Neoplasms

Symptoms and General Pathology

All Conditions

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Neoplasm Metastasis

Liver Neoplasms

Neoplastic Processes

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Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

Patients with benign liver disease, who undergo liver resection

Patients with liver metastases and received chemotherapy, who undergo liver resection

Laparoscopic or open approach liver resection where at least 1 segment is removed

Liver resection

Rokas Račkauskas, MD

Kęstutis Strupas, Prof.

Liver is special organ, which can regenerate. On that ability there are many treatment modalities, where liver resection is performed, especially in cancer patients with liver metastases. Liver regeneration provides an opportunity for these patients to undergo multiple treatment regimes and liver resections to achieve curability. There are many factors that impair liver regeneration. One of these factors is chemotherapy. Literature data on impact of chemotherapy to liver regeneration is ambiguous. Therefore we aim to research impact of chemotherapy to liver regeneration.

Liver is the largest parenchymal organ responsible for over 500 different functions in human body, which are detoxification of various toxins, drugs, synthesis of proteins and enzymes, coagulation factors. Liver is special organ, which can regenerate. If 75% of liver is removed it can regenerate to its normal size. Liver volume is very important to liver function, if there is volume insufficiency it could lead to liver failure in addition to other factors that impair liver regeneration. On that regenerative ability there are many treatment modalities, when liver resection is performed, especially in cancer patients with liver metastases. Modern treatment modalities are based on combination of different treatments, surgical and chemotherapeutic. On the other hand, side effects of chemotherapy should not be discarded, which can increase patient morbidity and mortality. Thus, liver regeneration provides an opportunity for these patients to undergo multiple treatment regimes and liver resections to achieve curability. Literature data on impact of chemotherapy to liver regeneration is ambiguous. Therefore we aim to research impact of chemotherapy to liver regeneration.

Impact of Chemotherapy and Regenerative Markers of Liver Regeneration After Liver Resection for Liver Metastases

Impact of Chemotherapy and Regenerative Markers on Liver Regeneration After Liver Resection for Liver Metastases

Difference of liver volume preoperatively and postoperatively, meassured by CT

The dynamic of liver fibrosis will be measured by ultrasound elastography pre-op and post-op day 1, 7 and 30;

Expression of liver regeneration markers - hepatocyte growth factor and tumor growth factor beta1 - will be measured before and post-op day 1,3 and 7 in serum and also in liver tissue with immunohistochemistry

Complication rate will be assessed after 30 and 90 days post operatively

Vilnius University

Chair of Department of Surgery

Liver Failure

Hepatic Insufficiency

Experimental arm with PVE combined with RFA to induce accelerated liver hypertrophy.

In a previous experimental study on rats, the investigators have shown that PVE combined with radiofrequency ablation (RFA), hereafter called Associated Radiofrequency Ablation and Portal Vein Ligation for Staged Hepatectomy (ARAPS), can induce accelerated growth of the FLR

ARAPS

Anders Knudsen, PhD

Anders Riegels Knudsen, MD, PhD

Liver resection is the golden standard in the treatment of hepatic malignancies. The size and function of the remnant liver is a major concern. If the future liver remnant (FLR) is below 30 % of the initial liver volume, the risk of post hepatectomy liver insufficiency rises. Several techniques have been developed to increase the size of FLR before liver resection. In this study a new technique ARAPS (portal vein embolization with radio frequency ablation) is compared to portal vein embolization alone for accelerated liver growth in the FLR. This is done in a randomized controlled trial.

Curative intent liver resection is the gold standard for treatment of hepatic malignancies, including metastases from colorectal cancer (CRLM), but liver resection can only be performed if future liver remnant (FLR) volume is at least 25 %. Unfortunately, many cancer patients have multiple liver lesions at the time of diagnosis, rendering radical resection impossible due to a marginal FLR, thereby increasing the risk of posthepatectomy liver failure and subsequent death.

Several techniques have been designed to increase the size of the FLR, allowing more patients to undergo surgery. These techniques include portal vein embolization (PVE), portal vein ligation (PVL), two-stage partial hepatectomy, and the associating liver partition with PVL for staged hepatectomy (ALPPS). The ALPPS procedure seems to be superior to the other techniques for achieving increased size and accelerated growth of the FLR. Especially the kinetic growth rate (KGR) is superior to what has been previously described. The major drawback of ALPPS is, however, that the patient is subjected to two open procedures that are associated with high morbidity and mortality.

In a previous experimental study on rats, The investigators have shown that PVE combined with radiofrequency ablation (RFA), hereafter called Associated Radiofrequency Ablation and Portal Vein Ligation for Staged Hepatectomy (ARAPS), can induce accelerated growth of the FLR as potent as that seen after ALPPS. In humans, the ARAPS procedure can (the first step), in contrast to the two-stage ALPPS procedure, be performed percutaneously, and the investigators expect this to reduce the high morbidity and mortality associated with the ALPPS. In the present study, the investigators want to examine the effect of ARAPS compared with PVE alone on liver regeneration and function of the FLR.

Study rationale In order to allow more patients to undergo radical surgery for CRLM, implementation of new methods to enhance liver regeneration is vital.

Aim In the present study, the investigators test the hypothesis that the ARAPS approach is superior to PVE alone in achieving growth of the FLR in patients with CRLM.

Hypothesis the investigators expect to see higher growth of the FLR in the ARAPS arm compared with the PVE arm one week after intervention.

Study design The study is an investigator-initiated prospective, randomized study. Any patient eligible for this study will be offered enrollment. Patients enrolled in the study will be randomized (1:1) to either the intervention (ARAPS) or control (PVE) as

Recruitment of study subjects Potential study subjects will be given the option to participate after the study is presented during their first visit to the outpatient clinic. The visit will take place in a consultation room, where the surgeon will provide verbal and written information regarding the study prior to enrollment. Patients are allowed a companion for this interview. At least 24 hours are given before an informed consent is obtained. Patient consent can be withdrawn at any time, and all data collected for the project, will be destroyed without any consequence for their subsequent treatment.

Data analysis plan Power calculations Total liver volume is \~1500 mL. Assuming that FLR is 20 % of the total liver volume, FLR comprises 300 mL. Based on previous literature, the investigators expect a growth in the FLR of 10 % (30 mL, KGR ≈ 4.3 ml/day) in the PVE arm and 50 % (150 mL, KGR ≈ 21.4 ml/day) in the ARAPS arm. At alpha=0.05, power 80 %, and a standard deviation of 200 mL, 12 patients in each arm is needed to show a statistically significant difference between the two interventions. In order to be able to deal with potential dropout of up to 20%, the investigators aim to include 15 patients in each arm; 30 patients in total.

Statistical methods Liver regeneration will be measured as the increase in anatomical (CT) and functional (PET) liver volume seven and thirteen days following intervention (quantified in milliliters). Further, the KGR will be calculated as volume increase per day (ml/day). Differences in the two arms will be expressed as means or medians with associated standard deviations or interquartile ranges (depending on the distribution of data). Differences between the two arms will be analyzed using a t-test or non-parametric test where appropriate. P\<0.05 will be considered statistically significant.

Data on patients Data on age, diagnosis, comorbidity, and tumor imaging material will be passed on from the medical records in order to assess if the patient is eligible for inclusion in the study. Information on sex, tumor size, tumor histology, number and size of metastases, medications, tobacco/alcohol exposure, and blood sample results will be retrieved on from the patient's medical records. Radiological, biochemical, and pathological reports will also be retrieved for use in the statistical analyses.

Study procedures Intervention Portal vein embolization The standard-of-care procedure, which would be offered to the patients regardless of this study, is PVE. PVE will be used to redirect portal flow to segments of the FLR: The portal venous system is assessed through the tumor-bearing part of the liver (i.e. the part that is later going to be removed). The portal vein is assessed under guidance by ultrasonography, and a catheter is then advanced under fluoroscopic guidance for subsequent embolization. In the case of a planned extended right hepatectomy, the portal branches to segment 4 should be selectively embolized. As embolization material plugs are preferred.

Radio-frequency ablation Under guidance of ultrasonography a single-electrode RFA-needle is placed in the part of the liver that has just been deportalized. The needle is placed in normal parenchyma, and within a period of ten minutes a necrosis of approx. 3 cm is created. In literature, complication rates following RFA treatment are low, making it a feasible procedure.

Both treatments will be performed in general anesthesia. Patients will be equipped with two bandages, which they have to wear until after the second PET/CT scan in order to blind them to the treatment received.

PET/CT scanning Accurate liver volume estimation relies on precise segmentation of the liver by multi-phase CT images according to the Couinaud classification. A thicknesses of ≥ 1 mm will be used to ensure accurate results. Total liver volume, volume of the deportalized part of the liver, and volume of the FLR will be estimated before and after intervention. Positron emission tomography (PET) with the radioactively labelled galactose analogue 2-\[18F\]fluoro-2-deoxy-D-galactose (FDGal) can be used to quantify whole-liver and regional hepatic metabolic function as well as to measure functional liver volume. The method is validated, simple and with insignificant day-to-day variation. The PET scan is performed after a 4h fast, but the patient is allowed to drink water. In Aarhus, the scanner is a 64-slice Siemens Biograph TruePoint PET/CT camera (Siemens AG, Erlangen, Germany). FDGal (100 MBq) is injected intravenously and a low-dose CT scan (50 effective mAs with CAREDose4D, 120 kV, pitch 0.8, slice thickness 5 mm) is performed for attenuation correction of the PET data and anatomical co-registration. A static PET scan of the mean tissue radioactivity concentration is performed from 10-20 minutes after tracer injection (12). The PET data are corrected for radioactive decay back to injection time and reconstructed with resolution modeling (4 iterations, 21 subsets and 2 mm (18F-FDGal) or 3 mm (18F-FDG) Gaussian filter) and 336 x 336 matrix. The standardized uptake value (SUV; unit-less) is calculated dividing tissue radioactivity concentration (kBq/mL tissue) with the ratio between injected dose (kBq) and body weight (mL tissue, assuming an average tissue density of 1 g/mL tissue). Whole-liver and regional hepatic FDGal-SUVs as well as the functional liver volume are estimated.

Potential benefits, risks, and side-effects Potential benefits As the potential impact of this study is extensive, including the possibility for more patients with CRLM to undergo curative-intent resection, it is our opinion that the benefits by far outweigh the few potential side effects. Only two PET and two CT scans with minimal radiation will be conducted. The blood samples drawn is part of the standard work-up procedure. No additional blood samples will be drawn on the basis of participation in this study.

Radiation dose from PET/CT scans Patients participating in the present study are not sustained to more radiation from imaging modalities than patients not participating. From the low-dose CT-scans, the patient receives an irradiation dose of up to 1 mSv. For FDGal the effective radiation dose is 0.032 mSv/MBq, the administration of 100 MBq FDGal thus gives a dose of 3.2 mSv. The total irradiation dose that each patient receives from two PET and two CT scans is approximately 8.4 mSv which equals three times the average yearly background dose in Denmark. This presents an estimated risk of 1:10.000 for cancer development due to participation in the study. These doses should be seen in connection with the potential benefit for the patient in participating in the study, as mentioned above.

Interventions Potential risks related to the RFA treatment are extremely sparse, and include bleeding, hepatic abscesses, hepatic infarcts, and bile duct injuries. PVE is a safe procedure that causes few adverse effects and can be performed in an outpatient setting. Most large series report 0 % procedure related mortality. Risks include bleeding, infection and displacement of the embolization material. Especially the latest is extremely rare.

Further patient treatment Following calculation of KGR and increase in FLR, patients are re-evaluated with regard to the timing of the second-stage partial hepatectomy. Some patients, especially in the PVE arm, are expected to need further liver hypertrophy before advancing to the partial hepatectomy. Further hypertrophy in a period of 1-3 weeks and a new CT evaluation might be necessary. In some patients, the hypertrophy might be impaired or absent. These patients will be evaluated with regard to other treatment options including salvage ALPPS, which have previously been used in patients with impaired hypertrophy following PVE. The resection rate in each arm will be reported as a secondary endpoint.

Time schedule This study will commence on 1. November 2019. Total study duration is expected to be 24 months for subject recruitment, and an additional six months for data analysis. The investigators expect to finalize the data analysis and present our findings during 2021. The project will begin at Aarhus University Hospital, while the other participating centers will be enrolled as appropriate.

Publications Both positive, negative, and inconclusive results will be published, and presented at scientific meetings. Results will be presented at international scientific congresses, and the investigators will aim for publications in high-impact journals with focus on oncology, radiology, and liver surgery. The study will be registered at www.clinicaltrials.gov.

Financial aspects This study is investigator-initiated, and supported by several Danish foundations (Vissing Fonden \[322.000 DKK (Danish Kroner)\], Knud \& Edith Eriksens Mindefond \[50.000 DKK\], Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat \[148.000 DKK\], Familien Erichsens Mindefond \[98.000 DKK\], Tømmerhandler Vilhelm Bangs Fond \[98.000 DKK\], Riisfort Fonden \[198.000 DKK\], and Neye Fonden \[98.000 DKK\]). Grants from these foundations are given to the principal investigator Prof. Frank Viborg Mortensen, and are administered by Aarhus University Hospital. The grants support running costs related to the project (CT/PET scans, blood samples, RFA needles, etc). The researchers participating in this study are independent from any financial interests. No fee will be paid to the study subjects. Salaries for the scientific staff are already financed by their respective employers.

Ethical considerations The study will be conducted according to the Helsinki Declaration, and following approval by the local ethics committee. The project is registered at the Danish Data Protection Agency in accordance with the Central Denmark Region common registration system. No patient will be included before these permissions are granted. All information involving patients will be handled according to national law on personal data information. The study is covered by the Danish Patient Compensation Authority.

ARAPS Study on Accelerated Liver Regeneration

ARAPS Study: Comparison of Portal Vein Embolization With Radiofrequency Ablation Versus Portal Vein Embolization Alone for Accelerated Liver Regeneration: A Randomized Controlled Trial

FDGal-PET to quantify whole-liver and FLR hepatic metabolic function. The standardized uptake value SUV (unit-less) is calculated for whole liver and FLR.

Number of patients resected following the interventions

Rigshospitalet, Denmark

University of Aarhus

Infections

Behaviors and Mental Disorders

Carcinoma

Liver Cirrhosis

Carcinoma, Hepatocellular

Hepatitis A

Hepatitis C

Hepatitis

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Hepatitis, Viral, Human

Virus Diseases

Communicable Diseases

RNA Virus Infections

Adenocarcinoma

Blood-Borne Infections

Flaviviridae Infections

Quality of Life

Living liver donors. This label may also refer to those evaluated for liver donation who did not go on to donate, i.e., potential living liver donors.

Liver transplant recipients (either living or deceased donor). This label may also refer to those who were evaluated for liver transplantation, but never received a transplant, i.e., potential recipients.

Robert M Merion, MD

Carl L Berg, MD

Jean Emond, MD

There are two principal purposes of this study: 1) to determine whether it is more beneficial for a liver transplant recipient candidate to pursue a living donor liver transplant (LDLT) or wait for a deceased donor liver transplant (DDLT), and 2) to study the impact of liver donation on the donor's health and quality of life.

Adult to adult living donor liver transplantation (LDLT) is a relatively new procedure increasingly used at major transplantation centers. Relatively small numbers of cases are performed at any one center and approaches to the patient and donor are too diverse across centers to provide reliable and generalizable information on donor and recipient outcomes from individual centers. Therefore, a network of nine leading liver transplantation centers and a data coordination center (DCC) has been organized to accrue and follow sufficient numbers of patients being considered for and undergoing LDLT to provide generalizable results from adequately powered studies. This network has established the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL) that will conduct both retrospective and prospective studies of LDLT.

The primary study objective is to analyze the effect of choosing to pursue living liver donation. The principal hypothesis is that pursuit of a living liver allograft leads to decreased pre-transplant morbidity and mortality and better long term outcomes for patients starting from the point at which listed patients have a potential donor evaluated (at least a history and physical examination). Emerging data suggest that LDLT provides an inferior graft because of reduced parenchymal mass and added technical complexity when compared to a whole liver used for DDLT. The magnitude of the disadvantage to the LDLT graft will be assessed by comparing results between LDLT and DDLT from the time of transplant. Finally, a careful and detailed series of studies of potential and actual living liver donors is included as a primary objective because of the tremendous importance of this issue to our understanding of the impact of the procedure.

Secondary objectives will address selected biological and clinical issues in transplantation structured around the comparison between DDLT and LDLT.

whole blood, serum, fixed tissue samples, frozen tissue samples

Adult-to-Adult Living Donor Liver Transplantation Study

Adult-to-Adult Living Donor Liver Transplantation Cohort Study

Donor complications are recorded, and graded using the Clavien scale.

Recipient complications are recorded, and graded using the Clavien scale.

Time from evaluation of a living liver donor until death of the potential recipient, to test the benefit of living liver donation.

Recipient survival from transplant to death. The goal is to compare survival among living donor versus deceased donor recipients.

American Society of Transplant Surgeons

Health Resources and Services Administration (HRSA)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Arbor Research Collaborative for Health

ALPPS is the most recent modification of the techniques developed for Two-stage hepatectomies. ALPPS allows to remove an extensive part of the liver in two steps. In the first step the liver parenchyma is transected along the intended line of resection and the future liver remnant cleaned by partial resections from all tumor tissue in the case of bilobar tumors. To this a portal ligation of the larger liver lobe that will have to be removed is added. After a waiting period of 1-2 weeks the second step is performed in which the deportalized liver is removed to render the patient completely tumor-free. (Ann Surg 2012; 255(3):405-14.)

Other procedures related to ALPPS like banding of the parechyma with portal vein ligation etc.

ALPPS

Pierre Alain Clavien, Prof, MD, PhD

Recently a new method of induce similar hypertrophy in the liver as is observed after hepatectomy has been described and was given the eponym "ALLPS". "ALPPS" stands for Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy (ALPPS).

Since the procedure is used worldwide this international registry was created to enable tracking of cases performed worldwide for safety and outcomes and innovations by the groups involved as well as allows a non-randomized comparison to the conventional methods of portal vein occlusion.

The ALPPS registry is accessible online through the data portal www.allps.net. Registered members recieve access through a member ID and password. Data submission is supported by the SECUTRIAL software, supported by the Clinical Trials center of the University of Zurich.

All data submitted are anonymized before entry through the SECUTRIAL Software. Administration of the registry data is performed through the Department of Visceral and Transplantation Surgery in the University Hospital Zurich and the Clinical Trials Center of the University of Zurich, Switzerland, in collaboration with the Italian Hospital in Buenoas Aires, Argentina.

A Scientific Committee has been appointed to give approval for any data analysis. Any participating center may apply for data analysis.

Particiating International Centers have responsibility for the validity of the data submitted and the respective local institutional review procedures.

Registry of Major Liver Resections Including ALPPS and Other Liver Resections in Two Stages

International Registry to Assess Outcomes of Major Liver Resections Requiring Two Interventions Including the New Operation Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS)

The registry will evaluate the criteria used by study participants to include patients to the ALPPS procedure including tumor type, size, number extent, liver parechymal quality, starting volumes, resection volumes and specific methods of resection or sequneces of methods of resection used.

Primary outcome variablesis perioperative mortality and complications and survival status after 3 months. Data will be entered following the widely accepted Clavien-Dindo classification system .

Outcome variables include long term survival after 3, 6, 12, 18 and 24 month, survival status after 3, 4, and 5 years. If the patient is still alive the data about hepatic recurrence and systemic recurrence will be collected. If there is a recurrence the type of treatment will be recorded.

Outcome variables include liver and renal function after surgery. INR and Total bilirubin as well as creatinine prior to surgery and 5 days after stage 1 and five days after stage 2 are recorded and commonly accepted citeria for postoperative liver and postoperative renal failure are used to assess these 2 types of complications.

Outcome variables include disease specific failure to cure (to completely resect) or disease specific recurrence after 3, 6, 12, 18 and 24 month, survival status after 3, 4, and 5 years. If there is a failure to cure or recurrence, the type of treatment will be recorded.

Outcomes variables include Liver Growth as assessed by imaging-based volumetry between stage 1 and stage 2 (1-12 weeks)as assessed either by computer tomography or magnetic resonance based volumetry

University of Zurich

Hypertrophy

Pathological Conditions, Anatomical

Liver preparation before major hepatectomy : portal vein embolization (PVE) in patient with liver metastases from colo-rectal origin considered as resectable.

Liver preparation before major hepatectomy : Patients with the liver venous deprivation (LVD) technique that combines both PVE and hepatic vein embolization (HVE) during the same procedure.

Simultaneous portal and hepatic vein embolization versus Portal vein embolization, also called venous deprivation OR portal vein embolization.

Liver preparation before major hepatectomy

Boris GUIU, MD

Antoine Bouvier, MD

Bruno LAPUYADE

Romaric Loffroy, MD

Christian Sengel, MD

Agnès Rode, MD

Charles MASTIER, MD

Patrick Chevallier, MD

Anthony DOHAN

Guillaume Vesselle, MD

Oriana Ciacio, MD

Thierry BAERE

The hypothesis is that liver venous deprivation (LVD) could strongly improve hypertrophy of the future remnant liver (FRL) at 3 weeks, as compared to portal vein embolization (PVE) in patient with liver metastases from colo-rectal origin considered as resectable.

Portal vein embolization (PVE) has been widely used to generate hypertrophy of the nonembolized lobe in patients undergoing major hepatectomy in order to prevent small-for-size remnant liver resulting in post-operative liver insufficiency.

Although PVE is a safe and effective procedure, it does not always induce sufficient hypertrophy of the future remnant liver (FRL) even after a long time. In case of insufficient liver regeneration following PVE, some authors suggested to embolize hepatic vein(s) (Hwang, Ann Surg 2009).

Interestingly, the sequential right hepatic vein embolization (HVE) after right PVE demonstrated an incremental effect on the FRL. Although attractive, this approach requires two different procedures and does not spare time as compared to PVE alone.

To shorten and optimize the phase of liver preparation before surgery,the so-called liver venous deprivation (LVD) technique that combines both PVE and HVE during the same procedure was developed.

The aim of this randomized phase II trial is to compare the percentage of change in FRL volume at 3 weeks after LVD or PVE using MRI or CT-scan.

Simultaneous Portal and Hepatic Vein Versus Portal Vein Embolizations for Hypertrophy of the Future Liver Remnant

Simultaneous Portal and Hepatic Vein Embolization Versus Portal Vein Embolization for Hypertrophy of the Future Liver Remnant Before Major Hepatectomy of Non-cirrhotic Liver : a Multicentric Comparative Randomized Phase II Trial

The primary outcomes is to compare the increase in volume of the future remnant liver (FRL)

Toxicities are evaluated according to NCI-CTCAE version 4.03 published 14 June 2010

Post-operative mortality defined as any death within 90 days after surgery or within the hospital stay

Post-operative morbidity defined as the percentages of grade I/II/III/IV/V complications according to Clavien-Dindo classification within the 90 days after surgery or within the hospital stay.

Post-hepatectomy liver failure defined according to the "50-50" criteria or peak bilirubin \>7mg/dL.

Rate of non-resectability due to insufficient FRL defined as the percentage of patients for whom resection will be not attempted due to insufficient FRL

Rate of non-resectability due to tumor progression defined as the percentage of patients for whom resection will not be attempted due to tumor progression.

Rate of per-operative difficulties defined as the percentage of patients for whom per-operative difficulties are encountered by the surgeon

Blood loss are evaluated in mL. Operating time avec evaluated in minutes and transfusion are evaluated by number of packed red blood cells

Rate of R0 resection defined as no microscopic tumor residual

Rate of R1 resection defined as the percentage of patients resected with margin \<1mm

Pre and post-operative liver volumes will be evaluated through CT or MRI acquisitions by calculating whole liver, tumor and FRL volumes

Recurrence-free survival defined as the time from date of randomization to date of recurrence or death from their tumor. Patients alive will be censored at the date of last news.

Overall survival defined as the time from date of randomization to date of death from any cause. Patients alive will be censored at the date of last news.

Evaluation of pre and post-operative liver function will be evaluated using 99mTc mebrofenine scintigraphy through SPECT/CT acquisitions by calculating mebrofenin clearance in %/min/m² of whole liver and FRL at the same time points as CT/MRI

Biomarkers predictive of liver hypertrophy/regeneration are evaluated by blood samples and liver biopies

Federation Francophone de Cancerologie Digestive

University Hospital, Montpellier

Hepatic vein embolization after portal vein embolization

Only portal vein embolization, historical control group

Right hepatic vein embolization

Shin Hwang, MD, PhD

Portal vein embolization (PVE) induces shrinkage of the embolized lobe and compensatory enlargement of the non-embolized lobe, but it does not always induce sufficient liver regeneration. There was no effective method to accelerate liver regeneration in addition to PVE yet.

This study intends to assess the effect of ipsilateral hepatic vein embolization (HVE) performed after Portal vein embolization (PVE) on liver regeneration. During a 1-year study period, preoperative HVE would be performed on 10 or more patients who had shown limited liver regeneration after PVE awaiting right hepatectomy. Sequential application of PVE and HVE may be safe and effective in facilitating contralateral liver regeneration by inducing more severe liver damage than PVE alone.

To prospectively assess the effect of ipsilateral HVE after PVE on liver volume change, this study was designed to continue for 12 months, from March 2007 to February 2008.

This study protocol was approved by our institutional review board, under the condition that, for patient safety, more than one occurrence of accidental coil migration into the heart or lung would lead to study discontinuation. The clinical significance of this risk had not been fully assessed, although it might not be seriously harmful. In addition, informed consent and permission for each PVE and HVE were obtained separately from each patient and/or his/her family members.

The indications for right PVE are patients undergoing right hepatectomy or more extensive liver surgery for hepatobiliary malignancy, but having small FLRs, with mean values less than 40% of total liver volume. Patients with large liver masses are excluded because their parenchymal resection rates were much lower than 60%. For patients with perihilar cholangiocarcinoma, placement of multiple biliary drains was preferred to decompress the entire biliary system, and the timing of PVE was set to when serum total bilirubin level became lower than 5 mg/dL.

The right internal jugular vein was punctured with an 18-gauge needle and a 9-F long sheath (Cook; Bloomington, IN) was inserted. The right hepatic vein (RHV) was selected using a 5-F cobra catheter (Cook) and a 0.035-inch guide wire (Terumo; Tokyo, Japan). Insertion of the guide wire toward the dorsal side was checked with a right lateral view to confirm that it was correctly inserted into the RHV. A 9-F sheath was inserted at the proximal portion of the RHV, followed by placement of a Tulip filter (retrievable vena cava filter; Cook) or a Trap-Ease filter (Cordis; Miami, FL) to prevent migration of deployed coils during embolization of the RHV. The cobra catheter was then advanced into the RHV and the main RHV branches were embolized with coils 8 to 12 mm in diameter (nester embolization coils; Cook).

Multidetector dynamic CT scans were routinely performed before PVE to assess gross liver volume change and tumor progression, and CT scans were performed every week after PVE, HVE, and hepatectomy. All CT images were reconstructed as sections 3 mm thick. The CT images were stored in a Picture Archiving and Communication System (PACS; Petavision; Asan Medical Center, Seoul, Korea), enabling image processing and various measurements including volumetry. In patients undergoing combined caudate resection, the volume of the caudate lobe was not included in the FLR volume. TLV and FLR volume before PVE were used as the baseline liver volumes for liver size comparison.

To assess the histological changes in the livers, 1 cm-sized pieces of liver tissue were excised from the ventral margins of the right posterior section, right anterior section, and left lateral section just after laparotomy. These samples were immediately fixed with 4% paraformaldehyde phosphate solution.

Immunohistochemical stainings were performed using antibody against albumin to assess the synthetic function of the hepatocytes, antibody against proliferating cell nuclear antigen (anti-PCNA) to assess cell replication, and antibody against cleaved caspase-3 to assess apoptosis. Apoptosis was also assayed by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining. Western blots using antibodies against the acute phase proteins TNF-α, caspase-3, Bax, and Bcl-2 were performed to assess the status of proinflammatory cytokine responses. PCNA-positive and caspase-3-positive events were counted in five randomly selected high-power fields on microphotographs.

Specimens for histological examination and histomorphometric analysis were stained with hematoxylin and eosin (H-E). For hepatocyte counts, 10 different HPFs in the same slide were randomly selected.

Ipsilateral Hepatic Vein Embolization After Portal Vein Embolization

Sequential Preoperative Ipsilateral Hepatic Vein Embolization After Portal Vein Embolization to Induce Further Liver Regeneration in Patients With Hepatobiliary Malignancy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Impact of Chemotherapy and Regenerative Markers of Liver Regeneration After Liver Resection for Liver Metastases	NCT04178759	Liver Regenerat... Liver Metastase...	Liver resection	18 Years - 90 Years	Vilnius University
ARAPS Study on Accelerated Liver Regeneration	NCT04107324	Liver Regenerat... Liver Cancer Liver Metastase... Liver Failure	ARAPS PVE	18 Years -	University of Aarhus
Adult-to-Adult Living Donor Liver Transplantation Study	NCT00096733	Cirrhosis Hepatitis C Hepatocellular ...		18 Years -	Arbor Research Collaborative for Health
Registry of Major Liver Resections Including ALPPS and Other Liver Resections in Two Stages	NCT01924741	Liver Neoplasms Liver Regenerat...	ALPPS	18 Years -	University of Zurich
Simultaneous Portal and Hepatic Vein Versus Portal Vein Embolizations for Hypertrophy of the Future Liver Remnant	NCT03841305	Liver Metastasi...	Liver preparati...	18 Years -	University Hospital, Montpellier
Impact of Chemotherapy and Regenerative Markers of Liver Regeneration After Liver Resection for Liver Metastases	NCT04178759	Liver Regenerat... Liver Metastase...	Liver resection	18 Years - 90 Years	Vilnius University
Impact of Chemotherapy and Regenerative Markers of Liver Regeneration After Liver Resection for Liver Metastases	NCT04178759	Liver Regenerat... Liver Metastase...	Liver resection	18 Years - 90 Years	Vilnius University
Ipsilateral Hepatic Vein Embolization After Portal Vein Embolization	NCT00698880	Procedure-Relat... Degree of Liver...	Right hepatic v...	20 Years - 75 Years	Asan Medical Center
Adult-to-Adult Living Donor Liver Transplantation Study	NCT00096733	Cirrhosis Hepatitis C Hepatocellular ...		18 Years -	Arbor Research Collaborative for Health

Spots Global Cancer Trial Database for liver regeneration