Axillary Ultrasound in the Management of the Newly Diagnosed Breast Cancer Patient

Axillary lymph node status remains an important prognostic factor in patients with breast cancer. Axillary ultrasound (AUS) is an important tool in the workup of patients with newly diagnosed breast cancer and also has an emerging role evaluating the axilla after neoadjuvant chemotherapy. This review discusses the value of AUS in the workup and management of patients with newly diagnosed breast cancer and describes its role given the recent changes in axillary management.     

Novel treatment of ovarian cancer cell lines with Imatinib mesylate combined with Paclitaxel and Carboplatin leads to receptor-mediated antiproliferative effects

Purpose  Imatinib is a small molecule inhibiting the tyrosine kinases bcr-abl, c-kit, PDGFR-α and PDGFR-β. Investigations were performed to screen ovarian cancer cell lines and tumor samples for target receptor expression. Effects of Imatinib on cell proliferation and apoptosis induction were measured with and without additional cytotoxic agents. Methods  Expression patterns of abl, c-kit, PDGFR-α and PDGFR-β (Imatinib targets) were studied in 5 cell lines and 111 tissue arrays by PCR and immunohistochemistry. Proliferation assays were performed with single agent Imatinib or combined with Paclitaxel and Carboplatin. Apoptosis was measured by DNA fragmentation. Results  All cell lines expressed abl and PDGFR-β. C-kit was only expressed in 2/5 cell lines and PDGFR-α in 4/5. Imatinib reduced cell growth and lead to pro-apoptotic changes. Combination of Carboplatin, Paclitaxel and Imatinib showed synergistic activity. Conclusions  Our results suggest that Imatinib may be useful for the specific treatment of ovarian cancer as an add-on to conventional chemotherapy. C. Mundhenke and M. T. Weigel contributed equally to this work.     

Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.T cell, or transmembrane, immunoglobulin domain and mucin domain (Tim-3) is a type I membrane protein expressed on a variety of innate and adaptive immune cell types. Tim-3 is often referred to as a checkpoint receptor due to its apparent inhibitory function on T cells and its association with activation-induced T cell exhaustion in tumors and chronic viral infection (Sánchez-Fueyo et al., 2003; Jones et al., 2008; Fourcade et al., 2010; Jin et al., 2010; Sakuishi et al., 2010). Recent studies, however, suggest a more nuanced picture of Tim-3 function in T cells, depending on the setting, e.g., acute versus chronic stimulation (Ferris et al., 2014; Gorman and Colgan, 2014). In addition to CD4 and CD8 T cells, Tim-3 is also expressed on other immune cell types, such as NK cells, macrophages, DCs, and mast cells, but its function on these cell types is less clear. Tim-3 blockade was shown to enhance macrophage function in response to sepsis (Yang et al., 2013), and also to regulate antigen (Ag) presentation by DCs, partly through Btk and c-Src (Maurya et al., 2014). On the other hand, Tim-3 expression on monocytes infiltrating the CNS during EAE was shown to promote inflammation (Anderson et al., 2007).Mast cells are first-line defenders against allergens and invading pathogens as a result of their proximity to the external environment. Cross-linking of IgE bound to the high-affinity IgE receptor FcεRI by Ag leads to the release of preformed mediators and de novo synthesis of proinflammatory and antiinflammatory mediators and cytokines, which together serve to regulate hypersensitivity, autoimmunity, cardiovascular disease, and tumor progression (Kalesnikoff and Galli, 2008). In addition to their well-known pathological roles in allergic responses, mast cells also contribute to defense against bacteria, helminthes, and tumors (Abraham and St John, 2010). It was reported that mast cells constitutively express cell surface Tim-3, and that cross-linking of Tim-3 could enhance cytokine production of IgE-sensitized and Ag-stimulated BM-derived mast cells (BMMCs) and peritoneal mast cells (pMCs) without affecting degranulation (Nakae et al., 2007). TGF-β has been shown to up-regulate expression of Tim-3 in tumor-infiltrating mast cells and a human mast cell line, through a mitogen-activated protein kinase Erk-kinase (MEK)–dependent pathway (Wiener et al., 2006; Yoon et al., 2011). Although previous data suggest that Tim-3 is a positive regulator of mast cell activation, the molecular mechanisms behind the contribution of Tim-3 to mast cell function are still unknown. Importantly, there was until now no genetic evidence addressing the function of Tim-3 in these cells. Given the important role of mast cells as sentinels in both allergic and nonallergic diseases, it is of interest to explore Tim-3 activity on this cell type and how antibody (Ab) modulation can affect its function.Here, we demonstrate through multiple approaches that Tim-3 functions to enhance proximal FcεRI signaling in mast cells. Cross-linking of Tim-3 with multiple independent antibodies enhanced mast cell degranulation and cytokine release in a dose-dependent manner. Acute knock-down or genetic deficiency of Tim-3 rendered mast cells less responsive to Ag cross-linking of FcεRI, resulting in decreased degranulation and cytokine production. The cytoplasmic tail of Tim-3 was required for co-stimulatory signal transduction in mast cells, together with FcεRI signaling pathways. This was shown in part with the use of recently reported Nur77-GFP transgenic models, which have not previously been used for the study of FcεRI signaling. Collectively, our data demonstrate that Tim-3 acts at a receptor-proximal level to intensify activation of FcεRI-dependent signaling pathways upon Ag cross-linking, while maintaining the threshold for negative signaling of Lyn.     

Histopathological and clinical findings in renal transplants with Banff type II and III acute cellular rejection without tubulointerstitial infiltrates

According to the Banff guidelines for renal transplants, pure endothelialitis without any tubulointerstitial infiltrates (with the Banff components v?≥?1, i0, t0) has to be called acute cellular rejection (ACR). The pathophysiology of this rare lesion abbreviated as v_only is currently unclear, as well as its clinical, serological, and prognostic implications. Therefore, we conducted this retrospective comparative study. We compared all 23 biopsies with v_only from Hannover Medical School between 2003 and 2010 with 23 matched biopsies with the Banff components v?≥?1, i?≥?1, and t?≥?1 (v_plus) and 23 biopsies with v0, i0, and t0 (v0i0t0). Serological (available in 10, 11, and 14 patients, respectively), histological, and clinical data were compared. Of all biopsies, 0.4 % had findings of v_only. v_only, v_plus, and v0i0t0 only showed minimal differences in the Banff components apart from the cohort-defining components. Endothelialitis in v_only more frequently involved the arcuate arteries than the smaller preglomerular vessels compared to v_plus and vice versa. Combining histopathological data and serological data, v_only more frequently showed criteria for acute humoral rejection than v0i0t0 (albeit not persistent after the Bonferroni–Holm correction in pairwise comparisons), while there was no difference between v_only and v_plus. No difference could be demonstrated regarding clinical presentation at biopsy or outcome. Our results show minimal differences regarding clinical presentation, outcome, and histological features between v_only and v_plus. Patients with v_only should be thoroughly investigated for evidence of acute humoral rejection.     

Incidence of microcracks after preparation of straight and curved root canals with three different NiTi instrumentation techniques assessed by micro‐CT

This study evaluated the effect of three different NiTi instrumentation techniques on the incidence of microcracks after the preparation of straight and curved root canals using micro‐CT. Roots from mandibular premolars and maxillary molars (n = 66) with the same mean canal curvatures were assigned to three groups of straight and three groups of curved roots (n = 11). After preoperative micro‐CT scans, root canals were prepared with Reciproc, OneShape and ProTaper Next to size 25. Specimens were scanned again, and pre‐ and post‐operative cross‐sectional images (n = 75 263) were screened to identify the presence of dentinal microcracks. Overall, microcracks were detected in 2.97% (n = 2236) of the cross‐sectional images. No new dentinal microcracks were observed after root canal instrumentation of straight and curved canals with the tested NiTi systems. Instrumentation with Reciproc, OneShape and ProTaper Next did not induce the formation of dentinal microcracks irrespective of canal curvature.