• cell proliferation
• in vivo crispr
• liver regeneration
• mir-30a-3p
• plk1

• Animals
• Liver Regeneration/genetics
• Mice
• Hepatectomy/methods
• Hepatocytes/metabolism
• Hepatocytes/physiology
• MicroRNAs/genetics
• Ligation
• Portal Vein/surgery
• Mice, Knockout
• Polo-Like Kinase 1
• Cell Proliferation/genetics
• Liver/surgery
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Male
• Disease Models, Animal
• Gene Expression Profiling
• CRISPR-Cas Systems
• Hydrolases/genetics
• Mice, Inbred C57BL
• Multiomics

• ALPPS
• future liver remnant
• liver regeneration
• portal hemodynamics
• proliferative factors

• Chongqing Municipal Health Commission
• Army Medical University

• Humans
• Liver Regeneration
• Hepatectomy/adverse effects
• Cohort Studies
• Portal Vein/surgery
• Liver/surgery
• Liver/pathology
• Liver Neoplasms/secondary
• Ligation
• Treatment Outcome

Although the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid liver regeneration than portal vein embolization, the mechanism remains unclear.

To assess the influence of inflammatory cytokines and endothelial nitric oxide synthase (eNOS) activation on liver regeneration in ALPPS.

The future liver remnant/body weight (FLR/BW) ratio, hepatocyte proliferation, inflammatory cytokine expression, and activation of the Akt-eNOS pathway were evaluated in rat ALPPS and portal vein ligation (PVL) models. Hepatocyte proliferation was assessed based on Ki-67 expression, which was confirmed using immunohistochemistry. The serum concentrations of inflammatory cytokines were measured using enzyme linked immune-solvent assays. The Akt-eNOS pathway was assessed using western blotting. To explore the role of inflammatory cytokines and NO, Kupffer cell inhibitor gadolinium chloride (GdCl₃), NOS inhibitor N-nitro-arginine methyl ester (L-NAME), and NO enhancer molsidomine were administered intraperitoneally.

The ALPPS group showed significant FLR regeneration (FLR/BW: 1.60% ± 0.08%, P < 0.05) compared with that observed in the PVL group (1.33% ± 0.11%) 48 h after surgery. In the ALPPS group, serum interleukin-6 expression was suppressed using GdCl₃ to the same extent as that in the PVL group. However, the FLR/BW ratio and Ki-67 labeling index were significantly higher in the ALPPS group administered GdCl₃ (1.72% ± 0.19%, P < 0.05; 22.25% ± 1.30%, P < 0.05) than in the PVL group (1.33% ± 0.11% and 12.78% ± 1.55%, respectively). Phospho-Akt Ser⁴⁷³ and phospho-eNOS Ser¹¹⁷⁷ levels were enhanced in the ALPPS group compared with those in the PVL group. There was no difference between the ALPPS group treated with L-NAME and the PVL group in the FLR/BW ratio and Ki-67 labeling index. In the PVL group treated with molsidomine, the FLR/BW ratio and Ki-67 labeling index increased to the same level as in the ALPPS group.

Early induction of inflammatory cytokines may not be pivotal for accelerated FLR regeneration after ALPPS, whereas Akt-eNOS pathway activation may contribute to accelerated regeneration of the FLR.

• Hepatectomy
• Nitric oxide
• Liver regeneration
• Cytokines
• NG-Nitroarginine methyl ester
• Molsidomine

• Rats
• Animals
• Liver Regeneration/physiology
• Nitric Oxide Synthase Type III
• Ki-67 Antigen
• Molsidomine
• NG-Nitroarginine Methyl Ester
• Proto-Oncogene Proteins c-akt
• Liver Neoplasms/surgery
• Liver/surgery
• Hepatectomy
• Portal Vein/surgery
• Focal Nodular Hyperplasia
• Ligation
• Cytokines

• ALPPS
• corosolic acid
• liver regeneration
• macrophage polarisation
• tumour growth

• Animals
• Hepatectomy/methods
• Liver Neoplasms/surgery
• Liver Regeneration/physiology
• Portal Vein/surgery
• Programmed Cell Death 1 Receptor
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta
• Triterpenes

Fewer than 30% of patients with liver metastases are eligible for major liver resection, because liver remaining after such a surgery would be insufficient to cover the patient’s needs; this is called a low percentage of future liver remnant (FLR). Folinic acid (FA) has been shown to play a crucial role in cellular synthesis, regeneration, and nucleotide and amino acid biosynthesis. The aim of this piece of research was to evaluate the effect of FA as a potential hypertrophic hepatic enhancer agent after selective portal vein ligation (PVL) to ensure adequate FLR. We have confirmed in our rodent model that FA accelerates liver regeneration after PVL and enhances recovery of liver function. These findings may allow more patients to be eligible for liver resection without jeopardizing postoperative liver function.

Liver resection remains the gold standard for hepatic metastases. The future liver remnant (FLR) and its functional status are two key points to consider before performing major liver resections, since patients with less than 25% FLR or a Child–Pugh B or C grade are not eligible for this procedure. Folinic acid (FA) is an essential agent in cell replication processes. Herein, we analyze the effect of FA as an enhancer of liver regeneration after selective portal vein ligation (PVL). Sixty-four male WAG/RijHsd rats were randomly distributed into eight groups: a control group and seven subjected to 50% PVL, by ligation of left portal branch. The treated animals received FA (2.5 m/kg), while the rest were given saline. After 36 h, 3 days or 7 days, liver tissue and blood samples were obtained. FA slightly but significantly increased FLR percentage (FLR%) on the 7th day (91.88 ± 0.61%) compared to control or saline-treated groups (86.72 ± 2.5 vs. 87 ± 3.33%; p < 0.01). The hepatocyte nuclear area was also increased both at 36 h and 7days with FA (61.55 ± 16.09 µm², and 49.91 ± 15.38 µm²; p < 0.001). Finally, FA also improved liver function. In conclusion, FA has boosted liver regeneration assessed by FLR%, nuclear area size and restoration of liver function after PVL.

• folinic acid
• future liver remnant
• hepatotrophic
• rodent model
• selective portal vein ligation

• liver perfusion
• liver regeneration
• liver surgery
• mechanoperception
• multi-scale modeling
• perfusion/function relationship
• rodent models of liver surgery

• Deutsche Forschungsgemeinschaft

Portal vein ligation (PVL) has been adopted to induce hypertrophy of the future liver remnant (FLR) in patients with primarily irresectable liver tumor. However, regeneration of the FLR is not always sufficient to allow curative resection of the portally-deprived tumor-bearing liver lobe. We hypothesize that simultaneous hepatectomy (PHx) and PVL augments regeneration of the FLR and that the effect is related to the extent of the additional resection. Seventy-two Lewis rats were enrolled into 3 groups: 20%PVL + 70%PHx; 70%PVL + 20%PHx; 90%PVL. Animals were observed for 1, 2, 3 and 7 days postoperatively (n = 6/time point). Liver enzymes, caudate liver/body-weight-ratio, BrdU-proliferation-index (PI), proliferating-cell-nuclear-antigen (PCNA)-mRNA-expression level and autophagy-related-proteins were evaluated. Compared with 90% PVL, additional PHx induced significantly more hypertrophy during the observation time, which was confirmed by significantly higher PI and higher level of PCNA-mRNA expression. Similarly, the additional PHx induced more autophagy in the FLR compared with PVL alone. However, both effects were not clearly related to the extent of additional resection. Additional resection augmented liver regeneration and autophagy substantially compared with PVL alone. Therefore, we concluded that autophagy might play a critical role in regulating hepatocyte proliferation and the size of the FLR after simultaneous PVL + PHx.

• Liver
• animal model
• liver cirrhosis
• liver regeneration
• portal vein ligation
• rat model
• two stage

Laparoscopic resection of giant hepatoblastoma (HB) in children has long been a subject of controversy. Here, a new procedure of two-stage laparoscopic resection of giant HB in infants was firstly reported and the feasibility was discussed.

The clinical data of three infants with HB were retrospectively reviewed, all of which received 3–5 cycles of neoadjuvant chemotherapy. Stage 1 laparoscopic selective hepatic artery ligation and liver partial partition were performed. Stage 2 laparoscopic hepatectomy was performed 2 weeks later.

The results demonstrated that (1) the tumors shrank considerably in size and had relatively clear boundaries after neoadjuvant chemotherapy; (2) after stage 1 surgery, the tumor volume further reduced, while the intratumoral necrosis expanded; (3) 2 weeks later, stage 2 laparoscopic hepatectomy was performed successfully; (4) none of the cases had intraoperative complications such as tumor rupture, air embolism, hemorrhage, biliary fistula, or liver failure, and there was no recurrence or metastasis during follow-up.

Two-stage laparoscopic hepatectomy associating selective hepatic artery ligation and liver partial partition for HB in infants has the benefits of small invasiveness, fast recovery, improved safety, and high feasibility. However, more cases and longer follow-up are needed to assess its long-term efficacy.

• Hepatoblastoma
• Infant
• Laparoscopy
• Staged surgery

The role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for hepatocellular carcinoma (HCC) remains controversial.

The records of 23 consecutive patients with hepatitis B virus (HBV)-related HCC who underwent ALPPS at our center between November 2013 and June 2018 were retrospectively reviewed. Oncological results were compared between patients who received ALPPS and those that received transarterial chemoembolization (TACE) using propensity score matching (PSM) analysis.

In patients with a single tumor (n=12) the median tumor diameter was 13.0 (range: 5.1–20.0) cm, whereas in patients with multiple tumors (n=11) the median total tumor diameter was 6.3 (range: 2.3–26.0) cm. After the stage-1 ALPPS, the median future liver remnant (FLR) increased by 50.0%. The stage-2 ALPPS was completed in 20 patients (87.0%) after a median of 12 days. The 90-day mortality rate was 13% (3/23). The overall survival (OS) rates at 1-, 2-, and 5-year were 61.1%, 34.9%, and 8.7%, respectively, whereas the disease-free survival (DFS) rates at 1-, 2-, and 5-year were 27.8%, 27.8%, and 0.0%, respectively. PSM analysis showed no difference in OS between patients who underwent ALPPS and those that received TACE [P=0.178, Barcelona Clinic Liver Cancer (BCLC) stage A–C patients; P=0.241, BCLC stage B and C patients].

ALPPS is a safe and effective treatment option for unresectable HBV-related HCC. However, for HBV-related intermediate and advanced HCC patients, ALPPS may not be superior to TACE.

• Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)
• hepatocellular carcinoma (HCC)
• propensity score matching (PSM)
• transarterial chemoembolization (TACE)

• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/surgery
• Hepatectomy/methods
• Humans
• Ligation/methods
• Liver/surgery
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Portal Vein/surgery
• Treatment Outcome

• Animals
• Cell Proliferation
• Disease Models, Animal
• Hepatectomy/methods
• Hepatectomy/mortality
• Inflammation/pathology
• Ligation
• Liver/blood supply
• Liver/pathology
• Liver/surgery
• Liver Neoplasms/blood supply
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Liver Regeneration
• Liver Transplantation
• Male
• Portal Vein/surgery
• Rats
• Rats, Sprague-Dawley
• Survival Rate
• Treatment Outcome

• GDXZ2019004 Hepatobiliary Research Foundation of Henan Digestive Disease Association, China
• SBGJ2018023 The research study was supported by the Medical Science and Technology Program of Henan, China

• Future liver remnant
• Major hepatectomy
• Portal vein embolization
• Post-hepatectomy liver failure

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3β were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3β expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3β could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

• ALPPS
• JAK2/STAT3 pathway
• Reg3α
• Reg3β
• liver hypertrophy

• transcriptomics
• hepatic portal vein
• translational research

• Animals
• Cell Cycle/genetics
• DNA Repair/genetics
• DNA Replication/genetics
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Ontology
• Hepatectomy/methods
• Hepatocytes/metabolism
• Ligation/methods
• Liver Regeneration/genetics
• Male
• Models, Biological
• Portal Vein/surgery
• Postoperative Period
• Rats
• Rats, Sprague-Dawley
• Sequence Analysis, RNA
• Transcriptome

• King Faisal Specialist Hospital and Research Centre (King Faisal Specialist Hospital)

Portal vein ligation (PVL) induces liver growth prior to resection. Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. This study aims at clarifying the crosstalk of hepatocytes (HC), hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) in accelerated liver growth. In vivo, liver volume, HC proliferation, vascular density and HSC activation were assessed in PVL, ALPPS, PVL+DMOG and DMOG alone. Proliferation of HC, HSC and LSEC was determined under DMOG in vitro. Conditioned media experiments of DMOG-exposed cells were performed. ALPPS and PVL+DMOG accelerated liver growth and HC proliferation in comparison to PVL. DMOG alone did not induce HC proliferation, but led to increased vascular density, which was also observed in ALPPS and PVL+DMOG. Activated HSC were detected in ALPPS, PVL+DMOG and DMOG, again not in PVL. In vitro, DMOG had no proliferative effect on HC, but conditioned supernatant of DMOG-treated HSC induced VEGF-dependent proliferation of LSEC. Transcriptome analysis confirmed activation of proangiogenic factors in hypoxic HSC. Hypoxia signaling in HSC induces VEGF-dependent angiogenesis. HSC play a crucial role in the cellular crosstalk of rapid liver regeneration.

Supplemental Digital Content is available in the text.

Graft recipient weight ratios are lower in adult-to-adult living-donor liver transplantation than in adult-to-adult deceased-donor liver transplantation. Rapid liver regeneration is essential for increased recipient survival rates in adult-to-adult living-donor liver transplantation. However, the influence of biliary reconstruction methods, including choledocho-choledochostomy and choledocho-jejunostomy, on small partial liver grafts remains unknown. Herein, we investigate the impact of these biliary reconstruction methods on small partial liver grafts.

• ALPPS
• cirrhosis
• hepatocellular carcinoma (HCC)
• portal vein embolization (PVE)
• tourniquet-ALPPS

• P30 CA008748 NCI NIH HHS

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in a rat model of liver cirrhosis has not, to the best of our knowledge, been previously investigated. The present study therefore aimed to establish a model of ALPPS in cirrhotic rats and to assess liver regeneration. Rats were randomly divided into an ALPPS group with carbon tetrachloride-induced cirrhosis (group A) and a normal liver (group B). Rat weight, cytokine levels, biochemical parameters and histopathology were assessed 1, 2, 3, 7 and 14 days after ALPPS. Higher aspartate aminotransferase and alanine aminotransferase levels were detected in group A on the first postoperative day. On the first, second and third days, hepatocyte proliferation rate was higher in group B than in group A. After 3 days, hepatocyte proliferation rate in group B began to decrease, but the rate in group A continued to increase until the 14th day. Higher levels of hepatocyte growth factor, interleukin-6 and tumor necrosis factor-α were detected in group A compared with group B, but the differences were not significant. The present study demonstrated that ALPPS promoted liver regeneration in a rat model of cirrhosis, but significantly impaired liver function. Compared with the ALPPS model, group B exhibited a delayed peak of proliferation. The mechanism of liver regeneration induced by ALPPS in cirrhotic rats may be associated with increased cytokine levels.

• Ki-67
• associating liver partition and portal vein ligation for staged hepatectomy
• cirrhosis
• cytokines
• liver regeneration

To avoid liver insufficiency following major hepatic resection, portal vein embolisation (PVE) is used to induce liver hypertrophy pre-operatively. Associating liver partition with portal vein ligation for staged hepatectomy assisted with radiofrequency (RALPPS) was introduced as an alternative method. A randomized controlled trial comparing PVE with RALPPS for the pre-operative manipulation of liver volume in patients with a future liver remnant volume (FLRV) ≤25% (or ≤35% if receiving preoperative chemotherapy) was conducted. The primary endpoint was increase in size of the FLRV. The secondary endpoints were length of time taken for the volume gain, morbidity, operation length and post-operative liver function. Between July 2015 and October 2017, 57 patients were randomised to RALPPS (n = 29) and PVE (n = 28). The mean percentage of increase in the FLRV was 80.7 ± 13.7% after a median 20 days following RALPPS compared to 18.4 ± 9.8% after 35 days (p < 0.001) following PVE. Twenty-four patients after RALPPS and 21 after PVE underwent stage-2 operation. Final resection was achieved in 92.3% and 66.6% patients in RALPPS and PVE, respectively (p = 0.007). There was no difference in morbidity, and one 30-day mortality after RALPPS (p = 0.991) was reported. RALPPS is more effective than PVE in increasing FLRV and the number of patients for surgical resection.

• ALPPS
• ALPPS-RF
• RALPPS
• hepatic resection
• portal vein embolisation
• portal vein ligation

• ALPPS
• Hepatocyte proliferation
• Kupffer cells
• Liver regeneration
• NAFLD

• Alanine Transaminase/blood
• Animals
• Aspartate Aminotransferases/blood
• Cholesterol/blood
• Diet, High-Fat
• Hepatectomy/methods
• Hepatocyte Growth Factor/blood
• Interleukin-6/blood
• Ligation
• Liver/pathology
• Liver Neoplasms/surgery
• Liver Regeneration
• Male
• Non-alcoholic Fatty Liver Disease/pathology
• Organ Size
• Portal Vein/surgery
• Postoperative Period
• Rats
• Rats, Sprague-Dawley
• Triglycerides/blood
• Tumor Necrosis Factor-alpha/blood

• Hepatectomy
• Humans
• Laparoscopy
• Ligation
• Liver Neoplasms/surgery
• Portal Vein/surgery

• Compensatory hypertrophy
• Future liver remnant
• Hedgehog
• JNK1
• Small-for-size syndrome

• AMP-Activated Protein Kinases/metabolism
• Aged
• Cell Cycle Proteins/metabolism
• Cell Proliferation
• Cytokines/metabolism
• Enzyme Activation
• Female
• Hepatectomy/adverse effects
• Hepatectomy/methods
• Hepatocytes/enzymology
• Hepatocytes/pathology
• Humans
• Ligation
• Liver/blood supply
• Liver/diagnostic imaging
• Liver/enzymology
• Liver/surgery
• Liver Circulation
• Liver Regeneration
• Male
• Middle Aged
• Portal Vein/physiopathology
• Portal Vein/surgery
• Prospective Studies
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome

• Associating liver partition and portal vein ligation for staged hepatectomy
• Colorectal liver metastases
• Future liver remnant
• Liver regeneration
• Portal vein occlusion

• ligature de la veine porte
• liver regeneration
• microarray
• microréseau
• modèle chez le rat
• portal vein ligation
• rat model
• régénération du foie

• Associating liver partition with portal vein ligation for staged hepatectomy
• Liver regeneration
• Liver transection
• Portal vein embolization
• Portal vein ligation

• Animals
• Cell Proliferation
• Cytokines/metabolism
• Embolization, Therapeutic
• Hepatectomy/methods
• Hepatocytes/cytology
• Humans
• Ligation
• Liver/physiology
• Liver/surgery
• Liver Neoplasms/pathology
• Liver Regeneration
• Liver Transplantation/methods
• Mice
• Portal Vein/pathology
• Portal Vein/surgery
• Regeneration
• Vascular Surgical Procedures