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Boni L.,Clinical Trials Coordinating Center | Taddei A.,University of Florence | Bencini L.,General Surgery and Surgical Oncology | Bernini M.,General Surgery and Surgical Oncology | And 11 more authors.
Clinical Cancer Research | Year: 2014

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. © 2014 American Association for Cancer Research.

Lastraioli E.,University of Florence | Bencini L.,General Surgery and Surgical Oncology | Bianchini E.,Clinical Trials Coordinating Center | Romoli M.R.,University of Florence | And 8 more authors.
Translational Oncology | Year: 2012

BACKGROUND: There is a need to identify new markers to assess recurrence risk in early-stage colorectal cancer (CRC) patients. We explored the prognostic impact of ether-a-gò-gò-related gene 1 channels and some hypoxia markers, in patients with nonmetastatic (stage I, II, and III) CRC. METHODS: The expression of hERG1, vascular endothelial growth factor A (VEGF-A), glucose transporter 1, carbonic anhydrase IX (CA-IX), epidermal growth factor receptor (EGF-R), and p53 was tested by immunohistochemistry in 135 patients. The median follow-up was 35 months. Clinicopathologic parameters and overall survival were evaluated. RESULTS: hERG1 displayed a statistically significant association with Glut-1, VEGF-A, CA-IX, and EGF-R; p53 with VEGF-A and CA-IX; Glut-1 with the age of the patients; and EGF-R with TNM and mucin content. TNM and CA-IX were prognostic factors at the univariate analysis; TNM, hERG1, and Glut-1, at the multivariate analysis. Risk scores calculated from the final multivariate model allowed to stratify patients into four different risk groups: A) stage I-II, Glut-1 positivity, any hERG1; B) stage I-II, Glut-1 and hERG1 negativity; C) stage I-II, Glut-1 negativity, hERG1 positivity; D) stage III, any Glut-1 and any hERG1. CONCLUSIONS: hERG1 positivity with Glut-1 negativity identifies a patient group with poor prognosis within stage I-II CRC. The possibility that these patients might benefit from adjuvant therapy, independently from the TNM stage, is discussed. IMPACT: More robust prognostic and predictive markers, supplementing standard clinical and pathologic staging, are needed for node-negative patients. © 2012 Neoplasia Press, Inc. All rights reserved.

PubMed | Alexandria University and General Surgery and Surgical Oncology
Type: | Journal: World journal of surgical oncology | Year: 2016

A number of patients treated conservatively for breast cancer will develop loco-regional and distant recurrences. Our aim was to determine how their occurrence may be linked to the evolution of the disease.We analyzed 238 women treated by conservative breast surgery and breast irradiation in a single institution. We evaluated the prognostic factors associated with loco-regional and distant recurrences and the prognostic value of local and regional recurrences on systemic progression.After a median follow-up of 5 year (range 1-10), 16 (6.72%) patients in the breast conservative surgery (BCS) groups had loco-regional recurrence. For distant recurrence, 10 (4.2%) patients had experienced distant recurrence. Lympho-vascular invasion (HR 2.55; 95% CI, 076 to 8.49) and an extensive intraductal component (HR, 2.22; 95% CI, 0.69 to 7.15) and nodal status are risk factors for loco-regional recurrence (LRR) after breast conservative therapy (BCT). Tumor size, nodal status, high histologic grade, and breast cancer diagnosed at a young age (35 years) are correlated with higher distant recurrence rates after BCT.Risk factors for LRR after BCS include lympho-vascular invasion, extensive inraductal component, and high nodal status, where as risk factors for distant recurrence include tumor size, nodal status, high histologic grade, and breast cancer diagnosed at a young age (35 years).

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