Article: Prognostic impact of Skp2, ER and PGR in male and female patients with soft tissue sarcomas.Sveinung W Sorbye, Thomas K Kilvaer, Andrej Valkov, Tom Donnem, Eivind Smeland, Khalid Al-Shibli, Roy M Bremnes, Lill-Tove Busund[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: 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). Optimized treatment of STS requires better identification of high-risk patients who will benefit from adjuvant therapy. S-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins. Skp2 has been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. 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.BMC Clinical Pathology 03/2013; 13(1):9.
Sveinung W Sorbye, Thomas K Kilvaer, Andrej Valkov, Tom Donnem, Eivind Smeland, Khalid Al-Shibli, Roy M Bremnes, Lill-Tove Busund[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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. 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.BMC Clinical Pathology 02/2012; 12:5.
Article: High expression of CD20+ lymphocytes in soft tissue sarcomas is a positive prognostic indicator.Sveinung W Sorbye, Thomas Kilvaer, Andrej Valkov, Tom Donnem, Eivind Smeland, Khalid Al-Shibli, Roy M Bremnes, Lill-Tove Busund[show abstract] [hide abstract]
ABSTRACT: The immune status is important in cancer patients. Tissue microarrays from 249 patients with soft tissue sarcomas were constructed. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. High density of CD20+ lymphocytes is an independent positive prognostic indicator for these patients.Oncoimmunology. 01/2012; 1(1):75-77.
Eivind Smeland, Thomas K Kilvaer, Sveinung Sorbye, Andrej Valkov, Sigve Andersen, Roy M Bremnes, Lill-Tove Busund, Tom Donnem[show abstract] [hide abstract]
ABSTRACT: Background. We aimed to explore the prognostic impact of the hypoxia-induced factors (HIFαs) 1 and 2, the metabolic HIF-regulated glucose transporter GLUT-1, and carbonic anhydrase IX (CAIX) in non-gastrointestinal stromal tumor soft tissue sarcomas (non-GIST STS). Methods. Duplicate cores with viable tumor tissue from 206 patients with non-GIST STS were obtained and tissue microarrays were constructed. Immunohistochemistry (IHC) was used to evaluate expression of hypoxic markers. Results. In univariate analyses, GLUT-1 (P < 0.001) and HIF-2α (P = 0.032) expression correlated significantly with a poor disease-specific survival (DSS). In the multivariate analysis, however, only high expression of GLUT-1 (HR 1.7, CI 95% 1.1-2.7, P = 0.021) was a significant independent prognostic indicator of poor DSS. Conclusion. GLUT-1 is a significant independent negative prognostic factor in non-GIST STS.Sarcoma 01/2012; 2012:541650.
Article: Inhibitor of neuronal nitric oxide synthase improves gas exchange in ventilator-induced lung injury after pneumonectomy.Evgeny V Suborov, Alexey A Smetkin, Timofey V Kondratiev, Andrey Y Valkov, Vsevolod V Kuzkov, Mikhail Y Kirov, Lars J Bjertnaes[show abstract] [hide abstract]
ABSTRACT: Mechanical ventilation with high tidal volumes may cause ventilator-induced lung injury (VILI) and enhanced generation of nitric oxide (NO). We demonstrated in sheep that pneumonectomy followed by injurious ventilation promotes pulmonary edema. We wished both to test the hypothesis that neuronal NOS (nNOS), which is distributed in airway epithelial and neuronal tissues, could be involved in the pathogenesis of VILI and we also aimed at investigating the influence of an inhibitor of nNOS on the course of VILI after pneumonectomy. Anesthetized sheep underwent right pneumonectomy, mechanical ventilation with tidal volumes (VT) of 6 mL/kg and FiO2 0.5, and were subsequently randomized to a protectively ventilated group (PROTV; n = 8) keeping VT and FiO2 unchanged, respiratory rate (RR) 25 inflations/min and PEEP 4 cm H2O for the following 8 hrs; an injuriously ventilated group with VT of 12 mL/kg, zero end-expiratory pressure, and FiO2 and RR unchanged (INJV; n = 8) and a group, which additionally received the inhibitor of nNOS, 7-nitroindazole (NI) 1.0 mg/kg/h intravenously from 2 hours after the commencement of injurious ventilation (INJV + NI; n = 8). We assessed respiratory, hemodynamic and volumetric variables, including both the extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI). We measured plasma nitrite/nitrate (NOx) levels and examined lung biopsies for lung injury score (LIS). Both the injuriously ventilated groups demonstrated a 2-3-fold rise in EVLWI and PVPI, with no significant effects of NI. In the INJV group, gas exchange deteriorated in parallel with emerging respiratory acidosis, but administration of NI antagonized the derangement of oxygenation and the respiratory acidosis significantly. NOx displayed no significant changes and NI exerted no significant effect on LIS in the INJV group. Inhibition of nNOS improved gas exchange, but did not reduce lung water extravasation following injurious ventilation after pneumonectomy in sheep.BMC Anesthesiology 06/2012; 12:10.