Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells.

RATIONALE: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs. OBJECTIVE: The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs. METHODS AND RESULTS: Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation-induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α-converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression. CONCLUSIONS: Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.

Pyogenic liver abscess following pancreaticoduodenectomy: risk factors, treatment, and long-term outcome.

BACKGROUND: Pancreaticoduodenectomy (PD) remains a challenging operation with a 40% postoperative complication rate. Pyogenic liver abscess (PLA) is an uncommon complication following PD with little information on its incidence or treatment. This study was done to examine the incidence, risk factors, treatment, and long-term outcome of PLA after PD. METHODS: We retrospectively reviewed 1,189 patients undergoing PD (N = 839) or distal pancreatectomy (DP) (N = 350) at a single institution over a 14-year period (January 1, 1994-January 1, 2008). Pancreatic databases (PD and DP) were queried for postoperative complications and cross-checked through a hospital-wide database using ICD-9 codes 572.0 (PLA) and 006.3 (amebic liver abscess) as primary or secondary diagnoses. No PLA occurred following DP. Twenty-two patients (2.6%) developed PLA following PD. These 22 patients were matched (1:3) for age, gender, year of operation, and indication for surgery with 66 patients without PLA following PD. RESULTS: PLA occurred in 2.6% (22/839) of patients following PD, with 13 patients (59.1%) having a solitary abscess and 9 (40.9%) multiple abscesses. Treatment involved antibiotics and percutaneous drainage (N = 15, 68.2%) or antibiotics alone (N = 7, 31.8%) with a mean hospital stay of 12 days. No patient required surgical drainage, two abscesses recurred, and all subsequently resolved. Three patients (14%) died related to PLA. Postoperatively, patients with biliary fistula (13.6 vs. 0%, p = 0.014) or who required reoperation (18.2 vs. 1.5%, p = 0.013) had a significantly higher rate of PLA than matched controls. Long-term follow-up showed equivalent 1-year (79 vs.74%), 2-year (50 vs. 57%), and 3-year (38 vs. 33%) survival rates and hepatic function between patients with PLA and matched controls. CONCLUSIONS: Postoperative biliary fistula and need for reoperation are risk factors for PLA following PD. Antibiotics and selective percutaneous drainage was effective in 86% of patients with no adverse effects on long-term hepatic function or survival.

Unplanned intubation: when and why does this deadly complication occur?

BACKGROUND: Risk factors for unplanned intubation have been delineated, but details regarding when and why reintubations occur as well as strategies for prevention have not been defined. METHODS: Over a 2-year period, 104 of 3,141 patients (3.3%) monitored via the American College of Surgeons-National Surgical Quality Improvement Program required unplanned intubation. These patients were compared to those who remained extubated and were characterized by (1) the operation performed; (2) the postoperative day when reintubation occurred; and (3) the underlying causes. RESULTS: Patients who required reintubation were significantly older (65.8 years) and were more likely to be male (55%) and to have several comorbidities, weight loss (16%), dependency (14%), or sepsis (9%). The operations complicated most commonly by unplanned intubation were gastrectomy (13%), nephrectomy (10%), colectomy (9%), pancreatectomy (8%), hepatectomy (7%), and enterectomy (6%). The most common causes and median postoperative days were sepsis (33%, day 8) and aspiration/pneumonia (31%, day 4). Sepsis was due most commonly to an abdominal or pelvic abscess (74%), which was frequently not recognized despite an inflammatory response. Aspiration occurred most commonly after upper abdominal operations (78%) despite signs of diminished bowel function. CONCLUSION: Postoperative sepsis and aspiration/pneumonia account for two thirds of unplanned intubations. Opportunities for management of patients exist for the prevention of this deadly complication.

Effect of celecoxib and the novel anti-cancer agent, dimethylamino-parthenolide, in a developmental model of pancreatic cancer.

OBJECTIVES: Cancer of the exocrine pancreas is the fourth leading cause of cancer-related deaths in the United States. The efficacy of a novel bioavailable anticancer agent, dimethylamino-parthenolide (DMAPT), and the cyclooxygenase 2 inhibitor, celecoxib, was evaluated in a carcinogen-induced developmental model of pancreatic cancer. METHODS: Syrian golden hamsters were injected with N-nitrosobis(2-oxopropyl)amine, once weekly for 6 weeks. Upon the first injection, hamsters were randomized as follows: placebo, low-/high-dose DMAPT (20 and 40 mg/kg per day), low-/high-dose celecoxib (10and 50 mg/kg per day), or combination DMAPT/celecoxib (low/low, high/high). RESULTS: The 32-week trial showed that 40 mg/kg DMAPT alone significantly decreased the size of gross pancreatic cancers relative to placebo. No significant difference in gross tumor number was observed between the treatment groups and placebo with the exception of 50 mg/kg celecoxib with a higher tumor incidence; this group also exhibited lower lymphotactin levels suggestive of decreased immune surveillance. Tumor invasion into adjacent organs and metastasis were not observed in the DMAPT/celecoxib treatment groups. Drug targets including prostaglandin E2, prostaglandin E2 metabolite and activated nuclear factor kappaB were significantly decreased. CONCLUSIONS: Dimethylamino-parthenolide and celecoxib have the potential to be novel chemotherapeutic agents for pancreatic cancer; however, further optimization or the use of other modalities may be required for chemoprevention.