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BACKGROUND: In cancer patients, circulating cell-free DNA (ccfDNA) can contain tumor-derived DNA (ctDNA), which enables noninvasive diagnosis, real-time monitoring, and treatment susceptibility testing. However, ctDNA fractions are highly variable, which challenges downstream applications. Therefore, established preanalytical work flows in combination with cost-efficient and reproducible reference materials for ccfDNA analyses are crucial for analytical validity and subsequently for clinical decision-making. METHODS: We describe the efforts of the Innovative Medicines Initiative consortium CANCER-ID (http:// www.cancer-id.eu) for comparing different technologies for ccfDNA purification, quantification, and characterization in a multicenter setting. To this end, in-house generated mononucleosomal DNA (mnDNA) from lung cancer cell lines carrying known TP53 mutations was spiked in pools of plasma from healthy donors generated from 2 different blood collection tubes (BCTs). ccfDNA extraction was performed at 15 partner sites according to their respective routine practice. Downstream analysis of ccfDNA with respect to recovery, integrity, and mutation analysis was performed centralized at 4 different sites. RESULTS: We demonstrate suitability of mnDNA as a surrogate for ccfDNA as a process quality control from nucleic acid extraction to mutation detection. Although automated extraction protocols and quantitative PCR-based quantification methods yielded the most consistent and precise results, some kits preferentially recovered spiked mnDNA over endogenous ccfDNA. Mutated TP53 fragments derived from mnDNA were consistently detected using both next-generation sequencing-based deep sequencing and droplet digital PCR independently of BCT. CONCLUSIONS: This comprehensive multicenter comparison of ccfDNA preanalytical and analytical work flows is an important contribution to establishing evidence-based guidelines for clinically feasible (pre)analytical work flows. © 2019 American Association for Clinical Chemistry.

Background Blue-light-filtering intraocular lenses have been developed to avoid the “blue-light-hazard,” which is thought to induce age-related macular degeneration. However, the intrinsically photosensitive retinal ganglion cells have their peak sensitivity at 480 nm, and their sent information influences melatonin production in the pineal gland.

The eLEcTRA trial compared efficacy and safety of letrozole combined with trastuzumab to letrozole alone in patients with HER2 and hormone receptor (HR) positive metastatic breast cancer (MBC). Patients were randomized to either letrozole alone (arm A, n = 31) or letrozole plus trastuzumab (arm B, n = 26) as first-line treatment. Additional 35 patients with HER2 negative and HR positive tumors received letrozole alone (arm C). Median time to progression in arm A was 3.3 months compared to 14.1 months in arm B (hazard ratio 0.67; p = 0.23) and 15.2 months in arm C (hazard ratio 0.71; p = 0.03). Clinical benefit rate was 39% for arm A compared to 65% in arm B (odds ratio 2.99, 95% CI 1.01-8.84) and 77% in arm C (odds ratio 5.34, 95% CI 1.83-15.58). The eLEcTRA trial showed that the combination of letrozole and trastuzumab is a safe and effective treatment option for patients with HER2 positive and HR positive MBC.

BRCA1 mutation carriers are at high risk for breast cancer (BC). The risk management strategy may include radiological investigations for early detection or prophylactic mastectomy (PM). For a mutation carrier, PM may be more significant than surveillance alone when pre-malignant and malignant changes occur increasingly in mastectomy specimens, given normal findings on radiological investigations. In the present study we retrospectively investigated the differences between histological findings in PM specimens of BRCA1 carriers and those of a control group.Twenty-four healthy and 28 affected carriers in the presence of normal preoperative radiological findings were included in the study. To compare the frequency of pre-malignant and malignant lesions in PM specimens, a control group matched for age and disease status was included. T-tests for independent samples and Wilcoxon's signed-rank test were used for comparison of groups.The entire study group differed significantly from the control group (42.3 vs. 5.8%; P0.001) in terms of the occurrence of pre-malignant and malignant lesions. Both, the sub-group comparison of healthy mutation carriers as well as diseased carriers with their controls, showed a significant difference in terms of the occurrence of pre-malignant and malignant changes (45.8 vs. 0%; P = 0.002; 39.3 vs. 10.7%; P = 0.03). In PM specimens of mutation carriers, carcinomas were identified in 5.8% (3/52) and pre-malignant changes in 36.5% (19/52).BRCA1 mutation carriers should be informed of the fact that pre-malignant and even malignant changes are frequently found in PM specimens despite normal radiological findings.

The effect of adjuvant treatment with tamoxifen on recurrence and survival rates was determined in a prospective randomized trial in 98 postmenopausal women (mean age 62.7 [49-77] years) with lymph node-negative breast cancer who had undergone modified radical mastectomy with axillary lymphadenectomy. The tamoxifen group (n = 48) received 10 mg of the drug twice daily for one year. After a mean period of 8 (6-11) years the tamoxifen group had a significantly higher rate of survival without recurrence than the control (no tamoxifen) group (83% vs 61.5%, P = 0.02) and a higher overall survival rate (95% vs 81.9%, P = 0.05). These results indicate that adjuvant tamoxifen favourably influences the prognosis for postmenopausal women with lymph node-negative breast cancer after radical mastectomy with axillary lymphadenectomy.

Purpose Previous studies have indicated that the immune system is involved in the pathogenesis of the AMD. Increased visceral fat, in addition, has a pro-inflammatory effect on the organism by producing or influencing different kinds of inflammatory factors. The aim of this study is to determine the relationship of body fat distribution in patients with age-related macula degeneration in comparison to a control group in the Austrian population. Methods In this case–control study, body weight and height, and body mass index (BMI) were measured for each subject in 54 patients with exudative AMD and compared to 46 gender- and age-matched healthy control subjects. Body composition and abdominal fat areas were measured using dual-energy X-ray absorptiometry (DEXA). Data on age, gender distribution, smoking history and systemic diseases, respectively, were compared. The inflammatory markers CRP, tumour necrosis factor-alpha (TNF-alpha), leptin, amyloid A, amyloid beta and interleukin-6 (IL-6) were assayed by ELISA (R&D). Results DEXA revealed central-abdominal-to-total body fat ratio of 0.073 +/− 0.011 in AMD patients compared to 0.061 +/− 0.013 in the controls (p

In this paper, a statistical model for the land mobile satellite (LMS) channel is presented. The model is capable of describing both narrow- and wide-band conditions. The other relevant characteristic is that it can be used to study links with geostationary as well as nongeostationary satellites. The model is of the generative type, i.e., it is capable of producing time series of a large number of signal features: amplitudes, phases, instantaneous power-delay profiles, Doppler spectra, etc. Model parameters extracted from a comprehensive experimental data bank are also provided for a number of environments and elevation angles at L-, S-, and Ka-bands.

Ka-band (20/30 GHz) will be used extensively for fixed and mobile satellite communications in the next few years, especially for wide-band and multimedia applications. For this reason, a good knowledge of the propagation impairments and adequate propagation models for that frequency range are needed. In this paper, cumulative distribution functions (CDFs) of the received signal variations due to shadowing/blockage events at Ka-band using the 18.7-GHz beacon of the Italsat satellite for a number of representative environment types are presented. Approximate availability levels for three shadowing/blockage margins (5, 10, and 15 dB) are provided for three orientations of the road with respect to the satellite and for different environments: urban, suburban, and tree-shadowed. All measurements correspond to an elevation angle between 28/spl deg/ and 36/spl deg/.

In recent years, obstetrical management reflecting the individual needs of parturient women and newborn children has acquired an increasing significance. Today, the majority of obstetrical departments provide alternatives to traditional methods of delivery. The purpose of this study was to analyze the current obstetric situation as perceived by the women concerned. During the lying-in period spent in the care of the obstetrical department, 386 women were interviewed as to their birth experience. The questionnaire employed used a predominantly structured format. The present study examined a total of six of Vienna's municipal hospitals. The majority of women interviewed were satisfied with the standard of care provided by obstetricians and midwives. However, certain administrative and organizational aspects were subject to criticism, for example, shift changes among the medical staff as well as the presence of an excessive number of people during delivery were felt to detract from the intimate character of giving birth. In general, the standards of care provided by urban obstetrical departments as well as the experience of giving birth itself confirmed women's expectations. However, certain areas remain where improvements seem both desirable and feasible without requiring undue effort. Women who gave a positive assessment of their personal experience of delivery also tended to carry away a favorable impression of their stay in hospital as a whole.

Ultrasound examination of the breast is used in three indications: the premenstrual syndrome, the examination of cyst and the short-time control of high-risk patients. The differential main point is the diagnosis of cysts, which may save the patient from "blind" puncture. In this field, ultrasound is more competent than mammography; furthermore, the oedematous changes occurring before the onset of menstruation can be easily seen with sonography. For the early detection of cancer of the breast, ultrasound is merely additional but its diagnostic value is bound to rise with progressing development.

In this paper a methodology for the characterization of environment-related (shadowing and multipath) propagation effects on multi-satellite systems is presented. This work is focused on availability and performance evaluation of global navigation satellite systems (GNSSs). The definition of next-generation GNSSs specially designed for civil applications requires the precise understanding of propagation effects; these include not only ionospheric and tropospheric but also environmental effects, since a large group of their expected users will no longer be located in open areas with clear visibility of several satellites but in densely built-up areas subject to high blockage probabilities. Issues such as constellation definition, signal design, codeword structure, etc. require the aid of powerful analysis tools. The basic ideas for the specification of such multi-satellite propagation analysis tools are presented. This paper describes part of the work being carried out under European Space Agency (ESA) contract ESA/ESTEC 12223/96/NL/JSC. © 1998 John Wiley & Sons, Ltd.

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.

Breast cancer varies widely in its incidence and associated mortality throughout the world. This paper reviews current breast cancer treatment in central and western Europe against a historic background of changing therapeutic theory and practice. Therapeutic options include radical or conservative surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy and emerging new modalities such as genetic therapy. Historically, mastectomy became accepted as standard treatment on the basis that breast cancer was a purely local disease. Only recently has the realization that breast cancer disseminates at an early stage led to an emphasis on breast-conserving surgery combined with systemic treatment; currently used modalities of these therapies are reviewed, including adjuvant treatment and chemotherapy, together with indications for breast-conserving therapy and mastectomy. The options in hormonal therapy for metastatic disease are also discussed. Key issues for the future include closer collaboration be...

The histological sections of 106 patients, who underwent a primary breast cancer operation in the years 1986 and 1987, were inspected for the presence of tumour vascular invasion. With immunohistochemical methods, tumour vessels were tomographed and the paraffin sections were stained with an antibody, which is sensitive to factor VHI-antigen. A tumour embolus was considered present, if a malignant cell was established within a positively stained lumen. The question of possible influence on the pathogenesis of breast cancer was examined in case of vascular invasion in the histological preparation. In 46 of the 106 patients (43.4 %), tumour emboli were found. After an average observation period of 59 months, no tumour progression was seen in 60 patients, 46 patients developed a recurrence of the tumour at the check-up date. The presence of vascular invasion correlates with undifferentiated tumour grading. The probability of relapse- free survival after 5 years was 83.9 % within the group without vascular invasion, compared with 47.9 % (p = 0.0001) within the group with established vascular invasion. In the multivariate analysis of the factors lymphonodular status, grading and vascular invasion, it was found, that the presence of tumour vascular invasion with a relative risk of 3.68 (95 % CI 1.93 - 7.03) was the strongest statistically significant prognostic factor for relapse - free survival (p = 0.0001).

Sentinel node biopsy is a widely accepted alternative to primary axillary lymph node dissection for ipsilateral nodal assessment in breast cancer. We have performed a retrospective chart review in 713 consecutive patients with primary, operable breast cancer who underwent sentinel node biopsy in order to identify factors that determine the sentinel node identification rate. Chi-squared test, univariate and multivariate analyses were used to evaluate the influence of different factors on the sentinel identification rate. Among the factors investigated, tumour size was correlated with sentinel lymph nodes detection rates (multiple logistic regression, P= 0.002). In addition, the patient's age showed to be a significant influencing factor (multiple logistic regression, P= 0.006). Body mass index and grade only exhibited a significant correlation with the identification rate in the univariate (P= 0.041, P= 0.025), but not in the multivariate analysis (P= not significant). All associations were found to be independent of the site of injection. Interestingly, surgeons with intermediate expertise (11-20 prior dissections) had the highest detection rates (P= 0.004). We conclude that sentinel identification rates are higher in larger tumours and in younger patients, independent of the injection site. Surgical experience in sentinel node dissection is not linearly correlated with higher identification rates.

During the past few years, the intensified detection of small (mammary) carcinomas causes an increase in the number of mammary cancers. Cancer of the mammary tissues has an almost individually unpredictable behavior and aggressiveness. Therefore, a better insight in the molecular biological defects, which are responsible for initiation and progressive aggressiveness of mammary cancer, is necessary. Proteomics are an alternative to identify proteins which initiate carcinogenesis and can be useful to predict cancer prognosis. Today, the most commonly used technique for large-scale protein identification in clinical samples is two-dimensional electrophoresis (2-DE) in combination with image analysis and MS. Using these techniques, qualitative and quantitative information can be achieved regarding protein forms and post-translational modifications. In the following article we review proteomic techniques that are now commonly used in order to elucidate the role of proteins in breast cancer.

In this paper we discuss the results of a measurement campaign investigating the environment of satellite navigation receivers for aeronautical applications, where reflections on the plane as well as from the ground decrease the accuracy of the positioning. The focus is on the most critical flight phase—the final approach. For this scenario a wideband model is derived, which allows to investigate the performance of present and future global navigation satellite systems. The work was carried out under an European Space Agency contract (ESTEC Contract number 16059/02/NL/DS) entitled ‘Navigation signal measurement campaign for critical environments’, by Joanneum Research (Austria) with subcontracts to DLR (Germany) and the University of Vigo (Spain). Copyright © 2007 John Wiley & Sons, Ltd.

Many patients with a history of breast cancer (BC) will suffer from vasomotor symptoms, which can be induced or exacerbated by treatment with tamoxifen or aromatase inhibitors. The LIBERATE trial was designed as a randomized, double-blind, multicenter trial to demonstrate that tibolone 2.5mg/day (Livial) is non-inferior to placebo regarding BC recurrence in women with vasomotor symptoms surgically treated for primary BC within the last 5 years. Secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density and health-related quality of life. Mean age at randomization was 52.6 years, and the mean time since surgery was 2.1 years. The mean daily number of hot flushes and sweating episodes was 7.3 and 6.1, respectively. For the primary tumor, Stage IIA or higher was reported for >70% of the patients. In subjects whose receptor status was known, 78.2% of the tumors were estrogen receptors positive. At randomization, tamoxifen was given to 66.2% of all patients and aromatase inhibitors to 7%. Chemotherapy was reported by 5% at randomization. The adjuvant tamoxifen use in LIBERATE allows a comparison with the Stockholm trial (showing no risk of BC recurrence associated with hormone therapy), which was stopped prematurely subsequent to HABITS. The LIBERATE trial is the largest, ongoing, well-controlled study for treatment of vasomotor symptoms in BC patients.

This paper describes preliminary results from a measurement campaign emulating, by means of a helicopter, the satellite-to-indoor channel at S-band. The modelling approach followed as well as model parameters for some of the measurement scenarios are also provided. (7 pages)

This paper describes the results of a mobile Ka-band experimental campaign carried out in different tree-shadowed environments. Given the narrow antenna beamwidth used only shadowing effects were measured. Statistical results are presented in the form of cumulative distribution functions (CDFs) and link margins.

Zielsetzung: Die Uberexpression von HER-Familienmitgliedern stellt einen bekannten Prognosefaktor dar und identifiziert potentielle Ziele fur die antikorper-basierte Rezeptorblockade. Wahrend viele Studien die Expression von HER2 und anderen Familienmitgliedern in malignem Tumorgewebe untersuchten, ist bisher wenig uber deren Expression und Aktivierungsstatus in nicht-malignem Brustgewebe von Brustkrebspatientinnen bekannt. Material und Methoden: Wir haben die Expression von EGFR, HER2 und ihren aktivierten Formen (ptyr-1248 HER2 und ptyr-845 EGFR) in 63 Tumorgewebsproben, welche malignes, epitheliales Gewebe (a), nicht-malignes Gewebe dem Tumor unmittelbar benachbart (b) und nicht-malignes Gewebe vom Tumor entfernt (c) beeinhalten, mittels Immunhistochemie untersucht. Ergebnisse: Wir fanden eine signifikant hohere HER2-Expression im malignen, epithelialen Gewebe als im nicht-malignen benachbarten und peripheren Gewebe (p=1,3×10–10 Fisher's Exact Test). Die epitheliale EGFR-Expression war in allen drei Gewebstypen (a-c) gleich, nur die stromale EGFR-Expression war im nicht-malignen Gewebe signifikant hoher als im Tumorgewebe (p=0,008 Fisher's Exact Test). Bei den aktivierten Rezeptorformen fanden wir epitheliale ptyr-1248 HER2-Expression in einer malignen, einer nicht-malignen benachbarten sowie peripheren Gewebsprobe. Wir beobachteten in keiner der drei Gewebstypen aktiviertes EGFR (ptyr845). Wir fanden eine signifikante Korrelation zwischen epithelialer und stromaler EGFR-Expression (r=0,442; p

The activator protein-1 (AP-1) is a dimeric transcription factor formed by members of the Jun and Fos protein family. AP-1 plays a role in a variety of physiological functions including cell proliferation and differentiation, although both c-Jun and c-Fos have also been implicated in oncogenic transformation and tumor progression. To further elucidate the role of AP-1 in breast cancer, we have investigated the expression of the AP-1 proteins c-Jun, JunB, JunD, phosphorylated c-Jun, c-Fos, Fral, Fra2 and the tumor supressor protein p53.Protein expression was evaluated on a breast cancer tissue microarray with 58 lymph node positive or negative breast cancer specimens, 29 corresponding lymph node metastases, and 11 tissue samples from surrounding tumor-free tissue, each cored as triplicate. Jun and Fos protein family expression was evaluated by immunohistochemistry and was correlated with clinicopathological parameters.High expression levels were observed for c-Jun, JunD, c-Fos and Fra2, whereas JunB and Fral exhibited lower staining. c-Jun protein expression was correlated to Fral staining (p = 0.007, Kendall's Tau) and Fral was further associated with c-Fos (p0.001), JunD (p = 0.001) and Fra2 (p = 0.011) expression. JunD expression correlated with c-Fos (p0.001), JunB (p = 0.035) and c-Jun (p = 0.05). Activated c-Jun correlated with c-Fos expression (p = 0.041). JunB was negatively correlated to tumor stage, (p = 0.093, corr coeff. = -0.293, Spearman's correlation) but was significantly increased in nodal negative tumors (p = 0.004, Mann Whitney test). In addition, increased Fral expression showed a trend towards an increased overall survival (p = 0.077, RR = 0.534, Cox regression).Our results suggest an important role for JunB and Fral in the biological behavior of malignant breast tumors.

Das Mammakarzinom ist die haufigste Krebserkrankung bei Frauen, wobei vor allem peri- und postmenopausale Patientinnen betroffen sind. Aufgrund verbesserter Fruherkennungs-masnahmen und der effektiveren Primartherapie erreicht aber auch eine zunehmende Zahl pramenopausaler Patientinnen mit Brustkrebs die Menopause und ist – so wie alle anderen Frauen – deren Problemen und Symptomen ausgesetzt. Hinweise, das eine langer dauernde Ostrogentherapie das Mammakarzinomrisiko steigert, mehren sich und haben neuerlich zu Diskussionen uber die Frage der Hormonersatztherapie nach Brustkrebs gefuhrt. Bis jetzt liegen zu dieser Frage allerdings weder grosere Fallzahlen vor, noch kann uber das Ergebnis randomisierter Studien berichtet werden. Aus den bisher bekannten Daten last sich ein nachteiliger Effekt einer Hormonersatztherapie (mit Ostrogenen und Gestagenen) nach Brustkrebs nicht nachweisen. Die Fallzahlen sind jedoch gering und die Beobachtungszeiten kurz. Bis zum Vorliegen gesicherter Daten ist daher bei jeder Patientin eine individuelle Vorgangsweise angezeigt, bei der das Risiko menopausaler Erkrankungen gegen das Risiko einer Brustkrebserkrankung und vor allem deren Wiederauftreten abgewogen werden mus. Eine generelle Empfehlung kann nicht gegeben werden. Grose Hoffnung liegt in der Entwicklung neuer antiostrogener Substanzen, welche selektiv das Brustdrusengewebe schutzen, in anderen Organsystemen aber die erwunschte ostrogene Wirkung entfalten.

Zielsetzung: Die tumorale Uberexpression des Her-2/neu Rezeptors ist mit einem aggressivem Wachstumsverhalten und einer ungunstigen Prognose verbunden. Obwohl Trastuzumab (Herceptin®) eine wesentliche Therapieoption fur die Behandlung Her-2/neu-uberexprimierender Tumoren darstellt, profitiert nur ein bestimmter Anteil der Patientinnen von der Antikorpergabe. Rezente Studien weisen auf eine wechselseitige Beeinflussung der Her-2/neu und EGFR-Rezeptoraktivierung und der damit verbundenen Signalwirkung hin. Das Ziel der vorliegenden Studie bestand darin, die Phosphorylierung bzw. Aktivierung des EGFR und Her-2/neu Rezeptors als moglichen pradiktiven Parameter fur den Therapieerfolg bei Patientinnen unter Trastuzumab (Herceptin) zu untersuchen. Material und Methoden: Der Aktivitatszustand beider Rezeptoren wurde immunohistochemisch mittels phospho-spezifischer Antikorper (pTyr1248, pTyr845, pTyr1173)) aus Tumormaterial von 46 Patientinnen mit metastasiertem, Her-2/neu uberexprimierenden Mammakarzinom bestimmt, die Spezifitat der verwendeten Antikorper mittels Western Blot evaluiert. Ergebnisse: Die Aktivierung des Her-2/neu Rezeptors konnte in 9 (20%), die des EGFR Rezeptors jeweils in 6 (13%) der Patientinnen nachgewiesen werden. Patientinnen mit aktivierten Her-2/neu und/oder EGFR wiesen signifikant hohere Ansprechraten im Vergleich zu nicht aktivierten Tumoren (p=0.021; p=0.021) auf, die alleinige Aktivierung des Her-2/neu tendierte zu hoheren Ansprechraten auf Trastuzumab (p=0.063). Weiters wiesen Patientinnen mit aktivierten Her-2/neu als auch jene mit aktiviertem EGFR ein signifikant verlangertes progressionsfreies Uberleben unter Herceptingabe auf (p=0.01; p=0.021), wobei Patientinnen mit aktiviertem EGFR auch zu einem langeren Gesamtuberleben tendierten (p=0.08). Zusammenfassung: Die Bestimmung des Aktivitatszustandes des Her-2/neu als auch EGFR Rezeptors konnte einen pradiktiven Stellenwert bezuglich dem Therapieansprechen unter Trastuzumab besitzen und sollte unter Einbeziehung groserer Patientenkollektive evaluiert werden.