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.

Associating liver partition and portal vein ligation for staged hepatectomy： the current role and development

BACKGROUND： Associating liver partition and portal vein ligation for staged hepatectomy （ALPPS） has recently been developed to induce rapid liver hypertrophy and reduce posthepatectomy liver failure in patients with insufficient future liver remnant （FLR）. ALPPS is still considered to be in an early developmental phase because surgical indications and techniques have not been standardized. This article aimed to review the current role and future developments of ALPPS. DATA SOURCES： Studies were identified by searching MED- LINE and PubMed for articles from January 2007 to October 2016 using the keywords ＂associating liver partition and portal vein ligation for staged hepatectomy＂ and ＂ALPPS＂ Addi- tional papers were identified by a manual search of references from key articles. RESULTS： ALPPS induces more hypertrophy of the FLR in less time than portal vein embolization or portal vein ligation. The benefits of ALPPS include rapid hypertrophy 47%-110% of the liver over a median of 6-16.4 days, and 95%-100% com- pletion rate of the second stage of ALPPS. The main criticisms of ALPPS are centered on its high morbidity and mortality rates. Morbidity rates after ALPPS have been reported to be 15.3%-100%, with ≥ the Clavien-Dindo grade III morbidity of 13.6%-44%. Mortality rates have been reported to be 0%-29%. The important questions to ask even if oncologic long-term results are acceptable are： whether the gain in quality and quantity of life can be off balance by the substantial risks of morbidity and mortality, and whether stimulation of rapid liver hypertrophy also accelerates rapid tumor progression and spread. Up till now, the documentations of the ALPPS procedure come mainly from case series, and most of these series include heterogeneous groups of malignancies. The numbers are also too small to separately evaluate survival for different tumor etiologies. CONCLUSIONS： Currently, knowledge on ALPPS is limited, and prospective randomized studies are lacking. From the reported preliminary results, safety of the ALPPS procedure remains questionable. ALPPS should only be used in experienced, high-volume hepatobiliary centers.

Role of associating liver partition and portal vein ligation for staged hepatectomy in colorectal liver metastases:A review

Colorectal cancer is the third most common cancer in the Western world. Approximately half of patients will develop liver metastases, which is the most common cause of death. The only potentially curative treatment is surgical resection. However, many patients retain a to small future liver remnant(FLR) to allow for resection directly. There are therefore strategies todecrease the tumor with neoadjuvant chemotherapy and to increase the FLR. An accepted strategy to increase the FLR is portal vein occlusion(PVO). A concern with this strategy is that a large proportion of patients will never be operated because of progression during the interval between PVO and resection. ALPPS(associating liver partition and portal vein ligation for staged hepatectomy) is a new procedure with a high resection rate. A concern with this approach is the rather high frequency of complications and high mortality, compared to PVO. In this review, it is shown that with ALPPS the resection rate was 97.1% for CRLM and the mortality rate for all diagnoses was 9.6%. The mortality rate was likely lower for patients with CRLM, but some data were lacking in the reports. Due to the novelty of ALPPS, the indications and technique are not yet established but there are arguments for ALPPS in the context of CRLM and a small FLR.

Associating liver partition and portal vein ligation for staged hepatectomy in the treatment of colorectal cancer liver metastases

Colorectal cancer(CRC)is a common malignancy of the digestive system.Colorectal liver cancer metastasis(CRLM)occurs in approximately 50%of the patients and is the main cause of CRC mortality.Surgical resection is currently the most effective treatment for CRLM.However,given that the remnant liver volume after resection should be adequate,only a few patients are suitable for radical resection.Since Dr.Hans Schlitt first performed the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)for CRLM in 2012,ALPPS has received considerable attention and has continually evolved in recent years.This review explains the technical origin of the ALPPS procedure for CRLM and evaluates its efficacy,pointing to its favorable postoperative outcomes.We also discuss the patient screening strategies and optimization of ALPPS to ensure long-term survival of patients with CRLM in whom surgery cannot be performed.Finally,further directions in both basic and clinical research regarding ALPPS have been proposed.Although ALPPS surgery is a difficult and high-risk technique,it is still worth exploration by experienced surgeons.

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 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.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-a fine balance

We read with interest the paper by Li et al.entitled“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”(1).

Associating liver partition and portal vein ligation or combined transarterial chemo-embolisation and portal vein embolisation for staged hepatectomy for HBV-related hepatocellular carcinoma

Many patients with hepatocellular carcinoma are diagnosed with large tumours at an advanced stage.In addition,conditions such as liver fibrosis,cirrhosis,portal hypertension,viral load,and portal vein thrombosis due to either non-neoplastic or portal vein tumour thrombus limit the indications for surgical management to a select subset of individuals(1).

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.

The role of associating liver partition and portal vein ligation for staged hepatectomy in the management of patients with colorectal liver metastasis

Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)approach emerged as a promising surgical strategy for rapid and large hypertrophy of the future liver remnant(FLR)when a major liver resection is necessary.Colorectal liver metastasis(CRLM)is their main indication.However,the promising results published so far,are very difficult to interpret since they usually focus on the technique and not on the underlying disease.Moreover,they are usually made up of complex populations,which received different chemotherapy schemes,with the ALPPS technical variations implemented over time and without consistent long-term follow-up results as well.Whereby,its role in CRLM should be analyzed as carefully as possible to indicate and select the best candidates who will benefit the most from this approach.We conducted a computerized search using PubMed and Google Scholar for reports published so far,using mesh headings and keywords related to the ALPPS and CRLM.

How should liver hypertrophy be stimulated?A comparison of upfront associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)and portal vein embolization(PVE)with rescue possibility

Background:The role of associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)in comparison to portal vein embolization(PVE)is debated.The aim of this study was to compare successful resection rates(RR)with upfront ALPPS vs.PVE with rescue ALPPS on demand and to compare the hypertrophy of the liver between ALPPS and PVE plus subsequent rescue ALPPS.Methods:A retrospective analysis of all patients treated with PVE for colorectal liver metastasis(CRLM)or ALPPS(any diagnosis,rescue ALPPS included)at five Scandinavian university hospitals during the years 2013-2016 was conducted.A Chi-square test and a Mann-Whitney U test were used to assess the difference between the groups.A successful RR was defined as liver resection without a 90-day mortality.Results:A total of 189 patients were included.Successful RR was in 84.5%of the patients with ALPPS upfront and in 73.3%of the patients with PVE and rescue ALPPS on demand(P=0.080).The hypertrophy of the future liver remnants(FLRs)with ALPPS upfront was 71%(48-97%)compared to 96%(82-113%)after PVE and rescue ALPPS(P=0.010).Conclusions:Upfront ALPPS offers a somewhat higher successful RR than PVE with rescue ALPPS on demand.The sequential combination of PVE and ALPPS leads to a higher overall degree of hypertrophy than upfront ALPPS.

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.

Portal vein embolization failure:Current strategies and future perspectives to improve liver hypertrophy before major oncological liver resection

Portal vein embolization(PVE)is currently considered the standard of care to improve the volume of an inadequate future remnant liver(FRL)and decrease the risk of post-hepatectomy liver failure(PHLF).PHLF remains a significant limitation in performing major liver surgery and is the main cause of mortality after resection.The degree of hypertrophy obtained after PVE is variable and depends on multiple factors.Up to 20%of patients fail to undergo the planned surgery because of either an inadequate FRL growth or tumor progression after the PVE procedure(usually 6-8 wk are needed before surgery).The management of PVE failure is still debated,with a lack of consensus regarding the best clinical strategy.Different additional techniques have been proposed,such as sequential transarterial chemoembolization followed by PVE,segment 4 PVE,intra-portal administration of stem cells,dietary supplementation,and hepatic vein embolization.The aim of this review is to summarize the up-to-date strategies to overcome such difficult situations and discuss future perspectives on improving FRL hypertrophy.

Modifications of ALPPS–from complex to more complex or from complex to less complex operations

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been developed to induce rapid liver hypertrophy to reduce the chance of post-hepatectomy liver failure in patients with borderline or insufficient future liver remnant. ALPPS is still in an early developmental stage and its techniques have not been standardized. This study aimed to review the technical modifications of the conventional ALPPS procedure. DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles published from January 2007 to December 2016 using the keywords 'associating liver partition and portal vein ligation for staged hepatectomy' and 'ALPPS'. Additional articles were identified by a manual search of references from key articles. RESULTS: There have been a lot of modifications of the conventional ALPPS. These are classified as: (1) modifications aiming to improve surgical results; (2) modifications aiming to expand surgical indications; (3) salvage ALPPS; (4) ALPPS using the minimally invasive approach. Some of these modifications have made the conventional ALPPS procedure to become even more complex, although there have also been other attempts to make the procedure less complex. The results of most of these modifications have been reported in small case series or case reports. We need better well-designed studies to establish the true roles of these modifications. However, it is interesting to see how this conventional ALPPS procedure has evolved since its introduction. CONCLUSIONS: There is a trend for the use of minimally invasive procedure in the phase 1 or 2 of the conventional ALPPS procedure. Some of these modifications have expanded the use of ALPPS in patients who have been considered to have unresectable liver tumors. The long-term oncological outcomes of these modifications are still unknown.

A novel comprehensive ALPPS preoperative risk assessment (CAPRA) score is beneficial in creating a treatment strategy for advanced liver malignancy

Curability and safety are essential for patients with advanced liver malignancy undergoing extended liver resection.If the future liver remnant(FLR)volume is insufficient,portal embolization with or without hepatic arterial or venous embolization or a conventional two-stage hepatectomy(TSH)can be performed(1,2).Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)was introduced in 2007.

ALPPS versus portal vein embolization for hepatitis B virus-associated hepatocellular carcinoma: a delicate balance between volume and morbidity

We have read with great interest the recent study published by Li et al.,entitled“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”(1).

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.

The incidence and severity of post-hepatectomy bile leaks is affected by surgical indications,preoperative chemotherapy,and surgical procedures

Background:Bile leaks are one of the most common complications after liver resection.The International Study Group of Liver Surgery(ISGLS)established a uniform bile leak definition including a severity grading.However,a risk factor assessment according to ISGLS grading as well as the clinical implications has not been studied sufficiently so far.Methods:The incidence and grading of bile leaks according to ISGLS were prospectively documented in 501 consecutive liver resections between July 2012 and December 2016.A multivariate regression analysis was performed for risk factor assessment.Association with other surgical complications,90-day mortality as well as length of hospital stay(LOS)was studied.Results:The total rate of bile leaks in this cohort was 14.0%:2.8%grade A,8.0%grade B,and 3.2%grade C bile leaks were observed.Preoperative chemotherapy or biliary intervention,diagnosis of hilar cholangiocarcinoma,colorectal metastasis,central minor liver resection,major hepatectomy,extended hepatectomy or two-stage hepatectomy,were some of the risk factors leading to bile leaks.The multivariate regression analysis revealed that preoperative chemotherapy,major hepatectomy and biliodigestive reconstruction remained significant independent risk factors for bile leaks.Grade C bile leaks were associated not only with surgical site infection,but also with an increased 90-day mortality and prolonged LOS.Conclusions:The preoperative treatment as well as the surgical procedure had significant influence on the incidence and the severity of bile leaks.Grade C bile leaks were clinically most relevant,and led to significant increased LOS,rate of infection,and mortality.