with either an intestinal (P < 0.05) or microcystic pattern (P < 0.01) was more common in survivors than in those who died. The age, preoperative serum alpha‐fetoprotein level, maximum tumor size, and tumor weight had no significant correlation with prognosis. In advanced cases, chemotherapy regimens including cisplatin gave better results than those containing vincristine, dactinomycin, and cyclophosphamide (P < 0.05). The optimal treatment of yolk sac tumors or tumors with yolk sac tissue as a component of the ovary is discussed in light of these results.

Seven Tumor Markers in Benign and Malignant Germ Cell Tumors of the Ovary

Seven tumor markers were analyzed clinically in 135 patients with germ cell tumors of the ovary who were treated in Tokai Ovarian Tumor Study Group, an association comprising Nagoya University and its affiliated hospitals, between January 1979 and September 1990. Positive rate of AFP was 100% (36/36) in yolk sac tumor, 61.9% (13/21) in immature teratoma, and 11.8% (2/17) in dysgerminoma, but there were no positive cases of mature cystic teratoma with malignant transformation (0/7) and mature cystic teratoma (0/31). Positive rate of CA125 was over 50% in all tumor types except mature cystic teratoma, which showed a positive rate of 23.7%. CA125 was useful for the screening of malignant germ cell tumors. CA19-9 showed a high positive rate in teratomatous tumors, which were immature teratoma, mature cystic teratoma with malignant transformation, and mature cystic teratoma. Dysgerminoma and yolk sac tumor, especially dysgerminoma, had a high positive rate of LDH. TPA and CEA were not considered useful tumor markers for germ cell tumors of the ovary.

α-Fetoprotein in malignant germ cell tumors of the ovary

To investigate the clinical significance of alpha-Fetoprotein (AFP) in malignant germ cell tumors of the ovary, we studied 46 patients who were treated by the Tokai Ovarian Tumor Study Group. The 46 patients had the following tumors: immature teratoma (IT), 17 cases; endodermal sinus tumor (EST), 16 cases; mixed germ cell tumor containing EST, 11 cases; embryonal carcinoma, 1 case; polyembryoma, 1 case. In all 29 non-IT cases, AFP was positive, and in 27 cases (93%) the level was above 1000 ng/ml. In 11 of 17 cases of IT (64.7%), AFP levels were elevated and in 1 case the level was above 1000 ng/ml. Elevation of the AFP level above 1000 ng/ml suggested the presence of EST. AFP levels were monitored in 27 of 29 cases without IT during treatment and follow-up. It was found that AFP levels should be monitored closely for at least 1 year after induction of remission. No recurrence was observed when AFP continued to be negative longer than 1 year. The mean interval to clinical recurrence from the reelevation of AFP was 4 months (1.4-9 months). An increase in the AFP to a positive level, even without clinical signs of recurrence, should be regarded as a recurrence. AFP was found to be a useful tumor marker for the diagnosis and management of malignant germ cell tumors of the ovary.

IMMATURE TERATOMA OF THE OVARY

The purpose of this study was to establish the optimal management of immature teratoma of the ovary. Pursuant to this, 20 previously untreated patients with immature teratoma were evaluated. Nine patients were at stage I of the disease, 2 had progressed to stage II, and 9 to stage III. Eight patients had grade 1 tumors, 11 had grade 2 tumors, and 1 had a grade 3 tumor. Postoperative chemotherapy was performed in 19 cases. Vincristine, actinomycin D, and cyclophosphamide (VAC) were administered in 9 cases, chemotherapy including cisplatin (P) was administered in 8 cases, and other regimens were followed in the 2 remaining cases. The median follow-up period was 62 months (range 19-108 months), and no patient was lost to follow-up. After completion of the follow-up period, 18 patients were alive and disease free, 1 was alive with liver metastasis, and 1 had died. The patient who died had suffered from a grade 3 tumor, and the recurrent tumor was a rhabdomyosarcoma. As a result of this study, it was found that immature teratoma of grades 1 and 2 can be managed successfully with VAC or P therapy. Thus, a hysterectomy should not be automatically performed in patients who still hope to give birth, yet suffer from a grade 1 or 2 immature teratoma at the time of a second operation.

Preservation of ovarian function and reproductive ability in patients with malignant ovarian tumors

In a study designed to determine the merit of preserving ovarian function and childbearing capability in women with unilateral malignant ovarian tumors, the results of radical surgery (n = 86) and conservative surgery (n = 106) were compared. The mean length of survival was slightly but not significantly shorter following conservative surgery. There were 15 recurrences (14%) and 11 deaths among the conservative surgery group. The incidence of metastasis to the preserved ovary was high. In the most cases restoration of normal menses was fairly rapid after initial treatment, but this appeared to depend on whether or not chemotherapy was given postoperatively, the specific agents used, and the duration of their administration. Hypergonadotropic hypogonadism was the most common finding among the anovulatory patients. Sixteen women experienced a total of 27 pregnancies and 18 normal infants were born. Abortion was induced when conception occurred during a course of chemotherapy. These findings are encouraging in terms of the feasibility of preserving childbearing capability in ovarian cancer patients. However, they also underscore the necessity for close, long-term follow-up, which will be improved as new technologies become available.

Mitomycin C cross-resistance induced by Adriamycin in human ovarian cancer cells in vitro

SummaryWe prepared Adriamycin-resistant cancer cells by exposing an ovarian serous cystadenocarcinoma cell line to the drug. The resistant cells also showed cross-resistance to a wide variety of other compounds, including vincristine, vinblastine, actinomycin D, daunorubicin, mitomycin C and carboquone. Against vincristine, the cells showed a >5,000-fold increase in resistance, far surpassing their resistance to the selection drug. The resistant cells displayed a decrease in intracellular Adriamycin content and an increase in the mRNA of themdr-1 gene coding for P-glycoprotein, with no amplification of the DNA. In revertant cells, resistance to Adriamycin was lost, but that to mitomycin C was maintained. Adriamycin resistance was partially overcome by the addition of verapamil or cyclosporin A, but cross-resistance to mitomycin C was not influenced at all. These results strongly suggest that the resistance to mitomycin C observed in our Adriamycin-resistant cells was due to some other mechanism than that causing multidrug resistance.

Accumulation of cis-diamminedichloroplatinum (II) and its analogues in sensitive and resistant human ovarian carcinoma cells.

Human ovarian carcinoma cell line (NOS2), established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise increase in cis-diamminedichloroplatinum (II) (CDDP) concentration to produce a CDDP-resistant cell line NOS2CR) as an experimental model for resistance to CDDP. NOS2CR cells showed a 7-fold resistance to CDDP and a lesser degree of cross-resistance to diammine (1,1-cyclobutanedicarboxylato)-platinum (II) (CBDCA) and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) (DWA2114R). In the absence of CDDP, cross-resistance to DWA2114R was reduced to the original level by 2 months, although 83% resistance to CDDP remained up to 6 months. To investigate CDDP-resistant mechanisms, alterations in the intracellular accumulation of CDDP and analogues were assayed by atomic absorption. In both NOS2 and NOS2CR cells, accumulation of CDDP increased linearly with time and was concentration-dependent. NOS2CR cells demonstrated 71, 52 and 12% reduction in accumulation of CDDP, CBDCA, and DWA2114R, respectively. These reductions did not seem to be due to P-glycoprotein, because expression of multidrug-resistant 1 gene was not detected in either NOS2 or NOS2CR cells. These studies indicate that the mechanisms of resistance to CDDP and analogues in NOS2CR cells are related in the main to reduced intracellular accumulation of drugs. DWA2114R might be helpful to treat CDDP-resistant and recurrent tumors which were treated by CDDP.

Three-year prospect of patients with common epithelial carcinoma of the ovary

In order to forecast the survival of patients, we collected 417 cases of common epithelial carcinoma of the ovary as a population for this study, then selected 141 cases who had survived more than 3 years and 131 cases who had died within 3 years as a sample of statistical inference. The sample was computerized inputting 25 factors which were obtained mainly on the first surgery. We selected 8 factors with 46 items considering their weight to forecast the prognosis on convenience. The selection of factors was carried out by following three basic principles. First, we selected factors that retained high partial correlation coefficients. Second, we selected factors which did not overlap each other in their contents. Third, we selected factors which were not decided intentionally. Accordingly, the score for forecasting the 3-year survival of patients with ovarian carcinoma was framed. The correct discrimination rate of the score when it was judged at the 0 point was 86.8% in the sample group. However, in the sample group outside the population, it was 83.1%.