Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Modulation of epithelial immunity by mucosal fluid

Mucosal epithelial cells, including those at the ocular surface, resist infection by most microbes in vivo but can be susceptible to microbial virulence in vitro. While fluids bathing mucosal surfaces (e.g. tears) contain antimicrobials, potentially pathogenic microbes often thrive in these fluids, suggesting that additional mechanisms mediate epithelial resistance in vivo. Here, tear fluid acted directly upon epithelial cells to enhance their resistance to bacterial invasion and cytotoxicity. Resistance correlated with tear fluid-magnified activation of NFκB and AP-1 transcription factors in epithelial cells in response to bacterial antigens, suggesting priming of innate defense pathways. Further analysis revealed differential regulation of potential epithelial cell defense genes by tears. siRNA knockdown confirmed involvement of at least two factors, RNase7 and ST-2, for which tears increased mRNA levels, in protection against bacterial invasion. Thus, the role of mucosal fluids in defense can include modulation of epithelial immunity, in addition to direct effects on microbes

Multiplicity: an organizing principle for cancers and somatic mutations

<p>Abstract</p> <p>Background</p> <p>With the advent of whole-genome analysis for profiling tumor tissue, a pressing need has emerged for principled methods of organizing the large amounts of resulting genomic information. We propose the concept of multiplicity measures on cancer and gene networks to organize the information in a clinically meaningful manner. Multiplicity applied in this context extends Fearon and Vogelstein's multi-hit genetic model of colorectal carcinoma across multiple cancers.</p> <p>Methods</p> <p>Using the Catalogue of Somatic Mutations in Cancer (COSMIC), we construct networks of interacting cancers and genes. Multiplicity is calculated by evaluating the number of cancers and genes linked by the measurement of a somatic mutation. The Kamada-Kawai algorithm is used to find a two-dimensional minimum energy solution with multiplicity as an input similarity measure. Cancers and genes are positioned in two dimensions according to this similarity. A third dimension is added to the network by assigning a maximal multiplicity to each cancer or gene. Hierarchical clustering within this three-dimensional network is used to identify similar clusters in somatic mutation patterns across cancer types.</p> <p>Results</p> <p>The clustering of genes in a three-dimensional network reveals a similarity in acquired mutations across different cancer types. Surprisingly, the clusters separate known causal mutations. The multiplicity clustering technique identifies a set of causal genes with an area under the ROC curve of 0.84 versus 0.57 when clustering on gene mutation rate alone. The cluster multiplicity value and number of causal genes are positively correlated via Spearman's Rank Order correlation (<it>r_s</it>(8) = 0.894, Spearman's <it>t </it>= 17.48, <it>p </it>< 0.05). A clustering analysis of cancer types segregates different types of cancer. All blood tumors cluster together, and the cluster multiplicity values differ significantly (Kruskal-Wallis, <it>H </it>= 16.98, <it>df </it>= 2, <it>p </it>< 0.05).</p> <p>Conclusion</p> <p>We demonstrate the principle of multiplicity for organizing somatic mutations and cancers in clinically relevant clusters. These clusters of cancers and mutations provide representations that identify segregations of cancer and genes driving cancer progression.</p

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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