Portal Vein Ligation Group Research Articles

Bile Acid Overload Induced by Bile Duct and Portal Vein Ligation Improves Survival after Staged Hepatectomy in Rats.

Compared to portal vein ligation (PVL), simultaneous bile duct and portal vein ligation (BPL) can significantly enhance hypertrophy of the intact liver. This study aimed to investigate whether BPL could improve survival after extended hepatectomy independently of an increased remnant liver. We adopted rat models of 90% BPL or 90% PVL. To investigate the role of bile acids (BAs) the BA pools in the PVL and BPL groups were altered by the diet. Staged resection preserving 10% of the estimated liver weight was performed 3 days after BPL; PVL; or sham operation. Histology, canalicular network (CN) continuity; and hepatocyte polarity were evaluated. At 3 days after BPL; PVL; or sham operation when the volumetric difference of the intended liver remained insignificant, the survival rates after extended hepatectomy were 86.7%, 47%, and 23.3%, respectively (P<0.01). BPL induced faster restoration of canalicular integrity along with an intensive but transient BA overload. Staged hepatectomy after BPL shortened the duration of the bile CN disturbance and limited BA retention. Decreasing the BA pools in the rats that underwent BPL could compromise these effects, whereas increasing the BA pools of rats that underwent PVL could induce similar effects. The changes in CN restoration were associated with activation of LKB1. In addition to increasing the future remnant liver, BPL shortened the duration of the spatial disturbance of the CN and could significantly improve the tolerance of the hypertrophied liver to staged resection. BPL may be a safe and efficient future option for patients with an insufficient remnant liver.

Extreme hepatectomy with modified ALPPS in a rat model: gradual portal vein restriction associated with hepatic artery restriction

Background & aimAssociating liver partition and portal vein ligation (PVL) for staged hepatectomy (ALPPS) is a creative strategy for enlarging the future liver remnant (FLR) and increasing the tumor resectability rate. However, the indications for ALPPS must have a certain limit when the FLR is too small. We aimed to establish a modified ALPPS model with more widen applicability in rats.MethodsAn extreme ALPPS model was established in rodents with only a 6.5% FLR. The portal vein (PV) was subjected to restriction to different degrees, then the portal vein pressure (PVP) was measured. Then, different modifications of ALPPS, including hepatic artery restriction (HAR), gradual portal vein restriction (GPVR), and GPVR-associated HAR (HAR+GPVR), were applied in the extreme ALPPS models.ResultsPVL or PVR provoked an immediate increase in the PVP. The PVP in the PVR -1.28 mm, PVR -0.81 mm, PVR -0.63 mm, and PVL groups was 11.05±1.57 cmH2O, 16.18±1.92 cmH2O, 20.66±1.99 cmH2O, and 24.10±3.33 cmH2O, respectively, and the corresponding 3-day survival rate was 100%, 90.09%, 36.33% and 0, respectively. Then, in the extreme ALPPS model, the growth ratio of the FLR in the control, HAR, GPVR, and HAR+GPVR groups was 0.43±0.21, 0.50±0.16, 4.80±0.86, and 7.40±2.56, and as a consequence, the corresponding 30-day survival rate was 9.09%, 15.38%, 84.61% and 92.90%, respectively.ConclusionALPPS itself has a limit, and high PVP after PVL contributes to postoperative death in the extreme ALPPS model. Furthermore, a modified method for extreme ALPPS is proposed, i.e., GPVR+HAR in place of PVL, which significantly improves the survival rate of extreme hepatectomy in rat models.

Impact of endothelial nitric oxide synthase activation on accelerated liver regeneration in a rat ALPPS model

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.

ANTI-TUMORAL EFFECT OF 5-FLUOROURACIL AND OXALIPLATIN IN A LIVER REGENERATION MODEL

Abstract Introduction Colorectal cancer liver metastases (CRCLM) continue to be a therapeutic challenge, since their resectability is usually limited by the functionality of the liver remnant. In this context, it is necessary to study the regenerative response of the liver in a selective portal vein ligation (PVL) model, after the administration of 5-fluorouracil and oxaliplatin, and to assess the effect of compensatory hypertrophy on tumor progression. Methods Twenty-eight WAG/RijHsd rats carrying CRCLM were divided into four groups: control, PVL, 5FU (50mg/kg) and 5FU+Oxaliplatin (50mg/kg+10mg/kg). After 18 days of tumor development, a dose of the corresponding treatment was administered, performing a PVL of 50% 72h later. Seven days later, tumor size was quantified and a biochemical profile was performed. Results The 5FU+Oxaliplatin and 5FU alone treatment decreased tumor growth by 6 and 3 times compared to the PVL and control groups, respectively (p&amp;lt;0.001). At a biochemical level, the combination of drugs resulted in a decrease in albumin levels (3.3 ± 0.39 mg/dl; p&amp;lt;0.02) and a significant weight loss of 10%; however, glucose (152±6.6 mg/dl), AST (161±27.1 IU/L), and ALT (46.7±9.4 IU/L) were not significantly altered. Seven days after PVL, the liver remnant did not change in either group (5FU+Oxaliplatin: 8±1; 5FU: 9.7±1.2; control 9.4±1.9 g; p&amp;gt;0.05). Conclusion In our model, the combined therapy of 5-Fluorouracil and oxaliplatin, prior to PVL, does not affect the necessary hepatic regeneration; while the volume of tumor implants decreases, no significant alteration of the biochemical parameters is detected.

Kupffer cells depletion alters cytokine expression and delays liver regeneration after Radio-frequency-assisted Liver Partition with Portal Vein Ligation

Radio-frequency-assisted Liver Partition with Portal Vein Ligation (RALPP) induces comparable hypertrophy of the liver remnant compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) in humans. However, whether it is significantly improved compared to ALPPS is unclear, and the underlying mechanisms of liver regeneration after RALPP need to further investigate. The present study was to develop an animal model mimicking RALPP and explore mechanisms of liver regeneration. The mice in RALPP group received liver radiofrequency ablation and 90% portal vein ligation (PVL), followed by resection of the targeted liver within two days after the first surgery. The mice in ALPPS group underwent 90% PVL combined with parenchyma transection. Controls received liver radiofrequency ablation (RAF group) or PVL (PVL group) or small left lateral lobe (LLL group) resection alone. Liver regeneration was assessed by liver weight and proliferation-associated molecules. The role of Kupffer cells (KCs) in liver regeneration was investigated after RALPP. The results showed that RALPP induced comparable liver regeneration compared to ALPPS, but with less liver injury and mortality in mice. RALPP led to over-expression of TNF-α and IL-6 in the circulating plasma compared with PVL. KCs infiltrating in liver tissues was a characteristic of mice in the RALPP group. KCs depletion markedly depressed cytokine expression and delayed liver regeneration after RALPP. These results suggested that RALPP in mice induced accelerated liver regeneration similar to ALPPS, but safer than ALPPS. KCs depletion altered cytokine expression and delayed liver regeneration after RALPP.

Intraoperative Indocyanine Green Retention Test of Left Hemiliver in Decision-Making for Patients With Hepatocellular Carcinoma Undergoing Right Hepatectomy

Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF).Methods: Twenty HCC patients who were preoperatively planned to undergo RH were enrolled. Intraoperative ICG-R15 of left hemiliver was measured after the right Glissonean pedicle was completely blocked. Patients then underwent RH if intraoperative ICG-R15 was ≤ 10%. Otherwise, patients underwent staged RH (SRH), either associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) or portal vein ligation (PVL), followed by stage-2 RH. The comparison group consisted of patients with a ratio of standard left liver volume (SLLV) of > 40% and preoperative ICG-R15 ≤ 10% who underwent RH. The clinical outcomes of these two groups were compared.Results: Of the 20 patients, six underwent stage-1 RH, six underwent ALPPS, five underwent PVL followed by stage-2 RH, and three failed to proceed to stage-2 RH after PVL. No significant differences were found among the 17 patients who underwent stage-1 or stage-2 RH in the study group, the 19 patients in the comparison group, the 11 patients in the stage-2 RH group, and the six patients in the stage-1 RH group in incidences of PHLF, postoperative complications, hospital stay, and HCC recurrence within 1 year after RH. Compared with the stage-1 ALPPS group, the mean operative time and blood loss of the stage-1 PVL group were significantly less (p <0.001 and p = 0.022, respectively). The stage-1 PVL group had a significantly longer waiting-time (43.4 vs. 14.0 days, p = 0.016) than the stage-1 ALPPS group to proceed to stage-2 RH. After stage-2 RH, tumor recurrence within 1 year was 20% (1/5) in patients after PVL and 50% (3/6) after stage-1 ALPPS.Conclusions: Intraoperative ICG-R15 ≤ 10% of left hemiliver was valuable in intraoperative decision-making for patients who were planned to undergo RH. There is a possibility that stage-1 PVL might help to select patients with more favorable biological behavior to undergo stage-2 RH.

Changes of Endocan and its effect on hepatic stem cells during the rapid proliferation process of residual liver after ALPPS procedure.

To establish a stable animal model of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), as well as to explore whether Endocan and HGF/c-Met signalling pathway participate in the regeneration of residual liver through hepatic stem cells after ALPPS procedure. C57BL/6J male mice weighing 18-22 g were used in this study. The liver regeneration index was expressed as the ratio of Future Liver Remnant (FLR)/Body weight (BW) × 100%. Expression of hepatic stem cell marker CK19 was assessed by immunohistochemical method. Serum levels of vascular endothelial growth factor (VEGF) and Endocan were detected by ELISA. VEGF, Endocan and c-Met contents in residual liver were observed by Western blot analysis. The expression levels of Endocan and HGF/c-Met pathway-related genes were evaluated by qRT-PCR. Compared with the portal vein ligation (PVL) group and sham group, the ALPPS group had more CK19 positive cells and a higher liver regeneration index (P < .05). The serum levels of VEGF in the ALPPS group were increased significantly (P < .05) from the first day and decreased from the second day after surgery, and maintained consistently higher than that of the sham group (P < .05). Western blot showed that the expressions of VEGF and Endocan in ALPPS group were significantly higher than those in both sham and PVL groups at different time points. The Endocan plays a role in the rapid regeneration of residual liver after ALPPS, likely through the interaction with the HGF/c-Met pathway to affect the hepatic stem cell population. SIGNIFICANCE OF THE STUDY: Our animal study provides valuable insights on the effect of Endocan in the process of rapid regeneration of residual liver after ALPPS, which would lead to the possible expansion of clinical research on ALPPS surgery and further studies on its molecular underpinning during liver regeneration.

Reg3α and Reg3β Expressions Followed by JAK2/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model.

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.

Effect of Portal Vein Ligation Plus Venous Congestion on Liver Regeneration in Rats

Introduction and aim. We developed a rat model of portal vein ligation (PVL) with venous congestion (PVL+C) to investigate beneficial effect PVL plus congestion for regeneration of intact liver segments.Materials and methods. In the PVL group, portal vein branches were ligated except the caudate lobe (CL). In the PVL + C group, the left lateral hepatic vein was ligated in addition to PVL. Chronological changes in the following variables were compared among the groups: CL weight to body weight ratio (CL/BW), embolized liver weight to body weight ratio (EL/BW), histological findings of the embolized/non-embolized liver, and expression of several mediators that affect liver regeneration in the non-embolized liver.Results. Weight regeneration of CL continued up to postoperative day (POD)7 in PVL + C, but terminated at POD2 in PVL. CL/BW at POD7 was significantly higher in PVL + C than in PVL (2.41 ± 0.33% vs. 1.22 ± 0.18%, P < 0.01). In contrast, EL/BW continued to decrease up to POD7 in PVL + C but reached nadir at POD2 in PVL. Furthermore, EL/BW at POD7 was significantly smaller in PVL + C than in PVL (0.35 ± 0.03% vs. 0.67 ± 0.08%, P < 0.01). Histologically-proven injury in the embolized liver was more severe in PVL + C than in PVL. Expression of Ki-67, IL-6, TNF -a, and HGF were greater and/or more prolonged in PVL + C than in PVL.Conclusions. Our rat model of PVL + C was considered useful for investigating the beneficial effect of congestion in addition to PVC. PVL + C caused increased devastation of the embolized liver, and higher and more prolonged expression of factors promoting liver regeneration in the non-embolized liver than in PVL.

ALPPS "Associating Liver Partition with Portal vein ligation for Staged Hepatectomy" (ALPPS) does not promote colorectal tumor growth

Background: The effect of ALPPS on tumor proliferation, remains a concern. This study investigated the impact of ALPPS on growth of colorectal metastases in mice and human. Methods: The effect of ALPPS and 90% portal vein ligation (PVL) on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging (MRI), histology and survival experiments. The effects of ALPPS, PVL and control sera on colorectal cancer cells (MC38 and CT26) were tested in vitro. Additionally, the international ALPPS registry enabled to identify patients with remaining tumor in the future liver remnant (FLR) after ALPPS stage 1. Results: Two and three weeks after ALPPS stage 1, PVL or sham surgery, liver MRI showed similar intrahepatic tumor numbers ((p=0.14/0.82), sizes (p=0.45/0.98) and growth kinetics (p=0.58/0.68). Tumor growth was not different between ALPPS and PVL groups after completion of stage 2. Survival after tumor cell injection was similar after sham surgery and completion of ALPPS and PVL (36 days (IQR 32-40) vs. 42 days (IQR 36-48) vs. 39 days (IQR 35-42), p=0.237). Pulmonary metastases progression and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify accelerated tumor growth in the FLR within the regenerative phase after ALPPS stage 1. Conclusion: The accelerated regeneration process associated to ALPPS does not enhance the growth of residual colorectal liver metastases.

A new technique for accelerated liver regeneration. an experimental study in rats.

Background Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to accelerate growth of the future liver remnant. We investigated alternative methods for increasing the future liver remnant. Methods A total of 152 rats were randomized as follows: (1) sham; (2) portal vein ligation; (3) portal vein ligation/surgical split (ALPPS); (4) portal vein ligation/split of the liver with a radiofrequency ablation needle; (5) portal vein ligation/radiofrequency ablation of the deportalized liver (portal vein ligation/radiofrequency ablation necrosis in the deportalized liver); (6) portal vein ligation/radiofrequency ablation of the future liver remnant (portal vein ligation/radiofrequency ablation–future liver remnant); and (7) controls. Animals were evaluated on postoperative days 2 and 4. Bodyweight, liver parameters, hepatic regeneration rate, proinflammatory cytokines, hepatocyte proliferation, and gene expression were measured. Results Hepatic regeneration rate indicated a steady increase in all intervention groups compared with sham rats ( P P = .039). On postoperative day 4, we found significant differences between the portal vein ligation group and the ALPPS ( P = .015), portal vein ligation/split of the liver with a radiofrequency ablation needle ( P = .010), and portal vein ligation/radiofrequency ablation necrosis in the deportalized liver ( P = .046) groups. Hepatocyte proliferation was significantly higher at all times compared with sham rats. On postoperative day 4, we found a significantly higher proliferation in groups 3, 4, 5, and 6 compared to portal vein ligation. Gene analysis revealed upregulation of genes involved in cellular proliferation and downregulation of genes involved in cellular homeostasis in all intervention groups. Between the intervention groups, gene expression was nearly identical. Biochemical markers and proinflammatory cytokines were comparable between groups. Conclusion The surplus liver regeneration after ALPPS is probably mediated through parenchymal damage and subsequent release of growth stimulators, which again upregulates genes involved in cellular regeneration and downregulates genes involved in cellular homeostasis. We also demonstrate that growth of the future liver remnant, comparable to that seen after ALPPS, could be achieved by radiofrequency ablation treatment of the deportalized liver, that is, a procedure in which the initial step in humans can be performed percutaneously.

Analyses of mitochondrial biogenesis and function after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)

Background: ALPPS is a novel 2-staged surgical procedure for liver tumors, which induces an unprecedented degree of liver regeneration. Despite the ALPPS induced accelerated regeneration, the postoperative mortality is relatively high, duo to the frequently occurring postinterventional liver failure. Our goal was to assess the background of this increased vulnerability via examination of mitochondrial biogenesis and function after ALPPS. Methods: Male Wistar rats (n=100) underwent ALPPS or portal vein ligation (PVL). The animals were sacrificed before (0) and 24-48-72-168h after the operations and the regeneration rate was calculated. Mitochondrial respiration and ATP production were determined, as well as peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), Nuclear respiratory factor 1– and 2 (NRF1, NRF2) expression and mitochondrial morphology were assessed. Results: After 48h in the ALPPS group the regeneration ratio was significantly higher, while mitochondrial respiration and ATP production decreased significantly compared to the PVL group. The PGC1α and NRF1 concentration was significantly decreased after 48h in the ALPPS group (p=0,004, p<0,001 vs. PVL, respectively), while the NRF2 concentration showed no significant differences. The ratio of smaller than 0,24μm2 mitochondria elevated significantly in the ALPPS group compared to the PVL group (p=0,023). Conclusion: According to our Results ALPPS causes major failures in mitochondrial biogenesis and function.

NAFLD Induction Delays Postoperative Liver Regeneration of ALPPS in Rats.

Associating liver partition and portal vein ligation (ALPPS) is a promising two-step hepatectomy that is beneficial for accumulative regeneration of the future liver remnant (FLR) and avoids postoperative liver failure. Our study aimed to evaluate whether nonalcoholic fatty liver disease affected the liver regeneration induced by ALPPS. Sprague-Dawley rats fed a high-fat diet were used to construct the NAFLD model. ALPPS were performed, and blood and future liver remnant samples were collected at postoperative days 1 (POD1), POD3, and POD7. The hepatic regeneration rate (HRR) of ALPPS was higher than that of portal vein ligation (PVL) at POD3 and POD7 (p < 0.05), and the number of Ki-67-positive hepatocytes (POD3) and CD68-positive Kupffer cells (POD7) per visual field was higher in the ALPPS group than in the PVL group (p < 0.05). The serum TNF-α, hepatocyte growth factor protein, and the serum IL-6 level were higher in the ALPPS group than in the PVL group at POD3 and POD7. Compared with those of the standard laboratory diet (SLD)-fed rats, the rats with NAFLD exhibited a decrease in the HRR, Ki-67-positive hepatocytes, and CD68-positive Kupffer cells in the FLR. The number of CD68-positive Kupffer cells was lower in rats with NAFLD than that in SLD-fed rats; noteworthily, the serum level of IL-6 and TNF-α changed dramatically after surgeries. NAFLD induction delayed liver regeneration induced by the ALPPS procedure, which might be associated with hepatocyte proliferation and the number of Kupffer cells.

Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy to induce rapid regeneration of the remnant liver. The technique has been associated with high mortality and morbidity rates. This study aimed to evaluate mitochondrial function, biogenesis and morphology during ALPPS-induced liver regeneration. Male Wistar rats (n = 100) underwent portal vein ligation (PVL) or ALPPS. The animals were killed at 0 h (without operation), and 24, 48, 72 or 168 h after intervention. Regeneration rate and proliferation index were assessed. Mitochondrial oxygen consumption and adenosine 5'-triphosphate (ATP) production were measured. Mitochondrial biogenesis was evaluated by protein level measurements of peroxisome proliferator-activated receptor γ co-activator (PGC) 1-α, nuclear respiratory factor (NRF) 1 and 2, and mitochondrial transcription factor α. Mitochondrial morphology was evaluated by electron microscopy. Regeneration rate and Ki-67 index were significantly raised in the ALPPS group compared with the PVL group (regeneration rate at 168 h: mean(s.d.) 291·2(21·4) versus 245·1(13·8) per cent, P < 0·001; Ki-67 index at 24 h: 86·9(4·6) versus 66·2(4·9) per cent, P < 0·001). In the ALPPS group, mitochondrial function was impaired 48 h after the intervention compared with that in the PVL group (induced ATP production); (complex I: 361·9(72·3) versus 629·7(165·8) nmol per min per mg, P =0·038; complex II: 517·5(48·8) versus 794·8(170·4) nmol per min per mg, P =0·044). Markers of mitochondrial biogenesis were significantly lower 48 and 72 h after ALPPS compared with PVL (PGC1-α at 48 h: 0·61-fold decrease, P =0·045; NRF1 at 48 h: 0·48-fold decrease, P =0·028). Mitochondrial size decreased significantly after ALPPS (0·26(0·05) versus 0·40(0·07) μm2 ; P =0·034). Impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS. Surgical relevance Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a well known surgical strategy that combines liver partition and portal vein ligation. This method induces immense regeneration in the future liver remnant. The rapid volume increase is of benefit for resectability, but the mortality and morbidity rates of ALPPS are strikingly high. Moreover, lagging functional recovery of the remnant liver has been reported recently. In this translational study, ALPPS caused an overwhelming inflammatory response that interfered with the peroxisome proliferator-activated receptor γ co-activator 1-α-coordinated, stress-induced, mitochondrial biogenesis pathway. This resulted in the accumulation of immature and malfunctioning mitochondria in hepatocytes during the early phase of liver regeneration (bioenergetic destabilization). These findings might explain some of the high morbidity if confirmed in patients.

Effect of Portal Vein Ligation Plus Venous Congestion on Liver Regeneration in Rats

Introduction and aim. We developed a rat model of portal vein ligation (PVL) with venous congestion (PVL+C) to investigate beneficial effect PVL plus congestion for regeneration of intact liver segments. Materials and methods. In the PVL group, portal vein branches were ligated except the caudate lobe (CL). In the PVL + C group, the left lateral hepatic vein was ligated in addition to PVL. Chronological changes in the following variables were compared among the groups: CL weight to body weight ratio (CL/BW), embolized liver weight to body weight ratio (EL/BW), histological findings of the embolized/non-embolized liver, and expression of several mediators that affect liver regeneration in the non-embolized liver. Results. Weight regeneration of CL continued up to postoperative day (POD)7 in PVL + C, but terminated at POD2 in PVL. CL/BW at POD7 was significantly higher in PVL + C than in PVL (2.41 ± 0.33% vs. 1.22 ± 0.18%, P &lt; 0.01). In contrast, EL/BW continued to decrease up to POD7 in PVL + C but reached nadir at POD2 in PVL. Furthermore, EL/BW at POD7 was significantly smaller in PVL + C than in PVL (0.35 ± 0.03% vs. 0.67 ± 0.08%, P &lt; 0.01). Histologically-proven injury in the embolized liver was more severe in PVL + C than in PVL. Expression of Ki-67, IL-6, TNF-α, and HGF were greater and/or more prolonged in PVL + C than in PVL. Conclusions. Our rat model of PVL + C was considered useful for investigating the beneficial effect of congestion in addition to PVC. PVL + C caused increased devastation of the embolized liver, and higher and more prolonged expression of factors promoting liver regeneration in the non-embolized liver tan in PVL.

Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases

BackgroundAssociating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. MethodsThe effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. ResultsTwo and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers (P = .14/0.82), sizes (P = .45/0.98), and growth kinetics (P = .58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27–57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35–49 days), and portal vein ligation (39 days; 95% confidence interval; 34–43 days, P = .237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups.Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. ConclusionThe accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases.

Assessment of liver regeneration after associating liver partition and portal vein ligation for staged hepatectomy: a comparative study with portal vein ligation

BackgroundTo investigate the diagnostic value of diffusion kurtosis imaging (DKI) and diffusion-weighted imaging (DWI) in assessing liver regeneration after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) compared with portal vein ligation (PVL). MethodsThirty rats were divided into the ALPPS, PVL, and control groups. DKI and DWI were performed before and 7 days after surgery. Corrected apparent diffusion (D), kurtosis (K) and apparent diffusion coefficient (ADC) were calculated and compared, radiologic–pathologic correlations were evaluated. ResultsThe volume of the right median lobe increased significantly after ALPPS. There were larger cellular diameters after ALPPS and PVL (P = 0.0003). The proliferative indexes of Ki-67 and hepatocyte growth factor were higher after ALPPS (P = 0.0024/0.0433). D, K and ADC values differed between the groups (P = 0.021/0.0015/0.0008). A significant correlation existed between D and the hepatocyte size (r = −0.523), no correlations existed in ADC and K (P = 0.159/0.111). The proliferative indexes showed moderate negative correlations with ADC (r = −0.484/−0.537) and no correlations with D and K (P = 0.100–0.877). DiscussionLiver regeneration after ALPPS was effective and superior to PVL. DKI, especially the D map, may provide added value in evaluating the microstructure of liver regeneration after ALPPS, but this model alone may perform no better than the standard monoexponential model of DWI.

Histogram analyses of diffusion kurtosis indices and apparent diffusion coefficient in assessing liver regeneration after ALPPS and a comparative study with portal vein ligation

To investigate the value of diffusion kurtosis imaging (DKI) histogram analysis in assessing liver regeneration and the microstructure basis after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), in comparison with portal vein ligation (PVL). Thirty rats were divided into the ALPPS, PVL, and control groups. Histograms of DKI using a 3T magnetic resonance imaging (MRI) scanner were performed for corrected apparent diffusion (D), kurtosis (K), and apparent diffusion coefficient (ADC). Mean, median, skewness, kurtosis, and the percentiles (5th , 25th , 50th , 75th , and 95th ) were generated and compared, and radiologic-pathologic correlations were evaluated. There were more significant volume increases of the right median lobe after ALPPS than PVL (P = 0.0304/0.0017). The ALPPS group had larger hepatocyte size (P = 0.009/0.000), higher Ki-67 and hepatocyte growth factor expression (P = 0.001-0.036) compared with both PVL and control groups. Mean, median, 5th , 25th , 50th , 75th percentiles of D map in ALPPS were lower than the control group (P = 0.001-0.022). Skewness and 75th , 95th percentiles of K map in ALPPS were higher than the PVL group (P = 0.011-0.042). No differences existed in the ADC map between groups (P = 0.073-0.291). Mean, median, 5th , 25th , 50th percentiles of D map, and 5th percentile of K map showed significant correlations with hepatocyte size (r = -0.582 to -0.426); no significant correlations were found in ADC parameters (P = 0.460-0.934). ALPPS induced true accelerated liver hypertrophy, superior to that seen with PVL. Histogram analysis of diffusion kurtosis indices may provide added values in evaluating liver regeneration and the intrinsic microstructure basis after ALPPS in comparison with the standard monoexponential ADC. 3 Technical Efficacy Stage: Stage 2 J. Magn. Reson. Imaging 2018;47:729-736.

A new technique for accelerated liver regeneration: An experimental study in rats

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to accelerate growth of the future liver remnant. We investigated alternative methods for increasing the future liver remnant. A total of 152 rats were randomized as follows: (1) sham; (2) portal vein ligation; (3) portal vein ligation/surgical split (ALPPS); (4) portal vein ligation/split of the liver with a radiofrequency ablation needle; (5) portal vein ligation/radiofrequency ablation of the deportalized liver (portal vein ligation/radiofrequency ablation necrosis in the deportalized liver); (6) portal vein ligation/radiofrequency ablation of the future liver remnant (portal vein ligation/radiofrequency ablation-future liver remnant); and (7) controls. Animals were evaluated on postoperative days 2 and 4. Bodyweight, liver parameters, hepatic regeneration rate, proinflammatory cytokines, hepatocyte proliferation, and gene expression were measured. Hepatic regeneration rate indicated a steady increase in all intervention groups compared with sham rats (P<.001). At postoperative day 2, the hepatic regeneration rate was significantly higher in the portal vein ligation/radiofrequency ablation necrosis in the deportalized liver group than in the portal vein ligation group (P=.039). On postoperative day 4, we found significant differences between the portal vein ligation group and the ALPPS (P=.015), portal vein ligation/split of the liver with a radiofrequency ablation needle (P=.010), and portal vein ligation/radiofrequency ablation necrosis in the deportalized liver (P=.046) groups. Hepatocyte proliferation was significantly higher at all times compared with sham rats. On postoperative day 4, we found a significantly higher proliferation in groups 3, 4, 5, and 6 compared to portal vein ligation. Gene analysis revealed upregulation of genes involved in cellular proliferation and downregulation of genes involved in cellular homeostasis in all intervention groups. Between the intervention groups, gene expression was nearly identical. Biochemical markers and proinflammatory cytokines were comparable between groups. The surplus liver regeneration after ALPPS is probably mediated through parenchymal damage and subsequent release of growth stimulators, which again upregulates genes involved in cellular regeneration and downregulates genes involved in cellular homeostasis. We also demonstrate that growth of the future liver remnant, comparable to that seen after ALPPS, could be achieved by radiofrequency ablation treatment of the deportalized liver, that is, a procedure in which the initial step in humans can be performed percutaneously.

Portal vein embolization and ligation induced liver regeneration in rats with hepatic fibrosis

Objective To investigate the portal vein embolization (PVE) and portal vein ligation (PVL) in liver regeneration of rats with hepatic fibrosis . Methods Fifty rats with liver fibrosis were prepared, including 10 rats were randomly chosen as pre-operative control group. The other 40 rats were divided into two groups: PVE group (A1, n=20) and PVL group (A2, n=20). We chose to embolize and ligate the right portal vein, respectively. The blood samples were obtained at different end points for measuring ALT and AST levels. Each liver lobes and whole liver were weighed, and non-embolized liver lobe/whole liver weight ratio, non-ligated liver lobe/whole liver weight were caculated at different end points. The samples from liver with/without embolization or ligation were were stained with hematoxylin-eosin, and the changes of microstructure of liver were observed. Immunostained for PCNA and Ki-67 were performed. Results Transient elevation of postoperative ALT and AST levels were noted in each group. Serum ALT and AST reached the peak on the first day in both of PVE and PVL groups [ALT, A1(66.5±6.3) U/L vs(491.5±48.0) U/L, A2 group(62.8±5.7) U/L vs(433.7±41.0) U/L; AST, A1group (113.4±12.5) U/L vs(685.2±65.7) U/L, A2 group (110.4±11.1) U/L vs(623.9±75.2) U/L, P 0.05). The weight percentage of non-embolized and non-ligated liver lobes/whole liver after PVE and PVL increased. There was no significant difference between the first day and pre-operative levels (P>0.05) . Nevertheless, there were significant differences observed from the third, seventh, fourteenth days (A1 group, 50.2±5.0, 57.7±5.7, 61.8±6.6; A2group, 49.6±3.5, 55.7±6.9, 63.0±5.1, respectively)compared with pre-operative groups (A1 group, 34.4±4.0; A2 group, 34.4±4.0) (P 0.05). The PCNA and Ki-67 were positive in hepatocytes and increased after operation, reached the peak in the third day (P 0.05). Conclusions Fibrosis rats had the ability of regeneration in the contralateral part of the liver after selective PVE and PVL and there was no significant difference on the proliferative degree. Therefore, the safety and reliability of PVE and PVL in inducing liver regeneration in rats with liver fibrosis were confirmed. Key words: Portal vein embolization; Portal vein ligation; Fibrosis; Liver regeneration