Michitaka Ohwada

Risk of Complications and Uterine Malignancies in Women Undergoing Hysterectomy for Presumed Benign Leiomyomas

Objectives: To determine the incidences of complications and uterine malignancies among women undergoing hysterectomies for presumed benign leiomyomas. Methods: We retrospectively reviewed the medical records of 923 women who underwent total hysterectomies between January 1983 and December 1997 at our hospital due to presumed benign leiomyomas. Results: The mean age (SD) of the patients was 44.5 ± 5.2 years, 105 ± 35 minutes was required for the procedure, and 405 ± 312 ml of blood was lost during the procedure. Forty-one (4.4%) women demonstrated complications of intraoperative hemorrhages and required transfused blood. Urinary tract and bowel injuries occurred in 10 (1.1%) and 2 (0.2%) women, respectively. One woman (0.1%) died from pulmonary embolism that occurred on postoperative day 1. One woman (0.1%) required relaparotomy to control intraabdominal hemorrhage. Uterine malignancies were discovered postoperatively in 4 (0.4%) women, including 2 endometrial carcinoma, 1 leiomyosarcoma, and 1 endometrial stromal sarcoma. Conclusions: The incidences of complications and unrecognized uterine malignancies were similar to the results of previous studies. Of patients undergoing hysterectomy for presumed benign leiomyomas, the risk of major complications was 6.0% (55/923) and the risk of preoperatively undiagnosed uterine malignancies was 0.4%.

PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy

The prognostic significance of PTEN expression in endometrial carcinoma has not been clear. We conducted the present study to clarify the relationship between PTEN expression and prognosis in advanced endometrial carcinoma. Of 784 patients with endometrial carcinoma who underwent primary treatment between 1985 and 2000 at 5 institutions, 98 pure endometrioid carcinomas with retroperitoneal lymph node metastasis were provided for our study. PTEN expression was determined by immunohistochemic staining. Negative or mixed PTEN staining was observed in 64 (65.3%) patients. The survival rate for PTEN‐positive patients was significantly higher than that for PTEN‐negative or ‐mixed patients. PTEN‐staining status was not associated with patient age, International Federation of Gynecology and Obstetrics (FIGO) stage, myometrial invasion or histologic grade. Of the 98 patients, 87 received radiation therapy (n = 25) or chemotherapy (n = 62) after surgery. PTEN expression did not relate to survival for patients receiving radiation therapy. In contrast, the survival rate for PTEN‐positive cases was significantly higher than that for PTEN‐negative or ‐mixed cases when patients underwent chemotherapy (62.4% vs. 11.8%). Subsequent multivariate analysis revealed that PTEN staining was an independent prognostic factor for patients undergoing chemotherapy. PTEN‐positive staining was a significant prognostic indicator of favorable survival for patients with advanced endometrial carcinoma who underwent postoperative chemotherapy.

A Retrospective Survey of Clinical, Pathologic, and Prognostic Features of Adnexal Masses Operated on during Pregnancy

Objectives: To evaluate retrospective data concerning patients with adnexal masses that were managed surgically during pregnancy and their effect on fetal outcome.

Mechanisms of Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Resistance of clear cell carcinoma (CCC) of the ovary to platinum-based chemotherapy is associated with a poor prognosis. However, the mechanism underlying the resistance of CCC to platinum has not yet been understood. We conducted the present study to clarify the mechanism of cisplatin (CDDP) resistance in CCC cells. Eleven CCC and 5 serous adenocarcinoma (SAC) cell lines were used in this study. The IC50 to CDDP ranged from 1.3 to 18.0 µM for CCC cells and from 2.2 to 13.0 µM for SAC cells. There was no correlation between multidrug resistance-associated protein expression and the sensitivity to CDDP in CCC cells. In contrast, the doubling time for CCC cells was significantly longer than that for SAC cells (61.4 vs. 29.8 h). A significant reverse correlation between the S-phase fraction and the response to CDDP was observed (r = 0.647, p < 0.05). The present study suggests that the resistance of CCC to CDDP may be caused by low cell proliferation.

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

SU6668 (TSU‐68) is a small‐molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk‐1/KDR, PDGFRβ, and FGFR1. Using a mouse model of peritoneally disseminated ovarian cancer, we investigated whether SU6668 inhibits peritoneal dissemination and prolongs survival time. BALB/c nude mice were intraperitoneally (i.p.) inoculated with SHIN‐3 (VEGF‐hypersecretory) or KOC‐2S (PDGF‐hypersecretory) ovarian serous adenocarcinoma cells with marked peritoneal dissemination ability. From the day after i.p. inoculation of tumor cells, SU6668 was orally administered 6 times weekly at a daily dose of 100 mg/kg or 400 mg/kg. The SU6668‐administered group and the vehicle‐administered control group were compared for the number of tumor vascular endothelial cells, weight of peritoneally disseminated tumors, amount of ascitic fluid and survival time. As a result, these 3 parameters were significantly smaller in the SHIN‐3‐inoculated, SU6668‐administered mice than in the control group (p = 0.03, p = 0.002, and p = 0.02, respectively). The mean survival time was significantly longer, at 58.1 ± 11.2 days, in the SU6668‐administered mice than that (34.5 ± 8.8 days) in the control group (p = 0.002). Similarly, in the KOC‐2S‐inoculated mice, the oral administration of SU6668 significantly reduced these 3 parameters (p = 0.04, p = 0.04, and p = 0.03, respectively), and significantly prolonged survival (16.6 ± 1.7 days vs. 11.0 ± 0.7 days, p = 0.008). Thus, the oral administration of SU6668 inhibited angiogenesis and peritoneal dissemination and prolonged survival in mice with peritoneally disseminated ovarian cancer. These effects were observed with both the VEGF‐ and PDGF‐hypersecretory cell lines. Our results suggest that molecular targeting with oral SU6668 will become a new therapeutic strategy targeting peritoneally disseminated ovarian cancer.

Serum Level of Macrophage Colony–Stimulating Factor as a Marker for Gynecologic Malignancies

We determined the serum levels of macrophage colony-stimulating factor (M-CSF) in 441 women with gynecologic diseases to evaluate its role as a marker for gynecologic malignancy. Serum M-CSF levels were above the normal baseline level of 1,056 U/ml in 64% (56/88) of patients with ovarian cancer, 27% (16/60) of those with cervical cancer, and 25% (15/61) of those with endometrial cancer. M-CSF was significantly elevated in the serum of patients with advanced as compared with early stage cancer (stage I) of the ovary (p < 0.01), cervix (p < 0.05), and endometrium (p < 0.05). Only 5.6% of the patients with benign ovarian tumors and 7.0% of those with endometrial cysts had serum levels of M-CSF that exceeded 1,056 U/ml. M-CSF was localized in the glandular epithelial cells as well as in the stromal macrophages and the endothelial cells of the ovarian cancers. M-CSF thus appeared to be a marker with high specificity for ovarian cancer.

Assisted Reproductive Technologies in Conjunction with Conservatively Treated Endometrial Adenocarcinoma

This case report illustrates the successful use of assisted reproductive technologies (ARTs) in a patient receiving conservative treatment for endometrial adenocarcinoma. A 31-year-old infertile woman, diagnosed as FIGO stage Ia endometrial adenocarcinoma (grade 1), received oral medroxyprogesterone acetate 400 mg/day for 12 weeks. Endometrial curettage was performed and the absence of endometrial carcinoma was confirmed. A single pregnancy was achieved with in vitro fertilization and embryo transfer. A healthy female infant was born via cesarean section at 42 weeks’ gestation. The carcinoma has not recurred, and the patient now desires a second child. We conclude that ART combined with progesterone treatment might be a powerful option for the treatment of infertile patients with early stage, well-differentiated endometrial adenocarcinoma.

Pelvic lymphocysts following retroperitoneal lymphadenectomy: Retroperitoneal partial “no‐closure” for ovarian and endometrial cancers

Background and Objectives: Pelvic lymphocysts have been reported mainly following pelvic lymphadenectomy for cervical cancer. We attempted to assess whether retroperitoneal partial “no‐closure” reduces the incidence of lymphocyst formation following retroperitoneal lymphadenectomy.

Enhanced expression of thymidylate synthase may be of prognostic importance in advanced cervical cancer.

The enhanced expression of thymidylate synthase (TS) has been associated with a poor prognosis in patients with several types of epithelial tumors. To determine the association between TS expression and the prognosis of patients with advanced cervical cancer after radiation therapy, we immunohistochemically assayed TS levels in paraffin-embedded tissue sections from 66 patients with stage IIIb cervical cancer using a polyclonal antibody to recombinant human TS. In the 30 patients with high TS expression, the cumulative 5- and 8-year survival rates were 36.8% (95% CI: 17.4–56.2) and 31.6% (95% CI: 12.4–50.7), respectively. In contrast, the 36 patients with low TS expression showed a significantly (p < 0.001) better prognosis, with cumulative 5- and 8-year survival rates of 87.2% (95% CI: 75.5–99.0) and 69.2% (95% CI: 50.7–87.7), respectively. These results suggest that TS expression may be useful in determining the prognosis of patients with advanced cervical cancer.

Opening the bladder for cesarean hysterectomy for placenta previa percreta with bladder invasion

Cesarean hysterectomy for placenta previa percreta with bladder invasion often induces not only massive hemorrhage but also severe bladder/ureter injuries. A 37‐year‐old woman with previous cesarean delivery suffered placenta previa percreta with bladder invasion. At the 34th week, we performed cesarean hysterectomy. Without separating the bladder from the uterus/cervix, we incised the bladder lateral wall using an automatic stapling/cutting device, leaving the bladder posterior wall adhering to the uterus and resecting it with the uterus. The bladder was easily repaired without urological sequelae. We suggest a new, simple and safe technique for cesarean hysterectomy for this disease.