Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases.

BACKGROUND: An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). METHODS: Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. RESULTS: 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CONCLUSION: CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased survival.

Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure.

Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1-9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome. LAY SUMMARY: Liver failure is the main cause of death after partial liver resection for cancer, and is presumably caused by an insufficient quantity and function of the liver remnant. Detection of liver failure is often too late, and current treatment focuses on relieve of symptoms. New research initiatives explore artificial support of liver function and stimulation of regrowth of the remnant liver.

Fast and accurate liver volumetry prior to hepatectomy.

BACKGROUND: Volumetric assessment of the liver is essential in the prevention of postresectional liver failure after partial hepatectomy. Currently used methods are accurate but time-consuming. This study aimed to test a new automated method for preoperative volumetric liver assessment. METHODS: Patients who underwent a contrast enhanced portovenous phase CT-scan prior to hepatectomy in 2012 were included. Total liver volume (TLV) and future remnant liver volume (FRLV) were measured using TeraRecon Aquarius iNtuition(®) (autosegmentation) and OsiriX(®) (manual segmentation) software by two observers for each software package. Remnant liver volume percentage (RLV%) was calculated. Time needed to determine TLV and FRLV was measured. Inter-observer variability was assessed using Bland-Altman plots. RESULTS: Twenty-seven patients were included. There were no significant differences in measured volumes between OsiriX(®) and iNtuition(®). Moreover, there were significant correlations between the OsiriX(®) observers, the iNtuition(®) observers and between OsiriX(®) and iNtuition(®) post-processing systems (all R(2) > 0.97). The median time needed for complete liver volumetric analysis was 18.4 ± 4.9 min with OsiriX(®) and 5.8 ± 1.7 min using iNtuition(®) (p < 0.001). CONCLUSION: Both OsiriX(®) and iNtuition(®) liver volumetry are accurate and easily applicable. However, volumetric assessment of the liver with iNtuition(®) auto-segmentation is three times faster compared to manual OsiriX(®) volumetry.

Validation of the peak bilirubin criterion for outcome after partial hepatectomy.

INTRODUCTION: Postoperative liver failure (PLF) is a dreaded complication after partial hepatectomy. The peak bilirubin criterion (>7.0 mg/dL or ≥120 µmol/L) is used to define PLF. This study aimed to validate the peak bilirubin criterion as postoperative risk indicator for 90-day liver-related mortality. METHODS: Characteristics of 956 consecutive patients who underwent partial hepatectomy at the Maastricht University Medical Centre or Royal Free London between 2005 and 2012 were analyzed by uni- and multivariable analyses with odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Thirty-five patients (3.7%) met the postoperative peak bilirubin criterion at median day 19 with a median bilirubin level of 183 [121-588] µmol/L. Sensitivity and specificity for liver-related mortality after major hepatectomy were 41.2% and 94.6%, respectively. The positive predictive value was 22.6%. Predictors of liver-related mortality were the peak bilirubin criterion (p < 0.001, OR = 15.9 [95%CI 5.2-48.7]), moderate-severe steatosis and fibrosis (p = 0.013, OR = 8.5 [95%CI 1.6-46.6]), ASA 3-4 (p = 0.047, OR = 3.0 [95%CI 1.0-8.8]) and age (p = 0.044, OR = 1.1 [95%CI 1.0-1.1]). CONCLUSION: The peak bilirubin criterion has a low sensitivity and positive predictive value for 90-day liver-related mortality after major hepatectomy.

Partial liver resection alters the bile salt-FGF19 axis in patients with perihilar cholangiocarcinoma: Implications for liver regeneration.

BACKGROUND: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. METHODS: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. RESULTS: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. CONCLUSIONS: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.

Surrogate endpoints in liver surgery related trials: a systematic review of the literature.

BACKGROUND: Although the safety of liver surgery has improved enormously, hepatic surgery continues to face challenging complications. Therefore, improvements supported by evidence-based guidelines are still required. The conduct of randomized controlled trials in liver surgery using dichotomous outcomes requires a large sample size. The use of surrogate endpoints (SEPs) reduces sample size but SEPs should be validated before use. AIM: The aim of this review was to summarize the SEPs used in hepatic surgery related trials, their definitions and recapitulating the evidence validating their use. METHOD: A systematic computerized literature search in the biomedical database PubMed using the MeSH terms 'hepatectomy' or 'liver resection' or 'liver transection' was conducted. Search was limited to papers written in the English language and published between 1 January 2000 and 1 January 2010. RESULTS: A total of 593 articles met the search terms and 49 articles were included in the final selection. Standard biochemical liver functions tests were the most frequently used SEP (32 of 49 the studies). The used definitions of SEPs varied greatly among the studies. Most studies referred to earlier published material to justify their choice of SEP. However, no validating studies were found. CONCLUSION: Many SEPs are used in liver surgery trials however there is little evidence validating them.

Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration.

The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor (FXR) was markedly up-regulated following surgery (P < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [IL-6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up-regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.

The influence of chemotherapy-associated sinusoidal dilatation on short-term outcome after partial hepatectomy for colorectal liver metastases: A systematic review with meta-analysis.

BACKGROUND DATA: Hepatic sinusoidal dilatation (SD) is a histopathological entity that occurs in up to 75% of patients undergoing oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM). OBJECTIVE: To study the influence of SD on outcome after partial hepatectomy in patients with CRLM. METHODS: Medline, Embase, CENTRAL, LILACS and CINAHL were searched for studies published between 01.01.2004 and 09.06.2015 with keywords: "sinusoidal obstruction syndrome", "hepatic veno-occlusive disease", and "Stuart-Bras syndrome". Studies comprising adults who underwent partial hepatectomy for CRLM with grading of SD and registration of postoperative morbidity and/or mortality were included. Risk of bias and quality of studies were evaluated with the Quality In Prognosis Studies Instrument (QUIPS) and modified GRADE framework. RESULTS: Search strategies produced 2007 hits from which 23 and 13 articles were extracted for qualitative and quantitative analyses, respectively. Meta-analysis on the influence of SD grade 2-3 vs. SD grade 0-1 on postoperative overall morbidity showed an odds ratio (OR) of 1.26 [95% CI 0.74, 2.15](p = 0.40), an OR of 1.03 [0.15, 6.89](p = 0.98) for liver failure, an OR of 1.21 [0.23, 6.35](p = 0.82) for overall mortality, and an OR of 3.52 [0.31, 39.91](p = 0.31) for liver-related morbidity. QUIPS showed a low to high risk of bias for studies, and GRADE showed very low quality of evidence per outcome. CONCLUSIONS: No significant effect of SD grade 2-3 on short-term outcome after partial hepatectomy was found. However, the data on which this conclusion was based were not very robust and therefore no solid conclusions could be drawn.