Katsuji Kokawa

Apoptosis in human chorionic villi and decidua during normal embryonic development and spontaneous abortion in the first trimester.

To investigate possible apoptotic changes, the cleavage of DNA in human chorionic villi and decidua was examined during the first trimester of pregnancy by molecular biochemical techniques. Very limited but detectable cleavage of DNA was recognized in the chorionic villi and decidua in normal pregnancy. The characteristic apoptotic breakdown of DNA was recognized in the chorionic villi and decidua in cases of spontaneous abortion. Quantitative analysis of low molecular weight fragments of DNA revealed a significant increase in cases of spontaneous abortion compared to those in normal pregnancy. However, the extent of apoptosis was not correlated with either urinary levels of human chorionic gonadotropin (hCG) and/or gestational age. An analysis in situ revealed cells undergoing apoptosis in the cytotrophoblast in normal pregnancy, and apoptotic cells were predominant in the syncytiotrophoblast in cases of spontaneous abortion. It is shown that apoptosis occurs in the human conceptus during the first trimester of normal pregnancy and is greatly intensified in cases of spontaneous abortion. In addition, the results indicate that apoptosis might play a critical role in embryonic development and wastage in humans.

Apoptosis in human chorionic villi and decidua in normal pregnancy, spontaneous abortion and ectopic pregnancy

Summary To investigate possible apoptotic changes, the cleavage of DNA in human chorionic villi and decidua was examined in normal pregnancy (NP), spontaneous abortion (SA) and ectopic pregnancy (EP). Very limited but detectable cleavage of DNA was recognized in the chorionic villi and decidua in NP. However, the degree of apoptosis was not correlated with either urinary levels of human chorionic gonadotropin and/or gestational age. A ladder pattern, characteristic of the apoptotic breakdown of DNA was identified in SA. The DNA laddering was present in the villi, but absent in the decidua in EP. Quantitative analysis of low molecular weight (mol. wt.) fragments of DNA revealed a significant increase in SA compared to that in NP. However, the levels of low mol. Wt. DNA showed a significant decrease in the decidual tissue, together with a significant increase in the villous tissue, in EP as compared to those in NP. An analysis in situ revealed cells undergoing apoptosis only in the cytotrophoblast in NP. By contrast, apoptotic cells were predominant in the syncytiotrophoblast in SA and EP. In the decidual tissue, labeled cells were occasionally seen in NP. Their numbers increased in SA but decreased in EP. The present study demonstrates that the occurrence of apoptosis differs in NP, SA and EP. These results indicate that apoptosis might play a critical role in normal embryonic development and wastage in humans.

Immunohistochemical localization of Activin A in Human endometrial tissues during the menstrual cycle and in early pregnancy

Objective To investigate the possible localization of activin A in human endometrial tissue. Methods Human endometrial tissue was collected from 33 patients who were undergoing abdominal hysterectomy. Human decidual tissue was collected from 11 patients, who were having a therapeutic abortion. Tissue was fixed in Bouins solution and made into paraffin sections. Tissue sections were stained with monoclonal antibodies against the inhibin/activin α- and βA-subunits and activin A using an avidin-biotin-peroxidase complex technique. Results No immunostaining with antibody against the α-subunit was observed in the human endometrium during the menstrual cycle or in the decidua during early pregnancy. By contrast, immunostaining for the βA-subunit and activin. A was observed in the cytoplasm of endometrial glands at all phases of the menstrual cycle and in the decidua during early pregnancy. The intensity of immuno-staining for the βA-subunit was strong during the menstrual phase, became weaker during the early proliferative phase, and was intense again at the late proliferative phase. The immunostaining for the βA-subunit was weak during the early secretory phase and became very intense toward the midsecretory and late secretory phases. The intensity of immunostaining for activin A changed during the menstrual cycle and showed a tendency similar to that for βA-subunit. The stromal cells were weakly immunoreactive with antibodies against the βA-subunit and activin A from the menstrual to the midsecretory phase and became strong in the late secretory phase. Intense staining for the βA-subunit and activin A was observed in the cytoplasm of decidual cells during early pregnancy. Conclusion Activin A, but not inhibins, is localized in the endometrial tissue. The endometrium may be a major source of activin A during the normal menstrual cycle, and the decidua may be one of the sources of activin A during early pregnancy.

Postmenopausal intravenous leiomyomatosis with high levels of estradiol and estrogen receptor.

BACKGROUND Intravenous leiomyomatosis is a rare variant of leiomyoma. CASE The patient was a 49-year-old gravida 3, para 3 woman with menopause at age 46. She presented with a history of syncope. Vaginal examination revealed an enlarged and elastic-soft mass of the uterus. A pelvic ultrasound, computed tomography scan, and magnetic resonance imaging showed a heterogeneous, irregularly shaped 8- to 10-cm tumor. In addition, the inferior vena cava was almost completely occluded. Cardiac ultrasound demonstrated a mobile mass in the right atrium. The serum estradiol was 208 pg/mL (normal 0–59). Intravenous leiomyomatosis with cardiac extension was diagnosed preoperatively. A resection of the intracardiac and intracaval mass and a subtotal hysterectomy with bilateral salpingo-oophorectomy were performed. The uterine tumor weighed 600 g, and the cordlike intravascular tumor extending from the internal iliac vein into the right ventricle was 40 cm long and weighed 60 g. Pathologic examination confirmed intravenous leiomyomatosis with no evidence of atypia. The level of estrogen receptor in the tissue was 140 fmol/mg protein. The postoperative course was uneventful, and she has been in good health for 17 months after the operation. CONCLUSION We report a case of intravenous leiomyomatosis extending into the right ventricle treated with a one-stage operation. It is possible that a high concentration of serum estradiol and high level of tissue estrogen receptor are related to the intravenous leiomyomatosis.

Apoptosis and the expression of Bax and bcl-2 in squamous cell carcinoma and adenocarcinoma of the uterine cervix

Apoptosis plays a crucial role in the suicide and turnover of cells in various tumors. This study was designed to investigate the relation between apoptosis and the histologic types of cell in invasive cervical carcinoma.

Phase II study of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin followed by radical hysterectomy for bulky stage Ib2 to IIb, cervical squamous cell carcinoma: Japanese Gynecologic Oncology Group study (JGOG 1065).

The efficacy and adverse events of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin were evaluated in patients with bulky stage Ib2 to IIb cervical squamous cell carcinoma. Eligibility included patients who received irinotecan (60 mg/m2) on days 1 and 8 and nedaplatin (80 mg/m2) on day 1 of a 21-day cycle. After 1-3 courses of chemotherapy, radical hysterectomy was performed. Sixty-eight patients were enrolled. Sixty-six were included in the full analysis set. Their median age was 47 years (range 22-71), the FIGO stage was Ib2 in 18 patients, IIa in 10, and IIb in 38. Radical hysterectomy was performed after NAC in 63 patients (95.5%). The number of administered courses of NAC was 1 in 13 patients, 2 in 43, and 3 in 10. The response rate, the primary endpoint of this study, was 75.8% (CR in 2 patients, PR in 48, SD in 12, PD in 0, and NE in 4). The mean number of treatment courses required for a response was 1.42 (1 course in 30 patients, 2 courses in 19, and 3 courses in 1). The incidences of grade 3 or 4 hematological toxicities were: neutropenia 72.2%, leukopenia 16.7%, anemia 13.6%, thrombocytopenia 7.6%, febrile neutropenia 1.5%, and elevations of alanine aminotransferase and aspartate aminotransferase 1.5%. Grade 3 or 4 non-hematologic toxicities were as follows: diarrhea 6.1%, nausea 3%, anorexia 1.5%, vomiting 1.5%, fever 1.5%, allergic reactions 1.5%, ileus 1.5% and vesicovaginal fistula 1.5%. Neoadjuvant chemotherapy with irinotecan and nedaplatin was an effective and well-tolerated treatment for patients with bulky stage Ib2 to IIb squamous cell carcinoma of the uterine cervix.

Transient increases of apoptosis and Bax expression occurring during radiotherapy in patients with invasive cervical carcinoma

Apoptosis plays a crucial role in radiation therapy (RT) in various carcinomas. This study was designed to investigate the relation between apoptosis and RT in invasive squamous cell carcinoma (ISCC) of the uterine cervix.