Future Liver Remnant Regeneration Research Articles

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

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.To investigate the effect of CD4+CD25+ Tregs on FLR regeneration after ALPPS.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.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.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.

Safety and Efficacy of Liver Venous Deprivation Following Transarterial Chemoembolization Before Major Hepatectomy for Hepatocellular Carcinoma.

This study aimed to evaluate the safety and efficacy of liver venous deprivation (LVD) following transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Between January 2021 and December 2022, HCC patients indicated for hepatectomy with initial insufficient future liver remnant (FLR) underwent LVD after TACE to induce preoperative liver hypertrophy. Twenty-seven HCC patients with a median age of 55 years underwent LVD. No TACE or LVD procedure-associated complications occurred, except for 1 case presenting with grade A liver failure after LVD (then recovered after 7 days). The FLR volume was 29.3% (interquartile range [IQR] = 7.5) and 48.9% (IQR = 8.6) of the total liver volume before and after LVD, respectively (p < 0.001). The degree of hypertrophy and FLR hypertrophy rate were 14.8% (IQR = 8.4) and 55.2% (IQR = 36.7), respectively. All 27 patients demonstrated sufficient FLR after LVD (24 patients at three weeks post-LVD, one at six weeks, and two at ten weeks), but only 21 patients accepted surgery. Postoperative histopathology showed 16 patients with cirrhosis and five with mild fibrosis (F1, F2). One patient presented with severe intraoperative bleeding due to damage of left hepatic vein and developed grade C liver failure, then died on day 32 postoperation. LVD following TACE seems to be a safe, effective, and feasible method of inducing significant FLR regeneration in HCC, even in well-selected cirrhotic livers. Comparative studies with a large patient population and multicenter data are needed for further evaluation.

Simultaneous Ipsilateral Dual Embolization (transarterial chemoembolization with degradable starch microspheres and portal vein embolization) of the liver- “SIDE” technique for preoperative augmentation of future liver remnant (FLR) in patients with solid liver malignancies

Portal vein embolization (PVE) is gold standard strategy to increase future liver remnant (FLR). Up to 30% of patient with liver malignance still couldn't underwent surgery after PVE due to tumor progression and/or insufficient FLR regeneration during waiting period. Nine patients with colorectal liver metastases (CRLM) and small FLR, in close proximity to FLR critical structures (portal and/or hepatocaval confluence), having more than three criteria of Fong Clinical Risk Score for CRLM were approved by Ethical Committee for Simultaneous PVE and Transarterial Chemoembolization with Degradable Starch Microspheres (DSM-TACE). For those patients, standard PVE was simultaneously followed by oxaliplatin based DSM-TACE with short-term embolic material of the whole tumor bearing liver to be resected that allowed to achieve both tumor control and postembolic infarction in liver to be removed, as a trigger of increased FLR regeneration, without biliary tree damage. Results were compared with 23 patients in control group after standard PVE. Unprecedented FLR regeneration with kinetic growth rate 23.5 cc/day (range from 17.6 to 57.25 cc/day) was observed enabling extended hepatectomies within 2 weeks compared with 5 weeks waiting period in control group. In all CRLM about 60% (range from 40% to 90%) necrosis was achieved. There was no severe morbidity (including posthepatectomy liver failure) and mortality. We propose method of preoperative FLR adaptation which is not only second to none in the achieving liver regeneration rate but also is the only one that allows tumor control targeting both main reasons for patient dropout during waiting period for FLR regeneration.

To turn weakness into a strength-preoperative future liver remnant (FLR) augmentation with special focus on local tumor control and in-situ immunization for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LC)

Portal vein embolization (PVE) provokes tumor progression. LC decreases FLR regeneration capacity doubling the risk for patient dropout. Our aim was to develop method of FLR augmentation that convert aggressive tumor into safe vaccine and prolonged waiting period for FLR regeneration into effective In situ immunization period. 3 initially unresectable patients due to small FLR with advanced hepatocellular carcinoma (HCC) and LC were treated. Selective transarterial chemoembolization with short term biodegradable starch microspheres (DSM-TACE), into tumor bearing liver to be resected, was followed by simultaneous PVE of latter. Upon completion of PVE selective intratumoral immunotherapy (HIT-IT) with antiPD-L1 (atezolizumab 1,200 mg) into restored after DSM-TACE tumor arterial feeders (for selective connection with PD-L1 ligands located on tumor cells but not on normal human tissues) was done. DSM-TACE and HIT-IT was repeated one more time in all patients after postzenith decrease of T-cytotoxic cells. Predominantly T and NK cells response was observed. All patients had successfully underwent major liver resection upon sufficient FLR regeneration. In all 3 cases we had achieved effective local tumor control via total or subtotal HCC necrosis, even more, in 1 (33%) case planned amount of liver resection was decreased due to achieved tumor downsizing. There were no severe morbidity or Immune-related adverse events (irAEs). Herein we had proposed new aggressive but safe method of FLR augmentation for patients with HCC and LC that could potentially preclude drop out of patients during anticipated prolonged waiting period of FLR augmentation and possible improves long-term outcomes by means of tumor downsizing and HCC immunoscore conversion.

Hepatic Arterioportal Fistula Is Associated with Decreased Future Liver Remnant Regeneration after Stage-I ALPPS for Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) patients often developed hepatic arterioportal fistula (APF). The aim of this study is to evaluate the impact of APF on future liver remnant (FLR) regeneration and surgical outcomes after the first stage of associating liver partition and portal vein ligation for staged hepatectomy (stage-I ALPPS). MethodsConsecutive HCC patients who underwent ALPPS at our center between March 2017 and May 2019 were retrospectively studied. Data for the association between APF and clinicopathological details, liver volume, and surgical outcomes were analyzed. ResultsThe enrolled 35 HCC patients were divided into three groups: 15 patients with preoperative APF were classified as the APF I group, 10 patients developed APF after stage-I ALPPS as the APF II group, whereas the other 10 patients without APF before and after stage-I ALPPS as the control group. After stage-I ALPPS, patients in the APF I and APF II groups had lower kinetic growth rate (KGR) of FLR volume (6.1±3.2%, 11.4±8.4%, 25.0±8.8% per week, respectively, P<0.001) and took longer median time to reach the sufficient FLR volume for stage-II ALPPS (17.5 days, 12 days, 6 days, respectively, P<0.001) than those in the control group. Meanwhile, the incidence of posthepatectomy liver failure (PHLF) in the APF I and APF II groups was significantly higher than that of the control group (P=0.007). There are 27 (77.1%) patients who completed stage-II ALPPS. The overall survival (OS) rates at 1 and 3 years were 59.3% and 35.1%, whereas the disease-free survival (DFS) rates at 1 and 3 years were 44.4% and 22.9%, respectively. ConclusionsHepatic APF is significantly associated with decreased FLR regeneration and a higher risk of PHLF after stage-I ALPPS. HCC patients who are to undergo ALPPS may benefit from the timely perioperative intervention of APF.

Simultaneous ipsilateral dual (DSM-TACE and PVE) embolization (SIDE Technique) for preoperative augmentation of future liver remnant (FLR)

Purpose: Portal Vein Embolization(PVE) is a gold standard strategy to increase FLR at level of Kinetic Growth Rate (KGR) about 2.3 cc/day and to prevent posthepatectomy liver failure (PHLF). Up to 30% of patient with liver malignance still couldn't underwent surgery after PVE due to tumor progression and/or insufficient FLR regeneration during waiting period. Currently there are no methods that resolves both mentioned issues. Our aim was to develop new method that potentially will increase number of the patients with insufficient FLR that will succeed to underwent liver surgery. Results also were compared with currently developed methods of FLR augmentation such as extended liver venous deprivation (eLVD) and ALPPS. Method: 9 initially unresectable, due to small FLR, patients with colorectal liver metastases (CRLM) having more than three criteria of Fong Clinical Risk Score for CRLM, in close proximity to FLR critical structures ), were approved by Ethical Committee for Simultaneous PVE and Transarterial Chemoembolization with Degradable Starch Microspheres (DSM-TACE). Simultaneously, immediately after standard PVE, was performed oxaliplatin based DSM-TACE with short-term embolic material of the whole tumor bearing liver to be resected that safely allowed to achieve I) postembolic infarction II) pharmacologically induced hepatic Veno-Occlusive Disease(VOD(Fig 2d)) in liver to be removed, as a trigger of increased FLR regeneration(Fig.1), without biliary tree damage(Fig. 2 a,c) and what distinguishes it advantageously III) local tumor control. Results: Unprecedented FLR regeneration with KGR 23.5 cc/day(range from 17.6 to 57.25 cc/day) was observed. The latter allow us to achieve safe FLR volume to perform extended hepatectomies within recommended 2-3 weeks period to avoid chemotherapy related neutropenic window in all 9 patients even so there were no myelosuppression observed. This allows us safely shortening time to resection to 15 days in 5 last consecutive patients. In all CRLM about 60% (range from 40% to 90%) necrosis was achieved(Fig. 2 a). All patients have successfully underwent major liver resection with 0% dropout. There was no severe morbidity and mortality. Conclusion: We propose safe method of preoperative FLR adaptation which is not only second to none in the achieving liver regeneration rate but also is the only one that allows local tumor control and/or downsize borderline resectable tumors.

Preoperative future liver remnant(FLR) augmentation with local tumor control and in-situ immunization for patients with advanced hepatocellular carcinoma (HCC)

Purpose: Portal vein embolization(PVE) provokes tumor progression. Liver Cirrhosis(LC) decreases FLR regeneration capacity doubling the risk for patient dropout. Our aim was to turn weakness into a strength- develop method of FLR augmentation that converts aggressive tumor into a safe vaccine and prolonged waiting period for FLR regeneration into effective In situ immunization period Method: 3 initially unresectable patients due to small FLR with advanced hepatocellular carcinoma(HCC) and liver cirrhosis were treated. Selective transarterial chemoembolization with short term biodegradable starch microspheres(DSM-TACE), into tumor bearing liver to be resected, was followed by simultaneous PVE of latter. Upon completion of PVE selective intratumoral immunotherapy(HIT-IT) with antiPD-L1(atezolizumab 1200mg) into restored after DSM-TACE tumor arterial feeders (for selective connection with PD-L1 ligands located on tumor cells but not on normal human tissues) was done. DSM-TACE and HIT-IT was repeated one more time in all patients after postzenith decrease of T-cytotoxic cells level in peripheral blood had started. Anticancer immune response was investigated by comparison of initial histopathology specimen with specimens obtained just before second DSM-TACE+ HIT-IT and finally with specimen of resected tumor bearing liver. Latter were analyzed along with peripheral blood flow cytometry. Results: Predominantly T and NK cells response was observed. All patients had successfully underwent extended liver resection upon sufficient FLR regeneration. In all 3 cases we had achieved effective local tumor control via total or subtotal HCC necrosis, even more, in 1(33%) case planned amount of liver resection was decreased due to achieved tumor downsizing. There were no severe morbidity or Immune-related adverse events (irAEs). Conclusion: Herein we had proposed new aggressive but safe method of FLR augmentation for patients with HCC and liver cirrhosis that could potentially preclude drop out of patients during anticipated prolonged waiting period of FLR augmentation and possible improves long-term outcomes by means of tumor downsizing and HCC immunoscore conversion.

Study protocol of the HYPER-LIV01 trial: a multicenter phase II, prospective and randomized study comparing simultaneous portal and hepatic vein embolization to portal vein embolization for hypertrophy of the future liver remnant before major hepatectomy for colo-rectal liver metastases

BackgroundIn patients undergoing major liver resection, portal vein embolization (PVE) has been widely used to induce hypertrophy of the non-embolized liver in order to prevent post-hepatectomy liver failure. PVE is a safe and effective procedure, but does not always lead to sufficient hypertrophy of the future liver remnant (FLR). Hepatic vein(s) embolization has been proposed to improve FLR regeneration when insufficient after PVE. The sequential right hepatic vein embolization (HVE) after right PVE demonstrated an incremental effect on the FLR but it implies two different procedures with no time gain as compared to PVE alone.We have developed the so-called liver venous deprivation (LVD), a combination of PVE and HVE during the same intervention, to optimize the phase of liver preparation before surgery. The main objective of this randomized phase II trial is to compare the percentage of change in FLR volume at 3 weeks after LVD or PVE.MethodsPatients eligible to this multicenter prospective randomized phase II study are subjects aged from 18 years old suffering from colo-rectal liver metastases considered as resectable and with non-cirrhotic liver parenchyma. The primary objective is the percentage of change in FLR volume at 3 weeks after LVD or PVE using MRI or CT-Scan. Secondary objectives are assessment of tolerance, post-operative morbidity and mortality, post-hepatectomy liver failure, rate of non-respectability due to insufficient FLR or tumor progression, per-operative difficulties, blood loss, R0 resection rate, post-operative liver volume and overall survival. Objectives of translational research studies are evaluation of pre- and post-operative liver function and determination of biomarkers predictive of liver hypertrophy. Sixty-four patients will be included (randomization ratio 1:1) to detect a difference of 12% at 21 days in FLR volumes between PVE and LVD.DiscussionAdding HVE to PVE during the same procedure is an innovative and promising approach that may lead to a rapid and major increase in volume and function of the FLR, thereby increasing the rate of resectable patients and limiting the risk of patient’s drop-out.Trial registrationThis study was registered on clinicaltrials.gov on 15th February 2019 (NCT03841305).

Return to intended oncologic treatment (RIOT) after trisectionectomy with associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) versus portal vein embolization

Background: Return to intended oncologic treatment (RIOT) has been suggested as an important outcome for hepatic tumors. Resection of multifocal, bilobar liver tumors through extended hepatectomy often necessitates liver molding for an adequate future liver remnant (FLR), however a delay to surgery and the morbidity of liver molding could impact RIOT. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been shown to stimulate faster FLR regeneration compared to portal vein embolization (PVE) which could reduce the chemotherapy-free interval and improve RIOT. This study aims to evaluate RIOT after liver molding with ALPPS compared to PVE with trisectionectomy. Methods: A retrospective review was conducted on all patients undergoing trisectionectomies (right or left) for liver tumors from 2008–2018 in a single tertiary institution. Tumor biology, chemotherapy treatment, operative and oncologic outcomes were compared between trisectionectomies with and without liver molding (ALPPS or PVE). FLR regeneration time was defined as the duration between portal vein occlusion (first ALPPS stage or PVE) and hepatic resection (second ALPPS stage or trisectionectomy). The chemotherapy-free interval (CFI) for RIOT was calculated for patients planned for neoadjuvant and adjuvant chemotherapy, including patients who died prior to receiving intended adjuvant treatment. Results: Of the 51 patients who underwent trisectionectomy, 25 (49%) required liver molding (11 ALPPS, 14 PVE). Median FLR regeneration time was 11 days for ALPPS and 44 days for PVE (p < 0.001). Patients who did not have adjuvant chemotherapy indicated (n = 15) or were lost to follow up shortly after surgery (n = 3) were not considered for RIOT. Successful RIOT was achieved in 89% (16/18) with liver molding and 87% (13/15) with trisectionectomy alone (p = 0.85). Patients receiving neoadjuvant and adjuvant chemotherapy had a shorter CFI when trisectionectomy did not require liver molding (110 vs 228 days, p = 0.014). For patients requiring liver molding, RIOT was similar between ALPPS (7/8) and PVE with trisectionectomy (9/10) (p = 0.87). Specifically for colorectal metastases requiring liver molding prior to resection, there was a 90-day difference in mean resumption of chemotherapy (CFI) between ALPPS and PVE (183 vs 273 days, p = 0.28). Conclusion: Liver molding for patients undergoing extended liver resections does not reduce the ability to achieve RIOT. While liver molding in general expectedly increases the CFI, the shorter FLR regeneration time in ALPPS may help to reduce the CFI compared to traditional PVE with trisegmentectomy.

Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study

BackgroundExcessive increase of portal flow and pressure following extended hepatectomy have been associated to insufficient growth or function of the future liver remnant (FLR), with the risk of post-hepatectomy liver failure (PHLF). We prospectively assess the influence of liver hemodynamics on FLR regeneration and function in Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). MethodsTwenty-three patients underwent ALPPS; liver hemodynamics were assessed throughout the procedures. Volume and function of the FLR were evaluated by angio-CT and 99mTc-Mebrofenin-scintigraphy. ResultsThe portal vein flow at the end of stage-1 correlated with the increase of the FLR volume (p = 0.002). Patients with portal vein pressure (PVP) < 20 mmHg and hepatic to portal vein gradients (HVPG) < 15 mmHg at the end of ALPPS-1 showed higher FLR regeneration (76.7% vs. 30.6%, p = 0.04) and function (26.7% vs. −0.13%, p = 0.02). FLR regeneration was inversely correlated with baseline FLR/Total Liver Volume (p = 0.002) and FLR/Body Weight (p = 0.02). No correlation was found between volumes and function (p = 0.13). ConclusionLiver hemodynamic stress at the end of ALPPS-1 influences the increase of the FLR volume and function, which is higher with PVP < 20 and HVPG < 15 mmHg. Liver volume overestimates liver function and could be imprecise to set stage-2 timing.

Effects of hepatic blood inflow on liver ultrastructure and regeneration after extensive liver resection in rats with cirrhosis.

The aim of the present study was to investigate the effects of hepatic blood inflow on liver function, liver ultrastructure and the regeneration of future liver remnant (FLR) following major hepatectomy in rats with liver cirrhosis. A rat model of cirrhosis was established through intraperitoneal injection of carbon tetrachloride for 8 consecutive weeks. Extensive liver resection and different blood inflow models by portal vein (PV) and/or hepatic artery (HA) stenosis were conducted on the cirrhosis rats. Animal models were constructed as follows: Control (group A), low-flow PV + high-flow HA (group B), low-flow PV + low-flow HA (group C), high-flow PV + high-flow HA (group D) and high-flow PV + low-flow HA (group E). Hepatic blood inflow was detected by laser speckle contrast analysis, liver function and pathological changes were analyzed, Masson staining was used to identify the fibrosis of the liver and Periodic acid-Schiff staining was used to identify glycogen synthesis and hepatocyte function. The liver cell ultrastructure was evaluated by transmission electron microscopy, and the expression of Ki-67 in hepatocytes and the weight of the FLR were recorded to determine the regeneration of the FLR. Five days after major hepatectomy and liver blood inflow modulation, pathological examination of the livers from groups B and C revealed less congestion and less extensive hepatocellular injury. The serum alanine aminotransferase level of group B at 1, 3 and 5 days after hepatectomy and blood inflow modulation was 460.9±31.7, 331.0±22.0 and 285.6±15.8 U/l, respectively (control group: 676.9±41.7, 574.9±28.0 and 436.1±32.7 U/l, respectively; P<0.05); the total bilirubin of group B at 1, 3 and 5 days was 20.4±1.5, 16.1±1.0 and 13.5±0.6 µmol/l, respectively (control group: 30.3±1.4, 26.5±0.8 and 22.1±1.2 µmol/l, respectively; P<0.05). The size of the endoplasmic reticulum in the low-flow PV groups increased significantly and the mitochondrial swelling was alleviated. The positive rate of Ki-67 in the hepatocytes of groups B, C and D was 23.9±3.6, 15.7±2.3 and 12.9±2.4%, respectively (control group: 10.1±2.1%, P<0.05), and the positive rate of Ki-67 in group E was 6.1±1.4% (compared with that of the control group, P<0.05). The remnant liver weight of group B was 15.4±1.0 g (compared with that of the control group, P<0.05). Therefore, decreased portal blood flow combined with increased hepatic arterial blood flow alleviated the congestion in the liver following major hepatectomy in cirrhotic rats, improved the pathological status and liver function, increased the expression of Ki-67 and promoted liver regeneration.

Combined Preoperative Portal and Hepatic Vein Embolization (Biembolization) to Improve Liver Regeneration Before Major Liver Resection: A Preliminary Report.

Insufficient volume of the future liver remnant (FLR) is a major cause of non-resectable disease in patients presenting with primary or metastatic liver tumours. The objective of this study was to evaluate the safety and efficacy of the combined preoperative portal and hepatic vein embolization (biembolization) before extended right liver resections. This retrospective study was performed in a tertiary centre between 2014 and 2015. Combined right portal and hepatic vein embolization (biembolization) was proposed, as an alternative to ALPPS procedure, for all patients with primary or metastatic liver tumour, before right extended hepatectomy. CT scan liver volumetry was assessed before biembolization, three weeks after biembolization and one week after surgery. Seven patients underwent biembolization. All patients had right portal vein embolization (PVE) combined with right hepatic vein embolization (HVE, n=4), median HVE (n=2) and right+median HVE (n=1). Three patients had preoperative liver disease and two received preoperative chemotherapy. No biembolization procedure-related complications occurred. The mean FLR regeneration rate was 52.6% (range: 18.2-187.9) after the biembolization. One patient with gallbladder carcinoma was not operated because of peritoneal carcinomatosis diagnosed after the biembolization. The remnant six patients did not develop postoperative liver failure. Biembolization seems to induce safe, reproducible and effective FLR growth before extended right hepatectomy, in patients with primary or metastatic liver tumour.

Remedial radiofrequency ablation or portal vein embolization combined with radiofrequency ablation-assistant associating liver partition and portal vein ligation for staged hepatectomy in the treatment of patients with hepatocellular carcinoma with cirrhosis

Objective To explore the clinical effect of remedial radiofrequency ablation (RFA) or portal vein embolization (PVE) combined with radiofrequency ablation-assistant associating liver partition and portal vein ligation for staged hepatectomy (RALPPS) in the treatment of patients with insufficient future liver remnant (FLR) after the first staged operation and hepatocellular carcinoma (HCC) with cirrhosis. Methods The retrospective and descriptive cross-sectional study was adopted. The clinical data of 5 patients with insufficient FLR after the first staged of RALPPS and HCC with cirrhosis who underwent remedial RFA or PVE at the Southwest Hospital of the Third Military Medical University between September 2014 and February 2016 were collected. Standard liver volume (SLV)=613.0×body surface area (BSA)+ 162.8, BSA=0.007 1×height+ 0.013 3×body mass. Patients with FLR<40% received RALPPS. In the first staged operation, RFA was used to cauterize a coagulated avascular area between the FLR and contralateral lobe, and then right branch of portal vein was ligated. After the operation, remedial RFA or PVE was performed in patients with insufficient FLR. Once the FLR achieved the target value, the second staged RALPPS was performed. Observation indicators included (1) perioperative complications and death, complications in stage IIIa and above of Clavien-Dindo as main complications, (2) changes of FLR and tumor progression, (3) intraoperative situation, (4) follow-up. The follow-up using outpatient examination was performed up to February 2016, including laboratory examination, tumor markers and imaging examinations (enhanced scan of computed tomography in the epigastric region or ultrasound). Measure-ment data with normal distribution were represented as ±s. Results (1) Perioperative complications and death: of 5 patients, 2 didn′t receive second staged RALPPS and 3 completed both stages. Five patients had no postoperative main complications and 1 died of renal failure and pulmonary infection after second staged RALPPS. (2) Changes of FLR and tumor progression: the average FLR and percentage of FLR to SLV were (329±80)cm3 , 25%±5% in 5 patients before first staged operation and (533±45)cm3, 43%±3% in 3 patients before second staged operation, with an average growth rate of 44%-113%. The average interval time of 5 patients was (29.0±2.2)days. For the 3 patients which completed both stages, the 1-week increased percentage of FLR was 33.5%-68.9% after first staged operation, 1.2%-14.3% and 9.7%-29.8% before and after remedial RFA or PVE. Two patients didn′t undergo the second staged operation, 1 patient was due to not reach standard of safe resection after 4 times remedial PVE, and 1 patient was due to tumor metastasis during intermittent stage after remedial RFA with average FLR after 2 weeks and average 1-week increased percentage of 762.0 cm3 and 10.6%. (3) Intraoperative situations: 1 patient underwent laparoscopic-assisted first staged RALPPS and 1 underwent RFA in the left lobe of liver. The first staged operation time, RFA time and volume of intraoperative blood loss were (240±43)minutes, (15±8)minutes and (190±136)mL, and no patient had blood transfusion. After first staged operation, 5 patients received 5 times remedial PVE and 7 times RFA. Two patients underwent right hemihepatectomy and 1 patient underwent hepatic trisegmentectomy in the second staged operation. The second staged operation time and volume of intraoperative blood loss of 3 patients were (257±33)minutes and (303±73)mL, and 3 patients received R0 resection and no intraoperative blood transfusion. (4) Follow-up: 1 patient was dead during hospitalization and 4 patients were followed up for 1-12 months with a median time of 6 months. Of 2 patients without second staged operation, 1 continued to undergo interventional treatment and then was dead after half year, and 1 continued to undergo transcatheter arterial chemoembolization (TACE) and had good survival up to the end of follow-up. Of the other 2 patients, 1 with tumor recurrence at postoperative month 2 received interventional treatment and traditional Chinese medicine and then was dead after 6 months, and 1 had no tumor recurrence and metastasis during the follow-up. Conclusion For the patients with HCC with cirrhosis who had insufficient FLR after the first staged RALPPS, remedial RFA or PVE could promote further regeneration of FLR and thus improve the completion rate of both stages. Key words: Liver neoplasms; Cirrhosis; Associating liver partition and portal vein ligation for staged hepatectomy; Radiofrequency ablation; Portal vein embolization; Future liver remnant

Optimizing segment 4 hypertrophy for bilateral hepatectomy – use of outflow modulation

Introduction: Stimulation of hepatic hypertrophy is a useful aid to accomplish hepatic resections when the future liver remnant (FLR) is small. Optimizing hypertrophy of the FLR is challenging when the segment 4 (±segment 1) is the only to be preserved. Objective: Description of a method to optimize segment 4 hypertrophy for bilateral hepatectomy in the context of bilobar liver metastases (LM). Method: Four patients with bilobar LM requiring right hepatectomy and left lateral sectionectomy (FLR being only segments 1+4) were managed with a two-stage procedure. The first stage consisted of a right hepatectomy and modulation of the left hepatic vein outflow through reduction of its diameter, with macroscopic congestion of segments 2–3. The second stage consisted of a left lateral sectionectomy six weeks later. Results: After the first stage (right hepatectomy) hypertrophy of non-congested area (segments 4+1) was 23%, 149%, 163% and 203%. Hypertrophy of congested area (segments 2–3) was 15%, 24%, 45% and 120%, respectively. Hypertrophy rate of non-congested segments was more than twice that of congested segments. The patient with minimal hypertrophy after first stage reached a FLR of 0.5% of body weight, developed small-for-size syndrome and died 3 months after the second stage. Another patient developed ascites. Postoperative course was uneventful for the other two patients. Conclusion: After right hepatectomy, modulation of liver outflow allowed maintenance of function in the segments to be resected (segments 2-3) while avoiding their hypertrophy. This strategy optimizes regeneration of FLR and represents an option for bilateral hepatectomy preserving only segment 4.

Associating portal embolization and artery ligation to induce rapid liver regeneration in staged hepatectomy

Insufficient volume of the future liver remnant (FLR) is a major cause of unresectability in patients with bilobar colorectal liver metastases (CLM). The objective of this study was to evaluate the safety and efficacy of the novel associating portal embolization and artery ligation (APEAL) technique before extended right hepatectomy during a two-stage procedure for CLM. All patients who had undergone extended right hepatectomy during two-stage surgery for CLM between 2012 and 2014 were identified retrospectively from a prospectively maintained database. In the first stage, right portal vein embolization, partial right hepatic artery ligation and devascularization of segment IVb along the round ligament without parenchymal transection were associated with clearance of the FLR and/or primary tumour resection. Liver volumetry was performed using OsiriX software on postoperative day (POD) 7 and 30. Ten patients underwent the APEAL procedure. During the first stage, APEAL was combined with colorectal resection in seven patients. The median (range) interval between the two stages was 45 (31-71) days. The FLR volume increased from 327 (214-537) cm(3) before surgery to 590 (508-1072) cm(3) on POD 7 and 701 (512-1018) cm(3) on POD 30. This corresponded to a FLR regeneration rate of 104 (42-185) and 134 (53-171) per cent respectively. There were no deaths. The overall morbidity rate was 60 per cent (6 of 10) after each procedure, with severe morbidity occurring in two and three of ten patients after the first and second procedures respectively. APEAL induces fast, safe, reproducible and effective FLR growth when an extended right hepatectomy is scheduled in patients with multiple bilobar CLM.

Autologous bone marrow-derived mesenchymal stem cell transplantation promotes liver regeneration after portal vein embolization in cirrhotic rats

BackgroundPreexisting cirrhosis usually leads to an inadequate and delayed regeneration of the future liver remnant (FLR) after portal vein embolization (PVE). Bone marrow-derived mesenchymal stem cells (BMSC) are promising candidates for therapeutic applications in liver diseases. In this study, the efficacy of autologous BMSCs transplantation to promote FLR regeneration was investigated in a rat cirrhotic model. MethodsAutologous BMSCs were expanded and labeled with PKH26, and then were injected immediately into nonembolized lobes after PVE through portal vein in cirrhotic rat. At 7, 14, and 28 d after this, liver weight and Ki-67 labeling index were measured, and blood analysis was performed. Cirrhotic degree of FLR was assessed by hydroxyproline content assay and histopathology. Gene expressions of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-10 (IL-10), and matrix metalloproteinase-9 (MMP-9) were detected with real-time reverse transcriptase-polymerase chain reaction. Distribution and hepatocyte differentiation of BMSCs in FLR were determined by confocal microscopy. ResultsAutologous BMSCs significantly increased the FLR weight ratio to the total liver and the Ki-67 labeling index, and serum albumin levels were significantly higher and total bilirubin levels were significantly lower in the BMSCs group compared with the controls without BMSCs transplantation 14 and 28 d post-PVE. BMSCs significantly decreased the hydroxyproline content and collagen accumulation, up-regulated the expressions of HGF, IL-10, VEGF, and MMP-9 28 d post-PVE, and expressed hepatocyte-specific markers, such as α-fetoprotein, cytokeratin 18, and albumin in a time-dependent manner in FLR. ConclusionsAutologous BMSCs can differentiate into hepatocyte and promote FLR regeneration after PVE in cirrhotic liver, which may be through improving local microenvironment by decreasing cirrhosis, up-regulating the gene expressions of VEGF, HGF, IL-10, and MMP-9.