Kim Erlend Mortensen

Consensus guidelines for enhanced recovery after gastrectomy. Enhanced Recovery After Surgery (ERAS®) Society recommendations

Application of evidence‐based perioperative care protocols reduces complication rates, accelerates recovery and shortens hospital stay. Presently, there are no comprehensive guidelines for perioperative care for gastrectomy.

Liver regeneration in surgical animal models - a historical perspective and clinical implications.

Methods/Aims: Despite improved preoperative evaluation, surgical techniques and perioperative intensive care, some patients still experience postoperative liver failure in part due to insufficient regeneration. The aim of this review is to give the reader a historical synopsis of the major trends in animal research on liver regeneration from the early experiments in 1877 up to modern investigation. A major focus is placed on the translational value of experimental surgery. Methods: A systematic review of the English literature published in Medline was undertaken with the search words ‘pig, porcine, dog, canine, liver regeneration, experimental’. Results: The evolution of the various models tentatively explaining the process of liver regeneration is described. Conclusions: We conclude by emphasizing the importance of large-animal surgical research on liver regeneration as it offers a more integrated, systemic biological understanding of this complex process. Furthermore, in our opinion, a closer collaboration between the hepatologist, liver surgeon/transplant surgeon and the laboratory scientist may advance clinically relevant research in liver regeneration.

Regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure

After parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic, and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase would be reflected in the gene expression profiles in the liver remnant by using a global porcine cDNA microarray chip with approximately 23,000 genes represented. Six pig livers were resected with 62% (low portal pressure resection) and 75% (high portal pressure resection), resulting in a portal venous pressure increase from a baseline of 6.1-8.2 and 12 mmHg, respectively. By sampling consecutive biopsies from the liver remnants, we found differentially expressed genes in the high portal pressure resection group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the low portal pressure resection group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation, development, and protein metabolism. Also common to both groups was both up- and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion, and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. In conclusion, the genetic regenerative response in the liver remnant to varies according to the level of resection.

The genetic regulation of the terminating phase of liver regeneration

BackgroundAfter partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration.ResultsMicroarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting the involvement of the caspase system at this time. Zinc Finger Protein (ZNF490) gene, with a potential negative effect on cell cycle progression, was only up-regulated at three and six weeks after PHx indicating a central role at this time. TGF-β regulation was not found to be significantly affected in the terminating phase of liver regeneration. Vasohibin 2 (VASH2) was down-regulated towards the end of regeneration, and may indicate a role in preventing a continued vascularization process.ConclusionsCARD11, ZNF490 and VASH2 are differentially expressed in the termination phase of liver regeneration. The lack of TGF-β up-regulation suggests that signalling by TGF-β is not required for termination of liver regeneration.

Predicting colorectal surgical complications using heterogeneous clinical data and kernel methods

OBJECTIVE In this work, we have developed a learning system capable of exploiting information conveyed by longitudinal Electronic Health Records (EHRs) for the prediction of a common postoperative complication, Anastomosis Leakage (AL), in a data-driven way and by fusing temporal population data from different and heterogeneous sources in the EHRs. MATERIAL AND METHODS We used linear and non-linear kernel methods individually for each data source, and leveraging the powerful multiple kernels for their effective combination. To validate the system, we used data from the EHR of the gastrointestinal department at a university hospital. RESULTS We first investigated the early prediction performance from each data source separately, by computing Area Under the Curve values for processed free text (0.83), blood tests (0.74), and vital signs (0.65), respectively. When exploiting the heterogeneous data sources combined using the composite kernel framework, the prediction capabilities increased considerably (0.92). Finally, posterior probabilities were evaluated for risk assessment of patients as an aid for clinicians to raise alertness at an early stage, in order to act promptly for avoiding AL complications. DISCUSSION Machine-learning statistical model from EHR data can be useful to predict surgical complications. The combination of EHR extracted free text, blood samples values, and patient vital signs, improves the model performance. These results can be used as a framework for preoperative clinical decision support.

Increased sinusoidal flow is not the primary stimulus to liver regeneration.

BackgroundHemodynamic changes in the liver remnant following partial hepatectomy (PHx) have been suggested to be a primary stimulus in triggering liver regeneration. We hypothesized that it is the increased sinusoidal flow per se and hence the shear-stress stimulus on the endothelial surface within the liver remnant which is the main stimulus to regeneration. In order to test this hypothesis we wanted to increase the sinusoidal flow without performing a concomitant liver resection. Accordingly, we constructed an aorto-portal shunt to the left portal vein branch creating a standardized four-fold increase in flow to segments II, III and IV. The impact of this manipulation was studied in both an acute model (6 animals, 9 hours) using a global porcine cDNA microarray chip and in a chronic model observing weight and histological changes (7 animals, 3 weeks).ResultsGene expression profiling from the shunted segments does not suggest that increased sinusoidal flow per se results in activation of genes promoting mitosis. Hyperperfusion over three weeks results in the whole liver gaining a supranormal weight of 3.9% of the total body weight (versus the normal 2.5%). Contrary to our hypothesis, the weight gain was observed on the non-shunted side without an increase in sinusoidal flow.ConclusionsAn isolated increase in sinusoidal flow does not have the same genetic, microscopic or macroscopic impact on the liver as that seen in the liver remnant after partial hepatectomy, indicating that increased sinusoidal flow may not be a sufficient stimulus in itself for the initiation of liver regeneration.

A sensitive method for the analysis of glutathione in porcine hepatocytes

Abstract Background. Reduced glutathione (γ-glutamylcysteinylglycine), GSH, is essential when protecting cells from oxidative stress and also an indicator of disease risk. Reported concentrations of GSH and its oxidized form, glutathione disulfide (GSSG), varies considerably, primarily due to the instability of GSH and various analytical methods. Methods. We designed a sensitive method to analyze GSH and GSSG in porcine hepatocytes using liquid chromatography–tandem mass spectrometry (LC–MS/MS) after stabilization with N-ethylmaleimide (NEM). This method includes stable isotope labeled internal standards and simple synthesis of labeled GSSG which commercial sources rarely offer. GSH and GSSG were analyzed in porcine liver biopsies giving a reference interval based on a large number of samples (26 pigs; 3 parallels). Results. The LC-MS/MS results revealed excellent linearity for both GSH and GSSG, with interday coefficient of variation (%CV) for GSH-NEM and GSSG <10 %. Accuracy for recovery tests was between 95.6% and 106.7% (n = 3) for GSH and between 92.3% and 107.7% (n = 3) for GSSG. The limits of quantification were 0.1 μM for GSH-NEM and 0.08 μM for GSSG. The mean concentration of GSH was 3.5 (95% CI = 1.5–8.1) mmol/liter and of GSSG 0.0023 (95% CI = 0.0003–0.019) mmol/liter. Conclusion. For the first time GSH and GSSG are analyzed in porcine hepatocytes by LC-MS/MS yielding a reference level of GSH and GSSG. The method is reproducible in any laboratory with LC-MS/MS service and will probably be applicable in all soft tissues and cell suspensions, essentially with no modification.

Neoadjuvant chemotherapy versus surgery first for resectable pancreatic cancer (Norwegian Pancreatic Cancer Trial - 1 (NorPACT-1)) – study protocol for a national multicentre randomized controlled trial

AbstractBackgroundPancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and early treatment of micrometastatic disease is the ideal goal. NorPACT–1 aims to test the hypothesis that overall mortality at one year after allocation of treatment can be reduced with neoadjuvant chemotherapy in surgically treated patients with resectable pancreatic cancer.Methods/DesignThe NorPACT– 1 is a multicentre, randomized controlled phase III trial organized by the Norwegian Gastrointestinal Cancer Group for Hepato-Pancreato-Biliary cancer. Patients with resectable adenocarcinoma of the pancreatic head are randomized to receive either surgery first (Group 1: SF/control) or neoadjuvant chemotherapy (Group 2: NT/intervention) with four cycles FOLFIRINOX followed by resection. Both groups receive adjuvant chemotherapy with gemicitabine and capecitabine (six cycles in Group 1, four cycles in Group 2). In total 90 patients will be randomized in all the five Norwegian university hospitals performing pancreatic surgery. Primary endpoint is overall mortality at one year following commencement of treatment for those who ultimately undergo resection. Secondary endpoints are overall survival after date of randomization (intention to treat), overall survival after resection, disease-free survival, histopathological response, complication rates after surgery, feasibility of neoadjuvant and adjuvant chemotherapy, completion rates of all parts of multimodal treatment, and quality-of-life. Bolt-on to the study is a translational research program that aims at identifying factors that are predictive of response to NT, the risk of distant cancer spread, and patient outcome.DiscussionNorPACT– 1 is designed to investigate the additional benefit of NT compared to standard treatment only (surgery + adjuvant chemotherapy) for resectable cancer of the pancreatic head to decrease early mortality (within one year) in resected patients.Trial registrationTrial open for accrual 01.02.2017. ClinicalTrials.gov Identifier: NCT02919787. Date of registration: September 14, 2016.

Quality of life as a prognostic factor for survival in hepatocellular carcinoma

Prognostication in hepatocellular carcinoma (HCC) is demanding. Not only tumour extent and performance status are to be considered, but also liver function, which is often limiting for both survival itself and for treatment possibilities. This study was conducted to assess whether patient‐reported questionnaires containing general and liver‐specific questions could improve prognostication of survival.

Tissue remodelling following resection of porcine liver

Aim. To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine. Methods. Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. Results. More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Massons Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei. Conclusions. The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration.