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Objective: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD). Background: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. BothALPPS and LLDare characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. Methods: Serumphosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro. Results: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92--1.23] and 1.07 mmol/L (IQR 0.91--1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy (P< 0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P=0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models (P<0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro. Conclusion: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage. [ABSTRACT FROM AUTHOR]

Only a few decades ago, the opinion that colorectal liver metastases were a palliative diagnosis changed. In fact, previously, the prevailing view was strongly resistant against resecting colorectal liver metastases. Constant technical improvement of liver surgery and, much later, effective chemotherapy allowed for a successful wider application of surgery. The clinical use of portal vein embolization was the starting signal of regenerative liver surgery, where insufficient liver volume can be expanded to an extent where safe resection is possible. Today, a number of these techniques including portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy, and bi-embolization (portal and hepatic vein) can be successfully used to address an insufficient future liver remnant in staged resections. It turned out that the road to success is embedding surgery in a well-orchestrated oncological concept of controlling systemic disease. This concept was the prerequisite that meant liver transplantation could enter the treatment strategy for colorectal liver metastases, ending up with a 5-year overall survival of 80% in highly selected cases. In particular, techniques combining principles of 2-stage hepatectomy and liver transplantation, such as "resection and partial liver segment 2–3 transplantation with delayed total hepatectomy" (RAPID) are on the rise. These techniques enable the use of partial liver grafts with primarily insufficient liver volume. All this progress also prompted a number of innovative local therapies to address recurrences ultimately transferring colorectal liver metastases from instantly deadly into a chronic disease in some cases. [ABSTRACT FROM AUTHOR]

Postoperative pancreatic fistula remains an unsolved challenge after pancreatoduodenectomy. Important in this regard is the presence of a soft pancreatic texture which is a major risk factor. Advances in machine learning and texture analysis of medical images allow identification of features of parenchyma that are invisible to the human eye. The aim of this study was to investigate the potential of machine learning to predict postoperative pancreatic fistula based on preoperative, non-contrast-enhanced computed tomography. We screened a prospectively assessed database including all patients undergoing pancreatoduodenectomy at a tertiary center from 2008 until 2018 for patients based on the occurrence of postoperative pancreatic fistula. In total, 110 patients were included, consisting of 55 patients who developed a postoperative pancreatic fistula and 55 without postoperative pancreatic fistula. For machine learning-based texture analysis preoperative, non-contrast-enhanced computed tomography axial images were used. Machine learning results were tested using 10-fold cross validation. Previously validated clinical fistula risk scores (original and alternative fistula risk scores) served as reference tests. Both the original and the alternative fistula risk scores showed good discrimination between patients without and with postoperative pancreatic fistula (area under the curve 0.76 and 0.72, respectively). Machine learning-based texture analysis showed potential to detect histologic fibrosis (area under the curve 0.84, sensitivity 75%; specificity 92%), histologic lipomatosis (area under the curve 0.82, sensitivity 78%; specificity 89%), and intraoperative pancreatic hardness (area under the curve 0.70, sensitivity 78%; specificity 74%). The features of the machine learning-based texture analysis were most accurate in predicting the occurrence of postoperative pancreatic fistula (area under the curve 0.95, sensitivity of 96%; specificity 98%) after pancreatoduodenectomy. This proof-of-principle study suggests the ability of machine learning in recognizing important features of pancreatic texture associated with an increased risk of postoperative pancreatic fistula based on preoperative computed tomography. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs. Summary of Background Data: Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown. Methods: We used a mouse model of simple, diet-induced steatosis and assessed the impact of exercise on metabolic parameters, ischemia-reperfusion injury and regeneration after hepatectomy. The same parameters were evaluated after treatment of mice with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Mice on a control diet served as age-matched controls. Results: A 4-week-exercising program reversed steatosis, lowered insulin levels, and improved glucose tolerance. Exercise markedly enhanced the ischemic tolerance and the regenerative capacity of fatty liver. Replacing exercise with AICAR was sufficient to replicate the above benefits. Both exercise and AICAR improved survival after extended hepatectomy in mice challenged with a Western diet, indicating protection from resection-induced liver failure. Conclusions: Exercise efficiently counteracts the metabolic, ischemic, and regenerative deficits of fatty liver. AICAR acts as an exercise mimetic in settings of fatty liver disease, an important finding given the compliance issues associated with exercise. Exercising, or its substitution through AICAR, may provide a feasible strategy to negate the hepatic consequences of energy-rich diet, and has the potential to extend the application of liver surgery if confirmed in humans. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to use the concept of benchmarking to establish robust and standardized outcome references after the procedure ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy). Background and Aims: The recently developed ALPPS procedure, aiming at removing primarily unresectable liver tumors, has been criticized for safety issues with high variations in the reported morbidity/mortality rates depending on patient, disease, technical characteristics, and center experience. No reference values for relevant outcome parameters are available. Methods: Among 1036 patients registered in the international ALPPS registry, 120 (12%) were benchmark cases fulfilling 4 criteria: patients ≤67 years of age, with colorectal metastases, without simultaneous abdominal procedures, and centers having performed ≥30 cases. Benchmark values, defined as the 75th percentile of the median outcome parameters of the centers, were established for 10 clinically relevant domains. Results: The benchmark values were completion of stage 2: ≥96%, postoperative liver failure (ISGLS-criteria) after stage 2: ≤5%, ICU stay after ALPPS stages 1 and 2: ≤1 and ≤2 days, respectively, interstage interval: ≤16 days, hospital stay after ALPPS stage 2: ≤10 days, rates of overall morbidity in combining both stage 1 and 2: ≤65% and for major complications (grade ≥3a): ≤38%, 90-day comprehensive complication index was ≤22, the 30-, 90-day, and 6-month mortality was ≤4%, ≤5%, and 6%, respectively, the overall 1-year, recurrence-free, liver-tumor-free, and extrahepatic disease-free survival was ≥86%, ≥50%, ≥57%, and ≥65%, respectively. Conclusions: This benchmark analysis sets key reference values for ALPPS, indicating similar outcome as other types of major hepatectomies. Benchmark cutoffs offer valid tools not only for comparisons with other procedures, but also to assess higher risk groups of patients or different indications than colorectal metastases. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To investigate the impact of remote ischemic preconditioning (RIPC) on liver regeneration after major hepatectomy. Summary Background Data: RIPC is a strategy applied at remote sites to mitigate ischemic injury. Unlike other preconditioning approaches, RIPC spares target organs as it acts via systemic VEGF elevations. In the liver, however, VEGF is an important driver of regeneration following resection. Therefore, RIPC may have pro-regenerative effects. Methods: RIPC was applied to C57BL/6 mice through intermittent clamping of the femoral vessels prior to standard 68%-hepatectomy or extended 86%-hepatectomy, with the latter causing liver failure and impaired survival. Liver regeneration was assessed through weight gain, proliferative markers (Ki67, pH3, mitoses), cell cycle-associated molecules, and survival. The role of the VEGF-ID1-WNT2 signaling axis was assessed through WIF1 (a WNT antagonist) and recombinant WNT2 injected prior to hepatectomy. Results: RIPC did not affect regeneration after 68%-hepatectomy, but improved liver weight gain and hepatocyte mitoses after 86%-hepatectomy. Importantly, RIPC raised survival from 40% to 80% after 86%-hepatectomy, indicating the promotion of functional recovery. Mechanistically, the RIPC-induced elevations in VEGF were accompanied by increases in the endothelial transcription factor Id1, its target WNT2, and its hepatocellular effector β-catenin. WIF1 injection prior to 86%-hepatectomy abrogated the RIPC benefits, while recombinant WNT2 had pro-regenerative effects akin to RIPC. Conclusion: RIPC improves the regenerative capacity of marginal liver remnants in a VEGF-dependent way. If confirmed in patients, RIPC may become the preconditioning strategy of choice in the setting of extended liver resections. [ABSTRACT FROM AUTHOR]

Background Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. Methods The effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. Results Two and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers ( P   =   . 14/0.82), sizes ( P   =   . 45/0.98), and growth kinetics ( P   =   . 58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27–57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35–49 days), and portal vein ligation (39 days; 95% confidence interval; 34–43 days, P   =   . 237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. Conclusion The accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the effect of Ω3 fatty acids (Ω3FA) on fatty and lean liver in hepatic surgery. Background: The global spread of energy-dense diets has led to an endemic rise in fatty liver disease and obesity. Besides metabolic pathologies, steatosis enhances hepatic sensitivity to ischemia reperfusion (I/R) and impedes liver regeneration (LR). Steatosis limits the application of liver surgery, still the main curative option for liver cancer. Ω3FA are known to reverse steatosis, but how these lipids affect key factors defining surgical outcomes--that is, I/R, LR, and liver malignancy--is less clear. Methods: We established a standardized mouse model of high fat diet (HFD)-induced steatosis followed by V3FA treatment and the subsequent assessment of Ω3FA effects on I/R, LR, and liver malignancy (n = 5/group), the latter through a syngeneic metastasis approach. Fatty liver outcomes were com- pared with lean liver to assess steatosis-independent effects. Nonparametric statistics were applied. Results: Ω3FA reversed HFD-induced steatosis and markedly protected against I/R, improved LR, and prolonged survival of tumor-laden mice. Remarkably, these beneficial effects were also observed in lean liver, albeit at a smaller scale. Notably, mice with metastases in fatty versus lean livers were associated with improved survival. Conclusions: Ω3FA revealed multiple beneficial effects in fatty and lean livers in mice. The improvements in I/R injury, regenerative capacity, and oncological outcomes await confirmatory studies in humans. [ABSTRACT FROM AUTHOR]

Background ALPPS induces rapid liver hypertrophy after stage-1 operation, enabling safe, extended resections (stage-2) after a short period. Recent studies have suggested that partial transection at stage-1 might be associated with a better safety profile. The aim of this study was to assess the amount of liver parenchyma that needs to be divided to achieve sufficient liver hypertrophy in ALPPS. Methods In a bi-institutional, prospective cohort study, nonfibrotic patients who underwent ALPPS with complete ( n = 22) or partial ( n = 23) transection for colorectal liver metastases were analyzed and compared with an external ALPPS cohort ( n = 23). A radiologic tool was developed to quantify the amount of parenchymal transection. Liver hypertrophy and clinical outcome were compared between both techniques. The relationship of partial transection and hypertrophy was investigated further in an experimental murine model of partial ALPPS. Result The median amount of parenchymal transection in partial ALPPS was 61% (range, 34–86%). The radiologic method correlated poorly with the intraoperative surgeon's estimation (r S = 0.258). Liver hypertrophy was equivalent for the partial ALPPS, ALPPS, and external ALPPS cohort (64% vs 60% vs. 64%). Experimental data demonstrated that partial transection of at least 50% induced comparable hypertrophy (137% vs 156%) and hepatocyte proliferation compared to complete transection. Conclusion The study provides clinical and experimental evidence that partial liver partition of at least 50% seems to be equally effective in triggering volume hypertrophy as observed with complete transection and can be re recommended as less invasive alternative to ALPPS. [ABSTRACT FROM AUTHOR]

To develop and validate a simple score to predict postoperative complications by severity after liver resection, using readily available preoperative risk factors.Although liver surgery has enjoyed major development with dramatic reduction in mortality rates, the incidence of serious yet nonlethal complications remains high. No scoring system is currently available to identify those patients at higher risk for a complicated course.Complications were prospectively assessed in 615 consecutive noncirrhotic patients undergoing liver resection at the same institution. In randomly selected 60% of the population, multivariate-logistic-regression analysis was used to develop a score to predict severe complications defined as complications grades III, IV, and mortality (grade V) (Clavien-Dindo classification). The score was validated by calibration within the remaining 40% of the patients.Grades III to V complications occurred in 159 (26%) of the 615 patients after liver resection, 90 (15%) were grade III, 48 (8%) grade IV, and 21 (3%) grade V. Four preoperative parameters were identified as independent predictors including American Society of Anesthesiologists category, transaminases levels (aspartate aminotransferase), extent of liver resection (>3 vs <3 segments), and the need for an additional hepaticojejunostomy or colon resection. A prediction score was calculated on the basis of 60% of the population (369 patients) using the 4 independent predictors ranging from 0 to 10 points. The risk to develop serious postoperative complications was 16% in “low risk” patients (0-2 points), 37% in “intermediate risk” patients (3-5 points) and 60% in “high risk” patients (6-10 points). The predicted mean for absolute risk for grades III to V complications was 27% in the validation population including 40% of the patients (n = 246), whereas the observed risk was 24%. Predicted and observed risks were similar throughout the different risk categories (P = 0.8). The score was significantly associated with hospital and intensive care unit stays. Costs of the entire procedure doubled among the 3 risk groups.This novel and simple score accurately predicts postoperative complications and cost in patients undergoing liver resection. This score allows early identification of patients at risk and may impact not only decision making for surgical intervention but also quality assessment and reimbursement. [ABSTRACT FROM AUTHOR]