Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

Peer reviewedPublisher PD

CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo

Thus far the clinical benefits seen in breast cancer patients treated with drugs targeting the vascular endothelial growth factor (VEGF) pathway are only modest. Consequently, additional antiangiogenic approaches for treatment of breast cancer need to be investigated. Thrombospondin-2 (TSP-2) has been shown to inhibit tumor growth and angiogenesis with a greater potency than the related molecule TSP-1. The systemic effects of TSP-2 on tumor metastasis and the underlying molecular mechanisms of the antiangiogenic activity of TSP-2 have remained poorly understood. We generated a recombinant fusion protein consisting of the N-terminal region of TSP-2 and the IgG-Fc1 fragment (N-TSP2-Fc) and could demonstrate that the antiangiogenic activity of N-TSP2-Fc is dependent on the CD36 receptor. We found that N-TSP2-Fc inhibited VEGF-induced tube formation of human dermal microvascular endothelial cells (HDMEC) on matrigel in vitro and that concurrent incubation of anti-CD36 antibody with N-TSP2-Fc resulted in tube formation that was comparable to untreated control. N-TSP2-Fc potently induced apoptosis of HDMEC in vitro in a CD36-dependent manner. Moreover, we could demonstrate a CD36 receptor-mediated loss of mitochondrial membrane potential and activation of caspase-3 in HDMEC in vitro. Daily intraperitoneal injections of N-TSP2-Fc resulted in a significant inhibition of the growth of human MDA-MB-435 and MDA-MB-231 tumor cells grown in the mammary gland of immunodeficient nude mice and in reduced tumor vascularization. Finally, increased serum concentrations of N-TSP2-Fc significantly inhibited regional metastasis to lymph nodes and distant metastasis to lung as shown by quantitative real-time alu PCR. These results identify N-TSP2-Fc as a potent systemic inhibitor of tumor metastasis and provide strong evidence for an important role of the CD36 receptor in mediating the antiangiogenic activity of TSP-2

Surgical treatment of benign hepatic mass lesions.

Benign hepatic mass lesions may require surgical treatment for symptomatic relief or prevention of hemorrhage. The most common benign hepatic mass lesions in the United States are hemangioma, focal nodular hyperplasia, hepatic adenoma, and congenital liver cyst. We report a series of liver resections performed for benign hepatic masses at our institution. All liver resections were performed with total inflow occlusion during the parenchymal transection time. None of our patients received perioperative blood products. No postoperative complications occurred, and the average length of hospital stay was 6 days. Surgeons performing hepatic resections for benign mass lesions should be able to complete these procedures with low operative blood loss and low operative morbidity

Reduction of transfusion requirements during major hepatic resection for metastatic disease.

BACKGROUND: Our purpose was to determine whether the combination of total liver vascular inflow occlusion (Pringle maneuver) and rapid hepatic transection with a clamp-crush technique results in significant reduction of blood loss and transfusion requirements during major hepatic resections. METHODS: A series of 49 adult patients underwent major hepatic resections for metastatic disease between April 1, 1992, and March 31, 1998. Group 1 patients (n = 15) had standard hilar dissection and finger-fracture hepatic transection without total liver inflow occlusion. Group 2 patients (n = 34) had total liver inflow occlusion and clamp-crush parenchymal transection. RESULTS: Median blood loss was 1600 mL for group 1 and 500 mL for group 2 (P = .001). Eleven (73%) patients in group 1 required intraoperative blood transfusion (median 2 units) compared with 7 (21%) in group 2 with a median of 0 units (P = .001 and P \u3c .001, respectively). Of the 7 patients in group 2 who required transfusion, 3 had a preoperative hemoglobin below 10 g/dL, 1 required splenectomy for operative injury, and 1 underwent a concomitant complicated small bowel resection. CONCLUSIONS: Major hepatic resections can be performed without transfusion of blood products when preoperative hemoglobin is above 10 g/dL and concomitant major surgical procedures are not required

Early postoperative complications of splenectomy for hematologic disease.

Splenectomy may be indicated in a variety of hematologic diseases for diagnostic reasons, therapeutic reasons, or both. Most reviews reveal a high proportion of procedures performed as part of the staging process for Hodgkin disease. Splenectomy for myelofibrosis has been associated with an increased postoperative complication rate. Other determinants of morbidity have been splenic weight and operative blood loss. The authors reviewed a series of 83 adult patients from a prospective database established in 1991 to determine the incidence of early postoperative complications associated with splenectomy for hematologic disease and to analyze patient characteristics that may predict their occurrence. Morbidity that occurred within 30 days of splenectomy was considered to be an early postoperative complication. Operative estimated blood loss and incidence of postoperative complications were correlated with patient age, preoperative platelet count, splenic weight, and diagnosis of myelofibrosis as regression covariates. Indications for splenectomy were therapeutic in 76 patients (92%). Median splenic weight was 760 g, and 22 patients had massive splenomegaly. Patients with splenic weight more than 1,500 g had a significantly higher median estimated blood loss (300 ml; p = 0.02). Splenic weight was the main determinant of estimated blood loss in a multiple linear regression analysis (p = 0.02). Twenty-two patients (27%) experienced postoperative complications and five of those patients died (6%). Patients with myelofibrosis had the highest incidence of complications (50%) and the highest postoperative mortality (21%; p = 0.04). In a logistic regression model, estimated blood loss was the only variable significantly correlated with postoperative complications (p = 0.02). Splenectomy for hematologic disease is associated with an acceptable early postoperative complication rate, even when the indication is predominantly therapeutic. Patients at particularly high risk include those with elevated operative blood loss, massive splenomegaly, and myelofibrosis

Mutant Gene Found in Pancreatic Juice Activated Chromatin From Peri-ampullary Adenocarcinomas

External pancreatic duct stents inserted after resection of pancreatic head tumors provide unique access to pancreatic juice analysis of genetic and metabolic components that may be associated with peri-ampullary tumor progression. For this pilot study, portal venous blood and pancreatic juice samples were collected from 17 patients who underwent pancreaticoduodenectomy for peri-ampullary tumors. Portal vein circulating tumor cells (CTC) were isolated by high-speed fluorescence-activated cell sorting (FACS) and analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) for K-RAS exon 12 mutant gene expression ( K-RASmut ). DNA, chromatin, and histone acetylated active chromatin were isolated from pancreatic juice samples by chromatin immunoprecipitation (ChIP) and the presence of K-RASmut and other cancer-related gene sequences detected by quantitative polymerase chain reaction (PCR) and ChIP-Seq. Mutated K-RAS gene was detectable in activated chromatin in pancreatic juice secreted after surgical resection of pancreatic, ampullary and bile duct carcinomas and directly correlated with the number of CTC found in the portal venous blood ( P  = .0453). ChIP and ChIP-Seq detected acetylated chromatin in peri-ampullary cancer patient juice containing candidate chromatin loci, including RET proto-oncogene, not found in similar analysis of pancreatic juice from non-malignant ampullary adenoma. The presence of active tumor cell chromatin in pancreatic juice after surgical removal of the primary tumor suggests that viable cancer cells either remain or re-emerge from the remnant pancreatic duct, providing a potential source for tumor recurrence and cancer relapse. Therefore, epigenetic analysis for active chromatin in pancreatic juice and portal venous blood CTC may be useful for prognostic risk stratification and potential identification of molecular targets in peri-ampullary cancers