NFAT4 deficiency results in incomplete liver regeneration following partial hepatectomy.

BACKGROUND: Liver regeneration following partial hepatectomy requires the orchestration of highly regulated molecular pathways; a change in the abundance or activity of a specific gene product has the potential to adversely affect this process. The nuclear factor of activated T-cells (NFAT) transcription factors represent a family of gene transcription signaling intermediates that translate receptor-dependent signaling events into specific transcriptional responses using the Ras/Raf pathway. MATERIALS AND METHODS: Eight-week old NFAT4 knockout (KO) mice and their wild type counterparts (Balb-c) underwent two-thirds partial hepatectomy. The animals were sacrificed and their livers were harvested at specific time points during regeneration. Recovery of liver mass was measured for each time point. PCR analysis was used to analyze expression levels of the immediate early genes c-fos, c-jun and c-myc as well as downstream effectors of NFAT4 including FGF-18 and BMP-4. RESULTS: Hepatocyte proliferation and thus liver regeneration following hepatectomy was suppressed in NFAT4 knockout (KO) mice. Statistical significance was reached at 1 h, 7 d, and 10 d (P < 0.05) with a 22% median reduction in regeneration of liver mass in the NFAT4 KO mice by 10 d, at which time liver regeneration should be complete in mice. The immediate early gene c-fos was elevated in NFAT4 KO mice during early regeneration with a median value at 1 h and 1 d of 1.60E-08 and 1.09E-08 versus 6.10E-09 and 1.55E-09 in the Balb-c mice. C-jun, in contrast, was elevated during late regeneration in the NFAT4 KO mice (3.40E-09 and 5.67E-09 at 7 and 10 d, respectively) in comparison with the Balb-c mice (7.76E-10 and 1.24E-09, respectively.). NFAT2 was also up-regulated in the NFAT4 KO mice; however, no changes were detected in its downstream effectors, CCR1 and CCL3. CONCLUSIONS: We demonstrated that NFAT4 deficiency impairs hepatic regeneration in a murine model proving that NFAT4 plays an important yet unclear role in liver regeneration; its absence may be compensated by c-fos, c-jun, and NFAT2 expression changes.

Warm hepatic ischemia-reperfusion promotes growth of colorectal carcinoma micrometastases in mouse liver via matrix metalloproteinase-9 induction.

Surgical resection remains the best treatment for colorectal metastases isolated to the liver; however, 5-year survival rates following liver resection are only 40% to 50%, with liver recurrence being a significant reason for treatment failure. The ischemia-reperfusion (I/R) injury incurred during liver surgery can lead to cellular dysfunction and elevations in proinflammatory cytokines and matrix metalloproteinases (MMP). In rodents, I/R injury to the liver has been shown to accelerate the outgrowth of implanted tumors. The mechanism for increased tumor growth in the setting of liver I/R injury is unknown. To investigate the effect of I/R on tumor growth, an experimental model was used whereby small hepatic metastases form after 28 days. Mice subjected to 30 min of 70% liver ischemia at the time of tumor inoculation had significantly larger tumor number and volume, and had elevated MMP9 serum and liver tissue MMP9 as evidenced by zymography and quantitative real-time PCR. Mice treated with doxycycline, a broad-spectrum MMP inhibitor, had reduced MMP9 levels and significantly smaller tumor number and volume in the liver. MMP9-null mice were used to determine if the effects of doxycycline were due to the absence of stromal-derived MMP9. The MMP9-null mice, with or without doxycycline treatment, had reduced tumor number and volume that was equivalent to wild-type mice treated with doxycycline. These findings indicate that hepatic I/R-induced elevations in MMP9 contribute to the growth of metastatic colorectal carcinoma in the liver and that postresection MMP9 inhibition may be clinically beneficial in preventing recurrence following hepatic surgery.

Congenital diaphragmatic hernia repair on extracorporeal life support: a decade of lessons learned.

Congenital diaphragmatic hernia (CDH) is a vexing anomaly that manifests with variable pulmonary compromise in neonates. More than one-third of neonates with CDH require extracorporeal membrane oxygenation (ECMO) for refractory pulmonary hypertension (PHN). To assess the outcome of neonates having CDH repair on ECMO, we reviewed our experience for babies treated between 1992 and 2003. Of 97 neonates with CDH, 40 required ECMO, and 30 were repaired on bypass. Eighteen were supported by veno-venous bypass (VV) and 12 by veno-arterial bypass (VA). While on ECMO, transfusion requirements increased twofold postoperatively (15 to 33 cc x kg(-1) day(-1), P = 0.03) and then significantly decreased after decannulation (1.5 cc x kg(-1) x day(-1), P < 0.01). Non-intracranial hemorrhage occurred in 7 (23%) infants and intracranial hemorrhage in 3 (10%). Twelve (40%) infants died; one (3%) on ECMO secondary to refractory PHN. The mean length of stay for the 18 (60%) survivors was 48 days. Comparisons between survivors and nonsurvivors showed a significantly increased mortality for infants placed on VA bypass (P < 0.01). However, no other variable was predictive of survival. We conclude that CDH repair on ECMO is technically feasible, shows similar survival to the Extracorporeal Life Support Organization (ELSO) registry, and is associated with few bleeding complications.

Bouveret's syndrome complicated by classic gallstone ileus: progression of disease or iatrogenic?

CASE PRESENTATION: Bouveret's syndrome is a rare variant of gallstone ileus resulting in gastroduodenal obstruction from an impacted gallstone. We report two cases of Bouveret's syndrome that were complicated by classic (distal) gallstone ileus, which has previously been reported only twice. The first patient presented with vomiting, epigastric pain, and what was initially believed to be a duodenal diverticulum on computed tomography scan and endoscopy. He initially improved, but later developed symptoms of a small bowel obstruction. Repeat imaging revealed a classic distal gallstone ileus. The second patient presented with nausea, abdominal pain, and imaging consistent with Bouveret's syndrome. Multiple non-operative endoscopic techniques and extracorporeal shock wave lithotripsy were employed to fragment and retrieve the obstructing stone, and she subsequently developed a distal gallstone ileus from a stone fragment. Both patients were managed operatively with enterotomy and stone removal. DISCUSSION: These cases highlight a rare complication of Bouveret's syndrome, classic (distal) gallstone ileus, and juxtapose the natural history of a stone passing versus an iatrogenic etiology. We review the presentation and management of Bouveret's syndrome though no clear consensus exists as to the optimal treatment of these patients. We recommend that therapy should be decided on a case-by-case basis.

Conventional Surgical Treatment of Hepatocellular Carcinoma.

Liver resection remains the standard therapy for solitary hepatocellular carcinoma in patients with preserved hepatic function. In well-selected patients, 5-year survival rates are good and can approach that of liver transplantation for early-stage disease. Patient selection is critical to optimizing therapeutic benefit, and the health of the native liver must be considered in addition to tumor characteristics. Hepatic recurrence after resection is common. The difficulty lies in deciding which patients with chronic liver disease and small solitary tumors are best served by resection and which should proceed with transplant evaluation; this is the focus of this article.

A clinical comparative analysis of crush/clamp, stapler, and dissecting sealer hepatic transection methods.

INTRODUCTION: Several methods for hepatic parenchymal division exist. The primary aim was to assess differences in postoperative bile leaks, operative blood loss, and margin status between three transection methods: crush/clamp (CC), stapler (SP), or dissecting sealer (DS). METHODS: A single institution, retrospective cohort study was performed on data collected over a three-year period in patients undergoing elective liver resection using the CC, SP, or DS. Patients were excluded if multiple methods of transection were used or for intraoperative death. The association of bile leak with transection type was assessed. A logistic regression model was tested to assess if blood loss was associated with the covariates of transection method, use of portal inflow occlusion, extent of liver resection, and other concurrent major operations. RESULTS: Analyses included 141 patients. The stapler method was quicker than the other methods (p=0.01). The risk of postoperative bile leak was no different between CC, SP, and DS transection methods (p=0.23). There was no difference in mean blood loss or transfusions; however, hepatectomies performed with DS were associated with an increased risk of blood loss > or = 1000 mL compared to CC (p=0.04). There were no differences in mean surgical margin between the three methods. CONCLUSION: The risk of bile leaks was not different between the three methods. While mean blood loss was similar, hepatectomy performed with the DS was associated with an increased risk of having operative blood loss > or = 1000 mL compared to CC. Margins were equal by all methods. The stapler method was quicker.