Advancing immunosuppression in liver transplantation: A narrative review

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Liver transplantation and liver resection as alternative treatments for primary hepatobiliary and secondary liver tumors: Competitors or allies?

Although Starzl designed in the 1960’s liver transplantation(LT)to treat unresectable primary and also secondary liver tumors,transplantation still occupies a(too)small place in the respective therapeutic algorithms[1].Due to the lack of(any)selection criteria,the concept of transplantation became rapidly challenged because of the prohibitively high incidence of tumor recurrence[1–3].

免疫抑制和肝移植

完美的手术技术和充分的免疫抑制是确保最佳移植物和患者存活的关键。不同药物的可用性导致了一些通常由行业驱动的不同类型的临床试验,以发现理想的免疫抑制方案。然而,大量且概念不同的研究设计未能明确定义最佳免疫抑制方案。基于钙调神经磷酸酶抑制剂他克莫司、抗代谢药物霉酚酸酯或硫唑嘌呤和短期类固醇(除了可能的诱导外)为基础的三联免疫抑制方案仍然是目前公认的肝移植标准免疫抑制方案。然而,鉴于排斥定义的变化、免疫抑制负荷的定制以及由于慢性免疫抑制引起的长期副作用,未来的试验最好包括一个以上的终点,而不是急性T细胞介导的急性排斥(a-TCMR)或肾衰竭。相反,需要一个涵盖患者和移植物存活率以及急性和慢性排斥反应发生率的综合终点。这些免疫现象应根据一系列长期的生物学和组织学随访进行检查。临床相关a-TCMR的诊断和治疗应基于综合生物学、免疫学和组织病理学发现。这两个要素对于朝着更谨慎的免疫抑制处理和有利于临床操作耐受性的方向发展至关重要。

Adult-to-adult living-donor liver transplantation: The experience of the Université catholique de Louvain

Background: Liver transplantation is the treatment for end-stage liver diseases and well-selected malignancies. The allograft shortage may be alleviated with living donation. The initial UCLouvain experience of adult living-donor liver transplantation(LDLT) is presented. Methods: A retrospective analysis of 64 adult-to-adult LDLTs performed at our institution between 1998 and 2016 was conducted. The median age of 29(45.3%) females and 35(54.7%) males was 50.2 years(interquartile range, IQR 32.9–57.5). Twenty-two(34.4%) recipients had no portal hypertension. Three(4.7%) patients had a benign and 33(51.6%) a malignant tumor [19(29.7%) hepatocellular cancer, 11(17.2%) secondary cancer and one(1.6%) each hemangioendothelioma, hepatoblastoma and embryonal liver sarcoma]. Median donor and recipient follow-ups were 93 months(IQR 41–159) and 39 months(22–91), respectively. Results: Right and left hemi-livers were implanted in 39(60.9%) and 25(39.1%) cases, respectively. Median weights of right-and left-liver were 810 g(IQR 730–940) and 454 g(IQR 394–534), respectively. Graft-to-recipient weight ratios(GRWRs) were 1.17%(right, IQR 0.98%-1.4%) and 0.77%(left, 0.59%-0.95%). One-and five-year patient survivals were 85% and 71%(right) vs. 84% and 58%(left), respectively. Oneand five-year graft survivals were 74% and 61%(right) vs. 76% and 53%(left), respectively. The patient and graft survival of right and left grafts and of very small( < 0.6%), small(0.6%–0.79%) and large( ≥0.8%) GRWR were similar. Survival of very small grafts was 86% and 86% at 3-and 12-month. No donor died while five(7.8%) developed a Clavien–Dindo complication IIIa, IIIb or IV. Recipient morbidity consisted mainly of biliary and vascular complications; three(4.7%) recipients developed a small-for-size syndrome according to the Kyushu criteria. Conclusions: Adult-to-adult LDLT is a demanding procedure that widens therapeutic possibilities of many hepatobiliary diseases. The donor procedure can be done safely with low morbidity. The recipient operation carries a major morbidity indicating an important learning curve. Shifting the risk from the donor to the recipient, by moving from the larger right-liver to the smaller left-liver grafts, should be further explored as this policy makes donor hepatectomy safer and may stimulate the development of transplant oncology.

Secondary non-resectable liver tumors:A single-center living-donor and deceased-donor liver transplantation case series

Background: During the last decades, deceased-donor liver transplantation (DDLT) has gained a place in the therapeutic algorithm of well-selected patients harbouring non-resectable secondary liver tumors. Living-donor LT (LDLT) might represent a valuable means to further expand this indication for LT. Methods: Between 1985 and 2016, twenty-two adults were transplanted because of neuroendocrine ( n = 18, 82%) and colorectal metastases ( n = 4, 18%);50% received DDLT and 50% LDLT. In LDLT, 4 (36%) right and 7 (64%) left grafts were used;the median graft-to-recipient-weight ratios (GRWR) were 1.03%(IQR 0.86%- 1.30%) and 0.59%(IQR 0.51%- 0.91%), respectively. Median post-LT follow-up was 64 months (IQR 17–107) in the DDLT group and 40 months (IQR 35–116) in the LDLT group. DDLT and LDLT recipients were compared in terms of overall survival, graft survival, postoperative complications and recurrence. Results: The 1- and 5-year actuarial patient survivals were 82% and 55% after DDLT, 100% and 100% after LDLT, respectively ( P < 0.01). One- and 5-year actuarial graft survivals were 73% and 36% after DDLT, 91% and 91% after LDLT ( P < 0.01). The outcomes of right or left LDLT were comparable. Donor hepatectomy proved safe, and one donor experienced a Clavien IIIb complication. Bilirubin peak was significantly lower after left hepatectomy compared with that after right hepatectomy [1.3 (IQR 1.2–2.2) vs. 3.3 (IQR 2.3–5.2) mg/dL;P = 0.02]. Conclusions: The more recent LDLT series compared favorably to our DDLT series in the treatment of secondary liver malignancies. The absence of portal hypertension and the use of smaller left grafts make recipient and donor surgeries safe. The safety of the procedures and lack of interference with the scarce allograft pool are expected to lead to a more frequent use of LDLT in the field of transplant oncology.

Indocyanine green fluoroscopy and liver transplantation:a new technique for the intraoperative assessment of bile duct vascularization

To the Editor:Biliary tract complications remain the Achilles’heel of liver transplantation（LT）;and the transplant commu nity is exploring ways of tackling this problem.A well vascularized bile duct is a prerequisite for successful bile duct reconstruction.Vascular assessment is usually per formed by evaluating the macroscopic aspects of both

Alpha-fetoprotein and 18F-FDG standard uptake value predict tumor recurrence after liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis:Preliminary experience

Background:Portal vein tumor thrombosis(PVTT)is regarded as a contraindication for liver transplantation(LT)in hepatocellular carcinoma(HCC).However,some of these patients may have a favorable prognosis after LT.In this study,we evaluated the biological behavior of HCC with PVTT using tumor biomarker(alpha-fetoprotein,AFP)and 18 F-FDG positron emission tomography(tumor standard uptake value)to identify a subset of patients who may be suitable for LT.Methods:Seventy-five HCC-PVTT liver recipients transplanted during February 2016 and June 2018 were analyzed.Different pre-transplant prognostic factors were identified by univariate and multivariate analyses.PVTT status was identified following Vp classification(Vp1-Vp4).Results:Three-year recurrence-free survival and overall survival rates were 40%and 65.4%in Vp2-Vp3 PVTT patients,21.4%and 30.6%in Vp4 PVTT patients(P<0.05).Total tumor diameter>8 cm,pretransplant AFP level>1000 ng/m L and intrahepatic tumor maximal standard uptake value(SUVmaxtumor>5)were independent risk factors for HCC recurrence and overall survival after LT in Vp2-3 PVTT patients.Low risk patients were defined as total tumor diameter≤8 cm;or if total tumor diameter more than 8 cm,with both pre-transplant AFP level less than 1000 ng/m L and intrahepatic tumor SUVmax less than 5,simultaneously.Twenty-two Vp2-3 PVTT HCC patients(46.8%)were identified as low risk patients,and their 3-year recurrence-free and overall survival rates were 67.6%and 95.2%,respectively.Conclusions:Patients with segmental or lobar PVTT and biologically favorable tumors defined by AFP and 18 F-FDG SUVmax might be suitable for LT.

Selection tool alpha-fetoprotein for patients waiting for liver transplantation: How to easily manage a fractal algorithm

Alpha-fetoprotein(AFP) behavior in patients with hepatocellular carcinoma(HCC) waiting for liver transplant(LT) represents a perfect biological example of a fractal model in which its progressive modification and possible future prediction of its values are very hard to capture. As a consequence, AFP represents a useful but poorly manageable tool to increase the ability to better select HCC patients waiting for LT. Trying to find a "filrouge" in the recent literature, no definitive answers can be done to several open questions:(1) the best AFP value to adopt;(2) the best cut-off measurement; and(3) the best way to comfortably capture the effective, time-related, fluctuations of this biological marker. More, structured and prospective, studies using serial determination of AFP values within and without the context of locoregional therapies are needed in order to find the "ideal"(static and dynamic) cut-off values allowing to respond to all the still open questions in this field of transplant oncology.

How regenerative medicine and tissue engineering may complement the available armamentarium in gastroenterology?

The increasing shortage of donors and the adverse effects of immunosuppression have restricted the impact of solid organ transplantation.Despite the initial promising developments in xenotransplantation,roadblocks still need to be overcome and this form of organ support remains a long way from clinical practice.While hepatocyte transplantation may be effectively correct metabolic defects,it is far less effective in restoring liver function than liver transplantation.Tissue engineering,using extracellular matrix scaffolds with an intact but decellularized vascular network that is repopulated with autologous or allogeneic stem cells and/or adult cells,holds great promise for the treatment of failure of organs within gastrointestinal tract,such as endstage liver disease,pancreatic insufficiency,bowel failure and type 1 diabetes.Particularly in the liver field,where there is a significant mortality of patients awaiting transplant,human bioengineering may offer a source of readily available organs for transplantation.The use of autologous cells will mitigate the need for long term immunosuppression thus removing a major hurdle in transplantation.

From portal to splanchnic venous thrombosis:What surgeons should bear in mind

The present study aims to review the evolution of surgical management of portal(PVT) and splanch-nic venous thrombosis(SVT) in the context of liver transplantation over the last 5 decades. PVT is more commonly managed by endovenous thrombectomy, while SVT requires more complex technical expedients. Several surgical techniques have been proposed, such as extensive eversion thrombectomy, anastomosis to collateral veins, reno-portal anastomosis, cavo-portal hemi-transposition, portal arterialization and combined liver-intestinal transplantation. In order to achieve satisfactory outcomes, careful planning of the surgical strategy is mandatory. The excellent results that are ob-tained nowadays confirm that, even extended, splanch-nic thrombosis is no longer an absolute contraindication for liver transplantation. Patients with advanced portal thrombosis may preferentially be referred to specialized centres, in which complex vascular approaches and even multivisceral transplantation are performed.

Three-dimensional modeling in complex liver surgery and liver transplantation

Liver resection and transplantation are the most effective therapies for many hepatobiliary tumors and diseases.However,these surgical procedures are challenging due to the anatomic complexity and many anatomical variations of the vascular and biliary structures.Three-dimensional(3D)printing models can clearly locate and describe blood vessels,bile ducts and tumors,calculate both liver and residual liver volumes,and finally predict the functional status of the liver after resection surgery.The 3D printing models may be particularly helpful in the preoperative evaluation and surgical planning of especially complex liver resection and transplantation,allowing to possibly increase resectability rates and reduce postoperative complications.With the continuous developments of imaging techniques,such models are expected to become widely applied in clinical practice.

Complex hepatic outflow reconstruction in domino liver transplantation

Domino liver transplantation has been accepted as a safe procedure to further expand the organ donor pool. The most important technical challenge of the procedure resides in restoring a proper hepatic venous allograft outflow in the familial amyloidotic polyneuropathy-liver recipient. To overcome this issue, combined techniques were used to perform an innovative outflow reconstruction. A domino liver transplantation was successfully performed with reconstruction of complex venous outflow. The inferior vena cava sparing hepatectomy technique in the familial amyloidotic polyneuropathy-donor was used to cut the hepatic vein to the liver parenchyma. To overcome this issue the venous outflow tract was reconstructed using a longitudinally opened iliac vein graft from a post-mortem donor to create a new outflow tract using a diamond patch between the right and middle/left hepatic veins.

Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience

Background:During the last decades,several risk factors for the recurrence of hepatocellular carcinoma(HCC)after liver transplantation(LT)have been investigated.However,the impact of two important drivers of oncogenesis,namely the immunosuppression and the treatment of acute cellular rejection(ACR)have been marginally addressed.This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population.Methods:Seven hundred and eighty-one adult patients transplanted between February 1,1985 and June 30,2016 were retrospectively analyzed.After propensity score match,116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR.Results:Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients(16.4%vs.0.9%;P<0.0001).At multivariate Cox regression analysis,steroid boluses used to treat ACR were an independent risk factor for HCC recurrence(HR=14.2;95%CI:1.8–110.4;P=0.010).Conclusions:The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results.Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.

Symptomatic Val122del mutated hereditary transthyretin amyloidosis: Need for early diagnosis and prioritization for heart and liver transplantation

Background: Hereditary transthyretin(ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and misfolding they reassemble as insoluble fibrils(i.e. amyloid). Apart from the common Val30 Met mutation there is a very heterogeneous group of non-Val30 Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy. Methods: A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122 del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed. Results: Three patients needed a staged(1 patient) or simultaneous(2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac(allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months. Conclusions: This is the first report in(liver) transplant literature about the rare Val122 del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.

Meso-Rex bypass for the management of extrahepatic portal vein obstruction in adults(with video)

Background:Extrahepatic portal vein obstruction(EHPVO)results in severe portal hypertension(PHT)leading to severely compromised quality of life.Often,pharmacological and endoscopic management is unable to solve this problem.Restoring hepatic portal flow using meso-Rex bypass(MRB)may solve it.This procedure,uncommon in adult patients,is considered the treatment of choice for EHPVO in children.Methods:From 1997 to 2018,8 male and 6 female adults,with a median age of 51 years(range 22-66)underwent MRB procedure for EHPVO at the University Hospitals Saint-Luc in Brussels,Belgium.Symp-toms of PHT were life altering in all but one patient and consisted of repetitive gastro-intestinal bleedings,sepsis due to portal biliopathy,and/or severe abdominal discomfort.The surgical technique consisted in interposition of a free venous graft or of a prosthetic graft between the superior mesenteric vein and the Rex recess of the left portal vein.Results:Median operative time was 500 min(range 300-730).Median follow-up duration was 22 months(range 2-169).One patient died due to hemorrhagic shock following percutaneous transluminal interven-tion for early graft thrombosis.Major morbidity,defined as Clavien-Dindo score≥III,was 35.7%(5/14).Shunt patency at last follow-up was 64.3%(9/14):85.7%(6/7)of pure venous grafts and only 42.9%(3/7)of prosthetic graft.Symptom relief was achieved in 85.7%(12/14)who became asymptomatic after MRB.Conclusions:Adult EHPVO represents a difficult clinical condition that leads to severely compromised quality of life and possible life-threatening complications.In such patients,MRB represents the only and last resort to restore physiological portal vein flow.Although successful in a majority of patients,this procedure is associated with major morbidity and mortality and should be done in tertiary centers expe-rienced with vascular liver surgery to get the best results.

Living donor liver transplantation:A complex but worthwhile undertaking

Since its’first applications in clinical pediatric and adult liver transplantation practice by Strong et al.and Makuuchi in 1989[1,2],living donor liver transplantation(LDLT)has been an ever increasing part of the today’s practice of liver transplantation.Based on different donor demographics(living donation vs.deceased donation)and on much larger experiences with partial liver resection(aggressive resection in cirrhotic patients versus non-surgical,locoregional treatments),LDLT merely developped in Asian countries.Indeed nowadays,this technique accounts for more than 90%of the transplantation activity in the Eastern hemisphere,whereas it accounts only for 5%of activities in the Western one[3,4].

Gastrointestinal tract post-transplant lymphoproliferative disorder after liver transplantation

To the Editor:Post-transplant lymphoproliferative disorder（PTLD）is a rare and potentially fatal complication occurring after all types of solid organ transplantation.;PTLD accounts for 20%of all de novo post-transplant tumors.;The most important risk factors for PTLD are prolonged intense immunosuppression and Epstein-Barr virus（EBV）

Modern technology,liver surgery and transplantation

Since the first right hepatectomy performed by Jean-Louis Lortat-Jacob on October 16,1951 and the first liver transplantation by Thomas Earl Starzl on March 1,1963,hepatobiliary surgery and liver transplantation had a spectacular development[1,2].After the hesitating beginning in the 1950’s and 1960’s,their evolution really took off in the 1980’,reaching high-speed velocity in the 21st century.

5th INTERNATIONAL LIVING DONOR LIVER TRANSPLANTATION CONGRESS "EXCELLENCE THROUGH VERSATILITY"

OCTOBER 15-16,2021 WELCOME ADDRESS FROM THE CONGRESS PRESIDENTS Dear Members,Dear Colleagues,Dear Friends,It is our great pleasure and honor to invite you to particpate in the 5th International Congress of the iLDLT Group that will take place in Brussels on Friday October 15 and Saturday 16,2021.This event will be organised in collaboration with the Belgian Section of Hepato-Bilo-Pancreatic Surgery(BSHBPS)of the Royal Belgian Society for Surgery(RBSS).Indeed theⅩⅩⅠst annual,Postgraduate Course of the BHBPS has been officially integrated in the iLDLT Congress.The biennial iLDLT meeting follows the very successful previous ones,which took place twice in Seoul(SKr)and once in Dallas(US)and Kaohsiung(China).As the Western world still hesitates to embrace this therapeutic modality,the iLDLTG council found it opportune to"export"the congress to Europe.

5th INTERNATIONAL LIVING DONOR LIVER TRANSPLANTATION CONGRESS “EXCELLENCE THROUGH VERSATILITY” OCTOBER 15-16, 2021 WELCOME ADDRESS FROM THE CONGRESS PRESIDENTS

Dear Members,Dear Colleagues,Dear Friends,It is our great pleasure and honor to invite you to particpate in the 5th International Congress of the iLDLT Group that will take place in Brussels on Friday October 15 and Saturday 16,2021.This event will be organised in collaboration with the Belgian Section of Hepato-Bilo-Pancreatic Surgery(BSHBPS)of the Royal Belgian Society for Surgery(RBSS).Indeed the XXIst annual,Postgraduate Course of the BHBPS has been officially integrated in the iLDLT Congress.