Reduction in advanced breast cancer after introduction of a mammography screening program in Tyrol/Austria.

BACKGROUND: We analysed all female breast cancer (BC) cases in Tyrol/Austria regarding the shift in cancer characteristics, especially the shift in advanced BC, for the group exposed to screening as compared to the group unexposed to screening. METHODS: The analysis was based on all BC cases diagnosed in women aged 40-69 years, resident in Tyrol, and diagnosed between 2009 and 2013. The data were linked to the Tyrolean mammography screening programme database to classify BC cases as "exposed to screening" or "unexposed to screening". Age-adjusted relative risks (RR) were estimated by relating the exposed to the unexposed group. RESULTS: In a total of about 145,000 women aged 40-69 years living in Tyrol during the study period, 1475 invasive BC cases were registered. We estimated an age-adjusted relative risk (RR) for tumour size ≥ 21 mm of 0.72 (95% confidence interval (CI) 0.60 to 0.86), for metastatic BC of 0.27 (95% CI 0.17 to 0.46) and for advanced BC of 0.83 (95% CI 0.71 to 0.96), each comparing those exposed to those unexposed to screening, respectively. CONCLUSION: In our population-based registry analysis we observed that participation in the mammography screening programme in Tyrol is associated with a 28% decrease in risk for BC cases with tumour size ≥ 21 mm and a 17% decrease in risk for advanced BC. We therefore expect the Tyrolean mammography programme to show a reduction in BC mortality.

Can we use gonadotropin plasma concentration as surrogate marker for BMI-related incomplete estrogen suppression in breast cancer patients receiving anastrozole?

BACKGROUND: BMI has been suggested to impact on estrogenic activity in patients receiving anastrozole resulting in a reduced treatment efficacy in obese women. Current evidence in this regard is controversially discussed. Since estradiol is inversely correlated with gonadotropins it can be assumed that an impact of BMI is also reflected by gonadotropin plasma concentrations. We aim at investigating the impact of BMI on the hormonal state of breast cancer (BC) patients receiving anastrozole indicated by LH, FSH and SHBG as well as estradiol. METHODS: We determined gonadotropin-, estradiol- and anastrozole- serum concentrations from postmenopausal, early stage breast cancer patients receiving upfront anastrozole within routine after care. Gonadotropin plasma concentrations were derived from the routine laboratory examination report. A liquid chromatography tandem mass spectrometry method was used for the measurement of anastrozole serum concentrations. BMI was assessed within the routine after-care check-up. RESULTS: The overall sample comprised 135 BC patients with a mean age of 65.3 years. BMI was significantly correlated with LH, FSH and SHBG. This association was neither influenced by age nor by anastrozole serum concentrations according to the regression model. Despite aromatase inhibition 12% of patients had detectable estrogen levels in routine quantification. CONCLUSION: Obese women have an altered hormonal situation compared to normally weight women under the same dose of anastrozole. Our study findings are a further indicator for the relevance of BMI in regard of anastrozole metabolism and possible estrogenic activity indicated by gonadotropin plasma level.

Strain Elastography of Breast and Prostata Cancer: Similarities and Differences.

UNLABELLED: Typically both breast and prostate cancer present as tissue with decreased elasticity. Palpation is the oldest technique of tumor detection in both organs and is based on this principle. Thus an operator can grade a palpable mass as suspicious for cancer. Strain elastography as modern ultrasound technique allows the visualization of tissue elasticity in a color coded elastogram and can be understood as technical finger. The following article shows similarities and differences of ultrasound strain elastography in the diagnosis of breast and prostate cancer. KEY POINTS: • In prostata cancer elastography, in breast cancer B-mode is the primary sonographic search modality. • The diagnostic value of the search modalities change with increasing age.• A cut-off value for a strain ratio is hard to obtain in the elastography of the prostata, because there is no stabile reference tissue in the prostata.

Cost effectiveness of personalized treatment in women with early breast cancer: the application of OncotypeDX and Adjuvant! Online to guide adjuvant chemotherapy in Austria.

A Breast Cancer Outcomes model was developed at the ONCOTYROL research center to evaluate personalized test-treatment strategies in Austria. The goal was to evaluate the cost-effectiveness of a new 21-gene assay (ODX) when used in conjunction with the Adjuvant! Online (AO) decision aid to support personalized decisions about use of adjuvant chemotherapy in early-stage breast cancer patients in Austria. We applied a validated discrete-event-simulation model to a hypothetical cohort of 50 years old women over a lifetime horizon. The test-treatment strategies of interest were defined using three-letter acronyms. The first (second, third) letter indicates whether patients with a low (intermediate, high) risk according to AO were tested using ODX (Y yes, N no). The main outcomes were life-years gained, quality-adjusted life-years (QALYs), costs and cost effectiveness. Robustness of the results was tested in sensitivity analyses. Results were compared to a Canadian analysis conducted by the Toronto Health Economics and Technology Assessment Collaborative (THETA). Five of eight strategies were dominated (i.e., more costly and less effective: NNY, NYN, YNN, YNY, YYN). The base-case analysis shows that YYY (ODX provided to all patients) is the most effective strategy and is cost effective with an incremental cost-effectiveness ratio of 15,700 EUR per QALY gained. These results are sensitive to changes in the probabilities of distant recurrence, age and costs of chemotherapy. The results of the base-case analysis were comparable to the THETA results. Based on our analyses, using ODX in addition to AO is effective and cost effective in all women in Austria. The development of future genetic tests may require alternative or additional test-treatment strategies to be evaluated.

Clinical Practice Guideline for the prevention and early detection of breast and ovarian cancer in women from HBOC (hereditary breast and ovarian cancer) families.

An estimated 10% of breast cancer cases exhibit a higher familial incidence, and functional mutations in BRCA (breast cancer-gene) 1 or 2 are responsible for the development of malignant tumors in approximately half of these cases. Women with a germline mutation in either of the two genes have a lifetime risk of up to 85% to develop breast cancer, and of up to 60% risk to develop ovarian cancer. This clinical practice guideline defines the individual and familial tumor constellations that represent an indication for BRCA germline testing. It also describes the therapeutic options (early detection programme vs prophylactic surgery) that arise from the result of a BRCA mutational analysis. This guideline further includes recommendations regarding the use of multigene panels and therapeutic aspects that arise from the selective use of poly ADP ribose polymerase (PARP) inhibitors in patients with known BRCA1 or 2 mutations. It replaces the previous version of the "Clinical Practice Guideline for the Prevention and Early Detection of Breast- and Ovarian Cancer in women from HBOC (hereditary breast and ovarian cancer) families" which was published in 2012.

Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer.

Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be recommended while in those with predominant anxiety selective serotonin reuptake inhibitors might be the treatment of choice.

Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24).

BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions. CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov.

Evaluation of sample preparation methods for MALDI-TOF MS identification of highly dangerous bacteria.

AIMS: To propose a universal workflow of sample preparation method for the identification of highly pathogenic bacteria by MALDI-TOF MS. METHODS AND RESULTS: Fifteen bacterial species, including highly virulent Gram-positive (Bacillus anthracis and Clostridium botulinum) and Gram-negative bacteria (Brucella melitensis, Burkholderia mallei, Francisella tularensis, Shigella dysenteriae, Vibrio cholerae, Yersinia pestis and Legionella pneumophila), were employed in the comparative study of four sample preparation methods compatible with MALDI-TOF MS. The yield of bacterial proteins was determined by spectrophotometry, and the quality of the mass spectra, recorded in linear mode in the range of 2000-20,000 Da, was evaluated with respect to the information content (number of signals) and quality (S/N ratio). CONCLUSIONS: Based on the values of protein concentration and spectral quality, the method using combination of ethanol treatment followed by extraction with formic acid and acetonitrile was the most efficient sample preparation method for the identification of highly pathogenic bacteria using MALDI-TOF MS. SIGNIFICANCE AND IMPACT OF THE STUDY: The method using ethanol/formic acid generally shows the highest extraction efficacy and the spectral quality with no detrimental effect caused by storage. Thus, this can be considered as a universal sample preparation method for the identification of highly virulent micro-organisms by MALDI-TOF mass spectrometry.

Hepcidin is correlated to soluble hemojuvelin but not to increased GDF15 during pregnancy.

Increased maternal and foetal iron requirements during pregnancy are compensated by an increase of intestinal iron absorption. Animal studies have shown that the expression of the main iron regulator hepcidin is significantly suppressed during pregnancy, but the factors associated with hepcidin suppression remain unknown. To investigate possible suppressors of hepcidin expression during pregnancy we determined serum concentrations of growth-differentiation factor-15 (GDF15), erythropoietin (EPO), soluble hemojuvelin (HJV) and hepcidin in 42 pregnant women at different time points of gestation and correlated them with serum iron and haematological parameters. Serum iron parameters and serum hepcidin concentration significantly decreased during pregnancy, whereas serum concentrations of GDF15, EPO and soluble HJV significantly increased. A negative correlation of hepcidin with EPO and soluble HJV but no correlation between hepcidin and GDF15 was found. Hepcidin and ferritin were positively correlated throughout the pregnancy. Our findings suggest that hepcidin expression is controlled by body iron stores where soluble HJV and EPO may act as suppressors of hepcidin.

Axillary Dissection in the Case of Positive Sentinel Lymph Nodes: Results of the Innsbruck Consensus Conference.

The prognosis of breast cancer is most heavily influenced by the status of the axillary nodes. Until a few years ago, this knowledge was gained through radical axillary lymph node clearance. In the meantime, sentinel lymph node clearance has become an established part of the surgical treatment of breast cancer. With the development of this procedure, the morbidity caused by axillary dissection has been reduced significantly. Although comprehensive prospective, randomised data regarding the safe use of the sentinel concept are only now available, the focus currently, however, is on the question of whether in the case of positive sentinel lymph nodes, an axillary dissection can be done away with altogether without having any negative impact on the risk of loco-regional recurrence or on progression-free survival and overall survival. The results of the American ACOSOG-Z001 study have changed the fundamental perspective of this. In this study on the advantages of axillary dissection following the confirmation of tumour tissue in the sentinel lymph nodes, there were no statistically significant advantages from axillary dissection for women with a favourable overall risk profile who had received radiotherapy and systemic therapy. If this concept takes hold, the surgical treatment of node-positive breast cancer, at least in the axilla, would be reduced to a minimum, and the focus of treatment would in future lie more on the systemic treatment of this condition. As part of an interdisciplinary consensus meeting, a standardised approach for Austria with regard to this question was decided upon.

Regulation of transcription factor E2F3a and its clinical relevance in ovarian cancer.

Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (ρ=0.349, P=0.0001) and residual disease (ρ=0.254, P=0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P=0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P=0.013; OS: hazards ratio 4.651 (1.189-15.572), P=0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.

MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status.

This study analysed mRNA expression of two members of the methyl-CpG-binding protein family - MeCP2 and MBD2 - in human non-neoplastic (n=11) and neoplastic (n=57) breast tissue specimens using a quantitative real-time PCR method. We observed higher expression levels of MeCP2 mRNA in neoplastic tissues than in non-neoplastic tissues (P=0.001), whereas no significant differences for MBD2 were detected. When studying the relations between the most important clinicopathologic features of breast cancer and the mRNA expression level of both MBDs, we found that oestrogen receptor (OR)-positive breast cancer specimens contained higher levels of MeCP2 mRNA than did OR-negative cancers (P=0.005). Furthermore, we observed statistically significantly higher levels of MeCP2 in non-neoplastic tissues expressing high levels of OR as compared to those expressing low levels (P=0.017). Finally, using a linear regression model, we identified a statistically significant association between OR expression and MeCP2 mRNA expression in neoplastic and non-neoplastic breast tissue specimens (P=0.003). In conclusion, we were able to demonstrate for the first time that there exists a strong association between OR status and MeCP2 mRNA expression. Furthermore, we speculate that MeCP2, regulated by OR, plays a key role in the differentiation processes in human breast tissues.

Tailoring an antibacterial peptide of human lysosomal cathepsin G to enhance its broad-spectrum action against antibiotic-resistant bacterial pathogens.

Neutrophils contain several cationic antimicrobial proteins or peptides (CAPs) that exert antibiotic-like action against bacteria. These host-derived antibiotics kill susceptible bacteria by oxygen-independent mechanisms. Considerable interest in their activity has been generated in recent years due not only to their likely important role in innate host defense against infection, but also their possible use as therapeutic agents in treating infections caused by antibiotic-resistant pathogens. We have studied the antibacterial properties of human lysosomal cathepsin G (cat G). This highly cationic serine protease contains at least three antibacterial regions that by themselves can exert antibacterial action against Gram-negative bacteria, such as Pseudomonas aeruginosa. Only one of these peptides, defined by residues 117-136 of full-length cat G, has bactericidal action against Gram-positive pathogens, such as Staphylococcus aureus. Due to the broad-spectrum antibacterial action of this peptide, we have sought to define the amino acids within its primary sequence required for this activity and have developed variants with improved activity. This review emphasizes the importance of both cationicity and hydrophobicity as necessary characteristics for the antibacterial action of CAPs. It also proposes the strategy that naturally occurring large human CAPs can be dissected to smaller CAPs and then modified to enhance their activity in vitro. This approach could prove beneficial to those interested in developing antimicrobial peptides as therapeutic agents.