Comparing indications, complexity and outcomes of laparoscopic liver resection between centers with and without a liver transplant program: a French nationwide study.

BACKGROUND: There are no data to evaluate the difference in populations and impact of centers with liver transplant programs in performing laparoscopic liver resection (LLR). METHODS: This was a multicenter study including patients undergoing LLR for benign and malignant tumors at 27 French centers from 1996 to 2018. The main outcomes were postoperative severe morbidity and mortality. RESULTS: A total of 3154 patients were included, and 14 centers were classified as transplant centers (N = 2167 patients, 68.7 %). The transplant centers performed more difficult LLRs and more resections for hepatocellular carcinoma (HCC) in patients who more frequently had cirrhosis. A higher rate of performing the Pringle maneuver, a lower rate of blood loss and a higher rate of open conversion (all p < 0.05) were observed in the transplant centers. There was no association between the presence of a liver transplant program and either postoperative severe morbidity (<10 % in each group; p = 0.228) or mortality (1 % in each group; p = 0.915). CONCLUSIONS: Most HCCs, difficult LLRs, and cirrhotic patients are treated in transplant centers. We show that all centers can achieve comparable safety and quality of care in LLR independent of the presence of a liver transplant program.

Long-Term Overall Survival After Selective Internal Radiation Therapy for Locally Advanced Hepatocellular Carcinomas: Updated Analysis of DOSISPHERE-01 Trial.

Interim analysis of the DOSISPHERE-01 study demonstrated a strong improvement in response and overall survival (OS) on using 90Y-loaded glass microspheres with personalized dosimetry compared with standard dosimetry in patients with nonoperable locally advanced hepatocellular carcinoma. This report sought to provide a long-term analysis of OS. Methods: In this phase II study (ClinicalTrials.gov identifier NCT02582034), treatment was randomly assigned (1:1) with the goal to deliver either at least 205 Gy (if possible >250-300 Gy) to the index lesion in the personalized dosimetry approach (PDA) or 120 ± 20 Gy to the treated volume in the standard dosimetry approach (SDA). The 3-mo response of the index lesion was the primary endpoint, with OS being one of the secondary endpoints. This report is a post hoc long-term analysis of OS. Results: Overall, 60 hepatocellular carcinoma patients with at least 1 lesion larger than 7 cm and more than 30% of hepatic reserve were randomized (intent-to-treat population: PDA, n = 31; SDA, n = 29), with 56 actually treated (modified intent-to-treat population: n = 28 in each arm). The median follow-up for long-term analysis was 65.8 mo (range, 2.1-73.1 mo). Median OS was 24.8 mo and 10.7 mo (hazard ratio [HR], 0.51; 95% CI, 0.29-0.9; P = 0.02) for PDA and SDA, respectively, in the modified intent-to-treat population. Median OS was 22.9 mo for patients with a tumor dose of at least 205 Gy, versus 10.3 mo for those with a tumor dose of less than 205 Gy (HR, 0.42; 95% CI, 0.22-0.81; P = 0.0095), and was 22.9 mo for patients with a perfused liver dose of 150 Gy or higher, versus 10.3 mo for those with a perfused liver dose of less than 150 Gy (HR, 0.42; 95% CI, 0.23-0.75; P = 0.0033). Lastly, median OS was not reached in patients who were secondarily resected (n = 11, 10 in the PDA group and 1 in the SDA group), versus 10.8 mo in those without secondary resection (n = 45) (HR, 0.17; 95% CI, 0.065-0.43; P = 0.0002). Only resected patients displayed favorable long-term OS rates, meaning an OS of more than 50% at 5 y. Conclusion: After longer follow-up, personalized dosimetry sustained a meaningful improvement in OS, which was dramatically improved for patients who were accurately downstaged toward resection, including most portal vein thrombosis patients.

A multi-national, video-based qualitative study to refine training guidelines for assigning an "unsafe" score in laparoscopic cholecystectomy critical view of safety.

BACKGROUND: The critical view of safety (CVS) was incorporated into a novel 6-item objective procedure-specific assessment for laparoscopic cholecystectomy (LC-CVS OPSA) to enhance focus on safe completion of surgical tasks and advance the American Board of Surgery's entrustable professional activities (EPAs) initiative. To enhance instrument development, a feasibility study was performed to elucidate expert surgeon perspectives regarding "safe" vs. "unsafe" practice. METHODS: A multi-national consortium of 11 expert LC surgeons were asked to apply the LC-CVS OPSA to ten LC videos of varying surgical difficulty using a "safe" vs. "unsafe" scale. Raters were asked to provide written rationale for all "unsafe" ratings and invited to provide additional feedback regarding instrument clarity. A qualitative analysis was performed on written responses to extract major themes. RESULTS: Of the 660 ratings, 238 were scored as "unsafe" with substantial variation in distribution across tasks and raters. Analysis of the comments revealed three major categories of "unsafe" ratings: (a) inability to achieve the critical view of safety (intended outcome), (b) safe task completion but less than optimal surgical technique, and (c) safe task completion but risk for potential future complication. Analysis of reviewer comments also identified the potential for safe surgical practice even when CVS was not achieved, either due to unusual anatomy or severe pathology preventing safe visualization. Based upon findings, modifications to the instructions to raters for the LC-CVS OPSA were incorporated to enhance instrument reliability. CONCLUSIONS: A safety-based LC-CVS OPSA has the potential to significantly improve surgical training by incorporating CVS formally into learner assessment. This study documents the perspectives of expert biliary tract surgeons regarding clear identification and documentation of unsafe surgical practice for LC-CVS and enables the development of training materials to improve instrument reliability. Learnings from the study have been incorporated into rater instructions to enhance instrument reliability.

Rescue Liver Transplantation for Posthepatectomy Liver Failure: A Systematic Review and Survey of an International Experience.

BACKGROUND: Rescue liver transplantation (LT) is the only life-saving option for posthepatectomy liver failure (PHLF) whenever it is deemed as irreversible and likely to be fatal. The goals were to perform a qualitative systematic review of rescue LT for PHLF and a survey among various international LT experts. METHODS: A literature search was performed from 2000 to 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Population, Intervention, Comparison, Outcome framework, and to this, the authors' experience was added. The international online open survey included 6 cases of PHLF extracted from the literature and submitted to 976 LT experts. The primary outcome was whether experts would consider rescue LT for each case. Interrater agreement among experts was calculated using the free-marginal multirater kappa methodology. RESULTS: The review included 40 patients. Post-LT mortality occurred in 8 (20%) cases (7/28 with proven cancer and 1/12 with benign disease). In the long term, 6 of 21 (28.6%) survivors with cancer died of recurrence (median = 38 mo) and 15 (71.4%) were alive with no recurrence (median = 111 mo). All 11 survivors with benign disease were alive and well (median = 39 mo). In the international survey among experts in LT, the percentage agreement to consider rescue LT was 28%-98%, higher for benign than for malignant disease ( P = 0.011). Interrater agreement for the primary endpoint was low, expected 5-y survival >50% being the strongest independent predictor to consider LT. CONCLUSIONS: Rescue LT for PHLF may achieve good results in selected patients. Considerable inconsistencies of decision-making exist among LT experts when considering LT for PHLF.

Laparoscopic cholecystectomy critical view of safety (LC-CVS): a multi-national validation study of an objective, procedure-specific assessment using video-based assessment (VBA).

BACKGROUND: A novel 6-item objective, procedure-specific assessment for laparoscopic cholecystectomy incorporating the critical view of safety (LC-CVS OPSA) was developed to support trainee formative and summative assessments. The LC-CVS OPSA included two retraction items (fundus and infundibulum retraction) and four CVS items (hepatocystic triangle visualization, gallbladder-liver separation, cystic artery identification, and cystic duct identification). The scoring rubric for retraction consisted of poor (frequently outside of defined range), adequate (minimally outside of defined range) and excellent (consistently inside defined range) and for CVS items were "poor-unsafe", "adequate-safe", or "excellent-safe". METHODS: A multi-national consortium of 12 expert LC surgeons applied the OPSA-LC CVS to 35 unique LC videos and one duplicate video. Primary outcome measure was inter-rater reliability as measured by Gwet's AC2, a weighted measure that adjusts for scales with high probability of random agreement. Analysis of the inter-rater reliability was conducted on a collapsed dichotomous scoring rubric of "poor-unsafe" vs. "adequate/excellent-safe". RESULTS: Inter-rater reliability was high for all six items ranging from 0.76 (hepatocystic triangle visualization) to 0.86 (cystic duct identification). Intra-rater reliability for the single duplicate video was substantially higher across the six items ranging from 0.91 to 1.00. CONCLUSIONS: The novel 6-item OPSA LC CVS demonstrated high inter-rater reliability when tested with a multi-national consortium of LC expert surgeons. This brief instrument focused on safe surgical practice was designed to support the implementation of entrustable professional activities into busy surgical training programs. Instrument use coupled with video-based assessments creates novel datasets with the potential for artificial intelligence development including computer vision to drive assessment automation.

Combined hepatocellular-cholangiocarcinoma compared to hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Different survival, similar recurrence: Report of a large study on repurposed databases with propensity score matching.

BACKGROUND: Combined hepatocholangiocarcinoma is a rare cancer with a grim prognosis composed of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma morphologic patterns in the same tumor. The aim of this multicenter, international cohort study was to compare the oncologic outcomes after surgery of combined hepatocholangiocarcinoma to hepatocellular carcinoma and intrahepatic cholangiocarcinoma. METHODS: Patients treated by surgery for combined hepatocholangiocarcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma from 2000 to 2021 from multicenter international databases were analyzed retrospectively. Patients with combined hepatocholangiocarcinoma (cases) were compared with 2 control groups of hepatocellular carcinoma or intrahepatic cholangiocarcinoma, sequentially matched using a propensity score based on 8 preoperative characteristics. Overall and disease-free survival were compared, and predictors of mortality and recurrence were analyzed with Cox regression after propensity score matching. RESULTS: During the study period, 3,196 patients were included. Propensity score adjustment and 2 sequential matching processes produced a new cohort (n = 244) comprising 3 balanced groups was obtained (combined hepatocholangiocarcinoma = 56, intrahepatic cholangiocarcinoma = 66, and hepatocellular carcinoma = 122). Kaplan-Meier overall survival estimations at 1, 3, and 5 years were 67%, 45%, and 28% for combined hepatocholangiocarcinoma, 92%, 75%, and 55% for hepatocellular carcinoma, and 86%, 53%, and 42% for the intrahepatic cholangiocarcinoma group, respectively (P = .0014). Estimations of disease-free survival at 1, 3, and 5 years were 51%, 25%, and 17% for combined hepatocholangiocarcinoma, 63%, 35%, and 26% for the hepatocellular carcinoma group, and 51%, 31%, and 28% for the intrahepatic cholangiocarcinoma group, respectively (P = .19). Predictors of mortality were combined hepatocholangiocarcinoma subtype, metabolic syndrome, preoperative tumor markers alpha-fetoprotein and carbohydrate antigen 19-9, and satellite nodules, and recurrence was associated with satellite nodules rather than cancer subtype. CONCLUSION: Despite data limitations, overall survival among patients with combined hepatocholangiocarcinoma was worse than both groups and closer intrahepatic cholangiocarcinoma, whereas disease-free survival was similar among the 3 groups. Future research on immunophenotypic profiling may hold more promise than traditional nonmodifiable clinical characteristics (as found in this study) in predicting recurrence or response to salvage treatments.

Immune checkpoints are predominantly co-expressed by clonally expanded CD4+FoxP3+ intratumoral T-cells in primary human cancers.

BACKGROUND: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. METHODS: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. RESULTS: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. CONCLUSIONS: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival.

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10-100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.

Open Versus Laparoscopic Right Hepatectomy for Hepatocellular Carcinoma Following Sequential TACE-PVE: A Multicentric Comparative Study.

BACKGROUND: Right hepatectomy (RH) for hepatocellular carcinoma (HCC) is ideally preceded by transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE). Laparoscopic approach improves short-term outcome and textbook outcome (TO), which reflects the "ideal" surgical outcome, after RH. However, laparoscopic RH on an underlying diseased liver and after TACE/PVE remains a challenging procedure. The aim of this study was to compare the outcomes in patients who underwent laparoscopic liver resection (LLR) or open liver resection (OLR) following TACE/PVE. PATIENTS AND METHODS: All patients with HCC who underwent RH after TACE/PVE in five French centers were retrospectively included. Outcomes were compared between the LLR group and the OLR group using propensity score matching (PSM). Quality of surgical care was defined by TO. RESULTS: Between 2005 and 2019, 117 patients were included (41 in LLR group, 76 in OLR group). Overall morbidity was comparable (51% versus 53%, p = 0.24). In LLR group, TO was completed in 66% versus 37% in OLR group (p = 0.02). LLR and absence of clamping were the only factors associated with TO completion [hazard ratio (HR) 4.27, [1.77-10.28], p = 0.001]. After PSM, 5-year overall survival (OS) and progression-free survival (PFS) were 55% in matched LLR versus 77% in matched OLR, p = 0.35, and 13% in matched LLR versus 17% in matched OLR, p = 0.97. TO completion was independently associated with a better 5-year OS (65.2% versus 42.5%, p = 0.007). CONCLUSION: Major LLR after TACE/PVE should be considered as a valuable option in expert centers to increase the chance of TO, the latter being associated with a better 5-year OS.

Early portal vein thrombosis after hepatectomy for perihilar cholangiocarcinoma: Incidence, risk factors, and management.

AIM: To study the incidence, risk factors and management of portal vein thrombosis (PVT) after hepatectomy for perihilar cholangiocarcinoma (PHCC). PATIENTS AND METHOD: Single-center retrospective analysis of 86 consecutive patients who underwent major hepatectomy for PHCC, between 2012 and 2019, with comparison of the characteristics of the groups with (PVT+) and without (PVT-) postoperative portal vein thrombosis. RESULTS: Seven patients (8%) presented with PVT diagnosed during the first postoperative week. Preoperative portal embolization had been performed in 71% of patients in the PVT+ group versus 34% in the PVT- group (P=0.1). Portal reconstruction was performed in 100% and 38% of PVT+ and PVT- patients, respectively (P=0.002). In view of the gravity of the clinical and/or biochemical picture, five (71%) patients underwent urgent re-operation with portal thrombectomy, one of whom died early (hemorrhagic shock after surgical treatment of PVT). Two patients had exclusively medical treatment. Complete recanalization of the portal vein was achieved in the short and medium term in the six survivors. After a mean follow-up of 21 months, there was no statistically significant difference in overall survival between the two groups. FINDINGS: Post-hepatectomy PVT for PHCC is a not-infrequent and potentially lethal event. Rapid management, adapted to the extension of the thrombus and the severity of the thrombosis (hepatic function, signs of portal hypertension) makes it possible to limit the impact on postoperative mortality. We did not identify any modifiable risk factor. However, when it is oncologically and anatomically feasible, left±extended hepatectomy (without portal embolization) may be less risky than extended right hepatectomy, and portal vein resection should only be performed if there is strong suspicion of tumor invasion.

Features Importance in Acute Kidney Injury After Liver Transplant: Which Predictors Are Relevant?

OBJECTIVES: Acute kidney injury after liver transplant results from several interconnected factors related to graft, recipient, intraoperative, and postoperative events. The random decision forest model enables an appreciation of each factor's contribution, which may be helpful in setting up a preventive strategy. This study aimed to evaluate the importance of covariates at different times (pretransplant, end of surgery, postoperative day 7) with a random forest permutation algorithm. MATERIALS AND METHODS: We used a retrospective singlecenter cohort of patients, without preoperative renal failure, who underwent primary liver transplants from deceased donors (N =1104). Significant covariates for stage 2-3 acute kidney injurywere included in a random forest model, and features importance was evaluated with mean decrease accuracy and Gini index. RESULTS: Stage 2-3 acute kidney injury occurred in 200 patients (18.1%) and was associated with lower patient survival, even after exclusion of early graftloss. At univariate analysis, recipient factors (serum creatinine level, Model for End-Stage Liver Disease score, body weight, body mass index), graft variables (weight, macrosteatosis), intraoperative factors (number of red blood cells, duration of surgery, cold ischemia time), and postoperative event (graft dysfunction) were associated with kidney failure. The pretransplant model found that macrosteatosis and graft weight contributed to acute kidney injury. The postoperative model indicated that graft dysfunction and the number of intraoperative packed red blood cells were ranked as the 2 most essential factors in posttransplant renal failure. CONCLUSIONS: The application of a random forestfeature identified graft dysfunction, even transient and reversible, and the number of intraoperative packed red blood cells as the 2 most crucial contributors to acute kidney injury,thus indicating that prevention of graft dysfunction and bleeding are key points to limit the risk of renal failure after liver transplant.

Post-hepatectomy liver failure: A timeline centered review.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is a leading cause of postoperative mortality after liver surgery. Due to its significant impact, it is imperative to understand the risk stratification and preventative strategies for PHLF. The main objective of this review is to highlight the role of these strategies in a timeline centered way around curative resection. DATA SOURCES: This review includes studies on both humans and animals, where they addressed PHLF. A literature search was conducted across the Cochrane Library, Embase, MEDLINE/PubMed, and Web of Knowledge electronic databases for English language studies published between July 1997 and June 2020. Studies presented in other languages were equally considered. The quality of included publications was assessed using Downs and Black's checklist. The results were presented in qualitative summaries owing to the lack of studies qualifying for quantitative analysis. RESULTS: This systematic review with 245 studies, provides insight into the current prediction, prevention, diagnosis, and management options for PHLF. This review highlighted that liver volume manipulation is the most frequently studied preventive measure against PHLF in clinical practice, with modest improvement in the treatment strategies over the past decade. CONCLUSIONS: Remnant liver volume manipulation is the most consistent preventive measure against PHLF.

Predictive nomograms for postoperative 90-day morbidity and mortality in patients undergoing liver resection for various hepatobiliary diseases.

BACKGROUND: Postoperative complications affect the long-term survival and quality of life in patients undergoing liver resection. No model has yet been validated to predict 90-day severe morbidity and mortality. METHODS: The prospective recruitment of patients undergoing liver resection for various indications was performed. Preoperative clinical and laboratory data, including liver stiffness, indocyanine green retention, and intraoperative parameters, were analyzed to develop predictive nomograms for postoperative severe morbidity and mortality. Calibration plots were used to perform external validation. RESULTS: The most common indications in 418 liver resections performed were colorectal metastases (N = 149 [35.6%]), hepatocellular carcinoma (N = 106 [25.4%]), and benign liver tumors (N = 60 [14.3%]). Major liver resections were performed in 164 (39.2%) patients. Severe morbidity and mortality were observed in 87 (20.8%) and 9 (2.2%) of patients, respectively, during the 90-day postoperative period. Post-hepatectomy liver failure was observed in 19 (4.5%) patients, resulting in the death of 4. The independent predictors of 90-day severe morbidity were age (odds ratio:1.02, P = .06), liver stiffness (odds ratio: 1.23, P = .04], number of resected segments (odds ratio: 1.28, P = .004), and operative time (odds ratio: 1.01, P = .01). Independent predictors of 90-day mortality were diabetes mellitus (odds ratio: 6.6, P = .04), tumor size >50 mm (odds ratio:4.8, P = .08), liver stiffness ≥22 kPa (odds ratio:7.0, P = .04), and operative time ≥6 hours (odds ratio: 6.1, P = .05). Nomograms were developed using these independent predictors and validated by testing the Goodness of fit in calibration plots (P = .64 for severe morbidity; P = .8 for mortality). CONCLUSION: Proposed nomograms would enable a personalized approach to identifying patients at risk of complications and adapting surgical treatment according to their clinical profile and the center's expertise.

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy.

Partial liver removal is an important therapy option for liver cancer. In most patients within a few weeks, the liver is able to fully regenerate. In some patients, however, regeneration fails with often severe consequences. To better understand the control mechanisms of liver regeneration, experiments in mice were performed, guiding the creation of a spatiotemporal 3D model of the regenerating liver. The model represents cells and blood vessels within an entire liver lobe, a macroscopic liver subunit. The model could reproduce the experimental data only if a biomechanical growth control (BGC)-mechanism, inhibiting cell cycle entrance at high compression, was taken into account and predicted that BGC may act as a short-range growth inhibitor minimizing the number of proliferating neighbor cells of a proliferating cell, generating a checkerboard-like proliferation pattern. Model-predicted cell proliferation patterns in pigs and mice were found experimentally. The results underpin the importance of biomechanical aspects in liver growth control.

Arterial Lactate Concentration at the End of Liver Transplantation is Independently Associated With One-Year Mortality.

BACKGROUND: Liver transplant patients who develop hyperlactatemia are at increased risk of postoperative morbidity and short-term mortality, but there are few data on longer-term outcomes. We therefore investigated if arterial lactate concentration obtained immediately after surgery, at the time of admission to the intensive care unit (ICU), was associated with 1-year mortality. METHODS: In this retrospective cohort study, all patients who underwent liver transplant surgery from a deceased donor between September 2013 and December 2019 were screened for inclusion. Patients who underwent combined transplantation surgery and those with a history of previous liver transplantation (ie, redo surgery) were not included. Logistic regression modeling included univariate and multivariate analyses. Receiver operating characteristic curves and areas under the curves were calculated. Lactate thresholds and association with outcome were analyzed for specificity, sensitivity, and Youden's index. RESULTS: Of 226 patients included, 18.4% died within 1 year of liver transplantation. Immediate postoperative lactate concentration was independently associated with 1-year mortality with an adjusted odds ratio of 1.35 (95% CI 1.16-1.59; P < .001) per mmol/L increase in lactate and an area under the curve of 0.80 (95% CI 0.72-0.87; P < .001). A lactate concentration of 2.25 mmol/L (cutoff determined using Youden's index) was associated with increased 1-year mortality with a sensitivity of 0.71 and a specificity of 0.72. CONCLUSIONS: Increased arterial lactate concentration on admission to the intensive care unit immediately after orthotopic liver transplantation is independently associated with increased 1-year mortality.

Indocyanine green fluorescence patterns of hepatocellular carcinoma correlate with pathological and molecular features.

BACKGROUND: Intraoperative Indocyanine Green Dye (ICG) routinely used in hepatobiliary surgery identifies different fluorescent patterns of hepatocellular carcinoma (HCC), a highly heterogeneous cancer. We aimed to correlate these patterns with gene mutations and extensive pathological features beyond the well-known tumor differentiation. METHODS: Between February 2017 and December 2019, 21 HCC in 16 consecutive patients who underwent intraoperative ICG fluorescence imaging were included. Pathological review was performed by one pathologist blinded to fluorescence features. Random forest machine learning algorithm correlated pathological features of the tumor, peritumoral and non-tumoral liver, and gene mutations from a 28 gene-panel with rim and intra-lesion fluorescence. RESULTS: Three HCC had negative intra-lesion and rim-like emission, 7 HCC had homogeneous pattern and 11 heterogeneous patterns in whom 3 with rim-like emission. Rim emission was associated with peritumoral vascular changes, lower differentiation and lower serum AFP level. Homogeneous intra-lesion fluorescence was associated with lower necrosis rate, thinner capsule, absence of peritumoral liver changes, and higher serum AFP level. Heterogeneous HCC without rim harbored lesser TP53 and ARID1A mutations. CONCLUSION: Tumoral and peri-tumoral fluorescence classification of HCC yielded a possible intraoperative pathological and molecular characterization. These preliminary observations could lead to intraoperative refinement in surgical strategy.

Towards refining the utility of dual (18F-FDG / 18F-Choline) PET/CT for the management of hepatocellular carcinoma: a tertiary center study.

BACKGROUND: The role of positron emission tomography/computed tomography (PET/CT) in hepatocellular carcinoma (HCC) management is not clearly defined. Our objective was to analyze the utility of dual-PET/CT (18F-FDG + 18F-Choline) imaging findings on the BCLC staging and treatment decision for HCC patients. METHODS: Between January 2011 and April 2019, 168 consecutive HCC patients with available baseline dual-PET/CT imaging data were retrospectively analyzed. To identify potential refinement criteria for surgically-treated patients, survival Kaplan-Meier curves of various standard-of-care and dual-PET/CT baseline parameters were estimated. Finally, multivariate cox proportional hazard ratios of the most relevant clinico-biological and/or PET parameters were estimated. RESULTS: Dual-PET/CT findings increased the score of BCLC staging in 21 (12.5%) cases. In 24.4% (N.=41) of patients, the treatment strategy was modified by the PET findings. Combining AFP levels at a threshold of 10 ng/mL with 18F-FDG or 18F-Choline N status significantly impacted DFS (P<0.05). In particular, the combined criteria of the N+ status assessed by 18F-Choline with AFP threshold of 10 ng/mL provided a highly predictive composite parameter for estimation of DFS according to multivariate analysis (HR=10.6, P<0.05). CONCLUSIONS: The 18F-Choline / AFP composite parameter appears promising, and further prospective studies are mandatory to validate its oncological impact.

Sensitivity Analysis of a Mathematical Model Simulating the Post-Hepatectomy Hemodynamics Response.

Recently a lumped-parameter model of the cardiovascular system was proposed to simulate the hemodynamics response to partial hepatectomy and evaluate the risk of portal hypertension (PHT) due to this surgery. Model parameters are tuned based on each patient data. This work focuses on a global sensitivity analysis (SA) study of such model to better understand the main drivers of the clinical outputs of interest. The analysis suggests which parameters should be considered patient-specific and which can be assumed constant without losing in accuracy in the predictions. While performing the SA, model outputs need to be constrained to physiological ranges. An innovative approach exploits the features of the polynomial chaos expansion method to reduce the overall computational cost. The computed results give new insights on how to improve the calibration of some model parameters. Moreover the final parameter distributions enable the creation of a virtual population available for future works. Although this work is focused on partial hepatectomy, the pipeline can be applied to other cardiovascular hemodynamics models to gain insights for patient-specific parameterization and to define a physiologically relevant virtual population.