Impact of increased resection rates and a liver parenchyma sparing strategy on long-term survival after surgery for colorectal liver metastases. A population-based study.

Background and aims: Expanded criteria for resection of colorectal liver metastases (CRLM) have led to a more aggressive surgical attitude. The aim is to evaluate any impact of expanded criteria on perioperative mortality and long-term survival. Materials and methods: A population based study from 2001 to 2015 for patients undergoing surgery for CRLM. The cohort was divided into three 5-year periods. Results: A total of 341 patients underwent resection of CRLM. Relative to the number of colorectal primaries, patients resected for CRLM increased from 82/2520 (3.3%) in 2001-2005 to 151/3071 (4.9%) in 2011-2015 (p = .007). The proportion of patients who underwent formal resections declined from 62% to 21%. There was a substantial increase in resections of synchronous liver metastases, portal vein embolizations, two-stage resections, and the share of octogenarians who underwent resection. The proportion of patients undergoing reresections of new liver recurrences increased from 6% to 24%. The 90-d postoperative mortality for 2001-2005, 2006-2010, and 2011-2015 were 7.9%, 0.8%, and 2.0%, respectively. The median overall survival was 47 months during the two first periods, for the last period not reached. The 5-year overall survival remained at 40% from 2001 to 2010, and estimated at 55.2% from 2011 to 2015. The 5-year disease-free survival was well above 30%. The 5-year overall survival following liver reresection was 52.6%. Conclusion: Postoperative mortality remained at approximately 2%, and the 5-year overall survival at 40% in the first 10 years, but increased to 55% in the last 5 years under study, despite a marked increase in resection rates.

Post-ischaemic restituted intestinal mucosa is more resistant to further ischaemia than normal mucosa in the pig.

OBJECTIVE: Ischaemic preconditioning may protect the intestine from subsequent prolonged ischaemia. This study evaluates whether a much longer initial ischaemia, encountered clinically, may modify intestinal resistance to further ischaemia in a pig model. MATERIAL AND METHODS: After cross-clamping of the superior mesenteric artery for 1 h, the intestine was either reperfused for 8 h or a second cross-clamping for 1 h was performed at 4 h of reperfusion. Based on microarray analysis of intestinal samples at 1, 4 and 8 h of reperfusion, mRNA of selected genes was measured with QRT-PCR. RESULTS: The first ischaemic period caused exfoliation of surface epithelial cells from the basement membrane comprising about 90 % of the villi tips, a marked increase in permeability and depletion of ATP. The second ischaemic challenge caused about 30 % less denudation of the basement membrane (p = 0.008), no increase in permeability (p = 0.008) and less depletion of ATP (p = 0.039). mRNAs for superoxide dismutase 2, heat shock proteins and signal transducer and activator of transcription 3, which may protect against ischaemia/reperfusion injury, were up-regulated throughout the reperfusion period. mRNAs for matrix metalloproteinase 1, connexin 43 and peripheral myelin 22, which may be associated with cell migration or tight junctions, showed a particular up-regulation at 4 h of reperfusion. CONCLUSION: One hour of initial ischaemia followed by 4 h of reperfusion is associated with increased intestinal resistance to further ischaemia. The differential regulation of genes identified in this study provides working hypotheses for mechanisms behind this observation.

Gut luminal lactate measured by microdialysis mirrors permeability of the intestinal mucosa after ischemia.

The aim of the present study was to investigate the influence of a prolonged initial intestinal ischemic insult on transmucosal permeability after a subsequent ischemic event and whether microdialysis of biomarkers released to the gut lumen is able to reflect changes in intestinal permeability. The superior mesenteric artery was cross-clamped for 60 min followed by 4 h of reperfusion in 16 pigs. Nine pigs had a second cross-clamp of 60 min and 3 h of reperfusion, whereas seven pigs were observed for a further 4 h of reperfusion. Intestinal mucosal integrity was assessed by permeability of C-polyethylene glycol (PEG-4000) over the gut mucosa, luminal microdialysis of lactate, glucose and glycerol, and tonometry. During reperfusion, the PEG-4000 amount in venous blood was two times higher after the first than after the second ischemia (area under the curve, 44,780 [13,441-82,723] vs. 22,298 (12,213-49,698] counts min mL(-1), P=0.026 [mean {range}]). There was less lactate detected in the gut lumen after the second ischemia compared with the first (area under the curve, 797 [412-1,700] vs. 1,151 [880-1,969] mmol min L(-1), P=0.02) and a lower maximum concentration (4.8 [2.7-9.4] vs. 8.5 [5.0-14.9] mM, P=0.01). The same pattern was also seen for luminal glycerol and glucose. During the second ischemia, the intestinal mucosal/arterial CO2 gap was identical to the level during the first ischemic episode. A prolonged ischemic insult of the intestine confers protection, for reduced hyperpermeability against further ischemia. Microdialysis of biomarkers mirrors permeability changes associated with this type of protection. Lactate reflects permeability across the intestinal mucosa more precisely than glycerol.

Gut luminal microdialysis of glycerol as a marker of intestinal ischemic injury and recovery.

OBJECTIVE: To evaluate microdialysis as a method to assess different degrees of intestinal damage and recovery during ischemia and reperfusion; to evaluate information obtained from microdialysis catheters in the peritoneum, the gut wall, and the gut lumen. DESIGN: Randomized, controlled animal experiment. SETTING: University laboratory animal center. SUBJECTS: Twenty-seven domestic pigs. INTERVENTIONS: The superior mesenteric artery was cross-clamped for 60 mins (n = 14) or 120 mins (n = 10) followed by 2 or 4 hrs of reperfusion. Three pigs served as controls. MEASUREMENTS AND MAIN RESULTS: Intestinal mucosal integrity was assessed by morphometry, adenosine triphosphate in the gut wall, and permeability of C-polyethylene glycol. Lactate, glycerol, pyruvate, and glucose were measured by microdialysis. Changes in adenosine triphosphate, permeability, or lactate did not correlate to different extents of intestinal damage caused by 60 or 120 mins of ischemia. During the reperfusion period, pigs with 60 mins of intestinal ischemia showed a faster recovery of these variables than pigs with 120 mins of intestinal ischemia. Glycerol increased with increasing duration of the ischemic insult. After 60 mins of intestinal ischemia, glycerol in the gut lumen decreased toward baseline but remained high after 120 mins of intestinal ischemia. There was a good correlation between gut luminal glycerol and recovery of mucosal damage throughout the reperfusion period. In the peritoneal cavity, both glycerol and lactate decreased to baseline relatively shortly after onset of reperfusion independent of the duration of intestinal ischemia. CONCLUSIONS: Microdialysis of glycerol provides information about the extent and severity of intestinal damage after ischemia and about the ensuing recovery. The gut lumen is to be preferred as a site for placement of microdialysis catheters.

Intestinal injury after thoracic aortic cross-clamping in the pig.

BACKGROUND: The mucosal surface epithelium is an essential part of the functional intestinal barrier, but its structural response to ischemia/reperfusion is only partly characterized. The purpose of this study was to provide a detailed morphological evaluation of intestinal surface epithelium after aortic cross-clamping. MATERIAL AND METHODS: Pigs were subjected to thoracic aortic cross-clamping for 60 min and subsequent reperfusion for 120 min. Tissue blood flow and high-energy phosphates were measured with microspheres and HPLC, respectively. Urinary excretion of (14)C polyethylene glycol (MW 4000 Da) (PEG-4000), loaded into an intestinal loop, provided an index of intestinal permeability. RESULTS: Jejunal blood flow was restored at 10 min after aortic declamping. Denudation of the basement membrane of the intestinal villi tips, as a consequence of epithelial shedding, increased markedly during the initial 60 min of reperfusion (P = 0.002). During the following 45 min, the denuded basement membrane was partly covered with low cuboidal and squamous-shaped cells extending lamellipodia over a wavy basement membrane. Restoration of ATP at 60 min after aortic declamping correlated inversely to the extent of denuded basement membrane (r = 0.75, P = 0.032). Permeability of PEG-4000 increased markedly after aortic declamping and was linearly correlated to the area of denuded basement membrane (r = 0.87, P = 0.01). CONCLUSIONS: Reperfusion for 2 h after aortic cross-clamping is associated with initial aggravation of ischemia-induced injury in the porcine jejunum, but thereafter with restitution of the surface epithelium. Restoration of ATP may be important to avoid intestinal injury after ischemia. Increased permeability of a macromolecule in response to reperfusion is closely correlated to injury of the surface epithelium.

Gut barrier dysfunction as detected by intestinal luminal microdialysis.

OBJECTIVE: To evaluate the use of gut luminal microdialysis as a tool for monitoring ischaemic metabolites, particularly glycerol, as markers of intestinal dysfunction during and after intestinal ischaemia. DESIGN: A randomised, controlled animal experiment. SETTING: National laboratory animal centre. INTERVENTIONS: In seven pigs the thoracic aorta was cross-clamped for 60 min followed by 2 h of reperfusion, while five pigs served as controls. MEASUREMENTS AND RESULTS: Glycerol, lactate and glucose in the intestinal lumen and mucosa were measured by microdialysis. Intestinal tissue blood flow was determined by means of colour-labelled microspheres. To assess intestinal permeability, (14)C-polyethylene glycol 4000 (PEG-4000) was instilled in a jejunal segment and then measured in venous blood. Intestinal blood flow was reduced to 10% of baseline by aortic cross-clamping ( p=0.001) and returned to baseline during reperfusion. Intestinal luminal lactate increased during ischaemia and further increased during reperfusion. The increase was paralleled by augmented intestinal permeability; there was a significant correlation between luminal lactate and venous PEG-4000 ( r=0.89, p<0.01). Aortic cross-clamping caused a marked increase in intestinal mucosal glycerol concentrations, which correlated with luminal glycerol during both ischaemia and reperfusion ( r=0.85, p<0.01). CONCLUSION: Microdialysis of lactate may be useful for monitoring intestinal ischaemia and reperfusion. Release of lactate into the intestinal lumen appears to be related to increased permeability. Intestinal luminal glycerol closely mirrored glycerol concentrations in the intestinal wall.