Markers of the pre-metastatic niche "knock on the door" of metastasis-free cervical lymph nodes in patients with oral cancer

Aim: To assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients. Materials: LNs from metastatic-free neck dissections (LN0/N0, N = 43) and metastatic-free LNs in the vicinity of metastasis-containing LNs (LN0/N+, N = 30) were immuno-histochemically stained for lysyl oxidase (LOX), fibronectin (FN), vascular-endothelial growth factor receptor (VEGFR)-1 and matrix metalloproteinase (MMP)-9. Staining was assessed as 0 (no or weak staining), 1 (strong stain in 25% cells or extracellular area), 2 (same as 1 but in up to 50%) and 3 (same as 1 but in > than 50% of cells/area). Assessment was performed in the lymph node capsule (CAP), sub-capsular sinus (SCS) and medullary sinus (MS). In addition, sections were stained with picrosirius red and examined with polarized microscopy for assessing the distribution of polarization colors of the collagen fibers in the LN capsular area. Results: All examined LNs were positive for markers of the PMN. In general, the distribution and intensity of the immunoreactivity was similar between the LN0/N0 and LN0/N +, with only a few differences regarding expression of LOX in the capsule (p = 0.002) and VEGFR1 and MMP9 in the SCS (p = 0.023 and p <0.001, respectively). Picrosirius red stain and polarized microscopy revealed a disrupted arrangement and distribution of the collagen fibers in both LN0/N0 and LN0/N +. Conclusion: Markers for PMN were shown for the first time to be expressed in cervical LN0/N0 from patients with oral cancer, suggesting the increased permissive pathway remotely paved by the primary oral tumor for the incoming metastatic cells.Peer reviewe

Applied system analysis and technology of designing the software

An analogy is made between the stages of applied system analysis and the stages of software Engineerin

Hairy cell leukemia presenting as multiple discrete hepatic lesions

The involvement of hairy cell leukemia in the liver is in the form of portal and sinusoidal cellular infiltration. Here we describe the first case of hepatic hairy cell leukemia presenting as multiple discrete lesions, which was treated successfully. We suggest that in the investigation of discrete hepatic lesions in cases of cancer of unknown primary, hairy cell leukemia should be considered. The excellent response of hairy cell leukemia to therapy highlights the need for such a consideration

Prognostic Significance of VEGF, VEGF Receptors, and Microvessel Density in Diffuse Large B Cell Lymphoma Treated with Anthracycline-Based Chemotherapy

Abstract Vascular endothelial growth factor (VEGF)-mediated signaling has at least two potential roles in diffuse large B cell lymphoma: potentiation of angiogenesis, and potentiation of proliferation and/or survival induced by autocrine VEGF receptor-mediated signaling by lymphoma cells. We have recently shown that diffuse large B cell lymphomas expressing high levels of VEGF protein also express high levels of VEGF receptors 1 and 2. We have now assessed a larger multi-institutional cohort of patients with de novo diffuse large B cell lymphoma treated with anthracycline-based therapy to address whether either tumor vascularity as assessed by microvessel density counting, or expression of VEGF protein and its receptors as assessed by immunohistochemistry, contribute to patient outcomes. Increased tumor vascularity (Figure 1a, b, c -- increasing microvessel density) is associated with poor overall survival (p=0.047), and is independent of the international prognostic index (Figure 1d). In contrast, high expression of VEGFR1 by lymphoma cells is associated with improved overall survival (p=0.044) and a trend toward improved progression-free survival (p=0.054). High expression of VEGF by lymphoma cells is also associated with a trend toward improved overall survival (p=0.089). The concordant trend toward improved survival with increased lymphoma cell expression of VEGF and its receptor VEGFR1, together with their coordinate overexpression in a subset of diffuse large B cell lymphomas (p=0.00025, chi value 21.5), suggests the presence of an autocrine VEGF-VEGFR1-mediated feedback loop in these lymphomas. Indeed the combination of high VEGF and VEGFR1 protein expression identifies a subgroup of patients with improved overall (p=0.003) and progression-free (p=0.026) survival; these findings are independent of the international prognostic index (Figure 2). The presence of improved survival in a cohort of patients whose lymphomas potentially depend on autocrine signaling via VEGFR1 suggests that dependence on this pathway may render patients susceptible to the effects of anthracycline-based therapy; indeed, downregulation of VEGF expression at the mRNA level by anthracyclines and other chemotherapeutic agents has been demonstrated in a variety of non-hematolymphoid neoplasms. The relative importance of autocrine VEGF-mediated signaling versus vascularity should certainly be taken into account in clinical trials of anti-VEGF/VEGF receptor therapy in diffuse large B cell lymphoma. Figure Figure Figure Figur

Correction: Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

[This corrects the article DOI: 10.1371/journal.pone.0155711.]