Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC

Expression of survivin detected by immunohistochemistry in the cytoplasm and in the nucleus is associated with prognosis of leiomyosarcoma and synovial sarcoma patients

<p>Abstract</p> <p>Background</p> <p>Survivin, a member of the inhibitor of apoptosis-protein family suppresses apoptosis and regulates cell division. It is strongly overexpressed in the vast majority of cancers. We were interested if survivin detected by immunohistochemistry has prognostic relevance especially for patients of the two soft tissue sarcoma entities leiomyosarcoma and synovial sarcoma.</p> <p>Methods</p> <p>Tumors of leiomyosarcoma (n = 24) and synovial sarcoma patients (n = 26) were investigated for their expression of survivin by immunohistochemistry. Survivin expression was assessed in the cytoplasm and the nucleus of tumor cells using an immunoreactive scoring system (IRS).</p> <p>Results</p> <p>We detected a survivin expression (IRS > 2) in the cytoplasm of 20 leiomyosarcomas and 22 synovial sarcomas and in the nucleus of 12 leiomyosarcomas and 9 synovial sarcomas, respectively. There was no significant difference between leiomyosarcoma and synovial sarcoma samples in their cytoplasmic or nuclear expression of survivin. Next, all sarcoma patients were separated in four groups according to their survivin expression in the cytoplasm and in the nucleus: group 1: negative (IRS 0 to 2); group 2: weak (IRS 3 to 4); group 3: moderate (IRS 6 to 8); group 4: strong (IRS 9 to 12). In a multivariate Cox's regression hazard analysis survivin expression detected in the cytoplasm or in the nucleus was significantly associated with overall survival of patients in group 3 (RR = 5.7; P = 0.004 and RR = 5.7; P = 0.022, respectively) compared to group 2 (reference). Patients whose tumors showed both a moderate/strong expression of survivin in the cytoplasm and a moderate expression of survivin in the nucleus (in both compartments IRS ≥ 6) possessed a 24.8-fold increased risk of tumor-related death (P = 0.003) compared to patients with a weak expression of survivin both in the cytoplasm and in the nucleus.</p> <p>Conclusion</p> <p>Survivin protein expression in the cytoplasma and in the nucleus detected by immunohistochemistry is significantly associated with prognosis of leiomyosarcoma and synovial sarcoma patients.</p

MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma

Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan–Meier survival analyses (p = 0.027, p = 0.001 and p = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; p = 0.031; RR = 2.59; p = 0.002 and RR = 4.76; p = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment

Low HIF-1α and low EGFR mRNA Expression Significantly Associate with Poor Survival in Soft Tissue Sarcoma Patients; the Proteins React Differently

In various tumors, the hypoxia inducible factor-1&#945; (HIF-1&#945;) and the epidermal growth factor-receptor (EGFR) have an impact on survival. Nevertheless, the prognostic impact of both markers for soft tissue sarcoma (STS) is not well studied. We examined 114 frozen tumor samples from adult soft tissue sarcoma patients and 19 frozen normal tissue samples. The mRNA levels of HIF-1&#945;, EGFR, and the reference gene hypoxanthine phosphoribosyltransferase (HPRT) were quantified using a multiplex qPCR technique. In addition, levels of EGFR or HIF-1&#945; protein were determined from 74 corresponding protein samples using ELISA techniques. Our analysis showed that a low level of HIF-1&#945; or EGFR mRNA (respectively, relative risk (RR) = 2.8; p = 0.001 and RR = 1.9; p = 0.04; multivariate Cox&#180;s regression analysis) is significantly associated with a poor prognosis in STS patients. The combination of both mRNAs in a multivariate Cox&#8217;s regression analysis resulted in an increased risk of early tumor-specific death of patients (RR = 3.1, p = 0.003) when both mRNA levels in the tumors were low. The EGFR protein level had no association with the survival of the patient&#8217;s cohort studied, and a higher level of HIF-1&#945; protein associated only with a trend to significance (multivariate Cox&#8217;s regression analysis) to a poor prognosis in STS patients (RR = 1.9, p = 0.09). However, patients with low levels of HIF-1&#945; protein and a high content of EGFR protein in the tumor had a three-fold better survival compared to patients without such constellation regarding the protein level of HIF-1&#945; and EGFR. In a bivariate two-sided Spearman&#8217;s rank correlation, a significant correlation between the expression of HIF-1&#945; mRNA and expression of EGFR mRNA (p &lt; 0.001) or EGFR protein (p = 0.001) was found, additionally, EGFR mRNA correlated with EGFR protein level (p &lt; 0.001). Our results show that low levels of HIF-1&#945; mRNA or EGFR mRNA are negative independent prognostic markers for STS patients, especially after combination of both parameters. The protein levels showed a different effect on the prognosis. In addition, our analysis suggests a possible association between HIF-1&#945; and EGFR expression in STS

In Vitro Populations of Rotifer Brachionus plicatilis Müller Demonstrate Inhibition When Fed with Copper-Preaccumulating Microalgae

6 páginas, 2 figuras, 5 tablas.Four marine microalgal species (Chlorella autotrophyca, Nannochloropsis gaditana, Tetraiselmis chuii, and Isochrysis aff. galbana) were exposed for 24 h to 1 mg L−1 dissolved copper and then transferred to fresh medium. After that, a group of 10 neonate rotifers were fed with these four microalgal species. The levels of accumulated copper in cellular concentrations of the microalgae were checked, with the result of around 40% of original concentration, with the exception of I. aff. galbana (25% of original concentration). In all cases, cells with preaccumulated metal caused a delay of 1 or 2 days in populational development of rotifers (increase in “lag phase”). The microalgae that were not fed to rotifers (disposed in parallel series) did not significantly transfer metal to the medium after the first day.Peer reviewe