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Background: MicroRNA (miR)-21 has been revealed as an oncogene in cancer development, and is one of the miRNAs closely connected to angiogenesis. We aimed to explore the impact of miR-21 expression in both tumor and stromal compartments of non-small cell lung cancer (NSCLC), and correlations between miR-21 and angiogenic protein markers., Methods: From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). In situ hybridization (ISH) was used to detect the expression of miR-21 separately in tumor cells and stromal cells of the tumor, and immunohistochemistry (IHC) was used to detect the expression of the protein markers protein kinase B (Akt), phosphatidylinositol-3-kinase (PI3K), hypoxia induced factor 1 (HIF1α) and vascular endothelial growth factor-A (VEGF-A)., Results: In univariate analyses, high tumor cell expression of miR-21 in patients with lymph node metastasis was a positive prognostic factor (P = 0.024). High stromal miR-21 expression had a negative prognostic impact (P = 0.022). In the multivariate analysis, low tumor mir-21 expression in node positive patients was an independent adverse prognostic factor (HR 2.03, CI 95% 1.09-3.78, P = 0.027)., Conclusions: In patients with lymph node metastasis, miR-21 expression in tumor cells is an independent positive prognostic factor. High stromal miR-21 expression is a negative prognostic factor.

Background: Soft-tissue sarcomas are rare malignant tumors of mesenchymal lineage that can arise in any part of the body. Prognosis, and hence also treatment may vary according to histologic subtype and localization. Angiogenesis is the process of forming new blood vessels from pre-existing ones. The deregulation of this process is thought to be an important step in malignant transformation. This study investigates the prognostic impact of platelet derived growth factor- (PDGF), vascular endothelial growth factor- (VEGF) and fibroblast growth factor (FGF) families in soft-tissue sarcomas of the extremities & trunk (ET) and visceral & retroperitoneal (VR) locations., Methods: Tumor samples from 181 patients (115 ET and 66 VR) with resected soft tissue sarcomas were collected and tissue microarrays were constructed. Immunohistochemistry was used to evaluate angiogenic marker expression. Recurrence-free survival (RFS), metastasis-free survival (MFS) and disease-specific survival (DSS) were used as endpoints in prognostic impact assessment., Results: In univariate analyses, almost all investigated angiogenic markers had prognostic impact in the ET group. In contrast, only FGFR-1 showed any significant prognostic impact in the VR group. In the multivariate analyses, PDGF-D (HR = 1.863, 95% CI = 1.057-3.283, P = 0.031), VEGFR-1 (HR = 2.106, 95% CI = 1.038-4.272, P = 0.039) and VEGF-A (HR 2.095, 95% CI 1.028-4.271, P = 0.042) were independent negative prognosticators for DSS, MFS and RFS, respectively, in the ET group. FGFR-1 was an independent positive prognosticator for DSS (HR = 0.243, 95% CI = 0.095-0.618, P = 0.003) in the VR group., Conclusions: Angiogenic molecules from the PDGF and VEGF families have prognostic impact in soft-tissue sarcomas arising in the ET, but not in VR locations. In the latter histological grade and resection margins are the most important prognostic factors.

Background: S-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins. The purpose of this study is to clarify the prognostic significance of expression of Skp2 related to gender, estrogen receptor (ER) and progesterone receptor (PGR) in soft tissue sarcomas (STS). Skp2 has been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. Optimized treatment of STS requires better identification of high-risk patients who will benefit from adjuvant therapy. The prognostic significance of Skp2 related to ER and PGR in STS has not been sufficiently investigated., Methods: Tissue microarrays from 193 STS patients were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the expression of Skp2, ER and PGR., Results: In univariate analyses, high tumor expression of Skp2 correlated (p = 0.050) with reduced disease-specific survival (DSS). In subgroup analyses expression of PGR in males (p = 0.010) and in patients older than 60 years (p = 0.043) were negative prognostic factors for DSS. Expression of ER in females was a positive prognostic factor for DSS (p = 0.041). In co-expression analyses in the whole cohort, low expression of Skp2 in combination with low expression of ER was positive for DSS (p = 0.049). In females high expression of Skp2 in combination with low expression of ER was a negative prognosticator (p = 0.021). In the multivariate analyses, age (p = 0.012), malignancy grade (p < 0.001), wide resection margins (P = 0.010), ER negative / PGR positive co-expression profile (p = 0.002) and ER positive / PGR negative co-expression profile (p = 0.015) were independent negative prognostic factors for DSS. In females expression of Skp2 (p = 0.006) was associated with shorter DSS., Conclusions: We found diverse prognostic impacts of expression of Skp2, ER, PGR and DSS in male and female patients with STS. In men, but not women, ER positive / PGR negative co-expression profile was an independent negative prognostic factor for DSS. In women, but not men, high expression of Skp2 was associated with reduced DSS.

Background: Prognostic markers in curable STS may have the potential to guide therapy after surgical resection. The purpose of this study was to clarify the prognostic impact of the presence of cells and growth factors belonging to the innate immune system in soft tissue sarcomas (STS). The significance of macrophages (CD68), their growth factor macrophage colony-stimulating factor (M-CSF), its receptor colony-stimulating factor-1 receptor (CSF-1R), natural killer cells (CD57) and the general immunomodulating molecule (TGF-beta) are all controversial in STS. Herein, these markers are evaluated and compared to the cell proliferation marker Ki67., Methods: Tissue microarrays from 249 patients with non-gastrointestinal (non-GIST) STS were constructed from duplicate cores of viable and representative neoplastic tumor areas and duplicate cores of peritumoral capsule. Immunohistochemistry was used to evaluate the expression of CD68, M-CSF, CSF-1R, CD57, TGF-beta and Ki67 in tumor and peritumoral capsule., Results: In univariate analyses increased expression of M-CSF (P = 0.034), Ki67 (P < 0.001) and TGF-beta (P = 0.003) in tumor correlated with shorter disease-specific survival (DSS). Increased expression of CD68 in tumor correlated significantly with malignancy grade (P = 0.016), but not DSS (P = 0.270). Increased expression of Ki67 in peritumoral capsule tended to correlate with a shorter DSS (P = 0.057). In multivariate analyses, co-expression of M-CSF and TGF-beta (P = 0.022) in tumor and high expression of Ki67 (P = 0.019) in peritumoral capsule were independent negative prognostic factors for DSS., Conclusions: Increased co-expression of M-CSF and TGF-beta in tumor in patients with STS, and increased expression of Ki67 in peritumoral capsule were independent negative prognostic factors for DSS.

Background: The purpose of this study was to clarify the prognostic significance of peritumoral lymphocyte infiltration in the capsule of soft tissue sarcomas (STS). Multiple observations in preclinical and clinical studies have shown that the immune system has a role in controlling tumor growth and progression. Prognostic markers in potentially curable STS should guide therapy after surgical resection. The immune status at the time of resection may be important, but the prognostic significance of peritumoral lymphocytes is unknown., Methods: Tissue microarrays from 80 patients with STS were constructed from duplicate cores of tissue from the tumor and the peritumoral capsule. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+ and CD20+ lymphocytes in the tumor and the peritumoral capsule., Results: In univariate analyses, increasing numbers of CD20+ (P = 0.032) peritumoral lymphocytes were associated with a reduced disease free survival (DSS). In multivariate analyses, a high number of CD20+ peritumoral lymphocytes (P = 0.030) in the capsule was an independent negative prognostic factor for DSS. There were no such associations of lymphocyte infiltration in the tumor., Conclusions: A high density of CD20+ peritumoral lymphocytes is an independent negative prognostic indicator for patients with STS. Further research is needed to determine whether CD20 cells in the peritumoral capsule of STS may promote tumor invasion in the surrounding tissue and increase the metastatic potential.