Rüdiger Schulz-Wendtland

Circulating micro-RNAs as potential blood-based markers for early stage breast cancer detection.

Introduction MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls. Methods We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718). Results Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA-expression were found for miR-202. Conclusions MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use.

Determination of average glandular dose with modern mammography units for two large groups of patients

Until recently, for mammography Mo anode-Mo filter x-ray tube assemblies were almost exclusively used. Modern mammography units provide the possibility to employ a variety of anode-filter combinations with the aim of adapting the x-ray spectrum to compressed breast thickness and composition. The present contribution provides information on the radiation exposure of two large groups of patients (one of 1678 and one of 945 women) who were mammographed with modern x-ray equipment, and on the dosimetry necessary for the evaluation. For dosimetric purposes spectral information is essential. X-ray spectra have been determined for various anode-filter combinations from measurements with a Ge detector. Based on these spectra, conversion factors from air kerma free in air to average glandular dose (g factors) have been calculated for different anode-filter combinations, compressed breast thickness ranging from 2 to 9 cm and breast compositions varying from 0 to 100% glandular tissue. Determinations of various quantities, including entrance surface air kerma (ESAK), tube output, tube loading (TL), fraction of glandular tissue (FGL) and compressed breast thickness, were made during actual mammography. Average glandular dose (AGD) was determined using g factors corrected for tissue composition as well as g values for standard breast composition, i.e. 50% adipose tissue and 50% glandular tissue by mass. It is shown that, on average, the influence of the actual breast composition causes variations of the order of about 15%. For group 1 and group 2, the mean values of average glandular dose (using g factors corrected for tissue composition) were 1.59 and 2.07 mGy respectively. The number of exposures per woman was on average 3.4 and 3.6 respectively. The mean value of compressed breast thickness was 55.9 and 50.8 mm respectively. The mean age of group 1 was 53.6 years (for group 2 the age was not recorded). The fraction by mass of glandular tissue FGL decrease with increasing compressed breast thickness and age of patient (from 75% at 25 mm to 20% at 80 mm, and from 65% at 20 years to 30% at 75 years). For a medium-sized breast, i.e. a compressed breast thickness of 55 mm, FGL is about 35%, indicating that the standard mix (FGL = 50%) might need some modification, particularly because of additional evidence from another investigation with similar results on FGL.

On a dark-field signal generated by micrometer-sized calcifications in phase-contrast mammography

We show that a distribution of micrometer-sized calcifications in the human breast which are not visible in clinical x-ray mammography at diagnostic dose levels can produce a significant dark-field signal in a grating-based x-ray phase-contrast imaging setup with a tungsten anode x-ray tube operated at 40 kVp. A breast specimen with invasive ductal carcinoma was investigated immediately after surgery by Talbot-Lau x-ray interferometry with a design energy of 25 keV. The sample contained two tumors which were visible in ultrasound and contrast-agent enhanced MRI but invisible in clinical x-ray mammography, in specimen radiography and in the attenuation images obtained with the Talbot-Lau interferometer. One of the tumors produced significant dark-field contrast with an exposure of 0.85 mGy air-kerma. Staining of histological slices revealed sparsely distributed grains of calcium phosphate with sizes varying between 1 and 40 μm in the region of this tumor. By combining the histological investigations with an x-ray wave-field simulation we demonstrate that a corresponding distribution of grains of calcium phosphate in the form of hydroxylapatite has the ability to produce a dark-field signal which would-to a substantial degree-explain the measured dark-field image. Thus we have found the appearance of new information (compared to attenuation and differential phase images) in the dark-field image. The second tumor in the same sample did not contain a significant fraction of these very fine calcification grains and was invisible in the dark-field image. We conclude that some tumors which are invisible in x-ray absorption mammography might be detected in the x-ray dark-field image at tolerable dose levels.

Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008

ZusammenfassungDie aktualisierte Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008 vermittelt den wissenschaftlichen Kenntnisstand in evidenz- und konsensbasierter Form und ist unter Beteiligung der Deutschen Gesellschaft für Chirurgie e.V, der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen e.V. und 29 weiterer Fachgesellschaften, Berufsverbänden und nichtärztlichen Organisationen erstellt. Ziel der Stufe-3-Leitlinie ist es, Ärzte sowie gesunde und betroffene Frauen durch evidenzbasierte und formal konsentierte Empfehlungen bei anstehenden medizinischen Entscheidungen im Rahmen der Diagnosekette zur Früherkennung von Brustkrebs zu unterstützen. Die Leitlinie umfasst neben den Empfehlungen zur Diagnosekette die Beschreibung zur Ausgestaltung der Qualitätssicherung von Struktur-, Prozess- und Ergebnisqualität (Outcomes) sowie deren Evaluation durch einen Qualitätsindikatorensatz.Die aktualisierte Stufe-3-Leitlinie 2008 löst die 2003 erstellte Leitlinie ab.Die Leitlinienempfehlungen werden dargestellt. Die Details sind der Publikation in Geburtsh Frauenh 2008; 68: 251–26 zu entnehmen. Die Langfassung der Leitlinie ist als Buch im W. Zuckschwerdt Verlag GmbH/München erschienen und ist, wie der Methodenreport und der Evidenzreport auch, über die Internetseite www.awmf-leitlinien.de (Reg.: Nr. 077/001) frei zugänglich.AbstractThe updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guideline’s recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251–261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.The updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guidelines recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251-261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.

Digital mammography: An update

Digital mammography has increasingly replaced conventional film-screen mammography and has become the gold standard in combination with soft copy reading in diagnostic as well as screening settings. Large international multi-center trials were able to demonstrate at least equivalence and for some aspects superiority of digital over conventional mammography with regard to detectability of breast cancer, especially in pre/perimenopausal women, women younger than 50 years and generally in dense breasts. Especially the experienced reader may benefit form CAD with an increase of specificity. Additionally digital mammography offers options of advanced processing such as digital tomosynthesis and contrast enhanced mammography. The future of breast imaging will be fusion of different imaging systems (hybrid systems).

Characterizing mammographic images by using generic texture features

IntroductionAlthough mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design.MethodsA case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model.ResultsOf the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model.ConclusionsUsing texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy.

Association of mammographic density with hormone receptors in invasive breast cancers: results from a case-only study.

For many breast cancer (BC) risk factors, there is growing evidence concerning molecular subtypes for which the risk factor is specific. With regard to mammographic density (MD), there are inconsistent data concerning its association with estrogen receptor (ER) and progesterone receptor (PR) expression. The aim of our study was to analyze the association between ER and PR expression and MD. In our case‐only study, data on BC risk factors, hormone receptor expression and MD were available for 2,410 patients with incident BC. MD was assessed as percent MD (PMD) using a semiautomated method by two readers for every patient. The association of ER/PR and PMD was studied with multifactorial analyses of covariance with PMD as the target variable and including well‐known factors that are also associated with MD, such as age, parity, use of hormone replacement therapy, and body mass index (BMI). In addition to the commonly known associations between PMD and age, parity, BMI and hormone replacement therapy, a significant inverse association was found between PMD and ER expression levels. Patients with ER‐negative tumors had an average PMD of 38%, whereas patients with high ER expression had a PMD of 35%. A statistical trend toward a positive association between PMD and PR expression was also seen. PMD appears to be inversely associated with ER expression and may correlate positively with PR expression. These effects were independent of other risk factors such as age, BMI, parity, and hormone replacement therapy, possibly suggesting other pathways that mediate this effect.

Grating-based darkfield imaging of human breast tissue

Mastectomy specimens were investigated using a Talbot-Lau X-ray imaging set-up. Significant structures in the darkfield were observed, which revealed considerably higher contrast than those observed in digital mammography. Comparison with the histomorphometric image proofs that the darkfield signal correlates with a tumor region containing small calcification grains of 3 to 30μm size.

Pathologic breast conditions in childhood and adolescence: evaluation by sonographic diagnosis.

The growing awareness of female breast cancer has led to increased sensitivity toward pathologic breast conditions in children and adolescents. Thus, approximately 15% of patients in child and adolescent gynecology are referred for the first time because of conspicuous features of the breast such as pain, palpable masses, and other findings on visual inspection. The aim of this study was to analyze the underlying diagnoses and diseases and determine the status of breast sonography in the diagnostic process.

2008 update of the guideline: early detection of breast cancer in Germany

IntroductionThe goal of the 2008 updated guideline: early detection of breast cancer in Germany is to support physicians as well as healthy and affected women in the decision-making process involved in the diagnostic chain for the early detection of breast cancer by providing them with evidence- and consensus-based recommendations. The updated guideline replaces the guideline issued in 2003.Materials and methodsThe guideline forms the basis for developing an effective and efficient national early breast cancer detection program that meets the standards set by the Council of Europe and WHO for cancer control programs. The guideline presents the current, evidence- and consensus-based state of scientific knowledge in a multidisciplinary approach for the entire diagnostic chain, consisting of history taking and risk consultation, information on health behavior, clinical breast examination, diagnostic imaging, image-guided percutaneous tissue-acquisition techniques, open surgical excisional biopsy and pathomorphological tissue evaluation. The guideline recommends a set of quality indicators to assure resource availability, performance quality and outcomes enhancing total quality management for early breast cancer diagnosis.Conclusion Currently, early detection of breast cancer offers the most promising possibility to optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality and improve health related quality of life in women.