Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM) with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor – liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both) and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively), and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to clinicopathological parameters. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

• Potential surgical treatment requires accurate radiological assessment of colorectal liver metastases • Magnetic resonance imaging with gadoxetic acid is the preferred imaging investigation. • MRI is better than multidetector CT for detecting small liver metastases.

These findings demonstrate the ability of the hypothalamic-pituitary-gonadal hormone axis and sex steroid metabolism to resume physiological function following orthotopic liver transplantation in men. Correspondingly, sexual function returns to normal in the majority of patients, despite significant alterations prior to orthotopic liver transplantation.

EphB6 is the most recently identified member of theEph receptors represent the largest family of receptor tyrosine kinases, with at least 14 members (1, 2). Ephs are activated by a group of ligands, all membrane-anchored either by glycosylphosphatidylinositol (ephrin-A1-A5) or a trans-membrane domain (ephrin-B1-B3) (3). Eph receptors are divided into two groups EphA and EphB according to their ligand binding preference; although within a group receptor-ligand specificity is degenerate (4). It is a characteristic of the Eph receptor family that their ligands must be membrane bound to be active (5-7). This requirement for membrane anchorage of the ligand makes cell-cell contact an obligatory event for activation of Eph receptors, and consequently, the activated receptors are concentrated in the area of cell-cell contact. In accordance with their membrane-anchored nature, ephrins are also involved in the process of reverse signaling. They interact with cytoplasmic signaling molecules and upon stimulation with appropriate receptors transmit signals inside the cell (8). Eph receptors and their ligands are typically most highly expressed in neural and endothelial cells (4), and most descriptions of their function concern development of the nervous system and angiogenesis (9 -11). Upon the formation of cell-cell contact, signaling through the Eph receptors results in modulation of integrin activity and reorganization of the actin cytoskeleton. As a result, Ephs generate adhesive or repulsive signals, and in the neural system guide the movement of axonal growth cones, cell migration, and synapse formation (12-18).Uncharacteristically, a recently discovered member of the EphB subfamily, EphB6 is predominantly expressed in the thymus and a subpopulation of mature T lymphocytes (19,20). While structural analysis of EphB6 reveals conservation of the major Eph receptor autophosphorylation sites (Tyr-638 and Tyr-644), there are several critical alterations in its kinase domain. These include substitution of a crucial lysine residue in the ATP binding site, resulting in a receptor without detectable kinase activity (19,21). We have previously shown that stimulation with ephrin-B1 induces EphB6 trans-phosphorylation by a catalytically active EphB partner and thus initiates its signaling (22). The predominant expression of EphB6 in the thymus (19) and a subset of T lymphocytes (20) indicates that it may play an important role in regulation of both T cell differentiation and function. Current evidence suggests that Eph receptors may interact with the T cell receptor (TCR) 1 signaling pathways as Eph receptors can regulate the activity of small GTPases (23, 24) and thus control MAPK pathway and integrin activation, as well as cytoskeletal rearrangement (23,(25)(26)(27), all crucial in TCR-induced responses (28 -35). Moreover, recent observations suggest that EphB6 interacts with a key member of TCR signaling pathways, c-Cbl (22, 36), and that co-cross-linking of EphB6 and CD3 with antibodies increases apoptotic cell death in Jurka...