Applying augmented reality in teaching of surgical residents-telementoring, a "stress-free" way to surgical autonomy?

BACKGROUND: Achieving surgical autonomy can be considered the ultimate goal of surgical training. Innovative head-mounted augmented reality (AR) devices enable visualization of the operating field and teaching from remote. Therefore, utilization of AR glasses may be a novel approach to achieve autonomy. The aim of this pilot study is to analyze the feasibility of AR application in surgical training and to assess its impact on intraoperative stress. METHODS: A head-mounted RealWear Navigator® 500 glasses and the TeamViewer software were used. Initial "dry lab" testing of AR glasses was performed in combination with the Symbionix LAP Mentor™. Subsequently, residents performed various stage-adapted surgical procedures semi-autonomously (SA) (on-demand consultation of senior surgeon, who is in theatre but not scrubbed) versus permanent remote supervision (senior surgeon not present) via augmented reality (AR) glasses, worn by the resident in theatre. Stress was measured by intraoperative heart rate (Polar® pulse belt) and State-Trait Anxiety Inventory (STAI) questionnaire. RESULTS: After "dry lab" testing, N = 5 senior residents performed equally N = 25 procedures SA and with AR glasses. For both, open and laparoscopic procedure AR remote assistance showed satisfactory applicability. Utilization of AR significantly reduced intraoperative peak pulse rate from 131 to 119 bpm (p = 0.004), as compared with the semi-autonomous group. Likewise, subjectively perceived stress according to STAI was significantly lower in the AR group (p = 0.011). CONCLUSION: AR can be applied in surgical training and may help to reduce stress in theatre. In the future, AR has a huge potential to become a stepping stone to surgical autonomy.

Liver Histology Predicts Liver Regeneration and Outcome in ALPPS: Novel Findings From A Multicenter Study.

BACKGROUND AND AIMS: Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. METHODS: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. RESULTS: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively). CONCLUSIONS: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.

Early Postoperative Serum Phosphate Drop Predicts Sufficient Hypertrophy After Liver Surgery.

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. Both ALPPS and LLD are characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. METHODS: Serum phosphate 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.

Outruling cholangiocarcinoma in patients with primary sclerosing cholangitis wait-listed for liver transplantation: A report on the Irish national experience.

BACKGROUND: The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort. METHODS: We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland. RESULTS: 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%. CONCLUSION: Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context.

Timing of surgical repair of bile duct injuries after laparoscopic cholecystectomy: A systematic review.

BACKGROUND: The surgical management of bile duct injuries (BDIs) after laparoscopic cholecystectomy (LC) is challenging and the optimal timing of surgery remains unclear. The primary aim of this study was to systematically evaluate the evidence behind the timing of BDI repair after LC in the literature. AIM: To assess timing of surgical repair of BDI and postoperative complications. METHODS: The MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to August 2021. Risk of bias was assessed via the Newcastle Ottawa scale. The primary outcomes of this review included the timing of BDI repair and postoperative complications. RESULTS: A total of 439 abstracts were screened, and 24 studies were included with 15609 patients included in this review. Of the 5229 BDIs reported, 4934 (94%) were classified as major injury. Timing of bile duct repair was immediate (14%, n = 705), early (28%, n = 1367), delayed (28%, n = 1367), or late (26%, n = 1286). Standardization of definition for timing of repair was remarkably poor among studies. Definitions for immediate repair ranged from < 24 h to 6 wk after LC while early repair ranged from < 24 h to 12 wk. Likewise, delayed (> 24 h to > 12 wk after LC) and late repair (> 6 wk after LC) showed a broad overlap. CONCLUSION: The lack of standardization among studies precludes any conclusive recommendation on optimal timing of BDI repair after LC. This finding indicates an urgent need for a standardized reporting system of BDI repair.

Regenerative Liver Surgery - ALPPS and Associated Techniques.

Hepatectomy is the only potentially curative treatment of hepatic tumors, but remains challenging in case of multiple, bilobar lesions and those located in the vicinity of the hepatic hilum and hepatic veins. Regenerative liver surgery utilizes the unique ability of the liver to re-grow after tissue loss and vascular deprivation. All concepts subsumed under this term aim to increase the resectability of hepatic tumors by stimulating growth of future liver remnant. Many of these techniques have evolved over the last decades. ALPPS (associated liver partition and portal vein ligation for staged hepatectomy) is an advanced technique combining portal vein ligation and parenchymal transection which gave rise to many variants, all with the common goal of extending resectability. This article reviews techniques currently available for regenerative liver surgery focusing on ALPPS, its mechanisms of liver regeneration, indications, advantages, drawbacks, results and future perspectives.

The evolution of surgery for colorectal liver metastases: A persistent challenge to improve survival.

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.

Can magnetic resonance imaging radiomics of the pancreas predict postoperative pancreatic fistula?

OBJECTIVES: To evaluate whether a magnetic resonance imaging (MRI) radiomics-based machine learning classifier can predict postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) and to compare its performance to T1 signal intensity ratio (T1 SIratio). METHODS: Sixty-two patients who underwent 3 T MRI before PD between 2008 and 2018 were retrospectively analyzed. POPF was graded and split into clinically relevant POPF (CR-POPF) vs. biochemical leak or no POPF. On T1- and T2-weighted images, 2 regions of interest were placed in the pancreatic corpus and cauda. 173 radiomics features were extracted using pyRadiomics. Additionally, the pancreas-to-muscle T1 SIratio was measured. The dataset was augmented and split into training (70 %) and test sets (30 %). A Boruta algorithm was used for feature reduction. For prediction of CR-POPF models were built using a gradient-boosted tree (GBT) and logistic regression from the radiomics features, T1 SIratio and a combination of the two. Diagnostic accuracy of the models was compared using areas under the receiver operating characteristics curve (AUCs). RESULTS: Five most important radiomics features were identified for prediction of CR-POPF. A GBT using these features achieved an AUC of 0.82 (95 % Confidence Interval [CI]: 0.74 - 0.89) when applied on the original (non-augmented) dataset. Using T1 SIratio, a GBT model resulted in an AUC of 0.75 (CI: 0.63 - 0.84) and a logistic regression model delivered an AUC of 0.75 (CI: 0.63 - 0.84). A GBT model combining radiomics features and T1 SIratio resulted in an AUC of 0.90 (CI 0.84 - 0.95). CONCLUSION: MRI-radiomics with routine sequences provides promising prediction of CR-POPF.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

The DNA hypermethylation phenotype of colorectal cancer liver metastases resembles that of the primary colorectal cancers.

BACKGROUND: Identifying molecular differences between primary and metastatic colorectal cancers-now possible with the aid of omics technologies-can improve our understanding of the biological mechanisms of cancer progression and facilitate the discovery of novel treatments for late-stage cancer. We compared the DNA methylomes of primary colorectal cancers (CRCs) and CRC metastases to the liver. Laser microdissection was used to obtain epithelial tissue (10 to 25 × 106 µm2) from sections of fresh-frozen samples of primary CRCs (n = 6), CRC liver metastases (n = 12), and normal colon mucosa (n = 3). DNA extracted from tissues was enriched for methylated sequences with a methylCpG binding domain (MBD) polypeptide-based protocol and subjected to deep sequencing. The performance of this protocol was compared with that of targeted enrichment for bisulfite sequencing used in a previous study of ours. RESULTS: MBD enrichment captured a total of 322,551 genomic regions (249.5 Mb or ~ 7.8% of the human genome), which included over seven million CpG sites. A few of these regions were differentially methylated at an expected false discovery rate (FDR) of 5% in neoplastic tissues (primaries: 0.67%, i.e., 2155 regions containing 279,441 CpG sites; liver metastases: 1%, i.e., 3223 regions containing 312,723 CpG sites) as compared with normal mucosa samples. Most of the differentially methylated regions (DMRs; 94% in primaries; 70% in metastases) were hypermethylated, and almost 80% of these (1882 of 2396) were present in both lesion types. At 5% FDR, no DMRs were detected in liver metastases vs. primary CRC. However, short regions of low-magnitude hypomethylation were frequent in metastases but rare in primaries. Hypermethylated DMRs were far more abundant in sequences classified as intragenic, gene-regulatory, or CpG shelves-shores-island segments, whereas hypomethylated DMRs were equally represented in extragenic (mainly, open-sea) and intragenic (mainly, gene bodies) sequences of the genome. Compared with targeted enrichment, MBD capture provided a better picture of the extension of CRC-associated DNA hypermethylation but was less powerful for identifying hypomethylation. CONCLUSIONS: Our findings demonstrate that the hypermethylation phenotype in CRC liver metastases remains similar to that of the primary tumor, whereas CRC-associated DNA hypomethylation probably undergoes further progression after the cancer cells have migrated to the liver.

ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry.

BACKGROUND: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM. METHODS: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM. RESULTS: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively. CONCLUSIONS: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution.

Exercise Improves Outcomes of Surgery on Fatty Liver in Mice: A Novel Effect Mediated by the AMPK Pathway.

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.

The potential of machine learning to predict postoperative pancreatic fistula based on preoperative, non-contrast-enhanced CT: A proof-of-principle study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Perioperative omega-3 fatty acids fail to confer protection in liver surgery: Results of a multicentric, double-blind, randomized controlled trial.

BACKGROUND & AIMS: In a variety of animal models, omega-3 polyunsaturated fatty acids (Ω3-FAs) conferred strong protective effects, alleviating hepatic ischemia/reperfusion injury and steatosis, as well as enhancing regeneration after major tissue loss. Given these benefits along with its safety profile, we hypothesized that perioperative administration of Ω3-FAs in patients undergoing liver surgery may ameliorate the postoperative course. The aim of this study was to investigate the perioperative use of Ω3-FAs to reduce postoperative complications after liver surgery. METHODS: Between July 2013 and July 2018, we carried out a multicentric, double-blind, randomized, placebo-controlled trial designed to test whether 2 single intravenous infusions of Omegaven® (Ω3-FAs) vs. placebo may decrease morbidity. The primary endpoints were postoperative complications by severity (Clavien-Dindo classification) integrated within the comprehensive complication index (CCI). RESULTS: A total of 261 patients (132 in the Omegaven and 129 in the placebo groups) from 3 centers were included in the trial. Most cases (87%, n = 227) underwent open liver surgery and 56% (n = 105) were major resections (≥3 segments). In an intention-to-treat analysis including the dropout cases, the mortality rate was 4% and 2% in the Omegaven and placebo groups (odds ratio0.40;95% CI 0.04-2.51; p = 0.447), respectively. Any complications and major complications (Clavien-Dindo ≥ 3b) occurred in 46% vs. 43% (p = 0.709) and 12% vs. 10% (p = 0.69) in the Omegaven and placebo groups, respectively. The mean CCI was 17 (±23) vs.14 (±20) (p = 0.417). An analysis excluding the dropouts provided similar results. CONCLUSIONS: The routine perioperative use of 2 single doses of intravenous Ω3-FAs (100 ml Omegaven) cannot be recommended in patients undergoing liver surgery (Grade A recommendation). LAY SUMMARY: Despite strong evidence of omega-3 fatty acids having liver-directed, anti-inflammatory and pro-regenerative action in various rodent models, 2 single omega-3 fatty acid infusions given to patients before and during liver surgery failed to reduce complications. Because single omega-3 fatty acid infusions failed to confer liver protection in this trial, they cannot currently be recommended. TRIAL REGISTRATION: ClinicalTrial.gov: ID: NCT01884948; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

Defining Benchmark Outcomes for ALPPS.

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.

Yes-associated protein promotes early hepatocyte cell cycle progression in regenerating liver after tissue loss.

The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo-YAP1 pathway, a key controller of organ size. Yes-associated protein 1 (YAP1)-a growth effector usually restrained by Hippo signaling-is believed to be of particular importance; however, its role in liver regeneration remains ill-defined. To explore its function, we knocked down YAP1 prior to standard 70%-hepatectomy (sHx) using a hepatocyte-specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S-phase/M-phase peaks at 32 hours/48 hours post-sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re-elevated at 48 hours post-sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection-induced liver failure (extended 86%-hepatectomy, eHx) featuring deficient S- and M-phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post-eHx, confirming its dissociation from M-phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S-phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.

Performance validation of the ALPPS risk model.

BACKGROUND: Based on the International ALPPS registry, we have recently proposed two easily applicable risk models (pre-stage1 and 2) for predicting 90-day mortality in ALPPS but a validation of both models has not been performed yet. METHODS: The validation cohort (VC) was composed of subsequent cases of the ALPPS registry and cases of centers outside the ALPPS registry. RESULTS: The VC was composed of a total of 258 patients including 70 patients outside the ALPPS registry with 32 cases of early mortalities (12%). Development cohort (DC) and VC were comparable in terms of patient and surgery characteristics. The VC validated both models with an acceptable prediction for the pre-stage 1 (c-statistic 0.64, P = 0.009 vs. 0.77, P < 0.001) and a good prediction for the pre-stage 2 model (c-statistic 0.77, P < 0.001 vs. 0.85, P < 0.001) as compared to the DC. Overall model performance measured by Brier score was comparable between VC and DC for the pre-stage 1 (0.089 vs. 0.081) and pre-stage 2 model (0.079 vs. 0087). CONCLUSION: The ALPPS risk score is a fully validated model to estimate the individual risk of patients undergoing ALPPS and to assist clinical decision making to avoid procedure-related early mortality after ALPPS.

Novel Benefits of Remote Ischemic Preconditioning Through VEGF-dependent Protection From Resection-induced Liver Failure in the Mouse.

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 ß-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.

Systematic review and meta-analysis of postoperative pancreatic fistula rates using the updated 2016 International Study Group Pancreatic Fistula definition in patients undergoing pancreatic resection with soft and hard pancreatic texture.

BACKGROUND: In 2016, the International Study Group of Pancreatic Fistula (ISGPS) proposed an updated definition for postoperative pancreatic fistula (POPF). Pancreas texture (PT) is an established risk factor of POPF. The definition of soft vs. hard texture, however, remains elusive. METHODS: A systematic search was performed to identify PT definitions and a meta-analysis linking POPF to PT using the updated ISGPS definition. RESULTS: 122 studies including 22 376 patients were identified. Definition criteria for PT varied among studies and most classified PT in hard and soft based on intraoperative subjective assessment. The total POPF rate (pooled grades B and C) after pancreatoduodenectomy was 14.5% (n = 10 395) and 15.5% (n = 3767) after distal pancreatectomy. In pancreatoduodenectomy, POPF rate was higher in soft compared to hard pancreas (RR, 4.4, 3.3 to 6.1; p < 0.001; n = 6393), where PT grouped as soft and hard. No data were available for intermediate PT. CONCLUSION: The reported POPF rates may be used in planning future prospective studies. A widely accepted definition of PT is lacking and a correlation with the risk of POPF is based on subjective evaluation, which is still acceptable. Classification of PT into 2-groups is more reasonable than classification into 3-groups.