Harald Meden

Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor.

Ovarian cancer is the leading cause of death in gynecological cancers. To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and the course of the disease. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erbB-2 (HER2/neu) in various human cancers, including ovarian cancer. The c-erbB-2 proto-oncogene is located on the long arm of chromosome 17. It encodes a 185 kD transmembrane glycoprotein receptor (p185HER2) that has sequence similarities with the epidermal growth factor receptor (EGF-R). In ovarian cancer, the percentage of c-erbB-2 positive cases varies from 9 to 32%. Correlation with tumor stage and the degree of histological differentiation was not observed. The overexpression of c-erbB-2 is a new and statistically independent prognostic factor. The overexpression of oncogene c-erbB-2 in ovarian cancer can-be detected by immunohistochemistry staining for the protein p185 and characterizes a group with unfavorable tumor biology and a significantly worse prognosis. Elevated serum levels of the c-erbB-2 oncoprotein have been identified in patients with various cancers known to overexpress the c-erbB-2 oncogene. The detection of a p185 oncoprotein fragment in the sera of ovarian cancer patients was recently published by our group. Antiproliferative effects of monoclonal antibodies directed against p185 have been demonstrated in breast cancer patients. This may lead to a new approach in ovarian carcinoma therapy, too, over and above the diagnostic aspects.

Overexpression of the oncogene c-erb B2 in primary ovarian cancer: evaluation of the prognostic value in a Cox proportional hazards multiple regression.

To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and disease behavior. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erb B2 in various human cancers. Concerning ovarian cancer, this is still a matter of discussion. In the present study, tumor tissue of 275 patients treated for ovarian cancer at the Department of Obstetrics and Gynecology of the University of Göttingen between 1982 and 1992 was immunohistochemically analyzed for overexpression of c-erb B2-encoded transmembrane protein p185. In 19% (51 of 275 cases), p185 overexpression was detected. The percentage of p185-positive cases varied from 7 to 46% according to histological subtype. Correlation with tumor stage and the degree of histological differentiation was not observed. Patients with p185-positive tumors had a significantly worse prognosis (p = 0.001); median survival was 20 months compared with 33 months for p185-negative tumors. In the Cox proportional hazards regression, p185 overexpression was identified as an independent prognostically relevant factor. These results suggest that overexpression of oncogene c-erb B2 in ovarian cancer characterizes a group with unfavorable tumor biology and a significantly worse prognosis.

Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer.

The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl-2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl-1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis (1-3). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma (4). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors (5-12). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer (6), breast (7-9), and, recently, in ovarian cancer (10-12). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast (13) and ovarian cancer (12). Moreover, the association of Bax-expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl-2-expression (12,13). The unexpected effect of Bcl-2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax-positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl-2-positive tumors (12). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery (12). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself (1-3). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death (2,3). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death (2,3), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.

Overexpression of the Oncogene c-erbb-2 (her2/neu) and Response to Chemotherapy in Patients with Ovarian Cancer

SummaryThis study was designed to determine whether c-erbB-2 overexpression could be used as a marker to identify a subgroup of patients with ovarian cancer more likely than others to benefit from chemotherapy. Paraffin sections from tissue blocks from 208 patients with newly diagnosed untreated ovarian cancer were analyzed for c-erbB-2 overexpression. All patients underwent postoperative platin-based chemotherapy. Patients with c-erbB-2 positive tumors had a significantly worse prognosis as compared to patients with c-erbB-2 negative tumors (p = 0.0003). c-erbB-2 findings were not related to tumor stage or histologie findings. There was clear evidence of a dose-response effect with regard to survival in patients with c-erbB-2 negative tumors, which could not be seen in patients with c-erbB-2 positive tumors (p = 0.0341 vs p = 0.3775). We conclude that there is a significant total dose-response effect of platin-based chemotherapy in ovarian cancer patients without overexpression of c-erbB-2 but not in patients with c-erbB-2 overexpression. Overexpression of c-erbB-2 may be a useful marker to identify patients who are most likely to benefit from high-dose chemotherapy.

Activated protein C resistance and Factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome ☆

Objective Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is characterized by a distinct activation of the coagulation system. A mutation of the gene coding for coagulation Factor V (Factor V Leiden) has been identified as the most frequent risk factor for thrombosis. To identify risk factors for HELLP syndrome, we determined coagulation parameters and the Factor V Leiden mutation in women who previously had developed HELLP syndrome. Methods Coagulation parameters (activated protein C resistance, antithrombin, protein C, protein S) were determined in 21 women 6 months to 9 years after they had developed HELLP syndrome in the third trimester. In addition, these women were analyzed for the presence of the Factor V Leiden mutation. Results Of these analyzed women, 33% (seven of 21) had an activated protein C resistance (activated protein C ratio less than 2.0). Another 38% of the women had subnormal activated protein C ratios (2.0-2.3). Only 57% of the women with an activated protein C resistance were identified as heterozygous carriers of the Factor V Leiden mutation (four of seven). Conclusion Women with HELLP syndrome have a higher incidence of Factor V Leiden mutations. This increased incidence does not, however, account fully for the increased frequency of activated protein C resistance in these patients.

Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.

Drug resistance is one of the most important clinical problems in the treatment of ovarian cancer. This study was designed to determine whether expression of p53 could be used as a marker for predicting the response to chemotherapy of ovarian cancer. Tissue blocks were obtained from 187 patients with diagnosed untreated ovarian cancer. Paraffin sections from the primaries were immunohistochemically analysed for p53 expression. All patients underwent platinum-based chemotherapy after surgery. We analysed whether the number of chemotherapy cycles was related to survival in women with p53 positive and p53 negative ovarian cancer. 27/187 cases were p53 positive. Expression of p53 was associated with other factors of unfavourable prognosis. Patients with p53 positive tumours had a significantly worse prognosis compared with patients with p53 negative tumours (P = 0.037). There was a statistically significant dose-response effect of platinum-based chemotherapy in patients with p53 negative tumours, which could not be seen in patients with p53 positive tumours (P = 0.01 versus P = 0.553). This could also be observed in patients with residual tumour after surgery (P = 0.0001 versus P = 0.8866). Expression of p53 may be an additional useful marker in predicting response to chemotherapy. Thus, it is possible to identify a subgroup of patients who may benefit from alternative therapy regimens.

Efficacy of black cohosh (Cimicifuga racemosa) medicines for treatment of menopausal symptoms – comments on major statements of the Cochrane Collaboration report 2012 “black cohosh (Cimicifuga spp.) for menopausal symptoms (review)”

Abstract Menopausal symptoms management with high-quality plant extracts from Actaea (Cimicifuga. racemosa rootstock is well-established. Efficacy and safety are supported by research and clinical trials since several decades and backed up by official monographs. However, the recent published Cochrane review on black cohosh neglects major evidence for beneficial effects. The authors’ negative conclusions are questionable and call for reply and clarification. Our careful reconsideration of all appropriate placebo-controlled clinical studies reveals a standardized mean difference of 0.385 in favor of black cohosh (p < 0.0001).

Extended phase II study of paclitaxel as a 3-h infusion in patients with ovarian cancer previously treated with platinum

An extended phase II study was performed to evaluate single-agent paclitaxel as salvage chemotherapy for ovarian cancer. The aim of this study was to evaluate the 3-h infusion schedule of paclitaxel in terms of toxicity and antitumour efficacy. Furthermore, we analysed the impact on response and survival of the extent of prior chemotherapy and status of resistance against platinum. This study was an open, non-randomised, multicentre trial. The dose of paclitaxel used was 175 mg/m2 in patients who had received one or two prior therapies, and 135 mg/m2 in patients who had received three prior therapies. Paclitaxel was given as a 3-h infusion. Courses were repeated every 3 weeks. 114 patients with platinum-pretreated epithelial ovarian cancer were recruited of whom 112 were found eligible and evaluable for toxicity. 104 patients with bidimensionally measurable disease who received more than one course of chemotherapy were evaluable for response, progression-free (PFS) and survival. Toxicity was generally manageable. Main toxicities were non-cumulative neutropenia with 22.3% of courses with WHO grade 3/4 and peripheral neuropathy which occurred in more than half of the courses and was of WHO grade 2 and 3 in 20.1 and 1.3% of the courses, respectively. Neuropathy was associated with the higher dose per course and with cumulative paclitaxel dose. Objective responses were reported in 20% (21/104) of the patients (95% CI 13-29%) with a median response duration of 36.7 weeks. Survival and PFS for the whole group were 45.9 and 15.1 weeks, respectively. Performance status, number of tumour lesions and extent of prior chemotherapy were found to be prognostic factors for survival. Extent of prior chemotherapy was the only prognostic factor for PFS. Platinum resistance did not predict response to treatment. Paclitaxel 175 mg/m2 given as a 3-h infusion is an appropriate treatment for patients with platinum-resistant ovarian cancer who have not previously received more than two chemotherapy regimens. Paclitaxel did not show results superior to historical data for platinum retreatment in patients with platinum-sensitive, recurrent ovarian cancer.

Effects of paclitaxel in combination with radiation on human head and neck cancer cells (ZMK-1), cervical squamous cell carcinoma (CaSki), and breast adenocarcinoma cells (MCF-7)

Abstract Background and purpose: The anticancer drug paclitaxel, a natural product from Taxus brevifolia, is a microtubule-stabilising agent, which has been shown to block different cells in the G2/M phase of the cell cycle and so modulate their radioresponsiveness. We investigated the radiosensitizing potential of paclitaxel in human head and neck cancer cells (ZMK-1), in cervical squamous cell carcinoma cells (CaSki) and in breast adenocarcinoma cells (MCF-7). Methods: ZMK-1 cells were incubated with paclitaxel for 3, 9, or 24 h before irradiation. ZMK-1-, CaSki- and MCF-7 cells were incubated with paclitaxel for 24 h after irradiation. The paclitaxel concentration (70 nM, 7 nM, 0.7 nM) was chosen to obtain equivalent toxicity at the different incubation times (3 h, 9 h, 24 h respectively). Radiation doses were from 0 to 8 Gy. Cell survival was measured by a standard clonogenic assay after a 9-day incubation. Flow cytometry was used to measure the capacity of paclitaxel to cause accumulation of cells in the G2/M phase of the cell cycle. Results: Paclitaxel alone was cytotoxic in a time- and concentration-dependent manner. Up to 36% of the ZMK-1 cells accumulated in G2/M after treatment for 24–36 h. If the cells were incubated with paclitaxel before irradiation the isoeffect enhancement ratios for ZMK-1 cells, determined at the 37% survival level, were 0.81, 1.48 and 1.15 for 3-h, 9-h, and 24-h pre-incubations respectively. For a paclitaxel incubation of 24 h after irradiation, the isoeffect enhancement ratios, determined at the 37% survival level, were 0.72, 0.76 and 1.2 for the ZMK-1, CaSki, and MCF-7 cells respectively. Conclusion: In the three cell lines no radiosensitizing effect of paclitaxel could be demonstrated unambiguously. The use of asynchronized cells or the support of cellular repair mechanisms while the cells are blocked in G2/M could partly explain the results.

Borderline Tumors of the Ovary : A Clinico-Pathologic and Immunohistochemical Study of 54 Cases

Objective:To study EGF‐R, HER‐2/neu (p185), p53, Mib‐1 (Ki‐67), Bax, Bcl‐2, ras expression and ploidy in borderline tumors of the ovary by assessing their frequency, and relationship to histologic type, tumor recurrence and survival.