Health Economic Evaluation of Patients With Colorectal Liver Metastases Randomized to ALPPS or TSH: Analysis From the LIGRO Trial.

Objective: This is a preplanned, health economic evaluation from the LIGRO trial. One hundred patients with colorectal liver metastases (CRLM) and standardized future liver remnant <30% were randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or two-staged hepatectomy (TSH). Summary Background Data: TSH, is an established method in advanced CRLM. ALPPS has emerged providing improved resection rate and survival. The health care costs and health outcomes, combining health-related quality of life (HRQoL) and survival into quality-adjusted life years (QALYs), of ALPPS and TSH have not previously been evaluated and compared. Methods: Costs and QALYs were compared from treatment start up to 2 years. Costs are estimated from resource use, including all surgical interventions, length of stay after interventions, diagnostic procedures and chemotherapy, and applying Swedish unit costs. QALYs were estimated by combining survival and HRQoL data, the latter being assessed with EQ-5D 3L. Estimated costs and QALYs for each treatment strategy were combined into an incremental cost-effectiveness ratio (ICER). Nonparametric bootstrapping was used to assess the joint distribution of incremental costs and QALYs. Results: The mean cost difference between ALPPS and TSH was 12,662€, [95% confidence interval (CI): -10,728-36,051; P = 0.283]. Corresponding mean difference in life years and QALYs was 0.1296 (95% CI: -0.12-0.38; P = 0.314) and 0.1285 (95% CI: -0.11-0.36; P = 0.28), respectively. The ICER was 93,186 and 92,414 for QALYs and life years as outcomes, respectively. Conclusions: Based on the 2-year data, the cost-effectiveness of ALPPS is uncertain. Further research, exploring cost and health outcomes beyond 2 years is needed.

Contemporary Surgical Management of Colorectal Liver Metastases.

Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer-related death. Approximately 20-30% of patients will develop hepatic metastasis in the form of synchronous or metachronous disease. The treatment of colorectal liver metastasis (CRLM) has evolved into a multidisciplinary approach, with chemotherapy and a variety of locoregional treatments, such as ablation and portal vein embolization, playing a crucial role. However, resection remains a core tenet of management, serving as the gold standard for a curative-intent therapy. As such, the input of a dedicated hepatobiliary surgeon is paramount for appropriate patient selection and choice of surgical approach, as significant advances in the field have made management decisions extremely nuanced and complex. We herein aim to review the contemporary surgical management of colorectal liver metastasis with respect to both perioperative and operative considerations.

CD4+CD25+ regulatory T cells decreased future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an innovative surgical approach for the treatment of massive hepatocellular carcinoma (HCC), the key to successful planned stage 2 ALPPS is future liver remnant (FLR) volume growth, but the exact mechanism has not been elucidated. The correlation between regulatory T cells (Tregs) and postoperative FLR regeneration has not been reported. AIM: To investigate the effect of CD4+CD25+ Tregs on FLR regeneration after ALPPS. METHODS: Clinical data and specimens were collected from 37 patients who developed massive HCC treated with ALPPS. Flow cytometry was performed to detect changes in the proportion of CD4+CD25+ Tregs to CD4+ T cells in peripheral blood before and after ALPPS. To analyze the relationship between peripheral blood CD4+CD25+ Treg proportion and clinicopathological information and liver volume. RESULTS: The postoperative CD4+CD25+ Treg proportion in stage 1 ALPPS was negatively correlated with the amount of proliferation volume, proliferation rate, and kinetic growth rate (KGR) of the FLR after stage 1 ALPPS. Patients with low Treg proportion had significantly higher KGR than those with high Treg proportion (P = 0.006); patients with high Treg proportion had more severe postoperative pathological liver fibrosis than those with low Treg proportion (P = 0.043). The area under the receiver operating characteristic curve between the percentage of Tregs and proliferation volume, proliferation rate, and KGR were all greater than 0.70. CONCLUSION: CD4+CD25+ Tregs in the peripheral blood of patients with massive HCC at stage 1 ALPPS were negatively correlated with indicators of FLR regeneration after stage 1 ALPPS and may influence the degree of fibrosis in patients' livers. Treg percentage was highly accurate in predicting the FLR regeneration after stage 1 ALPPS.

Case Report: The application of associating liver partition and portal vein ligation for staged hepatectomy in patients with hepatitis b virus-related hepatocellular carcinoma after undergoing treatment with an immune checkpoint inhibitor: a report of two cases.

Hepatocellular carcinoma (HCC) is often diagnosed at an unresectable stage without opportunities for curative therapy. Future liver remnant (FLR) insufficiency limits the range of patients who can undergo radical resection. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can ultimately achieve short-term hypertrophy of the FLR in patients with viral hepatitis-related fibrosis/cirrhosis and R0 resection. However, the influence of immune checkpoint inhibitors (ICIs) on liver regeneration remains unknown. We report two patients diagnosed with Barcelona Clinic Liver Cancer (BCLC)-B stage hepatitis B virus (HBV)-related HCC who underwent pioneering ALPPS after immunotherapy without posthepatectomy liver failure (PHLF). ALPPS has been shown to be safe and feasible in patients with HCC who underwent immunotherapy previously for the first time and might provide an alternative salvage option for future conversion therapy of HCC.

Recent advances in surgical strategies and liver transplantation for hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.

Research progress of three techniques for hepatic hyperplasia / 中华肝胆外科杂志

Surgical resection is one of the important means to achieve long-term survival for patients with liver malignant tumor. However, most of the liver malignant tumor has been diagnosed in the middle and late stage, and lose the chance of surgical treatment. For these patients who have lost the chance of surgery, some surgeons have proposed the concept of planned liver resection, which is to reduce tumor stage and increase future liver remnant (FLR) in a planned way, so as to improve the safety of surgery and prolong the survival time of patients after surgery. For patients with FLR insufficiency after prior evaluation or/and treatment, the technique of hepatic hyperplasia is an important part of planned hepatectomy, that is, to effectively increase FLR in a short period of time by various means. Portal vein ligation (PVL) and portal vein embolization (PVE), associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and liver venous deprivation (LVD) are three main techniques for hepatic hyperplasia. This article reviews the principle, effect and safety of three liver augmentation techniques.

Efficacy and safety of different options for liver regeneration of future liver remnant in patients with liver malignancies: a systematic review and network meta-analysis.

BACKGROUND: Several treatments induce liver hypertrophy for patients with liver malignancies but insufficient future liver remnant (FLR). Herein, the aim of this study is to compare the efficacy and safety of existing surgical techniques using network meta-analysis (NMA). METHODS: We searched PubMed, Web of Science, and Cochrane Library from databases for abstracts and full-text articles published from database inception through Feb 2022. The primary outcome was the efficacy of different procedures, including standardized FLR (sFLR) increase, time to hepatectomy, resection rate, and R0 resection margin. The secondary outcome was the safety of different treatments, including the rate of Clavien-Dindo≥3a and 90-day mortality. RESULTS: Twenty-seven studies, including three randomized controlled trials (RCTs), three prospective trials (PTs), and twenty-one retrospective trials (RTs), and a total number of 2075 patients were recruited in this study. NMA demonstrated that the Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) had much higher sFLR increase when compared to portal vein embolization (PVE) (55.25%, 95% CI 45.27-65.24%), or liver venous deprivation(LVD) (43.26%, 95% CI 22.05-64.47%), or two-stage hepatectomy (TSH) (30.53%, 95% CI 16.84-44.21%), or portal vein ligation (PVL) (58.42%, 95% CI 37.62-79.23%). ALPPS showed significantly shorter time to hepatectomy when compared to PVE (-32.79d, 95% CI -42.92-22.66), or LVD (-34.02d, 95% CI -47.85-20.20), or TSH (-22.85d, 95% CI -30.97-14.72), or PVL (-43.37d, 95% CI -64.11-22.62); ALPPS was considered as the highest resection rate when compared to TSH (OR=6.09; 95% CI 2.76-13.41), or PVL (OR =3.52; 95% CI 1.16-10.72), or PVE (OR =4.12; 95% CI 2.19-7.77). ALPPS had comparable resection rate with LVD (OR =2.20; 95% CI 0.83-5.86). There was no significant difference between them when considering the R0 marge rate. ALPPS had a higher Clavien-Dindo≥3a complication rate and 90-day mortality compared to other treatments, although there were no significant differences between different procedures. CONCLUSIONS: ALPPS demonstrated a higher regeneration rate, shorter time to hepatectomy, and higher resection rate than PVL, PVE, or TSH. There was no significant difference between them when considering the R0 marge rate. However, ALPPS developed the trend of higher Clavien-Dindo≥3a complication rate and 90-day mortality compared to other treatments.

Change of tumor-infiltrating lymphocyte of associating liver partition and portal vein ligation for staged hepatectomy for hepatocellular carcinoma.

BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in the growth and progression of hepatocellular carcinoma (HCC) has attracted widespread attention. AIM: To evaluate the feasibility of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for massive HCC by exploring the role of TIL in the tumor microenvironment. METHODS: Fifteen massive HCC patients who underwent ALPPS treatment and 46 who underwent hemi-hepatectomy were selected for this study. Propensity score matching was utilized to match patients in ALPPS and hemi-hepatectomy groups (1:1). Quantitative analysis of TILs in tumor and adjacent tissues between the two groups was performed by immunofluorescence staining and further analyses with oncological characteristics. In the meantime, trends of TILs in peripheral blood were compared between the two groups during the perioperative period. RESULTS: Continuous measurement of tumor volume and necrosis volume showed that the proportion of tumor necrosis volume on the seventh day after stage-I ALPPS was significantly higher than the pre-operative value (P = 0.024). In the preoperative period of stage-I ALPPS, the proportion of tumor necrosis volume in the high CD8+ T cell infiltration group was significantly higher than that in the low group (P = 0.048). CONCLUSION: TIL infiltration level maintained a dynamic balance during the preoperative period of ALPPS. Compared with right hemi-hepatectomy, the ALPPS procedure does not cause severe immunosuppression with the decrease in TIL infiltration and pathological changes in immune components of peripheral blood. Our results suggested that ALPPS is safe and feasible for treating massive HCC from the perspective of immunology. In addition, high CD8+ T cell infiltration is associated with increasing tumor necrosis in the perioperative period of ALPPS.

Hepatic epithelioid hemangioendothelioma (HEHE)-rare vascular malignancy mimicking cholangiocarcinoma: a case report.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed malignancy of vascular origin. We describe a case of a 36-year-old, who presented with a burning sensation in his chest on exercise and was believed to have bilobar intrahepatic cholangiocarcinoma. After receiving chemotherapy with partial response, the patient underwent staged resection with modified associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure-laparoscopic radiofrequency-assisted ALPPS (RALPPS). Histological examination of the stage 1 specimen revealed HEHE deposits in the left lobe of the liver. The patient proceeded to have stage 2 open right hepatectomy with concurring histology. Ninety-day follow-up computed tomography scan showed almost complete resolution of HEHE lesions. Low incidence, non-specific clinical and radiological characteristics all contribute to high HEHE misdiagnosis rate. Histological analysis can be used for confirmation of the diagnosis; however, specialist staining is required, which is not routinely performed. Multiple treatments are available against HEHE, but only liver resection and liver transplantation are potentially curative. ALPPS and its modifications (such as RALPPS) offer an alternative from conventional two-stage hepatectomy for patients with extensive bilobar HEHE, who are at risk of developing post-hepatectomy liver failure or patients with anomalous hepatic vasculature anatomy which makes portal vein embolisation (PVE) challenging.

Case Report: Combining liver partition and portal vein ligation after thrombectomy for tumor isolation (CLAPT) to treat advanced hepatocellular carcinoma with portal vein tumor thrombosis.

Background: Primary liver cancer is the third leading cause of cancer-related deaths worldwide in 2020, and hepatocellular carcinoma (HCC) is the major pathological type. Patients with HCC complicated with portal vein tumor thrombosis (PVTT) have a poor prognosis, and controversies regarding treatment options exist among international scholars. Patients with VP4 or Cheng's type III classification are generally considered ineligible for surgical treatment. Methods: We retrospectively analyzed three cases of HCC with PVTT who underwent a novel modified surgical procedure. The procedure included portal vein thrombectomy and portal vein ligation with liver parenchymal separation for the resection of the tumor thrombus involving the main portal vein trunk and for the isolation of the giant tumor. The three cases were then treated with targeted drugs postoperatively. Results: One case developed acute renal failure in the perioperative period, and the renal function gradually recovered after the treatment. The two remaining cases recovered uneventfully postoperatively. The prognosis of the three patients was encouraging. Only one patient died of lung metastasis after 13 months, and the remaining patients were still alive after 41 and 21 months, respectively. Conclusions: We provide a new possible surgical option for patients with advanced HCC with PVTT. The surgical procedure was inspired by associating liver partition with portal vein ligation for staged hepatectomy and portal vein thrombectomy. The survival time was significantly prolonged after the patients underwent thrombectomy, tumor isolation, and postoperative nonsurgical treatment. Hence, the combination of liver partition and portal vein ligation after thrombectomy for tumor isolation has the potential for the treatment of advanced HCC with PVTT.

Transcatheter arterial embolization-salvaged ALPPS, a novel ALPPS procedure especially for patients with hepatocellular carcinoma and severe fibrosis/cirrhosis.

Background: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for hepatocellular carcinoma (HCC) with fibrosis/cirrhosis is often associated with limited growth of future liver remnant (FLR). We introduced a new procedure named transcatheter arterial embolization-salvaged ALPPS (TAE-salvaged ALPPS) which was shown to be especially suitable for HCC patients with cirrhosis or fibrosis who failed adequately to respond to conventional ALPPS. The short-term efficacy and safety for the TAE-salvaged ALPPS on patients with HCC and fibrosis/cirrhosis were studied. Methods: Consecutive HCC patients who underwent TAE-salvaged ALPPS in our hospital between November 2016 and June 2020 were retrospectively studied. The new ALPPS procedure included conventional ALPPS stage-1 using associating liver partition and portal vein ligation. When FLR failed to reach sufficient hypertrophy, TAE was carried out 2 weeks later followed by liver resection 3 weeks after ALPPS stage-1. Results: Nine of 10 patients had a single tumor (median diameter 14.0 cm, range, 5.2-17 cm). The remaining patient had multiple tumors (diameter of one tumor 14.0 cm, and two satellite foci 2.0 and 3.0 cm). R0 resection was achieved in all patients (100%) after a median of 21 days. Six patients had cirrhosis, 1 had METAVIR grade-3 fibrosis, and 3 had METAVIR grade-2 fibrosis. The median increase in FLR volume after TAE-salvaged ALPPS was 69.7% (34.4-143.9%). The absolute and relative kinetic growth rates (KGRs) were 9.9 (7.1-17.3) mL/day and 3.4% (1.9-7.2%)/day, respectively. The median absolute KGRs were 15.7, 2.6, and 19.5 mL/day in the first, second, and third postoperative weeks after ALPPS stage-1, respectively. The rapid increase in KGR on the third week was induced by TAE. The overall postoperative morbidity rates were 50,0% (5/10), 20.0% (2/10) and 70.0% (7/10) after ALPPS stage-1, TAE and ALPPS stage-2, respectively. The 90-day mortality rate was 10.0% (1/10). The median overall survival was 40 months. Conclusions: The new TAE-salvaged ALPPS induced significant increases in FLR volumes within 3 weeks in patients with HCC and fibrosis/cirrhosis. The procedure is promising in treating patients with HCC and fibrosis/cirrhosis who fail to achieve sufficient FLR hypertrophy after conventional ALPPS stage-1.

Imaging-guided interventions modulating portal venous flow: Evidence and controversies.

Portal hypertension is defined by an increase in the portosystemic venous gradient. In most cases, increased resistance to portal blood flow is the initial cause of elevated portal pressure. More than 90% of cases of portal hypertension are estimated to be due to advanced chronic liver disease or cirrhosis. Transjugular intrahepatic portosystemic shunts, a non-pharmacological treatment for portal hypertension, involve the placement of a stent between the portal vein and the hepatic vein or inferior vena cava which helps bypass hepatic resistance. Portal hypertension may also be a result of extrahepatic portal vein thrombosis or compression. In these cases, percutaneous portal vein recanalisation restores portal trunk patency, thus preventing portal hypertension-related complications. Any portal blood flow impairment leads to progressive parenchymal atrophy and triggers hepatic regeneration in preserved areas. This provides the rationale for using portal vein embolisation to modulate hepatic volume in preparation for extended hepatic resection. The aim of this paper is to provide a comprehensive evidence-based review of the rationale for, and outcomes associated with, the main imaging-guided interventions targeting the portal vein, as well as to discuss the main controversies around such approaches.

MMP2/9 downregulation is responsible for hepatic function recovery in cirrhotic rats following associating liver partition and portal vein ligation for staged hepatectomy.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was introduced in 2007. The current study explored the mechanisms of rapid liver hypertrophy after ALPPS in cirrhotic rats. Methods: A cirrhotic rat model was constructed and portal vein ligation (PVL) or ALPPS treatments were administered. The liver hyperplasia rate of the rats was calculated, and hepatic function was evaluated using biochemical factors and the indocyanine green excretion test. Subsequently, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and hematoxylin and eosin (HE) staining were performed to determine the degree of liver regeneration. Differentially expressed genes during the rapid liver hypertrophy were detected by bioinformatics analysis, followed verification using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Results: The body weight of rats that underwent PVL and ALPPS changed during the first 1-4 days postoperatively, and the alterations were more pronounced in rats receiving ALPPS. The recovery of body weight in cirrhotic rats was slower than that in normal rats. The levels of biochemical factors and the indocyanine green retention rate increased 1 day after PVL and ALPPS, and then decreased gradually. PVL and ALPPS elevated the levels of cytokines, inflammatory factors, and proliferating cell nuclear antigen (PCNA) in rats at 1 day postoperatively. HE observation of rat liver condition showed that rats recovered faster within the first 4 days postoperatively. ALPPS surgery resulted in a significant downregulation of matrix metalloproteinase (MMP)2/9 expression in cirrhotic rats at postoperative day 4. Conclusions: Liver function was partially recovered in cirrhotic rats after ALPPS, and the underlying mechanisms may involve PCNA and MMP2/9.

Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and portal vein embolization in staged hepatectomy for HBV-related hepatocellular carcinoma: a randomized comparative study.

Background: Both portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) have merits and demerits when used in patients with unresectable liver cancers due to insufficient volumes in future liver remnant (FLR). Methods: This study was a single-center, prospective randomized comparative study. Patients with the diagnosis of hepatitis B related hepatocellular carcinoma (HCC) were randomly assigned in a 1:1 ratio to the 2 groups. The primary endpoints were tumor resection and three-year overall survival (OS) rates. Results: Between November 2014 to June 2016, 76 patients with unresectable HBV-related HCC due to inadequate volume of FLR were randomly assigned to ALPPS groups (n=38) and TACE + PVE groups (n=38). Thirty-seven patients (97.4%) in the ALPPS group compared with 25 patients (65.8%) in the TACE + PVE group were able to undergo staged hepatectomy (risk ratio 1.48, 95% CI: 1.17-1.87, P<0.001). The three-year OS rate of the ALPPS group (65.8%) (95% CI: 50.7-80.9) was significantly better than the TACE + PVE group (42.1%) (95% CI: 26.4-57.8) (HR 0.50, 95% CI: 0.26-0.98, two-sided P=0.036). However, no significant difference in the OS rates between patients who underwent tumor resection in the 2 groups of patients was found (HR 0.80, 95% CI: 0.35-1.83, two-sided P=0.595). Major postoperative complications rates after the stage-2 hepatectomy were 54.1% in the ALPPS group and 20.0% in the TACE + PVE group (risk ratio 2.70, 95% CI: 1.17-6.25, P=0.007). Conclusions: ALPPS resulted in significantly better intermediate-term OS outcomes, at the expenses of a significantly higher perioperative morbidity rate compared with TACE + PVE in patients who had initially unresectable HBV-related HCC.

Development and internal validation of the Comprehensive ALPPS Preoperative Risk Assessment (CAPRA) score: is the patient suitable for Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS)?

Background: Preoperative patient selection in Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is not always reliable with currently available scores, particularly in patients with primary liver tumor. This study aims to (I) to determine whether comorbidities and patients characteristics are a risk factor in ALPPS and (II) to create a score predicting 90-day mortality preoperatively. Methods: Thirteen high-volume centers participated in this retrospective multicentric study. A risk analysis based on patient characteristics, underlying disease and procedure type was performed to identify risk factors and model the Comprehensive ALPPS Preoperative Risk Assessment (CAPRA) score. A nonparametric receiver operating characteristic analysis was performed to estimate the predictive ability of our score against the Charlson Comorbidity Index (CCI), the age-adjusted CCI (aCCI), the ALPPS risk score before Stage 1 (ALPPS-RS1) and Stage 2 (ALPPS-RS2). The model was internally validated applying bootstrapping. Results: A total of 451 patients were included. Mortality was 14.4%. The CAPRA score is calculated based on the following formula: (0.1 × age) - (2 × BSA) + 1 (in the presence of primary liver tumor) + 1 (in the presence of severe cardiovascular disease) + 2 (in the presence of moderate or severe diabetes) + 2 (in the presence of renal disease) + 2 (if classic ALPPS is planned). The predictive ability was 0.837 for the CAPRA score, 0.443 for CCI, 0.519 for aCCI, 0.693 for ALPPS-RS1 and 0.807 for ALPPS-RS2. After 1,000 cycles of bootstrapping the C statistic was 0.793. The accuracy plot revealed a cut-off for optimal prediction of postoperative mortality of 4.70. Conclusions: Comorbidities play an important role in ALPPS and should be carefully considered when planning the procedure. By assessing the patient's preoperative condition in relation to ALPPS, the CAPRA score has a very good ability to predict postoperative mortality.

Current Surgical Management Strategies for Colorectal Cancer Liver Metastases.

Colorectal cancer is the third most common cancer diagnosis in the world, and the second most common cause of cancer-related deaths. Despite significant progress in management strategies for colorectal cancer over the last several decades, metastatic disease remains difficult to treat and is often considered incurable. However, for patients with colorectal liver metastases (CRLM), surgical resection offers the best opportunity for survival, can be curative, and remains the gold standard. Unfortunately, surgical treatment options are underutilized. Misperceptions regarding resectable and unresectable CRLM likely play a role in this. The assessment of factors that impact resectability status like medical fitness, technical considerations, and disease biology can be difficult, necessitating careful multidisciplinary input and discussion. The identification of ideal operative time windows that align with the multimodal management of these patients can also be perplexing. For all patients with CRLM it may therefore be advantageous to obtain surgical evaluation at the time of discovering liver metastases to mitigate these challenges and minimize the risk of undertreatment. In this review we summarize current surgical management strategies for CRLM and discuss factors to be considered when determining resectability.