Reference Curve for the Mean Uterine Artery Pulsatility Index in Singleton Pregnancies.

INTRODUCTION: Doppler sonography of the uterine artery (UA) is done to monitor pregnancies, because the detected flow patterns are useful to draw inferences about possible disorders of trophoblast invasion. Increased resistance in the UA is associated with an increased risk of preeclampsia and/or intrauterine growth restriction (IUGR) and perinatal mortality. In the absence of standardized figures, the normal ranges of the various available reference curves sometimes differ quite substantially from one another. The causes for this are differences in the flow patterns of the UA depending on the position of the pulsed Doppler gates as well as branching of the UA. Because of the discrepancies between the different reference curves and the practical problems this poses for guideline recommendations, we thought it would be useful to create our own reference curves for Doppler measurements of the UA obtained from a singleton cohort under standardized conditions. MATERIAL AND METHODS: This retrospective cohort study was carried out in the Department of Obstetrics of the Charité - Universitätsmedizin Berlin, the Department for Obstetrics and Prenatal Medicine of the University Hospital Halle (Saale) and the Center for Prenatal Diagnostics and Human Genetics Kurfürstendamm 199. Available datasets from the three study locations were identified and reference curves were generated using the LMS method. Measured values were correlated with age of gestation, and a cubic model and Box-Cox power transformation (L), the median (M) and the coefficient of variation (S) were used to smooth the curves. RESULTS: 103 720 Doppler examinations of the UA carried out in singleton pregnancies from the 11th week of gestation (10 + 1 GW) were analyzed. The mean pulsatility index (Mean PI) showed a continuous decline over the course of pregnancy, dropping to a plateau of around 0.84 between the 23rd and 27th GW, after which it decreased again. CONCLUSION: Age of gestation, placental position, position of pulsed Doppler gates and branching of the UA can all change the flow pattern. The mean pulsatility index (Mean PI) showed a continuous decrease over time. There were significant differences between our data and alternative reference curves. A system of classifying Doppler studies and a reference curve adapted to the current technology are urgently required to differentiate better between physiological and pathological findings.

Epidermal growth factor receptor changes during breast cancer metastasis.

BACKGROUND: Since the anti-HER2 monoclonal antibody trastuzumab made its triumphant advance into breast cancer therapy, new selective agents, including pan-HER inhibitors are entering clinical practice. MATERIALS AND METHODS: This study investigates the expression of the four HER-family members, HER1-4, in 48 primary breast carcinomas (PBC) and corresponding distant metastases (CDM) by immunohistochemistry and fluorescence in situ hybridisation. RESULTS: Concordance rate between PBC and CDM was 79% for HERI and HER2, 67% for HER3 and 56% or HER4. Expression of HER1-3 was associated with poor prognosis compared to HER-negative disease (p = 0.036). HER4 overexpression was associated with a better outcome (p = 0.003). CONCLUSION: Though most tumours demonstrate a stable HER expression pattern, both loss and acquisition of HER receptor overexpression can occur during metastasis. HER4 overexpression predicts prolonged survival compared to receptor negative disease, while the opposite is true for HER1-3. Consequences for modem antibody therapy are discussed.

Analysis of HER2 and HER4 in human myocardium to clarify the cardiotoxicity of trastuzumab (Herceptin).

PURPOSE: When combined with anthracyclines, the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) provides significant clinical benefit for women with HER2-overexpressing metastatic breast cancer. However, its use is limited by severe cardiotoxicity. To clarify whether myocardial HER2 and HER4 expression in response to anthracycline exposure and cardiac damage contributes to cardiotoxicity, we assessed expression of HER2 and HER4 in pathologically altered myocardium. EXPERIMENTAL DESIGN: Cardiac biopsies from 60 patients with severe heart disease and cardiac tissue from 35 patients with breast cancer were obtained. Twenty-five of the patients with breast cancer had previously received anthracyclines. Three of 10 anthracycline-naïve patients with breast cancer had received trastuzumab. Expression of HER2 and HER4 was analyzed immunohistochemically (HER2: HercepTest/A0485 (Dako), Cy3 detection (Dianova); HER4: Ab-4 (NeoMarkers)). FISH analysis (Ventana) was used to assess HER2 gene amplification. RESULTS: Immunohistochemistry revealed weak HER2 membrane staining in six cardiac biopsies, appearing as dotted staining of the whole cell membrane and intensified HER2 signal using fluorescent Cy3 labeling. No HER2 membrane staining was detected in the remaining 54 cardiac biopsies or in the myocardium of the 35 patients with breast cancer. HER2 gene amplification was not observed. All specimens showed the mild cytoplasmatic HER4 staining of normal myocardium. No strong HER4 expression was detected. CONCLUSIONS: Cardiac alterations are not associated with an strong increase in HER2 and HER4 levels. IHC detects potential low-level HER2 expression in some samples. However, a more sensitive technique may be needed for studies of the role of HER2 in cardiac tissue. These data do not exclude a role for inhibition of cardiac HER2 expression by trastuzumab in the onset of heart failure in trastuzumab-treated patients.

The prognostic significance of epithelial-mesenchymal transition in breast cancer.

BACKGROUND: This study investigates the influence of epithelial-mesenchymal transition on prognosis in breast cancer. MATERIALS AND METHODS: Eighty breast carcinomas as well as 6 breast cancer cell lines were analysed immunohistochemically for the expression of epithelial keratins (K) K8, K19 and mesenchymal vimentin. Protein expression was correlated with histopathological factors and clinical follow-up. RESULTS: Suppression of K8 and K19 occurred in the majority of the tumours (72.5% and 65%), while aberrant expression of vimentin was found in 21.2% of the tumours. Suppression of K8 as well as expression of vimentin was significantly correlated with short survival (p < 0.004 and p < 0.006). Moreover HER2 overexpression significantly correlated with K19 (p < 0.0004) and vimentin (p < 0.0005). In cell lines with increasing invasive potential, epithelial keratins were lost in favour of mesenchymal vimentin. CONCLUSION: The transition from epithelial keratin to mesenchymal vimentin expression marks an important step in the malignant progression of breast cancer.