Composite Biomarker Image for Advanced Visualization in Histopathology.

Immunohistochemistry (IHC) biomarkers are essential tools for reliable cancer diagnosis and subtyping. It requires cross-staining comparison among Whole Slide Images (WSIs) of IHCs and hematoxylin and eosin (H&E) slides. Currently, pathologists examine the visually co-localized areas across IHC and H&E glass slides for a final diagnosis, which is a tedious and challenging task. Moreover, visually inspecting different IHC slides back and forth to analyze local co-expressions is inherently subjective and prone to error, even when carried out by experienced pathologists. Relying on digital pathology, we propose "Composite Biomarker Image" (CBI) in this work. CBI is a single image that can be composed using different filtered IHC biomarker images for better visualization. We present a CBI image produced in two steps by the proposed solution for better visualization and hence more efficient clinical workflow. In the first step, IHC biomarker images are aligned with the H&E images using one coordinate system and orientation. In the second step, the positive or negative IHC regions from each biomarker image (based on the pathologists' recommendation) are filtered and combined into one image using a fuzzy inference system. For evaluation, the resulting CBI images, from the proposed system, were evaluated qualitatively by the expert pathologists. The CBI concept helps the pathologists to identify the suspected target tissues more easily, which could be further assessed by examining the actual WSIs at the same suspected regions.

Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems.

Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB-468 human TNBC cell lines, and in vitro effects on signaling and cytotoxicity, as well as in vivo effects on xenograft tumor growth and metastasis were assessed. The dual EGFR/HER2 inhibitor lapatinib (LPN) displayed greater cytotoxic potency and MAPK signaling inhibition than the EGFR inhibitor erlotinib, suggesting both EGFR and HER2 contribute to MAPK signaling in this TNBC model. The Raf inhibitor sorafenib (SFN) or the Mek inhibitor U0126 suppressed MAPK signaling to a greater extent than LPN; which correlated with greater cytotoxic potency of SFN, but not U0126. However, U0126 potentiated the cytotoxic efficacy of LPN and SFN in an additive and synergistic manner, respectively. This in-series Raf-Mek co-targeting synergy was recapitulated in orthotopic mouse xenografts, where SFN and the Mek inhibitor selumitinib (AZD6244) inhibited primary tumor growth and pulmonary metastasis. Raf and Mek co-inhibition exhibits synergy in TNBC models and represent a promising combination therapy for this aggressive breast cancer type.

Abundant expression of interleukin-21 receptor in follicular lymphoma cells is associated with more aggressive disease.

Recombinant interleukin-21 (IL-21) has potential utility in cancer therapy. Stimulation with IL-21 can induce apoptosis in follicular lymphoma (FL) cells, and existing studies have suggested that IL-21 signaling may function in tumor suppression. In order to elucidate the relationship between IL-21 receptor (IL-21R) expression and clinical and pathological features in FL, IL-21R was quantified in 114 pretreatment biopsy samples using either conventional immunohistochemistry or immunofluorescence microscopy and automated quantitative analysis (AQUA). Reduced expression of IL-21R was associated with favorable overall survival (p = 0.048). AQUA analysis showed an association with the presence of diffuse large B-cell lymphoma (DLBCL) in the biopsy sample (p = 0.03), and expression of IL-21R was up-regulated upon transformation of FL to DLBCL in two cases. Our results based on the largest survey to date raise the possibility that IL-21 signaling in FL cells, rather than being tumor suppressive, supports tumor progression and that therapeutic benefit could be realized by blocking IL-21R instead of stimulating it.