Search

In a recent study we could show that neopterin inhibits nitric oxide-induced apoptosis in ovarian carcinoma cells. This may provide an explanation for the correlation between increased levels of neopterin derivatives and the unfavorable prognosis in patients with ovarian cancer that has been described in the literature. To obtain additional information on the mode of action of neopterin derivatives within the tumor environment, we studied the effects of neopterin (100 and 1000 μΜ) and 7,8-dihydroneopterin (100, 500, and 1000 μΜ) on mitochondrial dehydrogenase activity in three different ovarian carcinoma cell lines (2774, HOC-1, and OVCAR-3). 7,8-dihydroneopterin was an effective stimulus of mitochondrial enzyme turnover rate in any cell culture model under investigation. This suggests that the pteridine compound stabilizes tumor cell viability and therefore acts as a promotor of tumor growth. In contrast to 7.8-dihydroneopterin, neopterin did not affect mitochondrial dehydrogenases in 2774, HOC-7, or OVCAR-3 cells. However, in HOC-7 and OCVAR-3, neopterin was found to antagonize the stimulating effects of 7,8-dihydroneopterin. This might be due to the different impact of both pteridine compounds on the redox status in these cells. Our new data provide further evidence of distinct biochemical effects of neopterin derivatives in ovarian carcinoma cells. Neopterin and 7,8-dihydroneopterin may be involved in separate stages of cellular changes that lead to malignancy or promote tumor progression.

Increases in serum neopterin concentrations are a regular finding in patients with ovarian cancer. The strong correlation between neopterin and tumor progression might be explained by a direct influence of the pteridine compound on tumor cell growth. In the present study we investigated whether neopterin affects the production of the angiogenic promotors vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in the human ovarian carcinoma cell line OVCAR-3. VEGF and EPO gene expression were detected via RT-PCR. and a possible involvement of hypoxiainducible factor-1 was assessed by electrophoretic mobility shift assays. Neopterin amplified the hypoxia-induced VEGF and EPO gene expression as well as protein synthesis in a concentration-dependent manner. In addition, generation of both VEGF and EPO could be detected following incubation of cells with neopterin under normoxic conditions, too. Neopterin-induced synthesis of VEGF and EPO was preceeded by a stimulation of hypoxiainducible factor-1 uptake into the nucleus of OVCAR-3 cells. From these data we conclude that neopterin acts as a mediator of angiogenesis. Stimulation of VEGF and EPO generation in ovarian carcinoma cells may promote vascularization of the malignant tissue and thus tumor growth and development.

In a Number of malignant diseases including ovarian carcinomas, increased serum or urine levels of neopterin serve as a valuable marker for the state of activation of the cellular immune system. Reported correlations benveen elevated neopterin concentrations and shorter survival time of the tumor host might be explained by direct biochemical actions exhibited by the pteridine compound. In the present study, we investigated the influence of neopterin on inducible nitric oxide synthase (iNOS) gene expression in two ovarian carcinoma cell lines. Qualitative and quantitative analyses of iNOS as well as measurements of nitric oxide (NO) metabolites in the cell supernatant revealed an inhibitory effect of neopterin (1000 11M) on NO generation induced by a combination ofinterferon-γ (100 U/ml), tumor necrosis factor-a (500 U/ml), and interleukin-1β (10 U/ml). Since NO is most likely involved in apoptotic cell death in ovarian carcinoma cells, it is conceivable that suppression of NO synthesis represents a biochemical mechanism mediated by neopterin that is advantageous to tumor progression and thus harmful to the host.

Abstract Background Current studies on adherence to endocrine therapy in breast cancer patients suffer from methodological limitations due to a lack of well-validated methods for assessing adherence. There is no gold standard for measuring adherence. The aim of our study was to compare four different approaches for evaluating adherence to anastrozole therapy for breast cancer with regard to concordance between methods. Methods Outpatients with early breast cancer treated with anastrozole completed the multi-method assessment of adherence. We implemented a self-report scale (the Simplified Medication Adherence Questionnaire), physician- ratings, refill records and determination of anastrozole serum concentration. Results Comparison of the four approaches using Spearman rank correlation revealed poor concordance across all methods reflecting weak correlations of 0.2-0.4. Considering this data incomparability across methods, we still observed high adherence rates of 78%-98% across measures. Conclusion Our findings contribute to the growing body of knowledge on the impact that methodological aspects exert on the results of adherence measurement in breast cancer patients receiving endocrine treatment. Our findings suggest that the development and validation of instruments specific to patients receiving endocrine agents is imperative in order to arrive at a more accurate assessment and to subsequently obtain more precise estimates of adherence rates in this patient population.

Abstract Introduction Well-documented cases of untreated cervical intra-epithelial dysplasia resulting in fatal progression of invasive cervical cancer are scarce because of a long pre-invasive state, the availability of cervical cytology screening programs, and the efficacy of the treatment of both pre-invasive and early-stage invasive lesions. Case presentation We present a well-documented case of a 29-year-old Caucasian woman who was found, through routine conventional cervical cytology screening, to have pathologic Papanicolaou (Pap) grade III D lesions (squamous cell abnormalities). She subsequently died as a result of human papillomavirus type 18-associated cervical cancer after she refused all recommended curative therapeutic procedures over a period of 13 years. Conclusion This case clearly demonstrates a caveat against the promotion and use of complementary alternative medicine as pseudo-immunologic approaches outside evidence-based medicine paths. It also demonstrates the impact of the individualized demands in diagnosis, treatment and palliative care of patients with advanced cancer express their will to refuse evidence-based treatment recommendations.

Abstract Background Efficiency and efficacy of organised mammography screening programs have been proven in large randomised trials. But every local implementation of mammography screening has to check whether the well established quality standards are met. Therefore it was the aim of this study to analyse the most common quality indices after introducing organised mammography screening in Tyrol, Austria, in a smooth transition from the existing system of opportunistic screening. Methods In June 2007, the system of opportunistic mammography screening in Tyrol was changed to an organised system by introducing a personal invitation system, a training program, a quality assurance program and by setting up a screening database. All procedures are noted in a written protocol. Most EU recommendations for organised mammography screening were followed, except double reading. All women living in Tyrol and covered by social insurance are now invited for a mammography, in age group 40-59 annually and in age group 60-69 biannually. Screening mammography is offered mainly by radiologists in private practice. We report on the results of the first year of piloting organised mammography screening in two counties in Tyrol. Results 56,432 women were invited. Estimated participation rate was 34.5% at one year of follow-up (and 55.5% at the second year of follow-up); 3.4% of screened women were recalled for further assessment or intermediate screening within six months. Per 1000 mammograms nine biopsies were performed and four breast cancer cases detected (N = 68). Of invasive breast cancer cases 34.4% were ≤ 10 mm in size and 65.6% were node-negative. In total, six interval cancer cases were detected during one year of follow-up; this is 19% of the background incidence rate. Conclusions In the Tyrolean breast cancer screening program, a smooth transition from a spontaneous to an organised mammography screening system was achieved in a short time and with minimal additional resources. One year after introduction of the screening program, most of the quality indicators recommended by the European guidelines had been reached. However, it will be necessary to introduce double reading, to change the rule for BI-RADS 3, and to concentrate on actions toward improving the participation rate.

Abstract Background The aim of this study was to analyse breast cancer incidence and mortality in Tyrol from 1970 to 2006, namely after performing more than a decade of opportunistic mammography screening and just before piloting an organised screening programme. Our investigation was conducted on a population level. Methods To study time trends in breast cancer incidence and mortality, we applied the age-period-cohort model by Poisson regression to the official mortality data covering more than three decades from 1970 to 2006 and to the incidence data ranging from 1988 to 2006. In addition, for incidence data we analysed data on breast cancer staging and compared these with EU guidelines. Results For the analysis of time trend in breast cancer mortality in age groups 40-79, an age-period-cohort model fits well and shows for years 2002-2006 a statistically significant reduction of 26% (95% CI 13%-36%) in breast cancer mortality as compared to 1992-1996. We see only slight non-significant increases in breast cancer incidence. For the past five years, incidence data show a 10% proportion of in situ cases, and of 50% for cases in stages II+. Conclusions The opportunistic breast cancer screening programme in Tyrol has only in part exploited the mortality reduction known for organised screening programmes. There seems to be potential for further improvement, and we recommend that an organised screening programme and a detailed screening database be introduced to collect all information needed to analyse the quality indicators suggested by the EU guidelines.

Abstract Background Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer. Methods We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry. Results SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002). Conclusion This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors.

Objective: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease., Methods: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days., Results: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively., Conclusion: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.