Combined MEK and PI3K/p110ß Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features.

Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110ß/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110ß/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110ß/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking. SIGNIFICANCE: Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.

Knotless choledochorraphy with barbed suture, safe and feasible.

PURPOSE: To describe the safety and feasibility of a running continuous unidirectional barbed suture (V-Loc, Covidien, Mansfield, MA) for primary common bile duct closure while performing laparoscopic common bile duct exploration (LCBDE). INTRODUCTION: LCBDE is nowadays the best approach for treating complex common bile duct lithiasis or cases where the endoscopic retrograde cholangiopancreatography has failed. It is clear that the primary closure of the common bile duct must be preferred over the T-tube drainage. The actual technical aspects offer room for improvement. We present our experience with barbed suture, for which recently, various fields of surgery have become interested in and which now has a series of studies that support it for several uses. METHODS: Between July 2012 and July 2014, 54 consecutive patients with bile duct stones underwent LCBDE by a single surgeon. Perioperative outcomes and 30-day complications were recorded. RESULTS: Upon the completion of the exploration, 50 patients had primary common bile duct closure using knotless unidirectional barbed 3-0 V-Loc 90 suture, and 4 patients were excluded. All of the sutures were performed without knot tying. The procedure in all patients was successfully performed with no intraoperative complications. There were no bile leaks in the 50 patients or other postoperative complications such as infection, need for reintervention or death. CONCLUSION: The use of unidirectional knotless barbed suture (V-Loc 90) is safe, feasible and effective on LCBDE for primary common bile duct closure. The biliary leak rate is acceptably low and comparable to the rate reported in the literature. This report is our initial experience that needs further clinical trials.

Somatic mosaicism: on the road to cancer.

Diversity is the basis of fitness selection. Although the genome of an individual is considered to be largely stable, there is theoretical and experimental evidence--both in model organisms and in humans--that genetic mosaicism is the rule rather than the exception. The continuous generation of cell variants, their interactions and selective pressures lead to life-long tissue dynamics. Individuals may thus enjoy 'clonal health', defined as a clonal composition that supports healthy morphology and physiology, or suffer from clonal configurations that promote disease, such as cancer. The contribution of mosaicism to these processes starts during embryonic development. In this Opinion article, we argue that the road to cancer might begin during these early stages.

Oncogenic HoxB7 requires TALE cofactors and is inactivated by a dominant-negative Pbx1 mutant in a cell-specific manner.

The homeobox containing gene HoxB7 is functionally associated with melanoma growth promotion through the direct transactivation of bFGF. Accordingly, the introduction of HoxB7 in the breast cancer line SkBr3 (SkBr3/B7), strongly increases its tumorigenic properties. Here we show that in SkBr3/B7 cells, HoxB7 regulates the expression of TALE Hox cofactors by increasing Pbx2 and Prep1 and decreasing Pbx1. The functional requirement of Hox cofactors in the oncogenic activity of HoxB7 was proven with a dominant-negative Pbx1 mutant, Pbx1NT, which sequesters Prep1 in the cytoplasm. The less aggressive phenotype of the SkBr3/B7/PbxNT cells, evaluated in vitro as well as in vivo, correlated well with increased apoptosis, decreased cycling and up-regulation of p16 and p53. Tumor cell-type specific functional effects of Pbx1NT were observed, possibly related to the presence of different Hox genes in melanoma or breast adenocarcinoma DNA-protein ternary complexes.