An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Comparison of transection techniques in pediatric major hepatectomy: a matched pair analysis.

BACKGROUND: Evidence on safety and efficacy of different liver transection techniques in pediatric major hepatectomy is completely lacking, as no study has been conducted so far. The use of stapler hepatectomy has never before been reported in children. METHODS: Three liver transection techniques were compared: (1) ultrasonic dissector (CUSA), (2) tissue sealing device (LigaSure™), and (3) stapler hepatectomy. All pediatric hepatectomies performed at a referral center in a 12-year study period were analyzed, patients were pair-matched in a 1:1:1-fashion. Intraoperative weight-adjusted blood loss, operation time, use of inflow occlusion, liver injury (peak-transaminase levels), postoperative complications (CCI), and long-term outcome were compared. RESULTS: Of 57 pediatric liver resections, 15 patients were matched as triples based on age, weight, tumor stage, and extent of resection. Intraoperative blood loss was not significantly different between the groups (p = 0.765). Stapler hepatectomy was associated with significantly shorter operation time (p = 0.028). Neither postoperative death nor bile leakage occurred, and no reoperation due to hemorrhage was needed in any patient. CONCLUSION: This is the first comparison of transection techniques in pediatric liver resection and the first report on stapler hepatectomy in children. All three techniques can be safely applied and may harbor individual advantages in pediatric hepatectomy each.

Is metabolic syndrome a risk factor in hepatectomy? A meta-analysis with subgroup analysis for histologically confirmed hepatic manifestations.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy. METHODS: The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed. RESULTS: The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low. CONCLUSION: Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications-PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF. TRIAL REGISTRATION: PROSPERO Nr: CRD42021253768.

The role of liver resection in metastatic nephroblastoma: a systematic review and Meta-regression analysis.

BACKGROUND: The impact of hepatic resection for liver metastases (LM) on the survival of pediatric patients with Wilms' tumor (WT) is unclear. So far, there is a lack of studies investigating the best suited treatment for patients with WTLM, and the role of liver resection has rarely been investigated. Thus, the development of evidence-based guidelines concerning indications of liver resection for WTLM remains difficult. AIM: To investigate the role of surgery in the therapy of WTLM. All available data on liver resections and subgroup outcomes of patients with WTLM are analyzed. Main research question is whether liver resection improves survival rates of patients with WTLM compared to non-surgical treatment. METHODS: A systematic literature search of MEDLINE, Web of Science, and Central provided the basis for this PRISMA-compliant systematic review. For the main analysis (I), all studies reporting on surgical treatment of pediatric WTLM were included. To provide a representative overview of the general outcome of WTLM patients, in analysis II all studies with cohorts of at least five WTLM patients, regardless of the kind of treatment, were reviewed and analyzed. A Multiple meta-regression model was applied to investigate the impact liver resection on overall survival. RESULTS: 14 studies with reports of liver resection for WTLM were found (Analysis I). They included a total of 212 patients with WTLM, of which 93 underwent a liver resection. Most studies had a high risk of bias, and the quality was heterogenous. For the analysis II, eight studies with subgroups of at least five WTLM patients were found. The weighted mean overall survival (OS) of WTLM patients across the studies was 55% (SD 29). A higher rate of liver resection was a significant predictor of better OS in a multiple meta-regression model with 4 covariates (I2 29.43, coefficient 0.819, p = 0.038). CONCLUSIONS: This is the first systematic review on WTLM. Given a lack of suited studies that specifically investigated WTLM, ecological bias was high in our analyses. Generating evidence is complicated in rare pediatric conditions and this study must be viewed in this context. Meta-regression analyses suggest that liver resection may improve survival of patients with WTLM compared to non-surgical treatment. Especially patients with persisting disease after neoadjuvant chemotherapy but also patients with metachronous LM seem to benefit from resection. Complete resection of LM is vital to achieve higher OS. Studies that prospectively investigate the impact of surgery on survival compared to non-surgical treatment for WTLM are highly needed to further close the current evidence gap. STUDY REGISTRATION: PROSPERO 2021 CRD42021249763  https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249763 .

Pushing the limit of liver regeneration - Safety and survival after monosegment-ALPPS: systematic review and individual patient data meta-analysis.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has expanded and spearheaded development in hepatobiliary surgery. Monosegment-ALPPS tests liver regeneration limits and may present as the last feasible curative treatment option. METHODS: Electronic databases (MEDLINE, Web of Science, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on mono-ALPPS using a predefined strategy without date or language restrictions. Individual patient data was extracted and analyzed. RESULTS: 237 publications were identified. 19 patients were identified to have undergone mono-ALPPS. Primarily, mono-ALPPS has been utilized as curative treatment for CRLM (17 of 19 cases). Successful mono-ALPPS was possible in FLR above 8% SLV. All patients received either chemotherapy alone or in combination with radiotherapy prior to surgery. 8 of 19 patients experienced PHLF grade A or B. There was no in-hospital mortality described. Recurrent disease has occurred in 7 of 19 patients and 3 have died during follow-up. CONCLUSION: Mono-ALPPS is an experimental procedure that provides a reasonably safe opportunity to curatively treat extensive liver malignancies in patients with FLR as low as 8% SLV. PHLF is the most prevalent complication in mono-ALPPS. Mono-ALPPS should be evaluated in a multicentral study setting.

Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience.

BACKGROUND: Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons. METHODS: Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018. RESULTS: Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection. CONCLUSION: FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.

Markers of liver regeneration-the role of growth factors and cytokines: a systematic review.

BACKGROUND: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.

Innovation for the Sake of Innovation? How Does Robotic Hepatectomy Compare to Laparoscopic or Open Resection for HCC-A Systematic Review and Meta-Analysis.

Robot-assisted hepatectomy is a novel approach to treat liver tumors. HCC is on the rise as the cause of cancer and mortality and is often preceded by cirrhosis. Robot-assisted hepatectomy has been suggested to offer benefits to cirrhotic patients. We aimed to evaluate current evidence for robot-assisted hepatectomy for HCC and compare it to open and laparoscopic approaches. This systematic review and meta-analysis has been conducted in accordance with most recent PRISMA recommendations and the protocol has been registered at PROSPERO (CRD42022328544). There were no randomized controlled trials available and no study focused on cirrhotic patients exclusively. Robot-assisted hepatectomy was associated with less major complications than the laparoscopic approach, but comparable with open hepatectomy. No difference was seen in overall or minor complications, as well as liver specific or infectious complications. Cumulative survivals were similar in robot-assisted hepatectomy and laparoscopic or open approaches. There is a clear lack of evidence to suggest particular benefits for robot-assisted hepatectomy in cirrhotic patients. Otherwise, the robot-assisted approach has similar complication rates as open or laparoscopic methods. Non-industry driven randomized controlled trials are needed to evaluate the efficacy of robot-assisted liver surgery.

Effect of Autotransfusion in HCC Surgery on Survival and Recurrence: A Systematic Review and Meta-Analysis.

BACKGROUND: The chronic blood shortage has forced clinicians to seek alternatives to allogeneic blood transfusions during surgery. Due to anatomic uniqueness resulting in a vast vasculature, liver surgery can lead to significant blood loss, and an estimated 30% of patients require blood transfusions in major hepatectomy. Allogeneic transfusion harbors the risk of an immunologic reaction. However, the hesitation to reinfuse a patient's own blood during cancer surgery is reinforced by the potentiality of reintroducing and disseminating tumor cells into an individual undergoing curative treatment. Two methods of autotransfusions are common: autotransfusion after preoperative blood donation and intraoperative blood salvage (IBS). We aim to investigate the effect of autotransfusion on recurrence and survival rates of patients undergoing surgery for HCC. METHODS: The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science and Cochrane Library were searched for publications on liver surgery and blood salvage (autologous transfusion or intraoperative blood salvage). Comparative studies were included. Outcomes focused on long-term oncologic status and mortality. Hazard ratios (HR) estimated outcomes with a fixed-effects model. Risk of bias was assessed using ROBINS-I, and certainty of evidence was evaluated with GRADE. Separate analyses were performed for liver transplantation and hepatectomies. RESULTS: Fifteen studies were included in the analysis (nine on transplantation and six on hepatectomies), and they comprised 2052 patients. Overall survival was comparable between patients who received intraoperative blood salvage (IBS) or not for liver transplantation (HR 1.13, 95% CI [0.89, 1.42] p = 0.31). Disease-free survival also was comparable (HR 0.97, 95% CI [0.76, 1.24], p = 0.83). Autotransfusion after prior donation was predominantly used in hepatectomy. Patients who received autotransfusion had a significantly better overall survival than the control (HR 0.71, 95% CI [0.58, 0.88], p = 0.002). Disease-free survival was also significantly higher in patients with autotransfusion (HR 0.88, 95% CI [0.80, 0.96], p = 0.005). Although overall, the certainty of evidence is low and included studies exhibited methodological heterogeneity, the heterogeneity of outcomes was low to moderate. CONCLUSION: Autotransfusion, including intraoperative blood salvage, does not adversely affect the overall or disease-free survival of patients with HCC undergoing resection or transplantation. The results of this meta-analysis justify a randomized-controlled trial regarding the feasibility and potential benefits of autotransfusion in HCC surgery.

A Multidisciplinary Approach to the Management of Fibrolamellar Carcinoma: Current Perspectives and Future Prospects.

Fibrolamellar carcinoma (FLC) is a rare primary liver tumor affecting predominantly younger and otherwise healthy patients. Typically, FLC presents with advanced disease due to the paucity of typical symptoms and no history of underlying liver disease. Depending on tumor characteristics and the patient's general condition, surgical treatment is the most promising treatment modality. Aggressive resection and liver transplantation have been utilized and are presently indispensable curative treatment options. Under certain circumstances surgical resection is also possible for metachronous metastases or local recurrence. Recent tumor biology discoveries have contributed to improved diagnostic specificity and systemic treatment options.

Evidence on Indications and Techniques to Increase the Future Liver Remnant in Children Undergoing Extended Hepatectomy: A Systematic Review and Meta-Analysis of Individual Patient Data.

Background: Techniques to increase the future liver remnant (FLR) have fundamentally changed the indications and criteria of resectability in adult liver surgery. In pediatric patients however, these procedures have rarely been applied and the potential benefit or harm as well as suited indications are unclear. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was conducted. Based on a PRISMA-compliant, predefined methodology, all studies reporting pediatric patients (< 18y) undergoing liver resection with either associating liver partition and portal vein ligation for stages hepatectomy (ALPPS) or preoperative portal vein embolization or ligation (PVE/PVL) were included. Baseline data, periinterventional morbidity, increase of FLR and outcomes were analyzed. Results: 15 studies reporting on 21 pediatric patients with a mean age of 4 years and 7 months (range 1.8 months - 17 years) were included. 12 ALPPS procedures, 8 PVE and 1 PVL were performed. The applied criteria for performing ALPPS or PVE were heterogenous and thresholds for minimally acceptable FLR varied. Mean FLR [% of total liver volume] before the intervention was 23.6% (range 15.0 - 39.3%) in the ALPPS group and 31.4% (range 21.5 - 56.0%) in the PVE group. Mean increase of FLR before stage 2 resection was 69.4% (range 19.0 - 103.8%) for ALPPS and 62.8% (range 25.0 - 108.0%) after PVE. No postoperative death occurred, one early intrahepatic recurrence after an ALPPS procedure was reported. Overall postoperative morbidity was 23.8%. Conclusion: Validated criteria for minimal FLR in pediatric liver resection are lacking and so are clear indications for ALPPS or PVE. In special cases, ALPPS and PVE can be valuable techniques to achieve complete resection of pediatric liver tumors. However, more data are needed, and future studies should focus on a definition and validation of posthepatectomy liver failure as well as the minimally needed FLR in pediatric patients undergoing extended hepatectomy. Systematic Review Registration: [www.clinicaltrials.gov], identifier [PROSPERO 2021 CRD42021274848].

Factors Influencing Overall Survival for Patients with Fibrolamellar Hepatocellular Carcinoma: Analysis of the Surveillance, Epidemiology, and End Results Database.

BACKGROUND: The study aimed to develop a nomogram to predict overall survival (OS) for patients with FLC using a national database. METHODS: The Surveillance, Epidemiology, and End Results database of the National Cancer Institute was reviewed to identify FLC cases with histological confirmation between 2004 and 2014. Cox proportional hazards models were used to identify factors associated with OS. The validation of the nomogram was performed using concordance index (C-index) and calibration curves. RESULTS: Out of 170 cases with complete follow-up, 87 received surgery/ablation and 12 received transplantation with significantly higher OS than chemotherapy alone while transplantation combined with chemotherapy showed better survival than solely transplantation. The combination of surgery and chemotherapy showed worse OS than surgery alone. Survival was negatively influenced by T4 stadium (HR = 5.91), while young age and surgery were positive predictive factors. There was no influence of gender, ethnicity or nodal status on survival. The rate of AFP positivity was comparable with and without the presence of distal metastases. CONCLUSION: FLC survival is greatly dependent upon appropriate surgical management irrespective of tumor stadium.

Routine Postoperative Antibiotic Prophylaxis Offers No Benefit after Hepatectomy-A Systematic Review and Meta-Analysis.

BACKGROUND: Prophylactic antibiotics are frequently administered after major abdominal surgery including hepatectomies aiming to prevent infective complications. Yet, excessive use of antibiotics increases resistance in bacteria. The aim of this systematic review and meta-analysis is to assess the efficacy of prophylactic antibiotics after hepatectomy (postoperative antibiotic prophylaxis, POA). METHOD: This systematic review and meta-analysis were completed according to the current PRISMA guidelines. The protocol has been registered prior to data extraction (PROSPERO registration Nr: CRD42021288510). MEDLINE, Web of Science and CENTRAL were searched for clinical reports on POA in hepatectomy restrictions. A random-effects model was used for synthesis. Methodological quality was assessed with RoB2 and ROBINS-I. GRADE was used for the quality of evidence assessment. RESULTS: Nine comparative studies comprising 2987 patients were identified: six randomized controlled trials (RCTs) and three retrospectives. POA did not lead to a reduction in postoperative infective complications or have an effect on liver-specific complications-post-hepatectomy liver failure and biliary leaks. POA over four or more days was associated with increased rates of deep surgical site infections compared to short-term administration for up to two days (OR 1.54; 95% CI [1.17;2.03]; p = 0.03). Routine POA led to significantly higher MRSA incidence as a pathogen (p = 0.0073). Overall, the risk of bias in the studies was low and the quality of evidence moderate. CONCLUSION: Routine POA cannot be recommended after hepatectomy since it does not reduce postoperative infection or liver-specific complications but contributes to resistance in bacteria. Studies into individualized risk-adapted antibiotic prophylaxis strategies are needed to further optimize perioperative treatment in liver surgery.

A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification.

Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan-Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.

Generating evidence for diagnosis and therapy of RarE LIVEr disease: the RELIVE Initiative for systematic reviews and meta-analyses.

BACKGROUND: Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present. MAIN TEXT: A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto. CONCLUSION: Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

Predicting liver regeneration following major resection.

Breakdown of synthesis, excretion and detoxification defines liver failure. Post-hepatectomy liver failure (PHLF) is specific for liver resection and a rightfully feared complication due to high lethality and limited therapeutic success. Individual cytokine and growth factor profiles may represent potent predictive markers for recovery of liver function. We aimed to investigate these profiles in post-hepatectomy regeneration. This study combined a time-dependent cytokine and growth factor profiling dataset of a training (30 patients) and a validation (14 patients) cohorts undergoing major liver resection with statistical and predictive models identifying individual pathway signatures. 2319 associations were tested. Primary hepatocytes isolated from patient tissue samples were stimulated and their proliferation was analysed through DNA content assay. Common expression trajectories of cytokines and growth factors with strong correlation to PHLF, morbidity and mortality were identified despite highly individual perioperative dynamics. Especially, dynamics of EGF, HGF, and PLGF were associated with mortality. PLGF was additionally associated with PHLF and complications. A global association-network was calculated and validated to investigate interdependence of cytokines and growth factors with clinical attributes. Preoperative cytokine and growth factor signatures were identified allowing prediction of mortality following major liver resection by regression modelling. Proliferation analysis of corresponding primary human hepatocytes showed associations of individual regenerative potential with clinical outcome. Prediction of PHLF was possible on as early as first postoperative day (POD1) with AUC above 0.75. Prediction of PHLF and mortality is possible on POD1 with liquid-biopsy based risk profiling. Further utilization of these models would allow tailoring of interventional strategies according to individual profiles.

Study protocol of REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I): a prospective observational study of antibiotic prophylaxis practice for patients undergoing major abdominal surgery.

INTRODUCTION: Surgical site infections (SSIs) are among the most common complications after abdominal surgery and develop in approximately 20% of patients. These patients suffer a 12% increase in mortality, underlying the need for strategies reducing SSI. Perioperative antibiotic prophylaxis is paramount for SSI prevention in major abdominal surgery. Yet, intraoperative redosing criteria are subjective and whether patients benefit from it remains unclear. METHODS AND ANALYSIS: The REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I) study is a single-centre, prospective, observational study investigating redosing of antibiotic prophylaxis in 300 patients undergoing major abdominal surgery. Adult patients scheduled for major abdominal surgery will be included. Current practice of redosing regarding number and time period will be recorded. Postoperative SSIs, nosocomial infections, clinically relevant infection-associated bacteria, postoperative antibiotic treatment, in addition to other clinical, pharmacological and economical outcomes will be evaluated. Differences between groups will be analysed with analysis of covariance. ETHICS AND DISSEMINATION: RESISTAAS I will be conducted in accordance with the Declaration of Helsinki and internal, national and international standards of GCP. The Medical Ethics Review Board of Heidelberg University has approved the study prior to initiation (S-404/2021). The study has been registered on 7 February 2022 at German Clinical Trials Register, with identifier DRKS00027892. We plan to disseminate the results of the study in a peer-reviewed journal. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00027892.

Impact of Type 2 Diabetes on Oncologic Outcomes of Hepatocellular Carcinomas in Non-Cirrhotic, Non-alcoholic Steatohepatitis: a Matched-Pair Analysis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) associated hepatocellular carcinomas (NASH-HCC) are increasing. NASH-HCC often develops in the fibrotic liver. Several analyses report conflicting results regarding the outcome of non-cirrhotic NASH-HCC. Furthermore, type 2 diabetes (T2D) is considered a risk factor for poor survival. The aim of this study was to investigate oncological outcomes of non-cirrhotic NASH-HCC and the impact of T2D. METHODS: Patients with non-cirrhotic NASH-HCC with T2D as determined by an expert pathologist conducting histological slide review were matched for risks factors for poor outcome (age, gender, body mass index) with patients with NASH-HCC without T2D. These patients were then matched 1:1 with HCCs of other underlying liver diseases with and without T2D. Oncological outcomes were assessed using Kaplan-Meier curves. RESULTS: Out of 365 HCCs resected between 2001 and 2017, 34 patients with non-cirrhotic NASH-HCC were selected (17 with T2D, 17 without T2D) and matched with 26 patients with hepatitis-HCC and 28 patients with alcohol-related HCC. Oncological risk factors such as tumor size, resection margin, and vessel invasion were comparable. There was no difference in overall survival (5-year survival 71.3% for NASH-HCC, 60.4% for hepatitis-HCC, 79.9% for alcohol-HCC). NASH-HCC was associated with longer disease-specific survival than hepatitis-HCC (5-year 87.5% vs. 63.7%, p = 0.048), while recurrence-free survival was identical. T2D had no impact on oncological outcomes in either liver disease. CONCLUSION: Non-cirrhotic NASH-HCC has outcomes comparable with other underling etiologies. Despite a lack of cirrhosis, patients with non-cirrhotic NASH-HCC have the same risks of HCC recurrence as patients with cirrhotic liver disease of other etiologies.

Influence of cytokines, circulating markers and growth factors on liver regeneration and post-hepatectomy liver failure: a systematic review and meta-analysis.

The pathophysiology of post-hepatectomy liver failure is not entirely understood but is rooted in the disruption of normal hepatocyte regeneration and homeostasis. Current investigations of post-hepatectomy liver failure and regeneration are focused on evaluation of circulating hepatic function parameters (transaminases, cholestasis, and coagulation parameters), volumetry and hepatic hemodynamics. However, identification of biochemical factors associated with regeneration and post hepatectomy liver failure is crucial for understanding the pathophysiology and identification of patients at risk. The objective of the present systematic review was to identify circulating factors associated with liver regeneration and post hepatectomy liver failure in patients undergoing hepatectomy. The quantitative analysis was intended if studies provided sufficient data. Electronic databases (MEDLINE via PubMed, Web of Knowledge, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on cell signaling factors in liver regeneration and post-hepatectomy liver failure following liver resection in clinical setting. No date restriction was given. No language restriction was used. Studies were assessed using MINORS. This study was registered at PROSPERO (CRD42020165384) prior to data extraction. In total 1953 publications were evaluated for titles and abstracts after exclusion of duplicates. Full texts of 167 studies were further evaluated for inclusion. 26 articles were included in the review and 6 publications were included in the meta-analyses. High levels of serum hyaluronic acid even preoperatively are associated with PHLF but especially increased levels early after resection are predictive of PHLF with high sensitivity and specificity. Postoperative elevation of HA to levels between 100 and 500 ng/ml is increased the risk for PHLF ([OR] = 246.28, 95% [CI]: 11.82 to 5131.83; p = 0.0004) Inteleukin-6 levels show contradicting result in association with organ dysfunction. HGF positively correlates with liver regeneration. Overall, due to heterogeneity, scarcity, observational study design and largely retrospective analysis, the certainty of evidence, assessed with GRADE, is very low. High levels of serum hyaluronic acid show a strong association with PHLF and increased levels after resection are predictive of PHLF with high sensitivity and specificity, even on POD1. Interleukin-6 levels need to be studied further due to contradictive results in association with organ dysfunction. For HGF, no quantitative analysis could be made. Yet, most studies find positive correlation between high HGF levels and regeneration. Prospective studies investigating HGF and other growth factors, hyaluronic acid and interleukins 1 and 6 in correlation with liver regeneration measured sequentially through e.g. volumetry, and liver function parameters, preferably expanding the analysis to include dynamic liver function tests, are needed to sufficiently illustrate the connection between biomolecule levels and clinical outcomes.

Biliary Rhabdomyosarcoma in Pediatric Patients: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND: The biliary tree is a rare location of pediatric rhabdomyosarcoma. Due to the low incidence, there is a lack of evidence concerning therapeutic guidelines for this tumor location. In particular, the impact of surgery is discussed controversially. PURPOSE: Objective is to generate evidence-based treatment guidelines for pediatric biliary rhabdomyosarcoma (BRMS). All available published data on therapeutic regimens and important prognostic factors are investigated with a focus on the role of surgery. METHODS: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed. Patient data were entered individually. Data was pooled and qualitative and quantitative analyses of demographic data, therapy, postoperative/interventional outcomes, relapse, and survival were conducted. In an individual patient data analysis, cox regression was applied to identify key factors predicting the outcome of patients with BRMS. RESULTS: 65 studies met the inclusion criteria, providing data on 176 patients with BRMS. Individual patient data analysis showed a 5-year overall survival and progression-free survival of 51% and 50% for the total study population. For patients treated after 2000, 5-year OS and PFS was 65% and 59%, respectively. Absence of surgical tumor resection was an independent risk factor for death (Hazard ratio 8.9, 95%-CI 1.8-43.6, p = 0.007) and significantly associated with recurrent disease and disease-related death. CONCLUSION: This analysis provides comprehensive information on the largest number of patients hitherto reported in the literature. BRMS is still associated with high morbidity and mortality. Surgical tumor resection is essential for appropriate oncological treatment of BRMS. International cooperation studies are needed to enhance evidence and improve the outcome of this orphan disease. PROTOCOL REGISTRATION: PROSPERO (CRD42021228911) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228911.