Peter Regitnig

Magnetic resonance imaging of the breast: Recommendations from the EUSOMA working group

The use of breast magnetic resonance imaging (MRI) is rapidly increasing. EUSOMA organised a workshop in Milan on 20-21st October 2008 to evaluate the evidence currently available on clinical value and indications for breast MRI. Twenty-three experts from the disciplines involved in breast disease management - including epidemiologists, geneticists, oncologists, radiologists, radiation oncologists, and surgeons - discussed the evidence for the use of this technology in plenary and focused sessions. This paper presents the consensus reached by this working group. General recommendations, technical requirements, methodology, and interpretation were firstly considered. For the following ten indications, an overview of the evidence, a list of recommendations, and a number of research issues were defined: staging before treatment planning; screening of high-risk women; evaluation of response to neoadjuvant chemotherapy; patients with breast augmentation or reconstruction; occult primary breast cancer; breast cancer recurrence; nipple discharge; characterisation of equivocal findings at conventional imaging; inflammatory breast cancer; and male breast. The working group strongly suggests that all breast cancer specialists cooperate for an optimal clinical use of this emerging technology and for future research, focusing on patient outcome as primary end-point.

Anisotropic Mechanical Properties of Tissue Components in Human Atherosclerotic Plaques

Knowledge of the biomechanical properties of human atherosclerotic plaques is of essential importance for developing more insights in the pathophysiology of the cardiovascular system and for better predicting the outcome of interventional treatments such as balloon angioplasty. Available data are mainly based on uniaxial tests, and most of the studies investigate the mechanical response of fibrous plaque caps only. However, stress distributions during, for example, balloon angioplasty are strongly influenced by all components of atherosclerotic lesions. A total number of 107 samples from nine human high-grade stenotic iliac arteries were tested; associated anamnesis of donors reported. Magnetic resonance imaging was employed to test the usability of the harvested arteries. Histological analyses has served to characterize the different tissue types. Prepared strips of 7 different tissue types underwent cyclic quasistatic uniaxial tension tests in axial and circumferential directions; ultimate tensile stresses and stretches were documented. Experimental data of individual samples indicated anisotropic and highly nonlinear tissue properties as well as considerable interspecimen differences. The calcification showed, however a linear property, with about the same stiffness as observed for the adventitia in high stress regions. The stress and stretch values at calcification fracture are smaller (179 +/- 56 kPa and 1.02 +/- 0.005) than for each of the other tissue components. Of all intimal tissues investigated, the lowest fracture stress occurred in the circumferential direction of the fibrous cap (254.8 +/- 79.8 kPa at stretch 1.182 +/- 0.1). The adventitia demonstrated the highest and the nondiseased media the lowest mechanical strength on average.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer

PURPOSE We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. METHODS A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). RESULTS The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. CONCLUSION The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

Aims: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. Methods: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. Results: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. Conclusions: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Determination of the layer-specific distributed collagen fibre orientations in human thoracic and abdominal aortas and common iliac arteries

The established method of polarized microscopy in combination with a universal stage is used to determine the layer-specific distributed collagen fibre orientations in 11 human non-atherosclerotic thoracic and abdominal aortas and common iliac arteries (63 ± 15.3 years, mean ± s.d.). A dispersion model is used to quantify over 37 000 recorded fibre angles from tissue samples. The study resulted in distinct fibre families, fibre directions, dispersion and thickness data for each layer and all vessels investigated. Two fibre families were present for the intima, media and adventitia in the aortas, with often a third and sometimes a fourth family in the intima in the respective axial and circumferential directions. In all aortas, the two families were almost symmetrically arranged with respect to the cylinder axis, closer to the axial direction in the adventitia, closer to the circumferential direction in the media and in between in the intima. The same trend was found for the intima and adventitia of the common iliac arteries; however, there was only one preferred fibre alignment present in the media. In all locations and layers, the observed fibre orientations were always in the tangential plane of the walls, with no radial components and very small dispersion through the wall thickness. A wider range of in-plane fibre orientations was present in the intima than in the media and adventitia. The mean total wall thickness for the aortas and the common iliac artery was 1.39 and 1.05 mm, respectively. For the aortas, a slight thickening of the intima and a thinning of the media in increasingly distal regions were observed. A clear intimal thickening was present distal to the branching of the celiac arteries. All data, except for the media of the common iliac arteries, showed two prominent collagen fibre families for all layers so that two-fibre family models seem most appropriate.

The PAM50 Risk-of-Recurrence Score Predicts Risk for Late Distant Recurrence after Endocrine Therapy in Postmenopausal Women with Endocrine-Responsive Early Breast Cancer

Purpose: To assess the prognostic value of the PAM50 risk-of-recurrence (ROR) score on late distant recurrence (beyond 5 years after diagnosis and treatment) in a large cohort of postmenopausal, endocrine-responsive breast cancer patients. Experimental Design: The PAM50 assay was performed on formalin-fixed paraffin-embedded whole-tumor sections of patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8). RNA expression levels of the PAM50 genes were determined centrally using the nCounter Dx Analysis System. Late distant recurrence-free survival (DRFS) was analyzed using Cox models adjusted for clinical and pathologic parameters. Results: PAM50 analysis was successfully performed in 1,246 ABCSG-8 patients. PAM50 ROR score and ROR-based risk groups provided significant additional prognostic information with respect to late DRFS compared with a combined score of clinical factors alone (ROR score: ΔLRχ2 15.32, P < 0.001; ROR-based risk groups: ΔLRχ2 14.83, P < 0.001). Between years 5 and 15, we observed an absolute risk of distant recurrence of 2.4% in the low ROR-based risk group, as compared with 17.5% in the high ROR-based risk group. The DRFS differences according to the PAM50 ROR score were observed for both node-positive and node-negative disease. Conclusion: PAM50 ROR score and ROR-based risk groups can differentiate patients with breast cancer with respect to their risk for late distant recurrence beyond what can be achieved with established clinicopathologic risk factors. Clin Cancer Res; 20(5); 1298–305. ©2014 AACR.

Layer-specific damage experiments and modeling of human thoracic and abdominal aortas with non-atherosclerotic intimal thickening

Many treatments for cardiovascular diseases include an endovascular insertion of stents or stent grafts into arteries, a procedure which may cause high tissue stresses and even damage in the arterial wall. In order to study such problems by using finite element methods, both appropriate constitutive models and experimental data on human tissue samples are required. Layer-specific experimental data for human tissue tested up to the supra-physiological loading range are rare in the literature. In this study, intact and layer-separated experimental data from uniaxial extension tests are presented for human thoracic and abdominal aortas with non-atherosclerotic intimal thickening undergoing supra-physiological loading. A novel pseudo-elastic damage model, proposed to describe discontinuous softening in aortic arterial tissues, is fit to the obtained experimental data. Fitting of the model with and without consideration of damage accumulation in the non-collagenous matrix material reveals that tissue damage is primarily related to the collagen fiber fabric. By employing the fit model, the effect of aortic tissue pre-conditioning on the material parameters from the resulting data fits is evaluated. Histological examination of the collagen fibers under different applied stretches is used to gain more insights into the structural changes of the tissue under supra-physiological loading.

Effects of Age on the Elastic Properties of the Intraluminal Thrombus and the Thrombus-covered Wall in Abdominal Aortic Aneurysms: Biaxial Extension Behaviour and Material Modelling

OBJECTIVE The intraluminal thrombus (ILT) present in the majority of abdominal aortic aneurysms (AAAs) plays an important role in aneurysm wall weakening. Studying the age-dependent elastic properties of the ILT and the thrombus-covered wall provides a better understanding of the potential effect of ILT on AAA remodelling. MATERIALS AND METHODS A total of 43 AAA samples (mean age 67 ± 6 years) including ILT and AAA wall was harvested. Biaxial extension tests on the three individual ILT layers and the thrombus-covered wall were performed. Histological investigations of the thrombi were performed to determine four different age phases, and to correlate with the change in the mechanical properties. A three-dimensional material model was fitted to the experimental data. RESULTS The luminal layers of the ILT exhibit anisotropic stress responses, whereas the medial and the abluminal layers are isotropic materials. The stresses at failure in the equibiaxial protocol continuously decrease from the luminal to the abluminal side, whereby cracks, mainly oriented along the longitudinal direction, can be observed in the ruptured luminal layers. The thrombi in the third and fourth phases contribute to wall weakening and to an increase of the mechanical anisotropy of their covered walls. The material models for the thrombi and the thrombus-covered walls are in excellent agreement with the experimental data. CONCLUSION Our results suggest that thrombus age might be a potential predictor for the strength of the wall underneath the ILT and AAA rupture.

The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma

Background: Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom recommended for the evaluation of sentinel lymph nodes in breast cancer patients. Objective: To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of patients with invasive lobular carcinoma. Methods: The value of IHC, the types of metastasis found by this method, and the involvement of non-sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by IHC when multilevel haematoxylin and eosin staining revealed no metastasis. Results: 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means. Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is higher than previously reported for breast cancer in general. Conclusions: IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated with a further metastatic nodal load.