Tadashi Sagawa

CYP1A1 polymorphism and risk of gynecological malignancy in Japan.

The incidence of endometrial cancer and ovarian cancer in Japan has been increasing in recent years. Results of epidemiologic studies suggest that the onset and multiplication of these cancers are associated with estrogen. Estrogens are metabolized by cytochrome P450 1A1 (CYP1A1) and converted into catecholestrogens, which are carcinogens. CYP1A1 has several polymorphisms, the major one being T6235C transition in the non-coding 3′-flanking region (MspI polymorphism), and another being A4889G transition in exon 7 (Ile/Val polymorphism). These polymorphisms can affect the metabolites of estrogens and contribute to the susceptibility to gynecological malignancy. In this study, to determine whether CYP1A1 polymorphism plays a role in the development of gynecological malignancy in the Japanese population, we assessed the association of CYP1A1 polymorphism in Japanese patients with gynecological malignancy in comparison to that in controls. The odds ratios (ORs) of Ile/Val polymorphism were 1.16 in ovarian cancer patients and 1.70 in endometrial cancer patients. The ORs of MspI polymorphism were 1.33 in ovarian cancer patients and 0.88 in endometrial cancer patients. No significant association was found between these CYP1A1 polymorphisms and gynecological malignancy. Although the frequency of CYP1A1 polymorphism in the Japanese population is higher than that in the Caucasian population, CYP1A1 polymorphism is not related to gynecological malignancies in Japanese population.

Prognostic significance of serous and clear cell adenocarcinoma in surgically staged endometrial carcinoma

Background. The serous adenocarcinoma (SA) and clear cell adenocarcinoma (CCA) of endometrium have been shown to be associated with high relapse rate and poor survival. It is not clear whether prognostic significance of these specific cell types of tumor is independent of retroperitoneal lymph node metastasis and other histopathologic prognostic factors in endometrial carcinoma.

Correlation between cytokine levels of amniotic fluid and histological chorioamnionitis in preterm delivery.

The aim of this study was to investigate the correlation between the cytokine levels in the amniotic fluid (AF) and the histological stage of chorioamnionitis (CAM) in premature labor. AF of 6 cases (7 samples of AF were obtained as one was a twin pregnancy) in whom CAM was diagnosed histologically, and 12 cases without CAM were included in this study. Amniotic fluid was obtained within 24 hours prior to delivery. Cytokine levels (IL-2, -4, -6, TNF-alpha, IFN-gamma) in AF were measured by an ELISA method. Levels of IL-2 and -6 in the CAM-positive group (mean +/-S.E., 52.9 +/- 83.9 pg/ml, and 20,537.9 +/- 8853.7 pg/ml, respectively) were higher than those in the CAM-negative group (i.e. undetectable, and 65.6 +/- 27.5, respectively) with a statistical significance of p < 0.05, p < 0.001, respectively. There was a positive linear relationship between IL-6 levels of AF and the placental histological inflammatory stages of Blanc in the CAM-positive group. From these results it would appear that the IL-6 level in AF is the most sensitive test in the detection of extraamniotic infection or intraamniotic infection in preterm labor with intact membranes and also indicates the severity infection.

A case of intrauterine medical treatment for cystic hygroma

We report the first case of an intrauterine treatment for cystic hygroma. Guided by ultrasonography, we first removed intracystic fluid from two cysts and then injected OK-432 into each fetal cyst at 21 and 28 weeks of gestation. No re-enlargement of the cysts was subsequently observed. At 38 weeks of gestation, a male infant was delivered transvaginally. Only a slight skin fold was observed in the nuchal area of the neonate, indicating the effectiveness of OK-432 for the intrauterine treatment of cystic hygroma.

Bcl-2 expression and prognosis of patients with endometrial carcinoma.

Bcl‐2 protein inhibits apoptosis, reduces the requirement for growth factors, and thereby extends the survival of cells. Recent findings of Bcl‐2 in several solid tumors suggest that it might contribute to the genesis of some types of cancer. Over‐expression of Bcl‐2 might play a role in carcinogenesis and malignant progression of endometrial carcinoma. The aims of this study were to determine Bcl‐2 expression in endometrial carcinoma in relation to other histopathologic prognostic factors, and to test its prognostic significance in patients with endometrial carcinoma. A total of 61 endometrioid‐type endometrial carcinomas were immunohistochemically investigated for Bcl‐2 expression on cryostat sections. Bcl‐2 localization was observed in cytoplasm in 18 tumors, in nucleus in 27 tumors, or in both in 5 tumors. In 11 tumors, Bcl‐2 was observed neither in cytoplasm nor in nucleus. There was not a statistically significant relationship between grade of tumor and Bcl‐2 expression. Cytoplasmic Bcl‐2 became less frequently expressed as the tumor invaded the myometrium deeper (p < 0.025). Retroperitoneal lymph‐node dissection was performed in 57 patients. Multiple‐regression analysis showed that lymph‐vascular space invasion and nuclear expression of Bcl‐2 were correlated to pelvic lymph‐node metastasis (p < 0.0001 and <0.05 respectively). Univariate Cox regression analysis revealed that nuclear Bcl‐2 expression was associated with shorter survival (p < 0.05) than that of patients with cytoplasmic Bcl‐2 expression. Pelvic node metastasis was a significant prognostic factor for patients who underwent systematic retroperitoneal lymph‐node dissection. Cox multivariate‐regression analysis revealed that pelvic node metastasis and cervical invasion were the most important prognostic factors in this series of patients. When the analysis was made after exclusion of pelvic node metastasis, histologic grade (hazard ratio = 2.4), cervical invasion (hazard ratio = 3.7) and nuclear Bcl‐2 expression (hazard ratio = 11.5) were shown to be significant predictors of survival of the patients. These results indicate that aberrant Bcl‐2 expression might be involved in malignant progression of endometrioid‐type endometrial carcinoma. Site of Bcl‐2 localization may be an important predictor of prognosis for patients with endometrioid‐type endometrial carcinoma. Int. J. Cancer (Pred. Oncol.) 79:153–158, 1998.© 1998 Wiley‐Liss, Inc.

Effects of Inflammatory Cytokines on Prostaglandin E2 Production from Human Amnion Cells Cultured in Serum-Free Condition

The effects of five inflammatory cytokines, i.e. interleukin(IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) on prostaglandin E2 (PGE2) production from amnion cells cultured in a serum-free condition was evaluated. After human amnion cells obtained from term placenta were incubated with the inflammatory cytokines at various concentrations, PGE2 production in the culture supernatant was determined using an enzyme immunoassay method. Under a serum-free culture condition, an increase in PGE2 production by IL-1α and IL-1β was observed at concentrations of 10 and 100 ng/ml compared to control cultures. However, the increases in PGE2 production by IL-6 and IL-8 were found at relatively high concentrations, i.e. at 100 and 200 ng/ml. TNF-α induced a significant increase in PGE2 production at 50 and 100 ng/ml, but not at 200 ng/ml. These data suggest that these inflammatory cytokines directly stimulate PGE2 production from amnion cells and may initiate premature labor if amniotic inflammatory cytokines are elevated, e.g. following intrauterine infection.

Outcome of non-immune hydrops fetalis and a fetus with hydrothorax and/or ascites: with some trials of intrauterine treatment.

The subject of this study was 38 cases of non-immune hydrops fetalis and 11 cases of fetal hydrothorax and/ or ascites (FH/A), a syndrome characterized by the accumulation of pleural effusion and/or ascitic fluid, without generalized skin edema, due to various etiologies, admitted to the obstetrics ward of Hokkaido University Hospital during the period between 1987 and 1994. Fetal treatment consisted of (1) intravascular transfusion or intra-abdominal transfusion for anemia, (2) frequent centesis or shunt insertion for pleural effusion and ascites, (3) reduction of cystic hygroma by puncturing and OK432 injection, and (4) intravascular or maternal injection with an anti-arrhythmic drugs to treat tachycardia. The outcome of NIHF and FH/A was assessed to be able to make a prognosis in NIHF and to compare the efficacy of fetal therapy in cases with (15 cases: 9 NIHF, 6 FH/A) and without (34 cases: 29 NIHF, 5 HF/A) intrauterine treatment. The average survival rates were 23.1% in NIHF and 54.5% in FH/A. None of fetuses with a chromosomal abnormality or cystic hygroma survived. The average GW at the time of detection of NIHF by ultrasonography was week 24.9 +/- 1.1 (mean +/- S.E., n = 38). The average GW at the time of detection of FH/A by ultrasonography was week 26.6 +/- 1.8 (n = 11). NIHF was detected significantly earlier in the IUFD and early neonatal death group (GW 22.4 +/- 1.4) than in the survivor group (GW 27.6 +/- 1.2) (p < 0.05). FH/A was also detected earlier in the IUFD/early neonatal death group than in the survivor group (GW 21.8 +/- 2.4 vs. 31.1 +/- 1.1, n = 11, p < 0.05). The survival rate in the intrauterine treatment group was higher than in the nontreatment group (treatment group: 10/15; non-treatment group: 5/34, p < 0.001). After the trial of intrauterine treatment in the 15 cases mentioned above, some efficacy was observed in 7 cases (reduction of cysts, effusion or edema, disappearance of arrhythmia).

Diagnosis of premature rupture of the membranes in preterm patients, using an improved AFP kit: comparison with ROM-check and/or nitrazine test

OBJECTIVE We developed a new kit for detecting AFP in leaked amniotic fluid. Later, we developed an improved AFP kit utilizing the same anti alpha-fetoprotein (AFP) monoclonal antibody. In this study, we evaluate the clinical usefulness of this improved kit in the diagnosis of preterm premature rupture of membranes (PROM). METHODS We compared this improved AFP test with the ROM-check and/or the nitrazine tests in 46 preterm patients. RESULTS The ROM-check and nitrazine tests showed a diagnostic accuracy of 89.1 and 87.0%, respectively, compared with 95.7% with the improved AFP test. The sensitivity of the improved AFP test on cervical samples was significantly higher than that of the nitrazine test on vaginal samples (P < 0.05). The reaction time with the improved AFP kit test is 90 s. CONCLUSION This study has confirmed a great clinical utility of the improved AFP test kit as a method of PROM diagnosis.

Recent trends in the prevalence of Down syndrome in Japan, 1980–1997

The aims of the present study were to determine recent trends in the prevalence of Down syndrome (DS) in Japan, and to determine whether recent changes in demographic and social habits and access to prenatal diagnosis have influenced the livebirth rates of DS. Livebirth statistics indicate that the birth rate in Japan has decreased for women in their 20s and has increased for those in their 30s and 40s. During an 18-year period between 1980 and 1997, 1,299 consecutive DS infants were born among a total of 2,232,694 births, a rate corresponding to approximately 10% of all births in Japan over the same period. The increasing risk of DS with advancing maternal age was confirmed. The overall prevalence was 5.82 DS births per 10,000 livebirths (8.3-9.7 per 10,000 after correction according to the estimated ascertainment ratio: 60-70%). The prevalence rate by year of child birth represents a statistically significant increase (P = 0.001). In conclusion, recent trends in the prevalence of DS in Japan from 1980 to 1997 failed to show a consistent tendency to decrease, probably because of the concomitant increase in pregnancy in advanced maternal age.

Serum concentration of endogenous G-CSF in women during the menstrual cycle and pregnancy

Abstract. Although granulocyte‐colony stimulating factor (G‐CSF) is commonly used in the field of supportive therapy for cancer treatment, the serum concentration of endogenous G‐CSF in healthy women is still obscure due to the low sensitivity (30 pg mL‐1) of the usual enzyme immunoassay. With the development of a highly sensitive (l.0 pg mL‐1) chemiluminescent immunoassay by Kiriyama et al., we have clarified the changes of serum G‐CSF levels in healthy women during the menstrual cycle and pregnancy. The G‐CSF concentration showed a peak value of 27.3± 2.5 pg mL‐1 (mean±SEM) at the ovulatory phase during the menstrual cycle, which is significantly higher than in all other phases (P < 0.0001, unpaired t‐test). A significantly higher value compared to the menstrual cycle, except during the ovulatory phase, was also revealed throughout pregnancy (P < 0.0001, unpaired t‐test). These results suggest that G‐CSF plays an important role in ovulation and the maintenance of pregnancy.