Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration.

BACKGROUND & AIMS: Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy. METHODS: Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data. RESULTS: Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF. CONCLUSIONS: The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF. IMPACT AND IMPLICATIONS: In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.

Comprehensive Review of Future Liver Remnant (FLR) Assessment and Hypertrophy Techniques Before Major Hepatectomy: How to Assess and Manage the FLR.

BACKGROUND: The regenerative capacities of the liver and improvements in surgical techniques have expanded the possibilities of resectability. Liver resection is often the only curative treatment for primary and secondary malignancies, despite the risk of post-hepatectomy liver failure (PHLF). This serious complication (with a 50% mortality rate) can be avoided by better assessment of liver volume and function of the future liver remnant (FLR). OBJECTIVE: The aim of this review was to understand and assess clinical, biological, and imaging predictors of PHLF risk, as well as the various hypertrophy techniques, to achieve an adequate FLR before hepatectomy. METHOD: We reviewed the state of the art in liver regeneration and FLR hypertrophy techniques. RESULTS: The use of new biological scores (such as the aspartate aminotransferase/platelet ratio index + albumin-bilirubin [APRI+ALBI] score), concurrent utilization of 99mTc-mebrofenin scintigraphy (HBS), or dynamic hepatocyte contrast-enhanced MRI (DHCE-MRI) for liver volumetry helps predict the risk of PHLF. Besides portal vein embolization, there are other FLR optimization techniques that have their indications in case of risk of failure (e.g., associating liver partition and portal vein ligation for staged hepatectomy, liver venous deprivation) or in specific situations (transarterial radioembolization). CONCLUSION: There is a need to standardize volumetry and function measurement techniques, as well as FLR hypertrophy techniques, to limit the risk of PHLF.

Full robotic versus open ALPPS: a bi-institutional comparison of perioperative outcomes.

BACKGROUND: In primarily unresectable liver tumors, ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy) may offer curative two-stage hepatectomy trough a fast and extensive hypertrophy. However, concerns have been raised about the invasiveness of the procedure. Full robotic ALPPS has the potential to reduce the postoperative morbidity trough a less invasive access. The aim of this study was to compare the perioperative outcomes of open and full robotic ALPPS. METHODS: The bicentric study included open ALPPS cases from the University Hospital Zurich, Switzerland and robotic ALPPS cases from the University of Modena and Reggio Emilia, Italy from 01/2015 to 07/2022. Main outcomes were intraoperative parameters and overall complications. RESULTS: Open and full robotic ALPPS were performed in 36 and 7 cases. Robotic ALPPS was associated with less blood loss after both stages (418 ± 237 ml vs. 319 ± 197 ml; P = 0.04 and 631 ± 354 ml vs. 258 ± 53 ml; P = 0.01) as well as a higher rate of interstage discharge (86% vs. 37%; P = 0.02). OT was longer with robotic ALPPS after both stages (371 ± 70 min vs. 449 ± 81 min; P = 0.01 and 282 ± 87 min vs. 373 ± 90 min; P = 0.02). After ALPPS stage 2, there was no difference for overall complications (86% vs. 86%; P = 1.00) and major complications (43% vs. 39%; P = 0.86). The total length of hospital stay was similar (23 ± 17 days vs. 26 ± 13; P = 0.56). CONCLUSION: Robotic ALPPS was safely implemented and showed potential for improved perioperative outcomes compared to open ALPPS in an experienced robotic center. The robotic approach might bring the perioperative risk profile of ALPPS closer to interventional techniques of portal vein embolization/liver venous deprivation.

Efficacy of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in hepatocellular carcinoma with macrovascular invasion: a single-center retrospective analysis.

Objective The influence of macrovascular invasion on the therapeutic efficacy of Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) in hepatocellular carcinoma (HCC) patients has not been previously reported. This study primarily examines the therapeutic effect of ALPPS in treating HCC with macrovascular invasion. Methods 89 patients who underwent ALPPS at the First Affiliated Hospital of Guangxi Medical University from December 2016 to December 2021 were included. Patients were categorized into three groups based on macrovascular invasion status: pure HCC, HCC with portal vein tumor thrombus (PVTT), and HCC with hepatic vein tumor thrombus (HVTT). Outcome measures such as postoperative complications, liver hyperplasia rates, and survival times were compared across the groups. Results The study comprised 44 patients without macrovascular invasion and 45 cases with it, including 37 PVTT and 8 HVTT cases. Patients with PVTT or HVTT had a higher rate of complications and liver failure after the first ALPPS stage compared to those without macrovascular invasion (P = 0.018, P = 0.036). This trend was also observed in the stratified analysis of severe complications. However, no significant differences were found in these outcomes after the second ALPPS stage among the groups. The volume and rate of future liver remnant proliferation between the two stages of ALPPS were not statistically different among the groups, with median overall survival times of 42, 39, and 33 months, and progression-free survival times of 30, 24, and 14 months, respectively (P = 0.412 and P = 0.281). Conclusion ALPPS for HCC with macrovascular invasion was considered safe, feasible, and effective, as it achieved therapeutic effects comparable to those in cases without macrovascular invasion.

Laparoscopic Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (L-ALPPS) After Conversion Therapy for BCLC-B Hepatocellular Carcinoma: A Video Article.

BACKGROUND: Despite the ALPPS technique remains a controversy, various ALPPS techniques have made many attempts.1-6 This video discusses the technical tips for L-ALPPS after conversion therapy. METHODS: A 56-year-old, HCC patient who performed the abdominal CT showed a 6.0*5.7-cm-sized mass with intrahepatic metastasis. After four cycles of conversion therapy, the patient achieved a radiologic complete response. However, the standardized, remnant liver volume ratio (SRLVR) was only 34%. Thus, L-ALPPS was contemplated. RESULTS: After full mobilization, intraoperative ultrasonography marked the main trunk of MHV. The concept of "Laennec membrane anatomy" was introduced.7 The anterior pedicle (AP) and the posterior pedicle (PP) were elastically suspended along the Laennec membrane. The conventional hilar dissection approach was used to isolate and suspend RHA and the right portal vein (RPV). Then, IRHV and short hepatic vein were clipped and cut. The Pringle maneuver was used intermittently during the parenchymal transection. Hepatic resection was performed from the caudal to the cranial side along MHV after RPV was ligated. The RHV was elastically suspended after hepatic resection. The omentum was used to cover the resection surface. Stage 2, preoperative SRLVR increased to 68.3%. The adhesion of the right hemiliver was bluntly separated. AP, PP, and RHV were divided by the stapler respectively. Operation time and bleeding volume for stage-1 surgery and stage-2 surgery were 240 min and 80 min, 200 ml and 250 ml, respectively. The postoperative recovery was uneventful. CONCLUSIONS: L-ALPPS as a surgical option seems to be feasible and safe for intermediate-advanced HCC after conversion therapy.

Associating liver partition and portal vein ligation for staged hepatectomy as bridging therapy for liver transplantation in an infant with an advanced hepatic rhabdoid tumor.

BACKGROUND: Malignant rhabdoid tumors (MRTs) are rare, aggressive tumors that mainly affect children and currently lack effective chemotherapeutic regimens. Liver MRTs are particularly challenging to manage due to the difficulty of performing one-stage liver resection, and preemptive liver transplantation is associated with high recurrence rates. However, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique offers a promising surgical approach for advanced-stage liver tumors where conventional liver resection is not feasible. CASE REPORT: A patient with a large liver rhabdoid tumor that had invaded the three main hepatic veins underwent four courses of cisplatin-pirarubicin chemotherapy. ALPPS was performed due to insufficient residual liver capacity, with hepatic parenchymal dissection between the anterior and posterior liver zones in the first stage of surgery. After confirming adequate remaining liver volume, the liver was resected except for S1 and S6 on postoperative day 14. LDLT was performed 7 months after ALPPS due to the gradual deterioration of liver function caused by chemotherapy. The patient was recurrence-free 22 and 15 months after ALPPS and LDLT, respectively. CONCLUSIONS: The ALPPS technique is a curative option for advanced-stage liver tumors that cannot be managed with conventional liver resection. In this case, ALPPS was used successfully to manage a large liver rhabdoid tumor. Then, liver transplantation was performed after chemotherapy. The ALPPS technique should be considered a potential treatment strategy for patients with advanced-stage liver tumors, particularly those who can undergo liver transplantation.

Evolution of minimally invasive techniques and surgical outcomes of ALPPS in Italy: a comprehensive trend analysis over 10 years from a national prospective registry.

BACKGROUND: Since 2012, Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has encountered several modifications of its original technique. The primary endpoint of this study was to analyze the trend of ALPPS in Italy over a 10-year period. The secondary endpoint was to evaluate factors affecting the risk of morbidity/mortality/post-hepatectomy liver failure (PHLF). METHODS: Data of patients submitted to ALPPS between 2012 and 2021 were identified from the ALPPS Italian Registry and evaluation of time trends was performed. RESULTS: From 2012 to 2021, a total of 268 ALPPS were performed within 17 centers. The number of ALPPS divided by the total number of liver resections performed by each center slightly declined (APC = - 2.0%, p = 0.111). Minimally invasive (MI) approach significantly increased over the years (APC = + 49.5%, p = 0.002). According to multivariable analysis, MI completion of stage 1 was protective against 90-day mortality (OR = 0.05, p = 0.040) as well as enrollment within high-volume centers for liver surgery (OR = 0.32, p = 0.009). Use of interstage hepatobiliary scintigraphy (HBS) and biliary tumors were independent predictors of PHLF. CONCLUSIONS: This national study showed that use of ALPPS only slightly declined over the years with an increased use of MI techniques, leading to lower 90-day mortality. PHLF still remains an open issue.

Future liver remnant augmentation preceding ex vivo hepatectomy with IVC replacement: a strategy to achieve R0 margins.

PURPOSE: Ex vivo hepatectomy with autotransplantation (EHAT) provides opportunity for R0 resection. As EHAT outcomes after future liver remnant (FLR) augmentation techniques are not well documented, we examine results of EHAT after augmentation for malignant tumors. METHODS: Retrospective analysis of six cases of EHAT was performed. Of these, four occurred after preoperative FLR augmentation between 2018 and 2022. RESULTS: Six patients were offered EHAT of 26 potential candidates. Indications for resection were involvement of hepatic vein outflow and inferior vena cava (IVC) with metastatic colorectal carcinoma (n = 3), cholangiocarcinoma (n = 2), or leiomyosarcoma (n = 1). Five patients were treated with neoadjuvant chemotherapy and four had preoperative liver augmentation. One hundred percent of cases achieved R0 resection. Of the augmented cases, three patients are alive after median follow-up of 28 months. Postoperative mortality due to liver failure was 25% (n = 1). CONCLUSIONS: For select patients with locally advanced tumors involving all hepatic veins and the IVC for whom conventional resection is not an option, EHAT provides opportunity for R0 resection. In addition, in patients with inadequate FLR volume, further operative candidacy with acceptable results can be achieved by combined liver augmentation techniques. To better characterize outcomes in this small subset, a registry is needed.

Simultaneous portal and hepatic vein embolization is better than portal embolization or ALPPS for hypertrophy of future liver remnant before major hepatectomy: A systematic review and network meta-analysis.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is the Achilles' heel of hepatic resection for colorectal liver metastases. The most commonly used procedure to generate hypertrophy of the functional liver remnant (FLR) is portal vein embolization (PVE), which does not always lead to successful hypertrophy. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been proposed to overcome the limitations of PVE. Liver venous deprivation (LVD), a technique that includes simultaneous portal and hepatic vein embolization, has also been proposed as an alternative to ALPPS. The present study aimed to conduct a systematic review as the first network meta-analysis to compare the efficacy, effectiveness, and safety of the three regenerative techniques. DATA SOURCES: A systematic search for literature was conducted using the electronic databases Embase, PubMed (MEDLINE), Google Scholar and Cochrane. RESULTS: The time to operation was significantly shorter in the ALPPS cohort than in the PVE and LVD cohorts by 27 and 22 days, respectively. Intraoperative parameters of blood loss and the Pringle maneuver demonstrated non-significant differences between the PVE and LVD cohorts. There was evidence of a significantly higher FLR hypertrophy rate in the ALPPS cohort when compared to the PVE cohort, but non-significant differences were observed when compared to the LVD cohort. Notably, the LVD cohort demonstrated a significantly better FLR/body weight (BW) ratio compared to both the ALPPS and PVE cohorts. Both the PVE and LVD cohorts demonstrated significantly lower major morbidity rates compared to the ALPPS cohort. The LVD cohort also demonstrated a significantly lower 90-day mortality rate compared to both the PVE and ALPPS cohorts. CONCLUSIONS: LVD in adequately selected patients may induce adequate and profound FLR hypertrophy before major hepatectomy. Present evidence demonstrated significantly lower major morbidity and mortality rates in the LVD cohort than in the ALPPS and PVE cohorts.

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

BACKGROUND & AIM: Associating 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. METHODS: An 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. RESULTS: PVL 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. CONCLUSION: ALPPS 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.