Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression

BACKGROUND/AIMS: Interleukin-6 stimulates liver regeneration and promotes hepatoprotection following experimental liver injury, but underlying mechanisms have not been fully characterized. Because studies suggest matrix metalloproteinase-2 (MMP-2) may promote liver injury, we examined whether IL-6 exerted its protective effects via regulation of MMP-2. METHODS: MMP-2 was analyzed in livers of IL-6-/- and IL-6+/+ mice following CCl(4) administration. IL-6-/- mice were pretreated with IL-6 and liver histology and MMP-2 expression were examined after liver injury. IL-6-/- mice were treated with an MMP-2 inhibitor and assessment of injury (histology and serum ALT levels), apoptosis by TUNEL assay, and hepatocyte proliferation by BRDU-labeling was performed. These studies were complemented by analysis of cultured stellate cells. RESULTS: MMP-2 mRNA, protein, and activity was increased in IL-6-/- livers. Restoration of IL-6 signaling in IL-6-/- mice rescued injury and restored MMP-2 expression to wild-type levels. Furthermore, pharmacologic inhibition of MMP-2 decreased hepatocellular injury and apoptosis in IL-6-/- mice. In cultured stellate cells, recombinant IL-6 suppressed endogenous MMP-2 mRNA and protein expression. CONCLUSIONS: IL-6 may be hepatoprotective in acute injury through down-regulation of MMP-2. These findings suggest a role for MMP-2 in amplifying liver injury in vivo.     

Local resection of ampullary tumors

There is no consensus on the appropriateness of local resection for ampullary tumors, because malignant recurrence of what were thought to be benign tumors has been reported. This study examined the role of local resection in the management of ampullary tumors. Thirty patients (mean age 66 years) had transduodenal local resections performed at UCSF-Moffitt Hospital or the San Francisco VA Medical Center (February, 1992 to March, 2004). Mean follow-up time was 5.8 years. Preoperative biopsies (obtained in all patients) showed 18 adenomas, four adenomas with dysplasia, five adenomas with atypia, one adenoma with dysplasia and focal adenocarcinoma, and two tumors seen on endoscopy, whose biopsies showed only duodenal mucosa. In comparison with the final pathology findings, the results of frozen section examinations for malignancy in 20 patients, during the operation, were false-negative in three cases. The final pathologic diagnosis was 23 villous adenomas, six adenocarcinomas, and one paraganglioma. On preoperative biopsies, all patients who had high-grade dysplasia and one of five patients with atypia turned out to have invasive adenocarcinoma when the entire specimen was examined postoperatively. Two (33%) adenocarcinomas recurred at a mean of 4 years; both had negative margins at the initial resection. Among the 23 adenomas, three (13%) recurred (all as adenomas) at a mean of 3.2 years; in only one of these cases was the margin positive at the time of resection. Tumor size did not influence recurrence rate. Ampullary tumors with high-grade dysplasia on preoperative biopsy should be treated by pancreaticoduodenectomy because they usually harbor malignancy. Recurrence is too common and unpredictable after local resection of malignant lesions for this to be considered an acceptable alternative to pancreaticoduodenectomy. Ampullary adenomas can be resected locally with good results, but the recurrence rate was 13%, so endoscopic surveillance is indicated postoperatively. Frozen sections were obtained during the operation, but they were less reliable than expected. No adenomas recurred as carcinomas, suggesting that local resection is appropriate for these tumors in the absence of dysplasia or atypia on preoperative biopsies. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (poster presentation).     

The use of acellular dermal matrix for contaminated abdominal wall defects: wound status predicts success

BACKGROUND: Contaminated abdominal wall fascial defects present a challenging problem. The use of human acellular dermal matrix (AlloDerm; LifeCell Corp., Branchburg, NJ) provides a novel method of primary closure of abdominal wall defects in this setting. The aim of the current study was to determine what factors predicted fascial wall failure as determined by the presence of hernia on follow-up exam after AlloDerm placement. METHODS: All patients who underwent surgery for contaminated abdominal wall fascial defects with placement of AlloDerm from June 2003 to September 2005 at a tertiary care Veterans Affairs hospital were included in the analysis. Patients were followed until hernia recurrence or last clinic visit. RESULTS: Eighteen patients had AlloDerm placed for contaminated fascial defects and all were included in the analysis. Primary wound closure was performed on 12/18 (67%) patients, with 6/18 (33%) patients initially left with open wounds. Patients with open wounds were treated with wound vacuum-assisted closure (VAC) devices (4/6) or saline dressings (2/6). Overall ventral hernia recurrence rate was 50% (9/18) with an average follow up of 9.1 months. Patients who had primary wound closure at the completion of the operation had a 33% (4/12) recurrence rate. Patients who did not have primary wound closure had an 83.3% (5/6) recurrence rate. The significant difference shows (P = .03) that open wound status predicts recurrence. The average size of AlloDerm sheets used was 164.0 cm2 in the closed group and 146.2 cm2 in the primary open wound group (P = .64). Average cost per patient was 4680 dollars for AlloDerm. CONCLUSION: These data suggest that an open wound in the postoperative period after AlloDerm placement for treatment of contaminated fascial defects is associated with a high probability of hernia recurrence. Our data do not support the use of this expensive material unless there is a good chance of having a closed wound.     

Air transportation of patients with end-stage liver disease to distant liver transplantation centers.

The Israeli population does not meet its transplantation organ needs. Therefore, liver transplantation (LTX) candidates are sometimes transported to centers abroad. We aimed to assess the demographic and clinical issues concerning this policy. Records of all candidates transported (2000-2004) were retrospectively reviewed. Data included etiology, disease severity, outcome, distances traveled and destinations, and medical complication arising en route. Forty-three candidates were transported overseas: 12 patients with fulminant hepatic failure (FHF) and 31 with cirrhosis. Average MELD score was 19.94, and the APACHE II score for patients with FHF was 20.5. Destinations included the United States, Colombia, Belgium, Germany, China, and Italy. Average distance traveled was 4,660 miles. Two patients were intubated and sedated during flight. All patients safely reached their destinations: 8 died prior to transplantation, 5 died after transplantation, 3 are awaiting transplantation, 3 recovered spontaneously, and the rest successfully underwent transplantation and returned home. In conclusion, our results suggest that long-distance transportation of patients awaiting liver transplantation is safe and technically feasible provided precaution measures are taken. Therefore, allocation regions may be broadened to include larger and more distant populations.     

Late cytomegalovirus disease following liver transplantation

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.     

A histochemical method that predicts local recurrence after curative resection in carcinoma of the colon and rectum

In an attempt to develop a method to predict local recurrence that may occur following radical resection for cure in patients with carcinoma of the colon and rectum, we have studied retrospectively the histochemical characteristics of mucins in 48 surgically resected specimens. This differential pattern of mucus production at the resection margin distinguished between the patients who had local recurrence develop and those who remained tumor free.