Characterization of early recurrences following liver resection by ALPPS and two stage hepatectomy in patients with colorectal liver-metastases and small future liver remnants; a translational substudy of the LIGRO-RCT.

BACKGROUND: Associated liver partition and portal vein ligation in staged hepatectomy (ALPPS) is an alternative resection method to portal vein embolization (PVE) in patients with small future liver remnants (FLR) but has been associated with early tumor recurrences. METHODS: Twenty-four patients with colorectal liver metastases (CRLM) patients from the randomized multicenter LIGRO trial comparing outcome of ALPPS (n = 13) vs PVE (n = 11) were included in the study. Mutational analyses of the KRAS, NRAS, BRAF, PIC3CA and TP53 genes of the metastases were performed in 21 patients and correlated to early tumor recurrence. RESULTS: Within 12 months, 13 patients experienced recurrences (6 in TSH group and 7 in ALPPS group). Nine of 13 patients with recurrences had mutations in the TP53 gene, while 3 of 8 patients without recurrence carried the same mutation. Only sporadic cases of the other mutations studied were identified. CONCLUSIONS: ALPPS did not appear to be associated with higher rate of rapid recurrences than PVE following radical resection of colorectal liver metastases. Mutations in genes associated with negative oncologic outcome after surgical resection most likely play a role for tumor recurrences in these patients.

Short-term outcomes after elective colon cancer surgery: an observational study from the Norwegian registry for gastrointestinal and HPB surgery, NoRGast.

BACKGROUND: To describe the real burden of major complications after elective surgery for colon cancer in Norway, and to assess which predictors that are significantly associated with the short-term outcome. METHODS: An observational, multi-centre analysis of prospectively registered colon resections registered into the Norwegian Registry for Gastrointestinal Surgery, NoRGast, between January 2014 and December 2016. A propensity score-adjusted subgroup analysis for surgical access groups was attempted, with laparoscopic resections grouped as intention-to-treat. RESULTS: Out of 1812 resections, 14.0% of patients experienced a major complication within 30 days following surgery. The over-all reoperation rate was 8.7%, and rate of reoperation for anastomotic leak was 3.8%. Twenty patients (1.1%) died within 30 days after surgery. Higher age was not a significant predictor of major complications, including 30-day mortality. After correction for all co-variables, open access surgery was associated with higher rates of major complications (OR 1.67 (CI 1.22-2.29), p = 0.002), higher 30-day mortality (OR 4.39 (CI 1.19-16.13) p = 0.026) and longer length-of-stay (HR 0.58 (CI 0.52-0.65) p < 0.001). CONCLUSIONS: Our results indicate a low complication burden and high rate of uneventful patient journeys after elective surgery for colon cancer in Norway. Age was not associated with higher morbidity or mortality rates. Open access surgery was associated with an inferior short-term outcome.

The New National Registry for Gastrointestinal Surgery in Norway: NoRGast.

BACKGROUND AND AIMS: There is an increasing demand for high-quality data for the outcome of health care. Diseases of the gastro-intestinal tract involve large patient groups often presenting with serious or life-threatening conditions. Complications may affect treatment outcomes and lead to increased mortality or reduced quality of life. A continuous, risk-adjusted monitoring of major complications is important to improve the quality of health care to patients undergoing gastrointestinal resections. We present the development of the Norwegian Registry for Gastrointestinal Surgery, a national registry for colorectal, upper gastrointestinal, and hepato-pancreato-biliary resections in Norway. MATERIALS AND METHODS: A narrative and qualitative presentation of the development and current state of the registry. RESULTS: We present the variables and the analysis tools and provide examples for the potential in quality improvement and research. Core characteristics include a strictly limited set of variables to reflect important risk factors, the procedure performed, and the clinical outcomes. CONCLUSION: A registry with the potential to present complete national cohort data is a powerful tool for quality improvement and research.

Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short-term surgical outcomes, overall survival and recurrence-free survival.

AIM: There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified 'liver-first' approach. METHOD: This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short-term surgical outcome, overall survival and recurrence-free survival are reported. RESULTS: Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty-four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7-116) and 60 (range 31-156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien-Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence-free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent. CONCLUSION: The modified liver-first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases.

Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases--Intermediate oncological results.

BACKGROUND: Colorectal liver metastases (CRLM) not amenable for resection have grave prognosis. One limiting factor for surgery is a small future liver remnant (FLR). Early data suggests that associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively increases the volume of the FLR allowing for resection in a larger fraction of patients than conventional two-stage hepatectomy (TSH) with portal vein occlusion (PVO). Oncological results of the treatment are lacking. The aim of this study was to assess the intermediate oncological outcomes after ALPPS in patients with CRLM. MATERIAL AND METHODS: Retrospective analysis of all patients with CRLM operated with ALPPS at the participating centres between December 2012 and May 2014. RESULTS: Twenty-three patients (16 male, 7 female), age 67 years (28-80) were operated for 6.5 (1-38) metastases of which the largest was 40 mm (14-130). Six (27.3%) patients had extra-hepatic metastases, 16 (72.7%) synchronous presentation. All patients received chemotherapy, 6 cycles (3-25) preoperatively and 16 (70%) postoperatively. Ten patients (43%) were rescue ALPPS after failed PVO. Severe complications occurred in 13.6% and one (4.5%) patient died within 90 days of surgery. After a median follow-up of 22.5 months from surgery and 33.5 months from diagnosis of liver metastases estimated 2 year overall survival was 59% (from surgery) and 73% (from diagnosis). Liver only recurrences (n = 8), were treated with reresection/ablation (n = 7) while lung recurrences were treated with chemotherapy. CONCLUSION: The overall survival, rate of severe complications and perioperative mortality associated with ALPPS for patients with CRLM is comparable to TSH.

Aetiology and prognostic implication of severe jaundice in surgical trauma patients.

BACKGROUND: Pronounced postoperative jaundice occurs not infrequently in trauma patients. The aim of this study was to elucidate the implication of early, pronounced jaundice (serum-bilirubin >100 micromol x l(-1)) for 30-day survival of such patients. METHODS: From 1995 through 2001, 53 surgical trauma patients developing pronounced postoperative jaundice were identified. Nine were excluded from the study because of major hepatobiliary injury or pre-existing liver disease. The clinical course and laboratory chemistry profiles of the remaining 44 patients were analysed. RESULTS: Thirty-one patients survived and 13 died within 30 days of trauma. Non-survivors had higher age, higher injury severity score (ISS) and lower probability of survival (PS) (P < 0.05) than survivors. ISS averaged 34 in survivors and 45 in non-survivors. Survivors and non-survivors received a mean of 46 (range 10-97) and 55 units of blood (range 11-128), respectively (P = 0.366). Systemic hypotension, local infections and sepsis were common in both groups. Bilirubin levels peaked around the 11th day in survivors (median 189 micromol x l(-1)). In non-survivors, serum bilirubin values rose progressively, reaching maximum levels at time of death (median 231 micromol x l(-1)). These patients died in a setting of sepsis and multiple organ failure. CONCLUSION: Large endogenous production of bilirubin because of rapid breakdown of transfused and extravasated blood can cause pronounced jaundice in multitransfused trauma patients. In such patients, serum bilirubin rising >100 micromol x l(-1) does not by itself signal poor outcome. However, progressive pronounced jaundice outlasting the trauma incident by 10-12 days portends fatal outcome for the patient.

Cholestatic effect of large bilirubin loads and cholestasis protection conferred by cholic acid co-infusion: a molecular and ultrastructural study.

BACKGROUND: Large intravenous bilirubin loads block biliary phospholipid secretion, produce canalicular membrane lesions and cause canalicular cholestasis. Cholic acid co-infusion forestalls these untoward effects. The aim of this study was first to determine whether bilirubin overload causes cholestasis through reducing the activity or the hepatic expression of the bile salt export pump (bsep) or Na-taurocholate co-transporting polypeptide (ntcp) and, secondly, whether cholic acid co-infusion forestalls cholestasis by upregulating bsep, ntcp or phosphoglycoprotein 3 (pgp3) expressions or activities. A further aim was to determine whether large bilirubin infusions also produce ultrastructural changes inside hepatocytes. METHODS: The effects of intravenous infusion of 2 g bilirubin over 150 min on hepatic expression of bsep, ntcp and pgp3 were studied in bile acid-depleted and cholic acid co-infused pigs, and related to canalicular bile acid transport and bile secretion. Effects on hepatocyte ultrastructural morphology were analysed by electron microscopy. RESULTS: Bilirubin-induced cholestasis reflected marked diminution of bsep and pgp3 transport activities and not reduced hepatic expression of these transporters. Hepatocyte ultrastructural abnormalities were predominantly confined to the hepatocyte canalicular membrane in cholestatic livers. Cholic acid co-infusion with bilirubin conferred complete cholestasis protection through enhancing pgp3 and bsep transporter activities and not through upregulating their expression. Bilirubin infusion did not change ntcp expression. CONCLUSION: Bilirubin-induced cholestasis is due to markedly impaired activity of the membrane-embedded bsep transporter consequent upon ultrastructural injury to the canalicular membrane. Cholic acid co-infusion with bilirubin enhances bsep and pgp3 activities and confers protection against canalicular membrane injury and bilirubin-induced cholestasis.

Intravenous bilirubin, dibromosulfophthalein, and bromosulfophthalein infusions uncouple biliary phospholipid and cholesterol secretion from bile acid secretion by inhibiting hepatic phosphoglycoprotein-3 activity in pigs.

BACKGROUND: Biliary secretion of organic anions disturbs the proportional relationship normally pertaining between biliary lipid and bile acid secretion. The mechanism causing this uncoupling of biliary lipid from bile acid secretion is incompletely understood. Impaired micellization of membrane lipids by bile due to biliary contamination with organic anions or lowering of biliary bile acid concentration by enhanced bile acid-independent bile flow has been proposed as causative factors. Recently, we found that hepatic phosphoglycoprotein 3 (pgp3) activity was reduced in pigs during bilirubin-induced uncoupling of biliary lipid from bile acid secretion. Pgp3 is the phosphatidylcholine flippase in the canalicular membrane sustaining biliary phospholipid secretion in pigs. This investigation was undertaken to examine whether bilirubin, dibromosulfophthalein, and bromosulfophthalein uncouple biliary lipid from bile acid secretion by the same mechanism. METHODS/RESULTS: Hepatic bile was collected from 24 anesthetized pigs before and during infusion of 0.63 micromol x kg body wt(-1) x min(-1) intravenous bilirubin, dibromosulfophthalein, or bromosulfophthalein. Bile acid secretion was varied by intraportal cholic acid infusion. Hepatic pgp3 expression was measured by means of Western blot, using C219 antibody. Bilirubin > dibromosulfophthalein > bromosulfophthalein lowered biliary lipid secretion without altering hepatic pgp3 expression, increased bile acid-independent bile flow (bromosulfophthalein > dibromosulfophthalein > bilirubin), and enhanced the capacity of bile to micellize membrane lipids as assayed by means of erythrocyte lysis. Biliary bile acid concentration did not determine biliary lipid secretion. CONCLUSION: Bilirubin, dibromosulfophthalein, and bromosulfophthalein in bile uncouple biliary lipid from bile acid secretion by inhibiting hepatic pgp3 phosphatidylcholine flippase activity, putatively through diffusing into the pgp3 pore.

Effect of intravenous bilirubin infusion on biliary phospholipid secretion, hepatic P-glycoprotein expression, and biliary cytotoxicity in pigs.

BACKGROUND: Infusion of large intravenous bilirubin loads in bile acid-depleted pigs reduces P-glycoprotein-dependent biliary phospholipid secretion and increases the cytotoxicity of bile. The reasons for the diminution of biliary phospholipid secretion and the increase in biliary cytotoxicity are not known. This study was undertaken to determine whether the bilirubin-induced lowering of biliary phospholipid secretion is associated with alterations in hepatic P-glycoprotein (P-gp) expression and to determine why bilirubin infusions increase biliary cytotoxicity. METHODS: Hepatic bile was collected from bile acid-depleted pigs before and during intravenous bilirubin infusion. Hepatic P-gp expression was measured with protein blot analysis, using the P-gp-specific antibody C219. Biliary cytotoxicity was assayed against erythrocytes. The biliary phospholipid fatty acid profile was determined by means of gas chromatography. RESULTS: Bilirubin infusions lowered biliary phospholipid secretion by 69% without changing hepatic P-gp expression, suggesting that bilirubin infusions have an inhibitory effect on hepatic P-gp activity. Bilirubin infusions did not cause P-gp losses into bile. An unequivocal, proportional relationship (r2 = 0.80) pertained between cytotoxicity and the bile acid to phospholipid ratio in bile secreted before and during bilirubin infusion and in phosphatidylcholine-supplemented bile. Unconjugated bilirubin in bile did not contribute to biliary cytotoxicity. Biliary phospholipids were always phosphatidylcholine >> phosphatidylethanolamine, mainly of C16:0, 18:2 and C16:0, 18:1 fatty acid configuration. CONCLUSIONS: Intravenous bilirubin loads reduce biliary phospholipid secretion without changing hepatic P-gp expression. Bilirubin infusions increase biliary cytotoxicity by augmenting the biliary bile acid to phospholipid ratio.

Large intravenous bilirubin loads increase the cytotoxicity of bile and lower the resistance of the canalicular membrane to cytotoxic injury and cause cholestasis in pigs.

BACKGROUND: Large intravenous bilirubin loads cause loss of hepatic canalicular membrane microvilli and cholestasis. This study examines whether these untoward effects might be due to canalicular membrane injury from cytotoxic bile. METHODS: The cytotoxicity of bile was assayed against pig erythrocytes before and throughout 4.5-h intravenous infusion of 170 microg kg(-1) body weight of bilirubin in anaesthetized pigs. The capacity to generate canalicular bile flow was tested before and after bilirubin infusion by means of short-term intraportal cholic acid infusion. RESULTS: Bilirubin infusion increased the cytotoxicity of hepatic bile, reduced biliary phospholipid secretion by 90%, and caused cholestasis. Cholic acid infusion before bilirubin also increased the cytotoxicity of bile but increased bile flow and doubled biliary phospholipid output. CONCLUSION: Large intravenous bilirubin infusions increase the cytotoxicity of bile, suppress biliary phospholipid secretion, and render hepatic canalicular membrane microvilli susceptible to injury from cytotoxic bile so that cholestasis occurs.

Bile acids protect the liver against the cholestatic effect of large bilirubin loads.

BACKGROUND: This study was undertaken to elucidate why large bilirubin loads cause canalicular cholestasis and whether bile acid infusions protect against bilirubin-induced cholestasis. METHODS: The effects of bilirubin infusion on canalicular bile secretion and canalicular membrane morphology were studied in bile acid-depleted pigs (BADP), bile acid-primed pigs (BAPP), and pigs co-infused with bile acids during bilirubin loading (BACIP). RESULTS: Bilirubin caused complete cholestasis in BADP, 38% bile flow reduction in BAPP, and no effect on bile flow in BACIP. Scanning electron micrographs showed loss of 70% of canalicular microvilli in BADP, 13% loss and pathologic changes in the remaining 75% of microvilli in BAPP, and no canalicular changes in BACIP. Cholestasis was not due to hydromechanical obstruction of bile ductules or bile Ca2+ depletion. CONCLUSION: Bilirubin causes cholestasis in BADP by injuring canalicular microvilli. Intravenous glycocholate infusions fully protect the liver against bilirubin-induced cholestasis and canalicular microvillar injury.

NSAID-associated gastroduodenal damage: does famotidine protection extend into the mid- and distal duodenum?

Eighteen healthy volunteers were included in a cross-over, double-blind study where 500 mg naproxen b.d. was given for 1 week with 20 mg famotidine b.d., 40 mg nocte or placebo. Endoscopic evaluation of the gastroduodenal mucosa was performed before and after each treatment period, with separate evaluation of the mid- and distal duodenum. 51Cr-EDTA-permeability tests were done to study effects on the mid- and distal gut, and, in addition, symptom registration was performed. The mucosal damage was significant in all treatment periods, and a statistically significant reduction was seen with 20 mg famotidine b.d. for erosive lesions in the stomach/duodenal bulb region as well as for the sum of damage score in the mid- and distal duodenum. The reduction was considerable in a few subjects with extensive duodenal damage. The reduction was considerable in a few subjects with extensive duodenal damage. Intestinal permeation increased significantly in all periods, and was not reduced by famotidine. Symptoms were modest and equal in all periods.

Comparison of the gastrointestinal side effects of naproxen formulated as plain tablets, enteric-coated tablets, or enteric-coated granules in capsules.

We studied the gastrointestinal side effects of three formulations of naproxen in 18 healthy male volunteers. In a Latin-square design crossover study, the subjects received 500 mg naproxen twice daily for 7 days as plain tablets, enteric-coated tablets, or enteric-coated granules in capsules. The 51Cr-EDTA absorption test was performed before and at the end of each drug period, to evaluate changes in the distal gut. The test dose was instilled distally in the duodenum to prevent lesions in the stomach from interfering with the evaluation. Upper endoscopy was performed at the same intervals, scoring changes in the middle and distal duodenum separately from findings in the stomach and duodenal bulb. The nature and severity of adverse effects were recorded for each treatment period. Non-parametric methods were used for statistical evaluation. All drugs induced a significant increase in 51Cr-EDTA absorption, but we did not detect any difference between the three formulations. All formulations were associated with a significant increase in all the endoscopic findings monitored. Enteric-coated tablets induced significantly less lesions than enteric-coated granules in the stomach and duodenal bulb, and an advantage over plain tablets was indicated. No difference was seen in the middle and distal duodenum. The proximal endoscopic scores were not correlated to those found in the middle and distal duodenum. Evaluation of the small and large bowel should probably be included in clinical studies of NSAIDs, but our findings suggest that the importance of transfer of mucosal lesions to the distal gut by enteric coating may have been overemphasized.