Low PTEN expression is associated with worse overall survival in head and neck squamous cell carcinoma patients treated with chemotherapy and cetuximab.

BACKGROUND: Platinum-based chemotherapy associated with cetuximab is the first-line treatment for inoperable recurrence or metastatic head and neck squamous cell carcinoma (HNSCC). There is no established biomarker for cetuximab efficacy in HNSCC. The PI3K pathway is one of the most frequently altered pathways in HNSCC. Loss of phosphatase and tensin homolog (PTEN) expression occurs in up to 30 % of cases. METHODS: This was a retrospective analysis of data from 61 patients with inoperable recurrence or metastatic HNSCC treated with cetuximab. PTEN, epidermal growth factor receptor and p16 expression were analyzed by immunohistochemistry and tested for association with clinical outcomes. RESULTS: Median overall survival was 11.4 months and progression-free survival was 6.9 months. Low PTEN expression was present in 26.2 % of patients and identified patients with worse prognosis. p16 was positive in only 8.5 % of tumors. CONCLUSIONS: Low PTEN expression in patients treated with cetuximab plus chemotherapy emerged as a prognostic biomarker and should be evaluated for its predictive role for cetuximab efficacy.

Prognostic impact of MUM1 expression by immunohistochemistry on primary mediastinal large B-cell lymphoma.

Diffuse large B-cell lymphoma can be classified into two prognostically distinct subgroups with germinal center B-cell-like (CG) and activated B-cell-like (post-CG) characteristics, based on CD10, BCL-6, and MUM1 expression. We performed a retrospective analysis of the clinical variables of 37 patients with primary mediastinal large B-cell lymphoma and the expression of BCL-6 and MUM1 in 22 patients with available tissue. The median age was 30 years, and 70% of the patients were female. BCL-6 and MUM1 were expressed in 64% and 45% of cases, respectively. Five-year overall survival (OS) and disease-free survival (DFS) were 47% and 81%, respectively. In univariate analysis, complete response (p = 0.0001), radiation therapy (p = 0.01), International Prognostic Index (p = 0.001), and MUM1 expression (p = 0.002) correlated with OS. For this group of patients with homogeneous clinical characteristics, response to initial chemotherapy and MUM1 expression were associated with prognosis.

Factors correlated with peritoneal carcinomatosis and survival in patients with gastric cancer treated at a single institution in Brazil.

BACKGROUND: Gastric cancer is the second leading cause of death due to cancer worldwide and is particularly prevalent in Brazil. Promising new therapeutic agents have already shown activity in some gastrointestinal malignancies and their role in gastric cancer will need to be evaluated. Determining the prognostic factors of survival for patients with gastric cancer can help in identifying patients with a worse prognosis after treatment with the current chemotherapeutic regimens. METHODS: A retrospective chart review of 186 patients diagnosed with gastric cancer and treated at a single institution in Brazil from January 1994 to December 2004 was carried out. Univariate and multivariate analyses were performed to identify patient- and tumor-related characteristics associated with peritoneal metastasis at diagnosis and with overall survival. RESULTS: Of the 186 patients, 76 were alive at the time of this analysis. The median survival for all patients was 30.1 months. Two independent factors associated with the presence of peritoneal metastasis at diagnosis were identified by multivariate analysis: signet-ring cell type (odds ratio [OR], 10.8; 95% confidence interval [CI], 3.1 to 37.5), and visceral metastasis (OR, 51.8; 95% CI, 12.4 to 215.4). The prognostic factors for poor survival were tumor stage T3 or T4 (hazard ratio [HR], 1.87; 95% CI, 1.09 to 3.22) and visceral metastasis (HR, 4.98; 95% CI, 3.02 to 8.20). CONCLUSION: Two factors correlated with peritoneal metastasis and two prognostic factors for survival were identified. These findings may contribute to clinical decision-making, treatment tailoring, and the design of future trials.

Predictors of peritoneal carcinomatosis in patients with gastric cancer treated at a single institution in Brazil.

BACKGROUND: Peritoneal carcinomatosis is a common pattern of recurrence in gastric cancer and is associated with a poor prognosis. Determining predictive factors for peritoneal recurrence can help the selection of patients suitable for more aggressive treatment strategies. METHODS: A retrospective chart review of 162 patients diagnosed with gastric cancer with no peritoneal carcinomatosis and treated at a single institution in Brazil from January 1994 to December 2004 was carried out. Univariate and multivariate analyses were performed to identify patient and tumor-related characteristics associated with the development of peritoneal metastasis. RESULTS: Twenty-three (14.2%) patients developed peritoneal carcinomatosis. Three independent factors associated with the development of peritoneal metastasis were identified by multivariate analysis: signet-ring cell histology (odds ratio [OR] = 4.9; P = 0.018), the presence of vascular invasion (OR = 4.8; P = 0.022), and the presence of visceral metastasis at diagnosis (OR = 5.1; P = 0.011). Tumor stages T3 or T4 showed a trend towards significance (P = 0.062). CONCLUSIONS: Patients with gastric cancer presenting with signet-ring histology, vascular invasion, or visceral metastasis appear to be at higher risk for the development of peritoneal carcinomatosis.

ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis.

The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with alpha(v)beta(3) integrin mediated by the disintegrin domain. Altered expression of alpha(v)beta(3) integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and alpha(v)beta(3) integrin might negatively modulate alpha(v)beta(3) activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for alpha(v)beta(3) integrin activation. Ablation of ADAM23 enhanced alpha(v)beta(3) integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic alpha(v)beta(3) integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating alpha(v)beta(3) integrin activation.