Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins.

The inhibitor of apoptosis proteins (IAPs) constitutes a family of highly conserved apoptosis suppressor proteins that were originally identified in baculoviruses. Although IAP homologs have recently been demonstrated to suppress apoptosis in mammalian cells, their expression and role in human ovarian epithelial cancer and chemotherapy resistance are unknown. In the present study we used cisplatin-sensitive and -resistant human ovarian surface epithelial (hOSE) cancer cell lines and adenoviral antisense and sense complementary DNA expression to examine the role of IAP in the regulation of apoptosis in human ovarian cancer cells and chemoresistance. Antisense down-regulation of X-linked inhibitor of apoptosis protein (Xiap), but not human inhibitor of apoptosis protein-2 (Hiap-2), induced apoptosis in cisplatin-sensitive and, to a lesser extent, in -resistant cells. Cisplatin consistently decreased Xiap content and induced apoptosis in the cisplatin-sensitive, but not cisplatin-resistant, cells. Hiap-2 expression was either unaffected or inhibited to a lesser extent. The inhibition of IAP protein expression and induction of apoptosis by cisplatin was time and concentration dependent. Infection of cisplatin-sensitive cells with adenoviral sense Xiap complementary DNA resulted in overexpression of Xiap and markedly attenuated the ability of cisplatin to induce apoptosis. Immunohistochemical localization of the IAPs in hOSE tumors demonstrated the presence of Xiap and Hiap-2, with their levels being highest in proliferative, but not apoptotic, epithelial cells. These studies indicate that Xiap is an important element in the control of ovarian tumor growth and may be a point of regulation for cisplatin in the induction of apoptosis. These results suggest that the ability of cisplatin to down-regulate Xiap content may be an important determinant of chemosensitivity in hOSE cancer.

An internet-based learning portfolio in resident education: the KOALA multicentre programme.

CONTEXT AND OBJECTIVES: To describe the Computerized Obstetrics and Gynecology Automated Learning Anaalysis (KOALAtrade mark), a multicentre, Internet-based learning portfolio and to determine its effects on residents' perception of their self-directed learning abilities. METHODS: The KOALA programme allows residents to record their obstetrical, surgical, ultrasound, and ambulatory patient encounters and to document critical incidents of learning or elements of surprise that arose during these encounters. By prompting the student to reflect on these learning experiences, KOALA encourages residents to articulate questions which can be directly pursued through hypertext links to evidence-based literature. Four Canadian residency training programmes participated in the pilot project, from February to May 1997, using a dynamic relational database with a central server. All participants completed the Self-directed Learning Readiness Scale and a learning habits questionnaire. The impact of the KOALA programme on residents' perception of their self-directed learning abilities was measured by comparing KOALA-naive schools (schools 2, 3, and 4) with school 1 (exposed to the KOALA prototype for 1 year). Ordered variables were compared using the Mann-Whitney U test and continuous variables with the Student t test (statistical significance P < 0. 05). RESULTS: During the study period, 7049 patient and 1460 critical incidents of learning were recorded by 41 residents in the four participating universities. Residents at the exposed school (school 1) had a significantly higher perception of their self-directed learning (P < 0.05) and believed their future learning was less likely to be from continuing medical education (P < 0.028), textbooks (P < 0.04), and didactic lectures (P < 0.011) and would be derived from a learning portfolio with online resources. CONCLUSION: This Internet-based, multi-user, multicentre learning portfolio has a significant effect on residents' perception of their self-directed learning abilities.

The efficacy of loop electrosurgical excision procedure as compared to cold-knife cone biopsy in patients with unsatisfactory colposcopy.

OBJECTIVES: Our aim was to determine whether the loop electrosurgical excision procedure (LEEP) is as efficacious as cone biopsy in patients with cervical dysplasia and unsatisfactory colposcopy. MATERIALS AND METHODS: Fifty-four patients with unsatisfactory coiposcopic findings underwent a LEEP procedure for the treatment of their cervical dysplasia. These patients were compared to 41 patients who had a cold-knife cone biopsy for the same indication. LEEP procedures were carried out to a standard ectocervical excision depth of 6 mm and then excised centrally to an endocervical depth of an additional 3 mm. An endocervical curettage was performed after the excision procedure. Patients were examined every 4 to 6 months after treatment with a Papanicolaou smear and colposcopy. The pretreatment cytology and cervical biopsies, histology of LEEP and cone biopsy specimens, and follow-up cytology between the two groups were compared by chisquare analysis. RESULTS: No statistical difference was seen in the pretreatment cervical smears between the LEEP and cone biopsy groups. All LEEP and cone biopsy specimen resection margins were negative. No difference was evident in the grade of cervical intraepithelial neoplasia between the LEEP and cone biopsy groups. Follow-up cervical smear results were similar in both groups. One patient required a cone biopsy for persistent disease 8 months after her LEEP treatment. CONCLUSIONS: LEEP appears to be as safe and effective as cone biopsy in patients with unsatisfactory colposcopy.

Is incidental prophylactic oophorectomy an acceptable means to reduce the incidence of ovarian cancer?

BACKGROUND: According to previous reports, the lifetime risk of developing ovarian carcinoma is 1.4%. This figure varies with age from 6.6 per 100,000 among women aged 35 to 39 years up to 55.1 per 100,000 among women aged 75 to 79 years. Prophylactic oophorectomy remains a modality to decrease the incidence of ovarian cancer. What proportion of women diagnosed with an ovarian malignancy had a preceding laparotomy at which time a prophylactic oophorectomy could have been performed? METHODS: We reviewed the new ovarian cancer diagnoses seen in patients between August 1988 and August 1993 at the Ottawa Regional Cancer Foundation. Four hundred and four patients were identified. These patients were analyzed for preceding abdominal surgery, age, time to disease progression, time to death, time to death from other causes, and average follow-up. The previous abdominal surgeries were divided into: (1) major gynecological surgery; and (2) general surgery procedures, which were further divided into laparotomy and pelvic surgery (group A surgeries) and general surgery that included other abdominal surgeries (ie, appendectomy, cholecystectomy) where access to the pelvis could be more difficult (group B surgeries). RESULTS: A total of 270 abdominal surgeries was performed, prior to the diagnosis of ovarian cancer. The group was stratified according to the timing of the surgery (< or =40 years, 41 to 45 years, 46 to 50 years, >50 years). Based on these data, and on the grouping of general gynecologic surgeries plus the general surgical procedures of group A, 10.9% of ovarian cancers would have been prevented if prophylactic oophorectomy had been performed in patients who had surgery over 40 years of age; over 45 years this was 6.7%, over 50 years it was 4%. If one adds all major surgeries, including general surgery groups A and B, the results were 26.9% over 40 years of age, 20% over 45, and 16.6% over 50. CONCLUSION: We found that, depending on the age of the patient, prophylactic oophorectomy results in a 4% to 10.9% reduction in the incidence of ovarian carcinoma. This increases to 16.6% to 26.9% if one considers general surgery procedures in which access could be more difficult. Although we are not advocating the frequent use of this procedure, we recommend that surgeons routinely discuss this option before surgery with their postmenopausal female patients over 49 years of age. Given that the decision for prophylactic oophorectomy is multifaceted, we feel that a risk scoring for ovarian cancer and a discussion of the risk and benefit ratio should be undertaken. The ultimate goal is to heighten patient awareness of the risk factors to ensure that an informed decision is made concerning this consistently lethal disease.

Should endocervical excision and curettage be done during LEEP?

OBJECTIVE: To evaluate the need for routine endocervical sampling and endocervical curettage at the time of loop electrosurgical excision procedure (LEEP) in patients with satisfactory colposcopic assessment being treated for dysplasia. STUDY METHODS: One hundred and eight patients having a satisfactory colposcopy referred for excision of their dysplasia with LEEP (four case) were studied. The procedure was carried out with a standard ectocervical excision to a depth of 6 mm and an endocervical excision centrally to a further 3 mm. An endocervical curettage was performed at the end of the procedure. RESULTS: Of the 108 patients, 94 (87%) had a negative endocervical excision and endocervical curettage. Thirteen percent had a positive endocervical excision or endocervical curettage. Only 2 patients had endocervical pathology worse than the ectocervical pathology. There was no difference in the distribution of CIN I to CIN III in patients who had a negative endocervical excision or a positive endocervical excision. In the overall group, complications arose in 2.7% of patients and were minor and self-limiting. The overall long-term follow-up cure rate was 99% in the entire group. CONCLUSIONS: Satisfactory colposcopy is not an adequate discriminant for the use of an ectocervical excision only for patients with dysplasia. Thirteen percent of patients would theoretically have had persistent disease if an endocervical excision was not performed. Adequate endo- and ectocervical excisions are an important component of the LEEP procedure and cannot be separated.

Treatment of recurrent and metastatic adenocarcinoma of the endometrium with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate.

We conducted a retrospective review of 44 patients with metastatic or recurrent endometrial carcinoma treated with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate. Thirty-six women had metastatic disease; eight had recurrent disease. In the metastatic group, 12 women had positive peritoneal cytology as the only criterion for metastatic disease. Grade 1 tumors represented 25%, grade 2, 47.7%, and grade 3, 27.3%. The series was divided into four groups based on disease volume before chemotherapy: positive peritoneal cytology only (N = 12), microscopic (N = 11), macroscopic less than 2 cm (N = 6), and macroscopic greater than 2 cm (N = 15). Fifteen patients had measurable disease and eight (53%) had an objective response. The median survival was 31 months for the whole group. Median survivals were not reached for the positive peritoneal cytology only and the microscopic groups. Median survival for the macroscopic less than 2 cm and greater than 2 cm groups were 15 and 10 months, respectively (P less than .0001). The volume of disease was the most important factor in determining survival as well as the time to progression (P less than .0001). The distribution of grade was similar in all groups (P = .88), and grade did not predict survival (P = .80) or recurrence (P = .87). The significant number of low-grade lesions in our series as well as the importance of positive cytology as a predictor of survival underscore the need for surgical pathologic staging in an effort to identify those patients in need of adjuvant therapy.

Tubular Krukenberg tumor in pregnancy with virilization.

A case of tubular Krukenberg tumor in pregnancy with virilization is presented. The pathology is reviewed. This rare tumor must be distinguished from a Sertoli-Leydig tumor. The index case adds to the previously recorded eight cases. All nine cases reviewed presented with progressive virilization between the third and eighth month of gestation, which regressed after surgery. The fetal outcomes of seven cases have been recorded. The fetuses were all female and of these five were virilized. A gastric primary was found in five cases. A primary breast carcinoma was postulated in another. In the remaining cases either no autopsy was performed or no primary tumor was found.