H. Junkermann

Pathophysiologic basis of contrast enhancement in breast tumors

While the diagnostic benefits of gadolinium (Gd)‐chelate contrast agents are firmly established in magnetic resonance imaging (MRI) of tumors, the pathophysiologic basis of the enhancement observed and its histopathologic correlate remained vague. Tumor angiogenesis is fundamental for growth and metastasis and also of interest in new therapeutic concepts. By correlative analysis of a) histology; b) vascular density (CD31); and c) vascular permeability (vascular permeability factor/vascular endothelial growth factor [VPF/VEGF]), we found a) significantly (Pu2009<u20090.001) faster exchange rates in malignant compared with benign breast lesions; b) distinct differences in enhancement characteristics between the histologic types (invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ); and c) dependence of enhancement kinetics on the VPF/VEGF expression. The pathophysiologic basis for the differences in contrast enhancement patterns of tumors detectable by MRI is mainly due to vascular permeability, which leads to more characteristic differences than vascular density. MRI is able to subclassify malignant breast tumors due to their different angiogenetic properties. J. Magn. Reson. Imaging 1999;10:260–266.

Circulating microRNAs in plasma as early detection markers for breast cancer

In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time‐point of diagnosis) and healthy control individuals using TaqMan low‐density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT‐qPCR. Four miRNAs (miR‐148b, miR‐376c, miR‐409‐3p and miR‐801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR‐148b, miR‐409‐3p and miR‐801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood‐based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests.

Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution.

Abstract. The aim of this study was to evaluate changes in both size and contrast enhancement of breast tumors during neoadjuvant chemotherapy, using dynamic MRI with high temporal resolution. Patients with advanced breast cancer (n=21) underwent a 1.5-T MRI scan prior to and following neoadjuvant chemotherapy with four cycles. Dynamic contrast enhancement was measured using a fast turbo-FLASH sequence and quantified using a two-compartment model with the parameters kep and amplitude. Image analysis was done on images overlayed with a color map of parameters. The correlation between tumor diameter measured by histopathology and MRI was 0.7 (p<0.003). A reduction of tumor size after chemotherapy of more than 25% was associated with a decrease of both analyzed contrast enhancement parameters (kep: p<0.002; amplitude: p<0.006), where kep began to drop already after the first cycle of chemotherapy (p<0.008). A clear reduction of tumor size was only noted after the third cycle (p<0.008). In patients without tumor regression there was also a trend towards an early reduction of contrast enhancement.We assume that MRI with high temporal resolution and color mapping is a novel tool to assess therapeutic effects of neoadjuvant chemotherapy in breast tumors, which deserves further prospective evaluation.

Plasma microRNA panel for minimally invasive detection of breast cancer.

Over the last few years, circulating microRNAs (miRNAs) have emerged as promising novel and minimally invasive markers for various diseases, including cancer. We already showed that certain miRNAs are deregulated in the plasma of breast cancer patients when compared to healthy women. Herein we have further explored their potential to serve as breast cancer early detection markers in blood plasma. Circulating miR-127-3p, miR-376a and miR-652, selected as candidates from a miRNA array-based screening, were found to be associated with breast cancer for the first time (nu200a=u200a417). Further we validated our previously reported circulating miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) in an independent cohort (nu200a=u200a210) as elevated in the plasma of breast cancer patients compared to healthy women. We described, for the first time in breast cancer, an over-representation of deregulated miRNAs (miR-127-3p, miR-376a, miR-376c and miR-409-3p) originating from the chromosome 14q32 region. The inclusion of patients with benign breast tumors enabled the observation that miR-148b, miR-652 and miR-801 levels are even elevated in the plasma of women with benign tumors when compared to healthy controls. Furthermore, an analysis of samples stratified by cancer stage demonstrated that miR-127-3p, miR-148b, miR-409-3p, miR-652 and miR-801 can detect also stage I or stage II breast cancer thus making them attractive candidates for early detection. Finally, ROC curve analysis showed that a panel of these seven circulating miRNAs has substantial diagnostic potential with an AUC of 0.81 for the detection of benign and malignant breast tumors, which further increased to 0.86 in younger women (up to 50 years of age).

Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS), mammography and pathology results

OBJECTIVESnHandheld breast ultrasound (HHUS) lacks standardization and reproducibility. The automated breast volume scanner (ABVS) could overcome this limitation. To analyze the interobserver reliability of ABVS and the agreement with HHUS, mammography and pathology is the aim of this study.nnnMETHODSnAll 42 study participants (=84 breasts) received an ABVS examination in addition to the conventional breast diagnostic work-up. 25 breasts (30%) showed at least one lesion. The scans were interpreted by six breast diagnostic specialists blinded to results of breast imaging and medical history. 32 lesions received histological work-up: 20 cancers were detected. We used kappa statistics to interpret agreement between examiners and diagnostic instruments.nnnRESULTSnOn the basis of the Breast Imaging Reporting and Data System (BI-RADS) classification of the 84 breasts an agreement (defined as ≥4 of 6 examiners) was achieved in 63 cases (75%) (mk=0.35) and even improved when dichotomizing the interpretation in benign (BI-RADS 1, 2) and suspicious (BI-RADS 4, 5) to 98% (mk=0.52). Agreement of ABVS examination to HHUS, mammography and pathology was fair to substantial depending on the specific analysis.nnnCONCLUSIONSnThe development of an ABVS seems to be a promising diagnostic method with a good interobserver reliability, as well as a comparable good test criteria as HHUS.

Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ).

OBJECTIVEnTo evaluate normal breast tissue stiffness with virtual touch tissue imaging quantification (VTIQ) using prospectively collected data.nnnMATERIALS AND METHODSnB-mode ultrasound and VTIQ were performed in 132 breasts in 97 women. Mean values of VTIQ for parenchyma and fatty tissue were compared between those measured in healthy breasts and in the surrounding of histologically proven benign and malignant breast lesions. Moreover we reviewed VTIQ values according to breast density measured by the American College of Radiology (ACR) categories. In addition we analyzed re-test reliability of VTIQ.nnnRESULTSnIn 132 breasts the mean VTIQ values in parenchyma were significantly higher than in fatty tissue (3.23 m/s ± 0.74 versus 2.5 m/s ± 0.61; p<0.0001). In healthy breasts as well as in the surrounding of a benign or malignant lesions the VTIQ values of parenchyma were similar (p=0.12). In fatty tissue, small differences between mean VTIQ values of 2.25 m/s ± 0.51, 2.52 m/s ± 0.48 and 2.65 m/s ± 0.71 (p=0.01) in the respective groups were observed. The comparison of mean VTIQ values of parenchyma and fatty tissue in more and less dense breasts (ACR 1+2 versus ACR 3+4 breasts) also yielded no statistically significant difference. The re-test reliability of VTIQ assessed with three independent measurements was moderate (interclass-correlation of 0.52 (p<0.0001)).nnnCONCLUSIONnVTIQ is a reliable method for measuring the stiffness of breast tissue. We propose standard values for healthy parenchyma and fatty tissues independent of the surrounding tissue or the ACR category.

Outcome analysis of patients with primary breast cancer initially treated at a certified academic breast unit.

INTRODUCTIONnEvaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit.nnnPATIENTS AND METHODSnWe prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses.nnnRESULTSnOf all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS.nnnCONCLUSIONnCompared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.

Konzept und Durchführung der Modellprojekte für Mammographiescreening in Deutschland

ZusammenfassungDie gemeinsame Selbstverwaltung im Gesundheitswesen ist zu der Erkenntnis gekommen, dass nur ein Mammographiescreening nach den europäischen Leitlinien in der Lage ist, eine Brustkrebsfrüherkennung mit vertretbarem Nutzen-Risiko-Verhältnis durchzuführen. Die deutschen Modellprojekte für Mammographiescreening sollen deshalb regional ein Mammographiescreening nach den europäischen Leitlinien unter den Bedingungen des deutschen Gesundheitssystems erproben. Die europäischen Leitlinien für das mammographische Screening fordern eine umfassende Qualitätssicherung aller relevanten Schritte der Screeningkette von der Einladung bis zur Therapie und Nachbehandlung, die auch in den Ländern, die das Screening schon etabliert haben, erst im Rahmen seiner Einführung entwickelt wurde. Diese Art des umfassenden Qualitätsmanagements erfordert die Einbeziehung einer Vielzahl von ärztlichen Fachdisziplinen, Assistenz- und Pflegeberufen über die Grenzen der ambulanten und stationären Strukturen hinaus und die langfristige Kooperation mit staatlichen Institutionen (Einwohnermeldeamt, Krebsregister). Aufgabe der Modellprojekte ist es die organisatorischen und rechtlichen Voraussetzungen zu überprüfen, um ein mammographisches Screeningprogramm nach den europäischen Leitlinien flächendeckend in Deutschland einführen zu können.AbstractThe carriers of the German Statutory Health Care System have recognized that only mammographic screening according to the European Guidelines for the Quality Assurance of Mammograpyh Screening will permit early detection of breast cancer with an acceptable risk/benefit ratio. In the German pilot projects, regional mammography screening programmes according to the European guidelines are being tested in the framework of the German health care system. The European guidelines require comprehensive quality assurance of all relevant steps in the chain of events involved in screening, from invitation on to therapy and follow-up. Such comprehensive quality assurance involves several medical specialities and other professional groups dealing with out-patient and in-patient health care and requires long-term cooperation with public institutions (population registries, cancer registries). The objective of the pilot projects is to test the organizational and legal conditions essential to introduction of a mammographic screening programme according to the European quality assurance guidelines in Germany.

Prediction of underestimated invasiveness in patients with ductal carcinoma in situ of the breast on percutaneous biopsy as rationale for recommending concurrent sentinel lymph node biopsy

AIMnTo develop a model to predict invasion and improve the indication of concurrent sentinel lymph node biopsy (SLNB) for patients with ductal carcinoma in situ (DCIS) on minimally invasive biopsy.nnnMETHODSnWe evaluated the data of 205 patients with DCIS in minimally invasive biopsy specimens. Clinical, radiological and histological variables were assessed in order to identify predictors of invasive carcinoma in final pathology using logistic regression analyses. We developed and retrospectively tested an algorithm to indicate concurrent SLNB.nnnRESULTSnInvasiveness was underestimated in 18.0% (37 of 205). Univariate analysis revealed the following significant risk factors: lesion palpability, a mass lesion on ultrasound, the presence of a mammographically detectable mass, architectural distortion or density, a BI-RADS score of 5, a lesion diameter ≥50xa0mm, and ≥50% of histologically affected ducts. With a palpable mass, which remained the only independent predictor of invasion after multivariate adjustment, and the presence of at least three of the remaining five risk factors, the probability of invasion was 56.0%. If the prediction model had been used to indicate SLNB 9.8% (20 of 205) of patients could have been benefited (i.e. spared unnecessary or correctly recommended concurrent SLNB) compared to the factual performed SLNB procedures. Those patients with pure DCIS treated with breast conserving surgery (BCS) benefited most with a relative risk reduction of nearly 50% for unnecessary SLNB.nnnCONCLUSIONnThe prediction model could rationally guide an informed discussion about risks and benefits of concurrent SLNB in patients with DCIS on minimally invasive biopsy.

Steroids in human myometrium and peripheral blood during the menstrual cycle.

Blood samples were collected prior to vaginal hysterectomy from nine women in the proliferative phase of the cycle and from 15 women in the secretory phase, and from each uterus five grams of the fundus were obtained. The concentrations of progesterone (P), 20alpha-dihydroprogesterone (20alpha-DHP), estradiol-17beta (E2), and estriol (E3) were determined in serum and in the tissue with the use of specific radioimmunoassays. The concentrations of P and 20alpha-DHP in serum and myometrium were significantly higher in the secretory than in the proliferative phase. Furthermore, the concentration of P in myometrium was significantly higher than in serum in the secretory phase, indicating a specific uptake of P by the myometrium. The concentration of E2 was about 10 times higher in the myometrium than in the serum during both phases of the cycle and appeared to be independent of the serum levels. This indicates a specific but limited uptake of E2 by the myometrium. The E3 levels in the tissue showed no significant differences during the menstrual cycle, whereas in the serum the E3 concentrations were higher in the secretory than in the proliferative phase of the cycle.