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KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.

Breast cancer in younger patients appears to be more aggressive than disease occurring in older patients. Even though large population-based studies suggest poorer survival of patients younger than 35 years, data demonstrating the relationship of age and prognosis within premenopausal cohorts are much more scarce and conflicting. In this retrospective analysis of 885 premenopausal patients, the relationship between age, typical prognostic factors, treatment, and patient outcome was investigated. Eight hundred four patients (90.8%) 35 years and 81 patients (9.2%) ≤ 35 years who had been treated for stage I/II breast cancer were evaluated. Median follow-up time was 71 months. The prevalence of adverse prognostic features such as tumor size, tumor type, tumor grading, pathologic lymph node status, and hormone receptor status were evenly distributed between the two age groups. Age ≤ 35 years proved to be a powerful independent prognostic factor in multivariate analyses of recurrence-free (P< 0.0001; relative risk [RR] = 2.5) and overall survival (P< 0.0039, RR = 2.2). Thus, in the face of evenly distributed risk factors in this strictly premenopausal, homogeneous population, young age was seen as the second most powerful risk factor after lymph node status. According to these findings, patients diagnosed with breast cancer at ≤ 35 years of age have a worse prognosis compared to premenopausal women above this age. Future studies should focus on unveiling the young age surrogate in order to improve treatment and prognosis.

Previous studies on prognostic factors in stage I invasive epithelial ovarian carcinoma have been too small for robust conclusions to be reached. We undertook a retrospective study in a large international database to identify the most important prognostic variables.

A randomised clinical trial was performed to test whether or not low-dose chemotherapy lasting only 35 days improves the outcome of breast cancer patients with stage I disease and negative oestrogen and progesterone receptors (ER-, PgR-). Between 1984 and 1990, 277 stage I breast cancer patients with tumours negative for both oestrogen and progesterone receptors were randomised to receive either low-dose short-term chemotherapy or no chemotherapy. Chemotherapy consisted of one cycle of doxorubicin, vincristin (AV) and one cycle of cyclophosphamide, methotrexate, fluorouracil (CMF). Patients were stratified for tumour stage, type of surgery, menopausal status and participating centre. Results were analysed both by univariate and multivariate statistical. After a median length of follow-up of 84 months, disease-free (DFS) and overall survival (OS) did not differ significantly between patients having received adjuvant chemotherapy and the control group. Uni- and multivariate analysis did not show any significant prognostic or therapy related factor. A low-dose short-term adjuvant chemotherapy is insufficient to improve the prognosis of patients with breast cancer stage I with ER-, PgR-tumours.

The purpose of the study was to determine the frequency of discovering a malignant ovarian mass when laparoscopy is used to manage an adnexal mass. A countrywide survey was undertaken in Austria, comprising questions about ovarian malignancy detected or accidentally treated by laparoscopy. The response rate of 66.7% represented a total of 54,198 laparoscopies, 16,601 laparoscopic surgeries on adnexal masses, and 108 cases of ovarian tumors subsequently found to be malignant (96 well-documented). Twenty patients were treated with laparoscopy alone. In 22 cases, laparoscopy was followed by immediate laparotomy. A delayed laparotomy (3–1415 days) was performed in 54 cases. Staging revealed FIGO classifications from stages Ia to IV. The follow-up time ranges from 2 to 220 months. Four recurrences have been reported. Thirteen patients died of tumor progression. Laparoscopic surgery on ovarian malignancies is a rare situation (0.65% of all endoscopic surgeries on adnexal masses). In cases of malignancy, a laparotomy has to be performed to ensure optimal staging and treatment.

Objective: Oncogene alterations are thought to be prognostic indices in patients with breast cancer. The present study was carried out to investigate the amplification of the HER-2/neu and INT-2 oncogenes in ovarian cancer. Methods: In a retrospective study of 196 patients with epithelial ovarian cancer, the amplification of the oncogenes HER-2/neu and INT-2 in the DNA of paraffin-embedded tumor cells was determined by quantitative PCR. The purpose of this study was to analyze whether the two oncogenes correlated with such predictive factors as FIGO stage, histological grade, ascites, postoperative residual tumor mass, hormone receptor content, and preoperative CA 125 serum levels. The effect of HER-2/neu and INT-2 amplification on patient survival was also studied. Results: The only correlation found in this study was between INT-2 and preoperative CA 125 levels (P= 0.03). No correlations were demonstrable between HER-2/neu (log-rank test;P= 0.67) and INT-2 (log-rank test;P= 0.75) amplifications and overall survival. Conclusion: Unlike the established prognostic factors, neither HER-2/neu nor INT-2 appears to be predictive for survival in patients with ovarian cancer.

Objective.To evaluate the possible risk of dealing with an unsuspected primary carcinoma of the fallopian tube during laparoscopic surgery.

To evaluate the prognostic importance of preoperative CA 125 levels in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer in comparison with the established prognostic factors: degree of differentiation, FIGO substage, and age.

Site of recurrence and histological type are significant prognostic factors for survival in recurrent endometrial carcinoma.The aim of this retrospective analysis of 56 patients suffering from recurrences of endometrial carcinoma following initial surgery was to establish the prognostic relevance that the following factors had on the survival rate: age, primary tumor stage, histological assessment (papillary vs non-papillary), postoperative adjuvant radiation therapy, recurrence free interval (<24 months, >24 months) and localisation of recurrence. The univariate analysis showed a significantly longer median survival time after recurrence for the following parameters: local recurrence vs extra vaginal recurrence (77.5 months vs 15.7 months, p=0.02), non-papillary vs papillary carcinoma (36.1 months vs 7.7 months, p=0.02), no adjuvant irradiation vs adjuvant irradiation (82.0 months vs 8.8 months, p = 0.007). Patients after adjuvant radiation treatment and patients suffering from papillary carcinomas have a significantly higher proportion of patients with distant metastasis (patients with adjuvant radiation treatment: Chi-square test: p = 0.001; patients suffering from papillary carcinomas: p=0.033).In the case of local recurrences, a three year survival rate of 54% can be achieved with radiation treatment. Recurrences of papillary endometrial carcinomas and patients suffering from distant metastasis on the other hand, show very low survival rates if they are treated with radiation therapy (papillary carcinomas: three-year survival rate of 18%, patients suffering from distant metastasis: 19%). These patients should be included in randomised studies with a view to examining the therapeutic effects of either additional or exclusive treatment with chemotherapy.

Tumor anemia is a common symptom in cancer patients. This study assessed the prognostic relationship of pretreatment serum hemoglobin levels to survival in a retrospective sample of 206 patients with epithelial ovarian carcinoma. Survival analysis was evaluated by univariate (Kaplan-Meier product limit method and log rank test) and multivariate (Cox proportional hazards model) analysis. Mean values were compared by the Kruskal-Wallis test. Serum hemoglobin levels were determined in each patient 24-48 hours before surgery. Anemia was defined as a serum hemoglobin value below 12 g/dL. Tumor anemia was present in 32% of the patients before primary surgery. Hemoglobin levels were significantly lower in patients with residual tumor than in those with no detectable residual tumor after initial surgery (P = 0.008). Although statistically not significant, we found a trend toward lower hemoglobin levels with advanced stage of disease. For 5 years, overall survival probability was 38.5% and 52.3% for patients with pretreatment hemoglobin levels P = 0.008). In multivariate analysis, the relative risk of death was significantly associated with decreasing serum hemoglobin levels. No interaction was found between the grade of anemia and chemotherapy or radiation therapy with respect to its influence on overall survival. After adjustment for established prognostic factors, tumor anemia was found to have an independent relationship to the overall survival of patients with ovarian carcinoma. Because no significant interaction could be found between the grade of anemia and chemotherapy, marked tumor anemia was considered an indicator of the presence of biologically aggressive tumor cell clones. Cancer 1998;83:726-731. © 1998 American Cancer Society.