Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis.

Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent nuclear factor of activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock-down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2 and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells.

Variant Two-Stage Ileal Pouch-Anal Anastomosis: An Innovative and Effective Alternative to Standard Resection in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis patients have been historically treated with standard single, 2-, and 3-stage operative approaches. We perform a variant 2-stage procedure beginning with total abdominal colectomy and end ileostomy followed by completion proctectomy and ileal pouch-anal anastomosis (IPAA) without a diverting loop ileostomy. This study evaluates the effectiveness of this innovative alternative. STUDY DESIGN: Patients with ulcerative colitis, admitted to the University of North Carolina Hospital between 2003 and 2010 for IPAA, were eligible for inclusion. The 3-year cumulative incidence of pouch leaks among patients undergoing variant 2-stage were compared with those undergoing classic 2-stage, using inverse probability-of-treatment weighted Kaplan- Meier survival curves, and 95% CIs were estimated using nonparametric bootstrapping. RESULTS: There were 248 patients who underwent IPAA; 139 (56.1%) underwent classic 2-stage and 109 (43.9%) underwent variant 2-stage. After standardization, there was no significant difference in the 3-year cumulative incidence of pouch leaks between patients undergoing variant 2-stage, compared with the standard single- or 2-stage procedure (risk difference 0.01; 95% CI -0.08, 0.15). At the time of the first surgical procedure, patients undergoing a variant 2-stage were more likely to have lower BMIs (median 22.5 kg/m2 vs 26.7 kg/m2; p < 0.0001), an urgent/emergent procedure (56.9% vs 0.0%; p < 0.0001), biologic use within 2 weeks of surgery (32.1% vs 17.5%; p = 0.003), and high dose steroid use (60.4% vs 16.7%; p ≤ 0.0001). CONCLUSIONS: Variant 2-stage IPAA is a safe and effective operative approach with comparable outcomes in a more acute population based on BMI, steroid use, and urgency of operation.

Postoperative Morbidity in Curative Resection of Gastroesophageal Carcinoma Does Not Impact Long-term Survival.

Significant morbidity and mortality have historically been reported for surgical resection of gastric and gastroesophageal junction tumors. We evaluated our experience to determine morbidity and mortality and evaluated demographic and pathologic risk factors associated with postoperative outcome and long-term survival. A retrospective, Institutional Review Board-approved, single-institution database identified 102 patients who underwent resection with curative intent for gastroesophageal junction or gastric carcinoma from 2004 to 2012. The method of Kaplan and Meier was used to describe overall survival and estimate median survival. Of 102 patients, 74 were male and 28 were female. Of these, 24 patients were > 70 years of age at surgery (median = 62.9). Forty esophagectomies, 25 total gastrectomies, and 37 subtotal gastrectomies were performed. Two patients died (one esophagectomy and one gastrectomy). Forty-one developed a complication: 17 minor and 35 major, including six anastomotic leaks. Patients with low preoperative albumin (P = 0.01) and increased age (P = 0.05) were associated with having a postoperative complication; extent of nodal dissection (P = 0.48), jejunostomy (0.24), performance status (P = 0.77), type of surgery (P = 0.74), and neoadjuvant therapy (P = 0.24) were not associated. More extensive nodal dissection was associated with a decreased risk of death (P = 0.007). Having any complication (P = 0.20), an anastomotic leak (P = 0.17), worse grade of complication (P = 0.15), presence of feeding jejunostomy tube (P = 0.17), and neoadjuvant therapy (P = 0.30) were not associated with changes in overall survival. Thorough lymph node dissection improves survival without increasing postoperative morbidity. The data advocate for increased lymph node yield and close attention to nutritional support in gastroesophageal carcinoma patients.

Ultrasound molecular imaging of secreted frizzled related protein-2 expression in murine angiosarcoma.

Angiosarcoma is a biologically aggressive vascular malignancy with a high metastatic potential. In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agents can monitor tumor progression non-invasively. Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. We hypothesize that SFRP2-directed imaging could be a novel approach to imaging the tumor vasculature. To develop an SFRP2 contrast agent, SFRP2 polyclonal antibody was biotinylated and incubated with streptavidin-coated microbubbles. SVR angiosarcoma cells were injected into nude mice, and when tumors were established the mice were injected intravenously with the SFRP2 -targeted contrast agent, or a control streptavidin-coated contrast agent. SFRP2 -targeted contrast agent detected tumor vasculature with significantly more signal intensity than control contrast agent: the normalized fold-change was 1.6 ± 0.27 (n = 13, p = 0.0032). The kidney was largely devoid of echogenicity with no significant difference between the control contrast agent and the SFRP2-targeted contrast agent demonstrating that the SFRP2-targeted contrast agent was specific to tumor vessels. Plotting average pixel intensity obtained from SFRP2-targeted contrast agent against tumor volume showed that the average pixel intensity increased as tumor volume increased. In conclusion, molecularly-targeted imaging of SFRP2 visualizes angiosarcoma vessels, but not normal vessels, and intensity increases with tumor size. Molecular imaging of SFRP2 expression may provide a rapid, non-invasive method to monitor tumor regression during therapy for angiosarcoma and other SFRP2 expressing cancers, and contribute to our understanding of the biology of SFRP2 during tumor development and progression.

Targeting angiogenesis and the tumor microenvironment.

The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Active contribution of tumor-associated stromal cells to cancer progression has been recognized. Stromal elements consist of the extracellular matrix, fibroblasts of various phenotypes, and a scaffold comprised of immune and inflammatory cells, blood and lymph vessels, and nerves. This review focuses on therapeutic targets in the microenvironment related to tumor endothelium, tumor associated fibroblasts, and the extracellular matrix.

Simultaneous rupture of bronchus and aortic valve from blunt trauma.

We report the case of a 29-year-old woman with combined bronchial rupture and aortic valve tear after blunt chest trauma. She was successfully treated with primary repair of both lesions. The importance of chest computed tomography and transthoracic echocardiography in the diagnosis of these lesions is discussed.