Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument.

PURPOSE: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor. PATIENTS AND METHODS: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n = 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points. RESULTS: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNA-ploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001. CONCLUSIONS: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

Prospectively detected cancer in familial breast/ovarian cancer screening.

BACKGROUND: Early diagnosis and treatment are shown to improve survival of breast and ovarian cancer. Identification and medical follow-up of high-risk groups may be important for early diagnosis. METHODS: A prospective study of 845 women from breast/ovarian- and ovarian cancer kindreds who were classified according to pre-set inclusion criteria (Table I), were offered genetic counseling and annual medical examinations of breasts and ovaries. The material consisted of three series: 1) 754 unaffected women, 2) 49 women with breast cancer, and 3) 42 women with ovarian cancer. RESULTS: In series 1) nine ovarian cancers and 20 breast cancers, in series 2) seven ovarian cancers, and in series 3) three breast cancers were found. All but one of the ovarian cancers were 40 years or older, and 4/16 (25%) were Borderline cancer. All breast cancers were 30 years or older, and 89% were detected before spread. CONCLUSIONS: This is to our knowledge the first prospective report of the combined breast/ovarian cancer findings in breast/ovarian cancer kindreds. A woman with both breast and ovarian cancer is the hallmark of inherited breast/ovarian cancer, and 50% of the ovarian cancers were detected in these families. Borderline ovarian cancer may represent a manifestation of this syndrome. If prophylactic oophorectomy prevents ovarian cancer, oophorectomy at age 45 would have prevented 75% of such cancers. Based on these results we revised our protocol for annual follow-up in these kindreds: 1) clinical breast examination and mammography (ultrasound/cytology if indicated) from 30 years of age, 2) gynecologic examination (including vaginal ultrasound, serum-CA125) from 35 years of age, and 3) discuss oophorectomy at 45 years of age.

Laser conization of cervical intraepithelial neoplasia grade 3: free resection margins indicative of lesion-free survival.

BACKGROUND: Various grades of cervical intraepithelial neoplasia may occur following laser conization for grade 3 lesions. The aim of this study was to assess lesion-free survival after laser conization in cases with/without free resection margins, and to test whether detection of human papillomavirus infection and/or p53 expression in the cone lesion were useful predictors of lesion-free survival. METHODS: In 598 women treated for cervical intraepithelial neoplasia grade 3 the state of the resection margins was recorded and related to the findings on follow-up, up to 15 years post-operatively. Lesion-free survival times were analyzed by the Kaplan-Meier method. The presence/absence of human papillomavirus infection and/or p53 expression in the primary lesion was investigated in every fifth case by in situ hybridization and immunohistochemistry respectively. RESULTS: Lesion-free survival was significantly more common after complete than incomplete excision of cervical intraepithelial neoplasia. In the latter, lesions tended to appear shortly after surgery, indicating the presence of residual disease. The few lesions appearing later were evenly divided between those with and those without complete excision. The results of the human papillomavirus and p53 investigations added no further information. CONCLUSIONS: The presence of cervical intraepithelial neoplasia in the cone margin gives strong indication of potential treatment failure. In its absence laser conization is highly effective in the treatment of cervical intraepithelial neoplasia, and has the advantage of providing a specimen suitable for the necessary histological investigation.

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience.

BACKGROUND: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m2, three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum. PATIENTS AND METHODS: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response. RESULTS: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P < or = 0.0001). No serious toxicity was registered. CONCLUSION: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses can be induced in a significant number of patients, the survival figures remain poor.

The incidence of ectopic pregnancy in Hordaland County, Norway 1976-1993.

OBJECTIVE: To gain longterm knowledge of incidence rates of ectopic pregnancy, as a basis for analysing risk factors. MATERIAL: The incidence of ectopic pregnancy was studied in the county of Hordaland, Western Norway, through 18 years, 1976-1993. The protocols of 1821 cases of ectopic pregnancy were registered. Population data of the county, the number of births and legal abortions were available. RESULTS: There was considerable increase in crude numbers of ectopic pregnancies throughout the period. Grouping the cases in three six-year periods showed an increased crude incidence rate per 100,000 women from 95 during 1976-81 to 154 during 1988-93. The corresponding rates per 1000 births increased from 13.6 to 22.2 and the rates per 1000 reported pregnancies from 11.2 to 18.0. All rates increased also in women aged 40-44 years. During the years 1979-1993 the rates per 1000 reported pregnancies increased by 25%, from 9.4 to 11.8 in age groups below 30 years, while the rates for women over 35 years increased by 98%, from 20.7 to 40.9. Compared to the age group 15-19, women over 35 years had an eightfold risk during the last period. In addition they also contributed to higher numbers of reported pregnancies by 58%. CONCLUSION: The rates of ectopic pregnancy increased in age groups older than 20 years during 1976-93, moderately in younger age groups, but considerably in older age groups, who also contributed with higher total rates of pregnancy. More older women, with presumably accumulated risk factors getting pregnant, thus explain part of the increased rates of this disease.

The localization and concentration of copper in the fallopian tube in women with or without an intrauterine contraceptive device.

The localization and concentration of copper in cryostat sections of human fallopian tubes from women using an intrauterine contraceptive device (IUCD) and controls was determined by light microscopic- and atomic absorption spectrophotometric techniques. The copper was visually accumulated in the epithelium and the copper concentration in the tubal tissue was increased in the IUCD user group. We also measured the concentration of copper and ceruloplasmin in serum, but there was no statistical difference between the two groups studied. Our results indicate that the IUCD has effects beyond the uterine cavity. The accumulation of copper may be associated with earlier observations of the morphological changes and infiltration of inflammatory cells observed in the fallopian tube in IUCD users.

PIP: During laparoscopic sterilization at a hospital in Bergen, Norway, surgeons removed a 1 cm segment of the macroscopic isthmic portion of the fallopian tube from 40 healthy, nonpregnant women. They used light microscopic and atomic absorption spectrophometric techniques to localize and measure the concentration of copper in cryostat sections of the fallopian tubes of 20 women who had used a copper releasing IUD for more than six months and of 20 other women who used neither an IUD nor an hormonal contraceptive. Copper was visually present in the epithelium, but weakly so, in few of the biopsies from the non-IUD users. In IUD users, it accumulated throughout the epithelium and dwindled in the lamina propria. Its mean concentration in the fallopian tube was 58% higher in IUD users than non-IUD users (128.3 vs. 81.4 nmol/mg protein; p = 0.003). IUD use did not affect protein levels. The IUD affected neither the concentration of copper nor of the copper-transporting protein, ceruloplasmin, in serum. These findings suggest that the accumulation of copper in the fallopian tube in IUD users may effect morphological changes and infiltration of inflammatory cells in the fallopian tube.

In situ characterization of leukocytes in the fallopian tube in women with or without an intrauterine contraceptive device.

Histological evaluation of sections from the human fallopian tube revealed an inflammatory reaction in 21 of 31 women using an intrauterine contraceptive device (IUCD) and in four of 29 controls (non-IUCD users). The inflammatory cells were mainly localized at the epithelium-lamina propria interface and at the center of the mucosal folds. The immunohistochemical study revealed leukocytes (CD45+), T lymphocytes (CD3+), T helper cells (CD4+), T suppressor/cytotoxic cells (CD8+), B lymphocytes (CD22+, CD19+), granulocytes, monocytes and null cells (CD11b+) mainly localized at the lamina propria in both groups. T lymphocytes were the predominant cell type, and the ratio between T helper and T suppressor/cytotoxic cells was fairly close to one both in IUCD-users and controls. B lymphocytes were the least frequent cell type identified. In IUCD users, the numbers of the different leukocytes were increased. In both groups, IgA-, IgG- and IgM-positive cells were demonstrated and were predominantly located at the lamina propria of the mucosal folds. The IgA-positive cells dominated in both groups, whereas IgG- and IgM-positive cells were less frequent. Cell positive for IgA, IgG or IgM were significantly increased in number in the IUCD users. The data confirm the presence of an immune system in the normal human fallopian tube and indicate that the IUCD can induce a prominent recruitment of inflammatory cells, with a tubal inflammation as the result. The IUCD may disturb the immunological function of the fallopian tube and its rôle in fertilization.

PIP: In Norway, a 1.5 cm segment of the isthmic portion of the fallopian tube was removed for immunohistochemical and histological analyses from 60 healthy nonpregnant women. Researchers compared data on the 31 women who had used a copper IUD for 2-10 years with data on the remaining 29 women who did not use any IUD for the last year to examine the localization, number, and subtypes of leukocytes in the tube. An inflammatory reaction was present in 68% of the IUD users compared to only 14% of controls (p = 0.005). A chronic inflammatory reaction was the predominant type in both groups (52% for IUD users and 8% in controls). The inflammatory cells were largely found in the epithelium-lamina propria interface and in the center of the mucosal folds. In both groups, leukocytes (CD45+), T lymphocytes (CD3+), T helper cells (CD4+), T suppressor/cytotoxic cells (CD8+), B lymphocytes (CD22+, CD19+), granulocytes, monocytes, and null cells (CD11b+) were chiefly located at the lamina propria. CD3+ cells were the primary cell type in both groups. The ratio of CD4+ and CD8+ was close to one in both groups. CD22+ and CD19+ were relatively rare in both groups. The number of the different leukocytes was significantly greater among IUD users than the controls (e.g., total leukocytes, 1127 vs. 609; p 0.0001). The lamina propria of the mucosal folds housed most IgA, IgG, and IgM positive cells. IgA positive cells were the most frequent cells in both groups. The number of cells positive for IgA, IgG, or IgM were significantly higher in the IUD user group than the control group (e.g., total Ig in endosalpinx, 188 vs. 50; p 0.0001). These findings show that the IUD can incite inflammatory cells, resulting in inflammation of the fallopian tube. Thus, the IUD may interfere with the immunological function of the tube and the tube's role in fertilization.

Sarcoidosis of the uterus.

Sarcoidosis rarely involves the female genital tract. A report is presented of 2 cases of sarcoidosis of the uterus. In the first, the diagnosis was made by biopsy of the portio vaginalis uteri which was amputated during the Manchester operation for genital prolapse. In the second case the diagnosis was made by endometrial curettage for postmenopausal vaginal bleeding. Neither of the women exhibited signs of generalized sarcoidosis.

[A phase II study of 5-fluorouracil/cisplatin in recurrent cervical cancer]. / En fase 2-studie av 5-fluorouracil/cisplatin ved residiverende cervixcancer.

50 patients with recurrent cervical carcinoma were included in a phase II study of cisplatinum and 5-fluorouracil. They were divided into patients with recurrent lesions outside the previously irradiated area (group 1) and those with at least one recurrent lesion inside this area (group 2). The treatment schedule consisted of 5-fluorouracil 1,000 mg/m2 intravenously during days 1 to 5, and cisplatinum 100 mg/m2 intravenously in day 1. 45 patients could be evaluated for response and toxicity with a median survival of 14+ months, (range 4-38+). In group 1 (29 patients) seven achieved complete response with a median duration of 14+ months, (range 3(+)-26+), median survival of 19+ months, (range 5(+)-28+), and 13 achieved partial response with a median duration of 8+ months, (range 3(+)-25+), median survival of 16 months, (range 6(+)-31+). In group 2 (16 patients) one patient achieved complete response and two partial response. One patient in this group with stationary disease is still alive after 38+ months. All the patients suffered from nausea and vomiting. The dose-limiting factor was bone marrow suppression. The response rate in group 1 of 69%, with a median survival of 19+ months, is higher than previously achieved with other cytostatic regimens. We found the regimen to be very toxic, however, for patients with central recurrences in previously irradiated areas, though some of these patients did achieve marked relief from pain.

Successful pregnancy following treatment of primary malignant lymphoma of the uterine cervix.

A case of primary histiocytic lymphoma in the uterine cervix of a 22-year-old nulligravid woman is reported. To avoid surgical or radiological castration she received six courses of combination chemotherapy (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg all iv on Day 1 and then together with oral prednisone 50 mg twice daily on Days 1-5). Approximately 20 months after therapy she delivered a healthy child. Six years have passed since primary treatment was initiated. No evidence of recurrent lymphoma has been observed.

Altered ciliary substructure in the endosalpinx in women using an IUCD.

Fallopian tube segments were removed from 20 women undergoing sterilization by laparoscopy or laparotomy. Ten of these patients used an intrauterine contraceptive device (IUCD). The other 10 had used neither IUCD nor oral contraceptives and served as controls. The ciliary ultrastructure was examined by light- and transmission electron microscopy. The IUCD users had a significantly reduced ciliary length and less well oriented cilia, as compared with the control group. Also, the proportion of cilia with a ciliary crown structure was significantly smaller in IUCD users than in the non-users. The mechanism that may cause these alterations and their putative consequences are discussed.

Computation of fertility rates following a defined reproductive risk event, by the life table method, with ectopic pregnancy used as an example.

We have adapted the life table for use in the observation study of subjects desirous of pregnancy following a well-defined risk event in their reproductive lives. The construction of the table is described and illustrated, with the fertility after ectopic pregnancy given as the example.

PIP: The life table method has been underutilized in clinical reproduction research, despite its advantages of recording every pertinent event on the time scale and having no observational time limit. This article constructs a life table for the purpose of computing fertility after ectopic pregnancy in IUD users. The study population was comprised of women who underwent surgery for an ectopic pregnancy at a Bergen hospital in 1979-83 and made subsequent attempts to conceive. These women were classified as current IUD users, and never users. Cumulative fertility rates were computed through use of 100% minus the cumulative proportion not achieving pregnancy. Columns in the life table included: postoperative observation time (in 6 month intervals), number of study subjects at the start of the interval, the total number of intrauterine pregnancies (including spontaneous abortion and legal abortion) during each interval, the number of women experiencing an ectopic pregnancy, the total number of women who conceived (intrauterine and ectopic) during each interval, the number of study subjects who withdrew or were lost to follow-up, the effective number exposed to the possibility of pregnancy during the interval, the proportion of subjects with intrauterine pregnancies, the proportion of subjects who did not experience conceptions resulting in an intrauterine pregnancy, the cumulative proportion of women experiencing conception resulting in intrauterine pregnancy during successive intervals, and the standard deviation of these cumulative proportions. Any research worker with access to a computer can easily produce a life table-based graphic display of time sequences of events in a population.

[The Dalkon shield. The infamous intrauterine device]. / Dalkon shield. Den fordømte spiralen.

PIP: This paper reviews the history of the Dalkon shield from its introduction in the late 1960s. The design of the Dalkon shield was based on the theory that an IUD with the greatest possible surface area would react with the endometrium in such a way as to inhibit conception. Studies in the early 70s established that there were more cases with complications, especially infections, among women who used IUDs with a thread extending down into the vagina compared with those who used IUDs without a thread. Later studies focused especially upon the multifilament thread used in the Dalkon shield. This thread, which consisted of 200-400 individual filaments within a thin nylon sheath, was found to have a wicking effect in which bacteria-contaminated fluids were transported from the vagina into the uterus. If a Dalkon shield remained in place during pregnancy, the normal expansion of the uterus drew the thread up through the cervix during the mid-trimester of pregnancy. This increased the rate at which bacteria could bypass the bactericidal environment of the endocervix and enter the cavity of the uterus. On the basis of these and other negative studies, the Dalkon shield was removed from the Norwegian market in 1974, although there are documented cases of Dalkon shields being inserted as late as 1980.^ieng

Fertility following ectopic pregnancy with special reference to previous use of an intra-uterine contraceptive device (IUCD).

A group of 304 women operated on for ectopic pregnancy were followed up with respect to subsequent reproductive performance. The group was distributed into current users, earlier users and non-users of an intra-uterine contraceptive device (IUCD). Pelvic inflammatory disease (PID) and infertility were more common among non IUCD users. Reproductive performance was statistically significantly better in ever-users of an IUCD than in never-users. The proportions of women wishing to become pregnant and who later gave birth to a live baby in the three groups were 69.2%, 61.4% and 38.0% respectively.

PIP: Pregnancy outcomes of 304 women operated for ectopic pregnancy from 1979-1983 in Bergen Norway were analyzed with regard to prior use of IUDs. It is commonly known that wearing an IUD increases the risk of ectopic pregnancy, and that ectopic pregnancy rates are increasing. The women were classified into those who never used an IUD, those ever using an IUD and those currently using an IUD. The never user group were slightly younger and of lower mean parity. During the study, the percentages of the groups who delivered live babies were 32.5% (69.2% corrected for contraception) among current users, 48.2% (61.14% corrected) among past users and 31% (38%) among never users of IUDs. Combining all pregnancies, miscarriages and legal abortions, the figures were 84.6%, 75% and 42.3%. Thus, fertility after ectopic pregnancy was significantly (p0.0001) better in IUD users than in nonusers. This held for both primigravidae and multigravidae. There was no difference in rates of subsequent ectopic pregnancy. Examining medical records, pelvic inflammatory disease (PID) and infertility were more common in non-IUD users and ex-IUD users. Apparently, the consequences for future fertility or PID were more severe in the group never using an IUD.

Ovarian pregnancy associated with the intra-uterine contraceptive device. A survey of two decades.

Records of 25 cases of ovarian pregnancy in the period 1965 to 1984 were reviewed. Seventeen cases (68%), had an IUCD in situ, and 15 of these had occurred during the last decade. The ratio of ovarian pregnancy to all ectopic pregnancies was 1:13 in the IUCD group versus 1:78 in the non-IUCD group (p less than 0.025). In contrast to patients with tubal pregnancies, those with ovarian pregnancy very seldom have a history of pelvic inflammatory disease (PID), infertility, or earlier pelvic operations. Subsequent fertility is good compared with patients with tubal pregnancies, for patients both with and without IUCD.

Repeat ectopic pregnancy. A twenty-year hospital survey.

Seventy-two patients with repeat ectopic pregnancy including 3 women with three ectopic pregnancies each during the period 1965 to 1984 were studied. In the same period there was a total of 842 ectopic pregnancies, giving a repeat ectopic pregnancy incidence of 9.4%. In the last decade the incidence of repeat ectopic pregnancy was 10.4%, and in the first decade it was 7.0% (p less than 0.025). None of the women used an intra-uterine contraceptive device, among those with repeat ectopic pregnancy in the first decade, vis-à-vis 17 (30.4%) in the last decade. A history of infertility was common among the patients with repeat ectopic pregnancy. Between the two events there was a total of 17 deliveries in 13 patients. Four out of 24 potentially fertile women completed full-term pregnancies following their second ectopic pregnancy.

Human chorionic gonadotropin in uterine and peripheral blood tested with an enzyme-linked immunosorbent assay and a radio-immuno assay in cases of spontaneous abortion.

Human chorionic gonadotropin (hCG) was analysed by a hCG-beta-subunit radio-immunoassay (hCG-beta-Ria) and a rapid serum test in uterine and peripheral blood in 29 cases of spontaneous abortion. The levels of hCG were significantly higher in uterine than in peripheral blood. The rapid serum test was correctly positive in all 29 samples of uterine and in 28 of peripheral blood.