Weight gain in menopause: systematic review of adverse events in women treated with black cohosh.

Weight gain is a frequent problem in perimenopausal and postmenopausal women. Cimicifuga racemosa (CR) is a popular treatment option for menopausal symptoms. The aim of this review was to investigate whether there is scientific evidence that CR causes weight gain. We searched our database for medically confirmed, spontaneous adverse events regarding weight gain, literature for case reports and randomized controlled trials. Thirty cases in total were spontaneously reported in 15 years. The causality was not considered certain/likely in any of the cases. A nurse (consumer) assessed the causality as possible. Only one case was published in the literature. However, no change in body fat composition was reported, and the causality seems unlikely. Of the 31 identified studies, 17 were double-blind placebo-controlled, five were double-blind reference-controlled and nine were open reference-controlled. In total, 1839 women were treated with CR for up to 12 months. Two studies reported weight gain as an adverse event; however, no significant differences in weight changes were observed between the groups. One case of weight gain (about 2 kg) was reported, but the authors did not specify in which treatment group. In conclusion, this study provides no scientific evidence that the use of Cimicifuga racemosa causes weight gain in menopausal women.

Isopropanolic black cohosh extract and recurrence-free survival after breast cancer.

OBJECTIVE: To investigate the influence of an isopropanolic Cimicifuga racemosa extract (iCR) on recurrence-free survival after breast cancer, including estrogen-dependent tumors. METHODS: This pharmacoepidemiologic observational retrospective cohort study examined breast cancer patients treated at general, gynecological and internal facilities linked to a medical database in Germany. The main endpoint was disease-free survival following a diagnosis of breast cancer. The impact of treatment with iCR following diagnosis was analyzed by Cox-proportional hazards models, controlling for age and other confounders. RESULTS: Of 18,861 patients, a total of 1,102 had received an iCR therapy. The mean overall observation time was 3.6 years. Results showed that iCR was not associated with an increase in the risk of recurrence but associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a recurrence, while the iCR group reached this proportion after 6.5 years. The primary Cox regression model controlling for age, tamoxifen use and other confounders demonstrated a protractive effect of iCR on the rate of recurrence (hazard ratio 0.83, 95% confidence interval 0.69 0.99). This effect remained consistent throughout all variations of the statistical model, including subgroup analyses. TNM status was unknown but did not bias the iCR treatment decision as investigated separately. Hence, it was assumed to be equally distributed between treatment groups. Correlation analyses showed good internal and external validity of the database. CONCLUSION: An increase in the risk of breast cancer recurrence for women having had iCR treatment, compared to women not treated with iCR is unlikely.

Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma.

PURPOSE: To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS: In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS: Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P < .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P < .0001). CONCLUSION: rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.

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.

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

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.

Elevated serum levels of a c-erbB-2 oncogene product in ovarian cancer patients and in pregnancy.

Amplification of the proto-oncogene c-erbB-2 (HER-2/neu) has been shown to be a prognostic marker in ovarian cancer. In order to obtain further information on the biological role of the c-erbB-2 gene product p185 it is necessary to quantify expression levels. In this study we evaluated an enzyme-linked immunosorbent assay (ELISA) for the extracellular domain of p185 to determine whether a soluble oncoprotein fragment can be detected in the serum of ovarian cancer patients and in the serum of pregnant women. Sera from 199 women (57 previously untreated ovarian cancer patients, 62 pregnant women and 80 healthy controls) were assayed in a sandwich ELISA utilizing two mouse monoclonal antibodies. To study c-erbB-2 overexpression in ovarian cancer tissue samples we have used an immunohistochemical technique involving a monoclonal antibody specifically reactive with the external domain of the protein p185. The mean serum value for the normal controls was 1203 HNU/ml with a standard deviation (SD) of 279 HNU/ml and a range of 595-1947 HNU/ml. We chose a level of 1761 HNU/ml (2 SD above the mean) as a cut-off to distinguish individuals with elevated levels. The ovarian cancer patients' serum values ranged from 526 to 16,332 HNU/ml. Immunohistochemically detectable p185 was noted in 8 of 57 ovarian cancer patients. The oncoprotein fragment levels in the sera from these 8 patients ranged from 878 to 16,332 HNU/ml. Of 8 patients with p185 overexpression in their tumors, 4 had elevated serum levels. In the sera from the 49 cancer patients without overexpression the values were distributed in the range 526-2892 HNU/ml. There was no association between serum oncoprotein fragment levels and tumor stage, histological type or grading. Serum concentrations of the p185 fragment in pregnancy ranged from 612 to 3265 HNU/ml. The highest levels were found in the third trimester. The results of the present study raise the possibility that the soluble c-erbB-2 protein level in serum is an indicator for cell proliferation and therefore deserves further evaluation as a diagnostic tool in ovarian cancer patients and pregnancy.

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).

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.

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.

Association of serum autoantibodies to tumor-suppressor gene p53 in patients with ovarian cancer according to status of the disease.

Sera from 130 ovarian cancer patients and from 118 normal control volunteers were assayed for serum autoantibodies to p53 using an enzyme-linked immunosorbent assay (ELISA). Overall, autoantibodies were detected in 41% of ovarian cancer patients as compared to 0.9% of healthy individuals (P<0.001). The incidence of autoantibodies was lower in patients with complete remission (20%) as compared to those with recurrence (48%, P<0.01) and before primary surgery (49%, P<0.05). There was no statistically significant correlation between p53 serum autoantibody status and tumor stage, degree of malignancy and histological subtype. Comparing the autoantibody status with p53 antigen expression in the corresponding tissue resulted in 57% consistent results. Thus, serological testing for p53 autoantibodies provides additional information and may be associated with the disease status in patients with ovarian cancer.

Maintenance chemotherapy with oral treosulfan following first-line treatment in patients with advanced ovarian cancer: feasibility and toxicity.

PURPOSE: To evaluate the feasibility and toxicity of maintenance oral treosulfan chemotherapy for ovarian cancer patients after surgical treatment and response to first-line chemotherapy. PATIENTS AND METHODS: Thirty-nine patients were entered onto this trial. This was a pretreated patient population. The pretreatment consisted of radical surgery and chemotherapy. The treatment that immediately preceded oral treosulfan was standard-dose platin-based chemotherapy. Daily oral treosulfan was administered at a dose of 1250 mg for 5 consecutive days every five weeks for at least three cycles. All patients started daily oral treosulfan while in complete remission. RESULTS: A total of 322 cycles of oral treosulfan was administered, with a median of 6 cycles (range 3-24). Treosulfan in this schedule was generally well tolerated. The major toxic effects were leukopenia and thrombocytopenia, which, however, were manageable and rapidly reversible. There were no episodes of bleeding or leukopenic fever. No anti-emetic drugs were required. Alopecia was not observed, 20 patients had progressive disease (after 3-6 months: n = 8, after > 6 months: n = 12). The median survival for all patients was 24 (range 9.44+) months, and median time to progression 8 (range 3-24) months. CONCLUSIONS: Maintenance oral treosulfan was well tolerated in this pretreated patient population. In an attempt to further improve overall survival in ovarian cancer patients, prospective random assignment trials will be necessary to determine the benefit of this approach.

Prognostic significance of p105 (c-erbB-2 HER2/neu) serum levels in patients with ovarian cancer.

BACKGROUND: Elevated serum levels of the oncoprotein p105 (c-erbB-2, HER2/neu) have been found in patients with ovarian cancer, but its role in this disease has not been clearly established. MATERIALS AND METHODS: The authors studied the relationship between p105 serum levels, various tumor parameters, and survival in 57 patients with newly diagnosed, untreated ovarian cancer. Serum specimens were obtained at the time of initial surgery, and p105 levels were determined using the human neu quantitative ELISA assay. RESULTS: Elevated p105 serum levels were correlated with a poor prognosis since patients with low p105 levels had a better survival than patients with high p105 levels (P = 0.02). This result was confirmed in stage III patients (n = 29; P = 0.08). p105 serum levels were not related to tumor stage, grade, histologic findings or serum CA 125 levels. CONCLUSIONS: Our results suggest that ovarian cancer patients with elevated p105 serum levels may have a poor clinical outcome.

Hormonal treatment with sex steroids in women is associated with lower p105 serum concentrations.

BACKGROUND: In breast and ovarian cancer patients elevated serum levels of the oncoprotein p105 were detected. We examined the influence of endocrine factors on the p105 serum concentration. MATERIALS AND METHODS: The sera of 115 and non-pregnant women were analysed. Of the premenopausal women (n = 77) hormonal contraception was used by 30 women, and of the postmenopausal women (n = 33) there were 15 women using hormonal replacement therapy (HRT). The serum specimens were analysed by ELISA. RESULTS: Women with hormonal contraception had significantly lower serum levels than premenospausal controls (82-138 fmol/ml, median 109 fmol/ml vs. 103-183 fmol/ml, median 130 fmol/ml; P < 0.001). In postmenopausal women with HRT serum levels were significantly lower than in postmenopausal controls (88-136 fmol/ml, median 117 fmol/ml vs. 99-261 fmol/ml, median 148 fmol/ml; P < 0.001). CONCLUSIONS: Sex steroids seem to modulate c-erbB-2 activity. These results are important with regard to clinical studies on p105 oncoprotein in cancer patients.

Effects of interfering and influencing factors on the analyses of p105 (c-erbB-2/HER-2) oncoprotein fragment in serum.

BACKGROUND: The 105 kDa extracellular domain of c-erbB-2 encoded protein p185 is detectable in serum. Elevated p105 serum levels were found in patients with breast and ovarian cancer and in pregnancy. The effects of interfering and influencing factors on the measurement are still unclear. MATERIAL AND METHODS: We used an ELISA based on the monoclonal capture antibody OD-3 and investigated possible interfering factors, like changing transporting and storing conditions of blood and serum samples. In order to evaluate a normal range of p105 serum values we examined 71 healthy women. RESULTS: In our tests we found no influence on the reproducibility of results by changing transporting and storing conditions. We could not find any dependency of p105 serum values on the menstrual cycle or the age of controls. Postmenopausal women showed significantly higher serum values than premenopausal women (p = 0.0127). CONCLUSIONS: Clinical interpretation of female p105 serum values requires comparison with normal ranges when considering the menopause as an influencing factor.

Wertheim's hysterectomy after neoadjuvant carboplatin-based chemotherapy in patients with cervical cancer stage IIB and IIIB.

BACKGROUND: To improve local response and survival, a prospective study was designed to determine the effects of neoadjuvant chemotherapy in the management of cervical carcinoma stage IIB and IIIB. PATIENTS AND METHODS: Fourteen patients were treated with preoperative neoadjuvant chemotherapy. Three courses of carboplatin were administered in combination with ifosfamide in 11/14 patients, whereas 3 patients received three courses of carboplatin and paclitaxel. RESULTS: After neoadjuvant chemotherapy, there were 8/14 clinical responses while 6/14 patients had no change. In 8 cases, Wertheim's hysterectomy was possible after neoadjuvant chemotherapy. Six of these 8 patients are still alive after a duration of 32 months median follow-up, 2 patients died of metastatic disease. In 6 cases with no change after chemotherapy, Wertheim's hysterectomy was impossible. In this subgroup, the median survival time was 15.5 months, and 4/6 patients died of metastatic disease. CONCLUSIONS: Neoadjuvant chemotherapy with carboplatin/ifosfamide or carboplatin/paclitaxel is safe, well-tolerated, effective and useful to enable Wertheim's hysterectomy.

Co-expression of the MDR1 gene and HSP27 in human ovarian cancer.

Heat-shock proteins seem to play a still undefined role in cancer. One of them particularly, the low molecular weight HSP27, seems to be involved in resistance to chemotherapy. This phenomenon has been reported in breast cancer cell lines, and the aim of this study was to investigate if it also takes place in clinical tumour samples from ovarian cancer patients. We studied ovarian carcinoma samples from 95 patients by means of immunohistochemistry for the overexpression of both the product of the multidrug-resistance gene (P-glycoprotein) and HSP27. The expression of the MDR1 gene in more than 50% of the tumour cells was associated with an almost significantly shorter survival of patients with stage II, III and IV tumours (p = 0.05), although intriguingly not with the response to chemotherapy. Tumours expressing the MDR1 gene, furthermore, also tended to co-express HSP27 (64.9% vs. 42.1%), and this difference was statistically significant (p = 0.026).

Weekly intravenous recombinant humanized anti-P185HER2 monoclonal antibody (herceptin) plus docetaxel in patients with metastatic breast cancer: a pilot study.

BACKGROUND: In patients with HER2-positive metastatic breast cancer (MBC), combined treatment of herceptin (H) and chemotherapy (CT) improves time to progression, response rates and survival compared with CT alone. MATERIALS AND METHODS: We evaluated the safety and efficacy of weekly Docetaxel combined with weekly H as treatment in HER2 overexpressing MBC. RESULTS: Preliminary toxicity data from 12 patients and 76 cycles of D and 80 cycles of H were analysed. No G3/4 toxicity was observed. The most frequent non-hematologic toxicities were fatigue (2 patients G2, 2 patients G1), dyspepsia (1 patients G2, 3 patients G1), diarrhea (1 patient G2, 3 patients G1), and nausea (1 patient G2, 3 patients G1). Six partial responses have been observed in 12 patients (ORR 50%). CONCLUSIONS: The combination of weekly Docetaxel and Herceptin is well tolerated with significant anti-tumor activity.

Docetaxel is effective in the treatment of metastatic endometrial cancer.

BACKGROUND: Systemic treatment of endometrial carcinoma with distant metastases is currently performed, inter alia, with anthracyclines, platinum, paclitaxel, if osfamid or progestins. This is the first report presenting experience in treatment of metastatic endometrial carcinoma with docetaxel. CASE REPORT: A 69-year-old women with adenocarcinoma of the endometrium was treated with primary combined radiotherapy. Two years later disseminated bilateral pulmonary metastases were detected and the patient was submitted to chemotherapy with epirubicin. After three cycles of chemotherapy with epirubicin examinations revealed metastatic progression. Thus, chemotherapy was changed to docetaxel. RESULTS: After three cycles of chemotherapy with docetaxel examinations revealed remission of the described pulmonary metastases more than 50%. A further three cycles of chemotherapy with docetaxel lead to continuing shrinkage of the detectable metastases to less than 25% of the original size. Because of various side effects, like increasing fatigue and asthenia, uncomfortable acral paresthesia and allergic skin reactions, the patient refused to continue chemotherapy. CONCLUSION: We conclude that docetaxel may be an active agent in patients with metastatic endometrial cancer, but care should be taken to minimize side-effects.

Mib-1 evaluated proliferative activity in ovarian cancer with respect to prognostic significance.

In the present study, tumor tissue of 251 patients with ovarian cancer was immunohistochemically analysed for proliferative activity using the monoclonal antibody mib-1 and the analyse system CAS 200. The rate of the growth fraction varied from 0% to 71% mib-1 positive tumor cells with a median of 17%. There was a strongly significant association between proliferative activity and the degree of histological differentiation (p = 0.0005), whereas there was no significant correlation with tumor stage and histological subtypes. Using the median as the cut-off point, patients with higher proliferating tumors (> or = 17%) had a statistically significant worse prognosis (p = 0.0431). Especially in the group of patients with grade 1 and grade 2 tumors, measurement of the proliferative activity is of help for prediction of the postoperative survival time of patients (p = 0.0336), suggesting that measurement of the growth fraction estimated by mib-1 reflects more closely the degree of tumor differentiation. However, multivariate analyses cannot confirm these results.

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

The prognostic value of various molecular markers, which adequately account for the tumor biology and disease behaviour of ovarian cancer, is still unclear. Recent studies have focused on the role of genes regulating the balance between proliferation and cellular suicide, apoptosis. In the present study, tumor tissue from 215 patients with ovarian cancer was immunohistochemically analysed for Bax- and Bcl-2-expression. There was an association between Bcl-2-expression (30%) and factors of favourable prognosis. In contrast, Bax-expression (47%) was related to bad clinical outcome, especially in cases without concomitant Bcl-2-expression. In patients with Bcl-2-positive/Bax-negative tumors, overall survival was significantly longer (p = 0.0379) than in patients with Bcl-2- and Bax-negative tumors. Respectively, expression of Bax without Bcl-2-expression was correlated with bad clinical outcome (p = 0.033). The difference in overall survival was most striking (p = 0.0007) between patients with Bax-positive/Bcl-2-negative and Bcl-2-positive/Bax-negative tumors. This could also be demonstrated for the various subgroups of different tumor grade and stage. It may be speculated, that alteration of the Bax/Bcl-2-balance may influence the clinical course by deregulation of programmed cell death and altered sensitivity to chemotherapy.

Expression of the mismatch repair protein hMSH2 in carcinoma in situ and invasive cancer of the breast.

BACKGROUND: Dysregulations in the mechanism of DNA-repair are contributed to tumorgenesis and tumorprogression in human cancer. The mismatch repair gene hMSH2 encodes a protein, which recognizes and binds to mismatch-sequences of the DNA. METHODS: Using immunohistochemical techniques hMSH2 expression was analyzed in invasive cancer (n = 85) and in situ carcinoma (n = 34) of the breast. RESULTS: The percentage of hMSH2 positive cases was significantly (p = 0.0001) decreased in invasive cancer as compared to in situ carcinomas. There was an association of hMSH2 expression with parameters of unfavorable prognosis, such as lymph node involvement (p = 0.03), higher degree of malignancy (p = 0.05) and higher proliferative activity (p = 0.05). CONCLUSIONS: During development from in situ to invasive cancer of the breast, hMSH2 expression seems to be downregulated. However, in invasive cancer, hMSH2 expression seems to be associated with tumor progression. This could be explained by the fact that enhanced proliferation of tumor cells results in increased mistakes within DNA replication procedures.