Graft procurement in adult living donor liver transplantation (LDLT) faces persistent challenges in balancing volumetric adequacy and donor safety. This study introduces two-stage portal vein ligation and reperfusion for graft procurement in LDLT (PVLR-LT), which aims to expand the left lateral lobe for achieving adequate grafts, thereby circumventing technical and anatomical limitations of conventional approaches. In a rat model, the PVLR-LT group underwent selective portal vein ligation (step I) to induce targeted hypertrophy, followed by reperfusion and transplantation (step II). Outcomes were compared among PVLR-LT, negative controls, and standard-volume controls. Staged portal flow modulation effectively redistributed hepatic mass allocation, yielding grafts with graft recipient weight ratio approximately double that of negative controls and equivalent to standard-volume controls. Donors experienced no mortality, with only transient enzyme elevation. Recipient survival in the PVLR-LT group significantly exceeded that of the negative control group and was non-inferior to that of the standard-volume control group, while hepatic enzyme peaks were markedly lower than those in standard-volume control recipients. This study provides a promising proof of concept, establishing the feasibility of using PVLR-LT to convert the surgically straightforward left lateral segment into right lobe-sized grafts through staged portal flow modulation and demonstrating the translational potential for laparoscopic LDLT.

Activated hepatic stellate cells are required for Hippo-YAP activation and functional liver regeneration following portal vein ligation in mice.

Colorectal cancer mortality is largely driven by metastatic spread, with colorectal liver metastases (CRLM) being the most frequent. Treatment often combines surgery and systemic therapy, including anti-EGFR agents such as cetuximab. This study evaluated the cytoreductive effect of cetuximab on CRLM and its influence on liver function and regeneration in a selective portal vein ligation (PVL) model. Sixty-six male WAG/RijHsd rats were used. Seven days before PVL, twelve tumor-bearing animals received intra-arterial cetuximab, while other six received vehicle (saline). Additional groups included tumor-bearing rats without PVL, rats undergoing PVL alone, and untreated controls (n = 6 each). Seven days after PVL, the future remnant liver volume (%FRL) and hepatocyte replication were quantified. Serum markers for hepatic, renal, and systemic injury were analyzed, and tumor volume was assessed by ultrasound before and after PVL. The regenerative response following PVL was not significantly affected by cetuximab, with %FRL reaching 80–90%. However, hepatocyte nuclei exhibited a smaller mean area compared with non-treated animals (45.35 ± 9.09 vs. 43.54 ± 9.87 μm²; p < 0.001). Liver function remained preserved, although glucose levels decreased after PVL. Cetuximab significantly reduced tumor growth driven by hepatic regeneration (1.12 ± 0.45 vs. 0.53 ± 0.16 mL; p < 0.01). Neoadjuvant intra-arterial cetuximab does not impair liver regeneration after PVL while effectively limiting tumor proliferation linked to regenerative stimuli. These findings support its perioperative safety and potential use to prevent tumor recurrence in patients with CRLM undergoing staged hepatectomy.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively induces rapid liver hypertrophy in patients with initially unresectable liver tumours, yet the immunological mechanisms remain unclear. We aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS. The cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world's largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as Cd177 knockout and CD177+ neutrophil infusion in vivo. scRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177+ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177+ neutrophils interacted with endothelial cells via CD177-PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8-CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177+ neutrophil infusion restored regeneration, which was abolished in Cd177-/- mice. CD177+ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177+ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.

Associating liver partition and portal vein ligation for staged hepatectomy in patients with hepatocellular carcinoma: laparoscopic versus open approach and its impact on future remnant hypertrophy.

Association of liver partition and portal vein ligation in staged hepatectomy (ALPPS) for breast cancer-related liver metastases: a case report

ASO Visual Abstract: Hepatic Hypertrophy Techniques: Comparing Perioperative Outcomes ofLiver Venous Deprivation (LVD) and Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy-Variants (vALPPS)among Two Referral Centers.

To investigate the mechanism of oral sodium taurocholate on liver regeneration after portal vein ligation. A rat model of 70% portal vein ligation (PVL) was established. The rats were randomly divided into a sodium taurocholate intervention group (PVL treatment, PVLT) and a normal diet control group (PVL control, PVLC). Histological damage and bile duct hyperplasia were assessed by H&E and CK19 staining. Liver regeneration capacity was evaluated by measuring the ratio of non-ligated liver lobe weight to total liver weight and the expression of Ki67 protein. Liver function was assessed by measuring serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), total bile acids (TBA), and hepatic TBA levels. Transcriptome analysis was performed using bulk RNA sequencing, combined with qPCR validation of gene expression related to bile acid metabolism. In the non-ligated lobes of both PVLT and PVLC groups, we found mild bile duct hyperplasia confined to the portal areas (p > 0.05), with no evident histological damage. Ki67 expression peaked on the second day after surgery in both groups, with more significant liver regeneration observed in the PVLT group. Sodium taurocholate administration led to bile acid accumulation and concomitant liver function injury. Transcriptome analysis revealed that differentially expressed genes were significantly enriched in the bile acid secretion pathway, and Gene Set Enrichment Analysis (GSEA) suggested activation of the Hippo signaling pathway. Sodium taurocholate promotes liver regeneration after portal vein ligation by regulating bile acid metabolism and the Hippo signaling pathway.

Sarcopenia is a progressive muscle wasting condition often associated with hyperammonemia. However, no approved animal models of sarcopenia with hyperammonemia were reported. This study aimed to provide a surgical modelling of sarcopenia with hyperammonemia. Male Wistar rats were assigned by the method of random numbers (n = 6 per group) into experimental group with ligation of portal and pyloric veins or control group with sham surgery. Blood ammonia levels were measured directly after the surgery (20 min), after 1 h to observe acute damage in functioning shunts, and at the final endpoint (30 days). Rats were sacrificed with histological study of the liver, spleen, cerebral cortex, and skeletal muscles. Experimental rats revealed hyperammonemia at 30 days compared to controls, 70 µmol/L versus 38 µmol/L, p <0.05. No significant changes were observed in liver morphology between the groups, approving hyperammonemia without liver damage. Splenomegaly and Gamna-Gandy bodies in the spleen of experimental rats indirectly evidenced functionable portosystemic shunting after the ligation. Cerebral cortex showed a significant decrease in neurons of experimental animals, 7.6 ± 2.5 NeuN+cells vs 13 ± 2 in controls, p <0.05. Skeletal muscles revealed a significant difference of muscle fiber diameter between the groups, 20.2 ± 2.1 µm in the experimental group vs 30.7 ± 4.3 µm in controls, at p < 0.001. A model of sarcopenia with hyperammonemia was established with concomitant changes in cerebral histology revealed. This model may be a valuable tool for studies of sarcopenia and related therapeutic options.

Optimizing future liver remnant (FLR) volumes is crucial for safe major liver resections; liver venous deprivation (LVD) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) variants (vALPPS) are widely used techniques to address this issue, but direct comparisons are limited. The study aimed to evaluate their perioperative and oncological outcomes. This was a retrospective cohort study on consecutive patients undergoing liver hypertrophy between January 2015 and July 2024 conducted at two referral centers. A total of 84 patients, according to exclusion criteria, completed the procedure (drop-out rate: 21.1%)-28 tourniquet-ALPPS (T-ALPPS), 22 hybrid-ALPPS (H-ALPPS) and 34 LVD. Clinical, surgical, and oncological variables were analyzed on the overall and colorectal liver metastases (CRLM) populations. T-ALPPS group included more CRLM (92.9% vs 50% vs 38.2%, p < 0.001) and achieved faster hypertrophy (28.5 vs 37 vs 47.5 days, p = 0.004), although pre- and post-hypertrophy techniques volumes were comparable (pre-sFLR ~28%; post-SFLR ~40%). Minimally invasive approach predominated in the LVD group (67.6% vs 27.3% vs 3.6%, p < 0.001) but implied longer operative times (426 vs 242 vs 180 min, p < 0.001). No significant differences in major complications (CD ≥ 3A), 90-day mortality, non-radical resections rates, DFS, and OS were found. In CRLM subgroup, T-ALPPS achieved higher and faster hypertrophy, while LVD presented fewer major complications rate and no 90-day mortality. Very early recurrence rate (< 6 months) was higher in the LVD group, but DFS and OS were comparable. vALPPS and LVD represent valid hypertrophy techniques, the first enabling faster regeneration and the latter allowing for more minimally invasive approaches. The choice of approach should be individualized on the basis of tumor biology, patient condition, and institutional expertise.

Liver venous deprivation (LVD) or ALPPS in the treatment of colorectal liver metastasis (CRLM): a comparison of oncological outcome.

Posthepatectomy liver failure (PHLF) remains the leading cause of morbidity and mortality following major liver resection. The preoperative conditioning of the future liver remnant (FLR) is therefore essential to optimize the resectability and avoid postoperative complications. The aim of this review article is the presentation and critical evaluation of current strategies for liver conditioning, including interventional, surgical and systemic strategies. Aselective literature search for databases was conducted in PubMed. The focus was on recent systematic reviews, randomized trials and registry analyses addressing portal vein embolization (PVE), liver venous deprivation (LVD), associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), selective internal radiation therapy (SIRT) and neoadjuvant chemotherapy. The PVE procedure has been the established standard for decades, with proven safety and reliable induction of hypertrophy but shows limitations due to insufficient growth or tumor progression in up to 20% of patients. In numerous studies the LVD procedure demonstrated a more rapid and extensive hypertrophy of the FLR compared with PVE, without compromising safety. The ALPPS provides the highest regeneration dynamics but is associated with high morbidity and mortality and requires strict patient selection. The SIRT (radiation lobectomy) enables both tumor control and a relevant compensatory hypertrophy, even though prospective comparative trials are lacking. Neoadjuvant chemotherapy, particularly FOLFOXIRI plus bevacizumab or biomarker-based treatment regimen selection, leads to high conversion and resection rates in initially nonresectable metastases. The current evidence shows that individualized strategies for liver conditioning are decisive to enable a safe resection. The selection of the procedure should be oriented to the patient characteristics, tumor biology and interdisciplinary treatment algorithms.

Our study focused on the spatiotemporal analysis of reactive oxygen species (ROS), a key factor in hepatic ischemia-reperfusion injury, using a rat model to evaluate potential clinical applications. By inducing partial hepatic ischemia-reperfusion in rats through ligation of left portal vein and hepatic artery (one hour ischemia followed by reperfusion), we explored ROS generation using an imaging probe, 1-acetoxy-3-carbamoyl-2,2,5,5-tetramethylpyrroline (ACP), which reacts with ROS to produce a detectable T1-enhanced magnet resonance imaging (MRI) signal. In the rat model, the region of the left liver ischemia-reperfusion showed extremely mild liver injury one hour after reperfusion. After 12 h of reperfusion, extensive hepatocellular necrosis was observed, mainly in the hepatic interlobular region. One hour after reperfusion, the ACP-derived MRI signal increased in the region of left lobe ischemia-reperfusion was significantly higher than that in the non-ischemia-reperfusion region of the same rat right lobe. Administration of edaravone targeting the period of excessive ROS production at 1 h after reperfusion significantly suppressed hepatic injury 12 h after ischemia-reperfusion. Given MRI’s crucial role in clinical diagnostics and its adaptability, our research suggests a promising strategy for early intervention in organ damage by monitoring and modulating ROS levels, potentially revolutionizing patient care.

Liver Augmentation: Rationale, Current Status, and Future Directions.

Time-series transcriptome profiling of liver regeneration in ALLPS models of mice identifies the Cyp8b1 as a potential target for hepatocyte proliferation.

Liver Vein Deprivation: Rationale, Technique, and Review of the Literature.

Portal hypertension is critical to the development of ascites in liver cirrhosis. The aim of our study was to evaluate the contribution of portal hypertension to ascites formation and explore the underlying mechanism. Here, the role of portal hypertension in cirrhotic ascites was determined through a meta-analysis of portal pressure in cirrhotic patients and animal models. The mechanism underlying the involvement of portal hypertension in ascites formation was explored. The meta-analysis showed hepatic venous pressure gradient in patients with cirrhosis with ascites was significantly higher than that in patients with cirrhosis without ascites. In carbon tetrachloride (CCl4)-treated rats, portal pressure of cirrhotic rats with ascites (19.83 cmH2O) was significantly higher than that in cirrhotic rats without ascites (14.90 cmH2O). In a novel murine model created by thioacetamide (TAA)/CCl4 administration plus partial portal vein ligation (PPVL), a significant increase in portal pressure and ascites amount was observed in the TAA/CCl4 + PPVL group compared with the TAA/CCl4 group. In the mice treated with TAA/CCl4 plus PPVL, the amount of ascites decreased significantly in mice with endothelial deletion of Piezo1 (Piezo1△EC) compared with Piezo1flox/flox mice. Finally, Piezo1 in liver sinusoidal endothelial cells and peritoneal endothelial cells promoted the development of portal hypertensive ascites via the nuclear factor kappa-B (NF-ĸB)−aquaporin1 (AQP1) pathway. In conclusion, Piezo1 in endothelium contributes to the formation of portal hypertensive ascites via the NF-ĸB−AQP1 pathway in liver cirrhosis, which indicates that blockage of the Piezo1−NFĸB−AQP1 pathway may be a useful strategy for the management of ascites in liver cirrhosis.

Liver transplantation may be a curative treatment option in patients with otherwise unresectable liver metastases. We sought to evaluate the long-term outcomes of transplantation candidates by comparing 2 groups: one treated with living-donor liver transplantation and the other, due to the absence of available living donors, receiving the current gold standard of chemotherapy only. Eligibility for inclusion of patients with unresectable liver metastases required either stable disease or tumor regression after systemic chemotherapy with no extrahepatic tumor burden. Patients were divided into 2 cohorts according to the availability of a suitable living donor. The fundamental technical principle is a 2-stage transplantation procedure, also referred to as the RAPID technique (Resection and Partial Liver Transplantation with Delayed Hepatectomy). In the first operation, a left hemihepatectomy is carried out in the recipient, followed by orthotopic transplantation of the left lateral liver lobe (segments II and III) from a living donor. To promote graft hypertrophy, portal vein ligation is undertaken. In the second step of the operation, the remaining right lobe of the liver will be removed. The 3-year and 5-year survival rates for the transplantation group were 71.3% and 57%, respectively, compared with 33.3% and 11.1%, respectively, for 15 patients with a negative donor evaluation. The recurrence rate among transplanted patients was 58%. The median disease-free survival time between liver transplantation and recurrence or death was 17.4 months. For those who experienced a recurrence, the median survival time from recurrence was 25.6 months. Liver transplantation for patients with unresectable colorectal liver metastases leads to a significant survival advantage compared with chemotherapy alone. Living-donor liver transplantation is a suitable and safe method to expand organ availability for selected patients.

Background:Hepatic surgery rests on the unique, however limited regenerative capacity of the liver. Metabolic duties may be a key factor regulating proliferative abilities of hepatocytes. During regeneration, division of labor leads to spatial separation of proliferation from metabolic tasks, suggesting these opposing activities compete for space. Here, we exploited two-stage-hepatectomy mouse models to explore whether metabolic needs constrain the regenerative capacity of the liver.Materials and methods:Mice were subjected to sham or associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) surgery (a two-stage-hepatectomy renowned for accelerated regeneration), which leaves one fast-regenerating lobe (FLR) plus portally ligated lobes (LLs) that do not grow but have an intact arteriocentral flow. FLR and LLs were analyzed by omics approaches. Functional surgery was applied to create ALPPS variants with differing metabolic capacity.Results:The FLR and the adjacent LL displayed a similar metabolite profile which however completely diverged during the major FLR growth phase. Combined transcriptomics-metabolomics and histology assigned proliferative activities explicitly to the FLR, while LLs were enriched with metabolic tasks, establishing macroscopic division of labor. In ALPPS variants differing in ligated volume, FLR growth was increased or reduced with gain or loss of metabolic capacity, respectively, revealing control of regeneration through metabolic duties. Notably, FLRs of slow-growing variants had upregulated metabolic activities, reflecting plastic adaptation to the increased metabolic pressure coming with little ligated volume. Transcriptomics disclosed macroscopic division of labor also in human ALPPS regeneration.Conclusion:LLs act as auxiliary livers after ALPPS, enabling the FLR to focus on growth. Our findings demonstrate the functional requirement for division of labor during regeneration. This transient division roots on plastic behavior of the different lobes during ALPPS regeneration and reveals how metabolic needs define the liver’s regenerative capacity.

BackgroundUpfront portal vein embolization (PVE) without prior future liver remnant (FLR) clearing followed by a one-stage hepatectomy (OSH) for bilateral colorectal liver metastases (CRLM) can reduce the surgical burden of a two-stage approach, but oncological safety is not well described and comparisons with alternative two-stage procedures are lacking.MethodsA retrospective cohort of patients with bilateral CRLM and tumour in the FLR, undergoing liver resection between 2013 and 2021, was studied. The patients were divided into three groups: patients who underwent PVE with no prior tumour clearance in the FLR followed by an OSH (PVE-OSH); patients who underwent tumour clearance in the FLR followed by PVE (TSH-PVE; where TSH stands for two-stage hepatectomy); and patients who underwent associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).ResultsIn total, 302 patients with bilateral CRLM were included, of whom 127 underwent PVE-OSH, 61 underwent TSH-PVE, and 114 underwent ALPPS. Except for age and Eastern Cooperative Oncology Group (ECOG) Performance Status, all baseline characteristics were comparable. The most rapid hypertrophy was experienced by ALPPS patients, followed by PVE-OSH patients. Successful resection could not be performed in 11% of PVE-OSH patients, 21% of TSH-PVE patients, and 4% of ALPPS patients (P < 0.001). During major resection, 23% of TSH-PVE patients required additional FLR resection/ablation and the median time from first intervention to major resection was 9 (interquartile range (i.q.r.) 7–13) weeks, compared with 6 (i.q.r. 5–8) weeks for PVE-OSH patients and 1 (i.q.r. 1–3) week for ALPPS patients (P < 0.001). Postoperative outcomes were comparable regarding liver failure, mortality, and overall survival. Multivariable regression analysis for liver recurrence identified the number of metastases (HR 1.04 (95% c.i. 1.00 to 1.07); P = 0.025) and ALPPS (HR 1.64 (95% c.i. 1.00 to 2.68); P = 0.048) as independent risk factors.ConclusionPVE-OSH can be performed safely for patients with a limited tumour burden in the FLR, thereby obviating the need for two-stage procedures.