Use of Transesophageal Echocardiogram and Interdisciplinary Approach to Intraoperative Management of Renal Cell Carcinoma With Inferior Vena Cava Invasion.

OBJECTIVE: Report experience of patients undergoing surgery for resection of renal cell carcinoma with inferior vena cava invasion and use of transesophageal echocardiogram (TEE). DESIGN: Retrospective and observational study. SETTING: Single large university hospital. PARTICIPANTS: The study comprised 55 consecutive who underwent resection of renal cell carcinoma. INTERVENTIONS: A transesophageal echocardiogram was performed by cardiac anesthesiologists in high grade tumors. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients had tumor thrombi classified as level III, and 6 patients were classified as level IV. There was increased use of TEE for higher level of tumor thrombi. CONCLUSIONS: The surgical management of renal cell carcinoma with inferior vena cava tumor extension is complex. High-grade tumors require individualized treatment. Successful outcomes require collaboration between surgeons and anesthesiologists. Patients with level IIIb to IV tumor invasion benefit from TEE assessment and monitoring, which may be life-saving, and cardiac anesthesia should be involved in those types of cases.

Integrin α4ß1 and TLR4 Cooperate to Induce Fibrotic Gene Expression in Response to Fibronectin's EDA Domain.

Alternative splicing of fibronectin increases expression of the EDA+ isoform of fibronectin (EDA+Fn), a damage-associated molecular pattern molecule, which promotes fibro-inflammatory disease through the activation of toll-like receptors. Our studies indicate that the fibronectin EDA domain drives two waves of gene expression in human dermal fibroblasts. The first wave, seen at 2 hours, consisted of inflammatory genes, VCAM1, and tumor necrosis factor. The second wave, evaluated at 24 hours, was composed of the fibrosis-associated cytokines IL-10 and IL-13 and extracellular matrix genes fibronectin and osteopontin. Gene expression was coordinately regulated by the α4ß1 integrin and the innate immune receptor toll-like receptor 4. Additionally, we found a significant toll-like receptor 4/α4ß1-dependent enrichment in the ratio of EDA+Fn to total fibronectin in response to EDA, consistent with EDA+Fn initiating further production of EDA+Fn. Our data also suggest that the EDA/α4ß1 integrin interaction primes the cell for an enhanced response to toll-like receptor 4 ligands. Our studies provide evidence that remodeling of the fibronectin matrix in injured or diseased tissue elicits an EDA-dependent fibro-inflammatory response in dermal fibroblasts. The data suggest a paradigm of damage-associated molecular pattern-based signaling whereby damage-associated molecular pattern binding integrins cooperate with innate immune receptors to stimulate inflammation and fibrosis.

Cryptic activity within the Type III1 domain of fibronectin regulates tissue inflammation and angiogenesis.

The fibronectin matrix provides mechanical and biochemical information to regulate homeostatic and pathological processes within tissues. Fibronectin consists of independently-folded modules termed Types I, II and III. In response to cellular contractile force, Type III domains unfold to initiate a series of homophilic binding events which result in the assembly of a complex network of intertwining fibrils. The unfolding of Type III modules provides elasticity to the assembled fibronectin matrix allowing it to function as a dynamic scaffold which provides binding sites for cellular receptors, growth factors and other matrix molecules. Access to bioactive sites within the fibronectin matrix is under complex regulation and controlled through a combination of mechanical and proteolytic activity. Mechanical unfolding of Type III modules and limited proteolysis can alter the topographical display of bioactive sites within the fibronectin fibrils by exposing previously cryptic sites and disrupting functional sites. In this review we will discuss cryptic activity found within the first Type III module of fibronectin and its impact on tissue angiogenesis and inflammation.