Christoph Tschuor

Early survival and safety of ALPPS: first report of the International ALPPS Registry.

Objectives:To assess safety and outcomes of the novel 2-stage hepatectomy, Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), using an international registry. Background:ALPPS induces accelerated growth of small future liver remnants (FLR) to allow curative resection of liver tumors. There is concern about safety based on reports of higher morbidity and mortality. Methods:A Web-based data entry system was created with password access and data pseudoencryption (NCT01924741). All patients with complete 90-day data were included. Multivariate logistic regression analysis was performed to identify independent risk factors for severe complications and mortality and volume growth of the FLR. Results:Complete data were available for 202 patients. A total of 141 (70%) patients had colorectal liver metastases (CRLM). Median starting standardized future liver remnants of 21% increased by 80% within a median of 7 days. Ninety-day mortality was 19/202 (9%). Severe complications including mortalities (Clavien-Dindo ≥IIIb) occurred in 27% of patients. Independent factors for severe complications were red blood cell transfusion [odds ratio (OR), 5.2), ALPPS stage I operating time greater than 300 minutes (OR, 4.4), age more than 60 years (OR, 3.8), and non-CRLM (OR, 2.7). Age, use of Pringle maneuver, and histologic changes led to less volume growth. In patients younger than 60 years with CRLM, 90-day mortality was similar to conventional 2-stage hepatectomies for CRLM. Conclusions:This is the first analysis of the ALPPS registry showing that ALPPS has increased perioperative morbidity and mortality in older patients but better outcomes in patients with CRLM.

ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration.

Objectives:To develop a reproducible animal model mimicking a novel 2-staged hepatectomy (ALPPS: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) and explore the underlying mechanisms. Background:ALPPS combines portal vein ligation (PVL) with liver transection (step I), followed by resection of the deportalized liver (step II) within 2 weeks after the first surgery. This approach induces accelerated hypertrophy of the liver remnant to enable resection of massive tumor load. To explore the underlying mechanisms, we designed the first animal model of ALPPS in mice. Methods:The ALPPS group received 90% PVL combined with parenchyma transection. Controls underwent either transection or PVL alone. Regeneration was assessed by liver weight and proliferation-associated molecules. PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from ALPPS-treated mice was injected into mice after PVL. Gene expression of auxiliary mitogens in mouse liver was compared to patients after ALPPS or PVL. Results:The hypertrophy of the remnant liver after ALPPS doubled relative to PVL, whereas mice with transection alone disclosed minimal signs of regeneration. Markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. Early initiators of regeneration were significantly upregulated in human and mice. Conclusions:ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.

Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry.

OBJECTIVES The aim of this study was to identify predictors of 90-day mortality after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), available after stage-1, either to omit or delay stage-2. BACKGROUND DATA ALPPS is a two-stage hepatectomy for patients with extensive liver tumors with predicted small liver remnants, which has been criticized for its high mortality rate. Risk factors for mortality are unknown. METHODS Patients in the International Registry undergoing ALPPS from April 2011 to July 2014 were analyzed. Primary outcome was 90-day mortality. Liver function after stage-1 was assessed using the criteria of the International Study Group for Liver Surgery (ISGLS) after stage-1 among others. A multivariable model was used to identify independent predictors of 90-day mortality. RESULTS Three hundred twenty patients registered by 55 centers worldwide were evaluated. Overall 90-day mortality was 8.8% (28/320). The predominant cause for 90-day mortality was postoperative liver failure in 75% of patients. Fourteen percent of patients developed liver failure according to ISGLS criteria already after stage-1 ALPPS. Those and patients with a model of end-stage liver disease (MELD) score more than 10 before stage-2 were at significantly higher risk for 90-day mortality after stage-2 with an odds ratio (OR) 3.9 [confidence interval (CI) 1.4-10.9, P = 0.01] and OR 4.9 (CI 1.9-12.7, P = 0.006), respectively. Other factors, such as size of future liver remnant (FLR) before stage-2 and time between stages, were not predictive. CONCLUSIONS This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied. These findings may help to make ALPPS safer.

Liver Failure After Extended Hepatectomy in Mice Is Mediated by a p21-Dependent Barrier to Liver Regeneration

BACKGROUND & AIMS Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant. METHODS Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21. RESULTS Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21(-/-) mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx. CONCLUSIONS Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.

GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids

BACKGROUND & AIMS Many of the beneficial effects of ω3-fatty acids (ω3FAs) are being attributed to their anti-inflammatory properties. In animal models, ω3FAs also protect from hepatic ischemia reperfusion injury (IRI), a significant cause of complications following liver surgery. Omegaven®, a clinical ω3FA-formulation, might counteract the exaggerated inflammatory response underlying IRI, but the according mechanisms are unresearched. Recently, GPR120 has been identified as a first receptor for ω3FAs, mediating their anti-inflammatory effects. Here, we sought to investigate whether Omegaven® protects from hepatic IRI through GPR120. METHODS Using a mouse model of liver IRI, we compared the effects of a GPR120 agonist with those of Omegaven®. RESULTS GPR120 in liver was located to Kupffer cells (KCs). Agonist and Omegaven® provided similar protection from IRI, which was abolished by clodronate-depletion of KCs or by pretreatment with an αGpr120-siRNA. In vitro and in vivo, both agents dampened the NFκB/JNK-mediated inflammatory response. Dampening was associated with an M1>M2 macrophage polarization shift as assessed by marker expression. In αGpr120-siRNA-pretreated mice with or without ischemia, Omegaven® was no more able to promote M2 marker expression, indicating its anti-inflammatory properties are dependent on GPR120 in liver. CONCLUSIONS These findings establish KC-GPR120 as a key mediator of Omegaven® effects and suggest GPR120 as a therapeutic target to mitigate inflammatory stress in liver.

Job satisfaction among young board-certified surgeons at academic centers in Europe and North America.

Objectives:To identify independent factors influencing job satisfaction of academic surgeons within their first 10 years after board certification. Background Data:Job satisfaction is increasingly recognized as a crucial factor for high performance of individuals and teams in most organizations. Sophisticated tools are now available to assess job satisfaction in medicine. Methods:A survey among 439 faculty surgeons from 16 European countries, United States, and Canada was conducted in 2011. Satisfaction at work was analyzed using the validated Global Job Satisfaction (GJS) instrument (score range, −36 to +36), modified to an extended version (eGJS) (score range, −87 to +87) covering additional personal and environmental factors. Independent factors were identified with multiple logistic regression analysis. Results:Response rate was high at 59% (439/744). Median age of responders was 39 years, with 17% women. North American surgeons scored higher on the eGJS when compared with Europeans (median: 21 vs. 33, respectively, P < 0.001). The surgical specialty with the highest median eGJS score was colorectal, whereas general surgery scored lowest (median: 33 vs 7, respectively, P = 0.002). On multivariate analysis, independent factors of high job satisfaction included protected time for research (odds ratio [OR]: 9), good team relationship (OR: 7), female sex (OR: 5), having a partner (OR: 4), feeling enthusiastic about work (OR: 4), being pleased with life accomplishments (OR: 4), having the standard of living one deserves (OR: 3), and clinical autonomy (OR: 3). In contrast, independent predictors of poor job satisfaction were feeling frustrated by work (ie, a burnout item) (OR: 37), worrying about per-sonal life at work (OR: 3), and having to work too many weekends (OR: 3). Conclusions:Satisfaction in young faculty members mostly relates to research opportunities, clinical autonomy, burnout, and lifestyle. Understanding satisfaction factors may improve productivity and competence.

Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss

BACKGROUND & AIMS Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for-size-syndrome (SFSS). The molecular processes underlying liver failure are ill-understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy. METHODS Activators of Car, various hepatectomies, Car(-/-) mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown. RESULTS Excessive tissue loss causing liver failure is associated with deficient induction of Car. Reactivation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices. CONCLUSIONS Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure. LAY SUMMARY The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size-syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS.

Job satisfaction among chairs of surgery from Europe and North America

BACKGROUND Strong evidence exists associating job satisfaction and risk of burnout with productivity, efficiency, and creativity in many organizations. However no data are available assessing chairs of surgery. This study assessed job satisfaction and risk for burnout of surgical chairs from Europe and North America and identified contributing factors. METHODS A survey among 650 chairs in surgery from 23 European and 2 North American countries was conducted in 2012. Satisfaction at work was analyzed using the validated Global Job Satisfaction (GJS) instrument and the abbreviated Maslach Burnout Inventory. Additional items targeting personal and environmental factors were included. RESULTS The rate of chairs reached successfully was 86%, the overall response rate was 29% (188/650), with 1% female. Median age was 58 years. 11% of chairs were dissatisfied with work. Younger age and being fewer years in practice as a chair was associated with higher job satisfaction (P = .054 and P = .003). Surgical specialty with the greatest median GJS score was hepatopancreatobiliary, whereas vascular surgery scored lowest. Chairs desire to devote 20% more of their time on research. Clerical support as well as the ability to be innovative was suggested by 51% and 45%, respectively, to improve job satisfaction. Compared with Europeans, North American chairs were overall more satisfied and would recommend their job to their children. CONCLUSION North American chairs seem to be more satisfied at work and at less risk for burnout than European chairs. The overall job satisfaction was greater among chairs compared with previously published reports of young, board-certified surgeons or residents (89% vs 87% and 66%, respectively). The superior satisfaction in chairs is strongest related to career achievements, innovation, and lifestyle.

Transplantation and Surgical Strategies in Patients With Neuroendocrine Liver Metastases: Protocol of Four Systematic Reviews

Background Hepatic metastases of neuroendocrine tumors (NETs) are considered a major prognostic factor associated with significantly reduced survival compared to patients without liver metastases. Several surgical and nonsurgical strategies are present to treat resectable and nonresectable liver metastases, some of which have the potential to cure liver mestatases. Objective The aims of the four systematic reviews presented in the paper are to determine the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases, to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, to assess the role of liver transplantation in patients presenting with unresectable bilateral hepatic metastases, and to evaluate the role of primary tumor resection in presence of unresectable liver metastases. Methods Literature search was performed on Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and the Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials). No language restrictions were applied. Randomized controlled trials, prospective and retrospective comparative cohort studies, and case-control studies will be used for the qualitative and quantitative synthesis of the systematic reviews. Case series will be only included in a separate database for descriptive purposes. Results This study is ongoing and presents a protocol system of four systematic reviews that will assist in determining the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases. This study is also assumed to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, the role of liver transplantation, and the relevance of primary tumor resection in presence of unresectable liver metastasis. Conclusions The systematic reviews will show the current evidence based on the effectiveness of surgical strategies in patients with NET liver metastases and serve as basis for clinical practice guidelines. Trial Registration The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews: liver resection (CRD42012002652); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002652 (Archived by WebCite at http://www.webcitation.org/6LQUqMnqL,). neoadjuvant and adjuvant treatment strategies (CRD42012002656); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002656 (Archived by WebCite at http://www.webcitation.org/6LQVvEHuf). liver transplantation (CRD42012002655); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002655 (Archived by WebCite at http://www.webcitation.org/6LQW7WFo3,). resection of the locoregional primary NET (CRD42012002654); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002654 (Archived by WebCite at http://www.webcitation.org/6LQWEIuGe).

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate.

Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment. Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. Results: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887–97. ©2016 AACR.