Application Of Liver Transplantation Research Articles

Development of a Direct Non-Puncture Device for Measuring Portal Venous Pressure during Liver Transplantation-A Swine Model.

Portal hypertension-related complications pose a significant risk for liver failure post-transplantation. Thus, accurate monitoring of intraoperative portal venous pressure (PVP) is crucial. However, current PVP monitoring techniques requiring direct percutaneous puncture carry the risk of graft damage. In this study, we present an innovative non-puncture PVP monitoring device (PVPMD) using a 3D-printed prototype. PVPMD design is inspired by the sphygmomanometer principle, and strategically encompasses the portal vein and enables precise PVP measurement through blood flow ultrasonography after temporary occlusion. By a series of mini-pig experiments, the prototype PVPMD demonstrated a strong correlation with invasive catheter measurements in the main trunk of the portal vein (rs = 0.923, p = 0.000). There was a significant repeatability and reproducibility between the prototype PVPMD- and invasive catheter-measured PVP. This indicates that the PVPMD holds immense potential for direct application in liver transplantation and surgery. Moreover, it has the potential to replace catheter-based central venous pressure (CVP) measurements, thereby mitigating catheter-related complications during many surgeries. In conclusion, our innovative device represents a significant advancement in PVP monitoring during liver transplantation, with comprehensive validation from principle exploration to successful animal experiments. We anticipate that this groundbreaking PVPMD will attract the attention of researchers and clinicians, propelling the noninvasive measurement of PVP or other venous/arterial pressures into a new era of clinical practice.

Central role of Prominin-1 in lipid rafts during liver regeneration

Prominin-1, a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigate the role of Prominin-1 in lipid rafts during liver regeneration and show that expression of Prominin-1 increases after 2/3 partial hepatectomy or CCl4 injection. Hepatocyte proliferation and liver regeneration are attenuated in liver-specific Prominin-1 knockout mice compared to wild-type mice. Detailed mechanistic studies reveal that Prominin-1 interacts with the interleukin-6 signal transducer glycoprotein 130, confining it to lipid rafts so that STAT3 signaling by IL-6 is effectively activated. The overexpression of the glycosylphosphatidylinsositol-anchored first extracellular domain of Prominin-1, which is the domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in liver-specific Prominin-1 knockout mice. In summary, Prominin-1 is upregulated in hepatocytes during liver regeneration where it recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis, suggesting that Prominin-1 might be a promising target for therapeutic applications in liver transplantation.

Volumetric assessment of hepatic grafts using a light detection and ranging system for 3D scanning: Preliminary data.

BACKGROUNDLiver transplantation has evolved into a safe life-saving operation and remains the golden standard in the treatment of end stage liver disease. The main limiting factor in the application of liver transplantation is graft shortage. Many strategies have been developed in order to alleviate graft shortage, such as living donor partial liver transplantation and split liver transplantation for adult and pediatric patients. In these strategies, liver volume assessment is of paramount importance, as size mismatch can have severe consequences in the success of liver transplantation.AIMTo evaluate the safety, feasibility, and accuracy of light detection and ranging (LIDAR) 3D photography in the prediction of whole liver graft volume and mass.METHODSSeven liver grafts procured for orthotopic liver transplantation from brain deceased donors were prospectively measured with an LIDAR handheld camera and their mass was calculated and compared to their actual weight.RESULTSThe mean error of all measurements was 17.03 g (range 3.56-59.33 g). Statistical analysis of the data yielded a Pearson correlation coefficient index of 0.9968, indicating a strong correlation between the values and a Student’s t-test P value of 0.26. Mean accuracy of the measurements was calculated at 97.88%.CONCLUSIONOur preliminary data indicate that LIDAR scanning of liver grafts is a safe, cost-effective, and feasible method of ex vivo determination of whole liver volume and mass. More data are needed to determine the precision and accuracy of this method.

Application of machine learning in liver transplantation: a review.

Machine learning (ML) has been increasingly applied in the health-care and liver transplant setting. The demand for liver transplantation continues to expand on an international scale, and with advanced aging and complex comorbidities, many challenges throughout the transplantation decision-making process must be better addressed. There exist massive datasets with hidden, non-linear relationships between demographic, clinical, laboratory, genetic, and imaging parameters that conventional methods fail to capitalize on when reviewing their predictive potential. Pre-transplant challenges include addressing efficacies of liver segmentation, hepatic steatosis assessment, and graft allocation. Post-transplant applications include predicting patient survival, graft rejection and failure, and post-operative morbidity risk. In this review, we describe a comprehensive summary of ML applications in liver transplantation including the clinical context and how to overcome challenges for clinical implementation. Twenty-nine articles were identified from Ovid MEDLINE, MEDLINE Epub Ahead of Print and In-Process and Other Non-Indexed Citations, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. ML is vastly interrogated in liver transplantation with promising applications in pre- and post-transplant settings. Although challenges exist including site-specific training requirements, the demand for more multi-center studies, and optimization hurdles for clinical interpretability, the powerful potential of ML merits further exploration to enhance patient care.

Current and Potential Applications for Indocyanine Green in Liver Transplantation.

Indocyanine green (ICG) is a fluorescent dye taken up and almost exclusively cleared by the liver. Measurement of its clearance and visualization of its fluorescence make it suitable for a number of potential applications in liver transplantation including assessment of liver function and real-time assessment of arterial, venous, and biliary structures. ICG clearance can be used to assess donor graft quality before procurement and graft metabolic function before transplant using normothermic ex vivo machine perfusion. ICG clearance in the post-liver transplantation period is able to predict recipient outcomes with correlations to early allograft dysfunction and postoperative complications. After absorbing light in the near-infrared spectrum, ICG also emits fluorescence at 835 nm. This allows the assessment of vascular patency after reconstruction and patterns of liver perfusion in real time. ICG perfusion patterns after revascularization are also associated with posttransplant graft function and survival. ICG fluorescence cholangiography is routine in a number of centers and acts as an aid to identifying the optimal point of bile duct division during living donor liver transplantation to optimize safety for both donor and recipient. In summary, ICG is a versatile tool and has a number of useful applications in the liver transplantation journey including assessment of liver function, perfusion assessment, and cholangiography. Further research and clinical trials are required to validate and standardize its routine use in liver transplantation.

Liver Transplantation in Patients with Acute-onChronic Liver Failure: Challenging the Limits

Acute-on-chronic liver failure (ACLF) is one of the main causes of death on the waiting list. Liver transplantation (LT) is the only curative treatment for patients with ACLF and therefore it should be considered in all cases. However, the applicability of LT in patients with ACLF is challenging, given the scarcity of donors and the high short-term mortality of these patients. Organ allocation has traditionally been prioritised according to the model for end-stage liver disease (MELD) system. However, the accuracy of MELD score is limited in patients with ACLF. In this article, the authors review the outcomes of patients with ACLF before and after LT, highlighting its clinical course, the feasibility of LT in the sickest patients, the role of the organ allocation system, and possible indicators of futility.

The Precise Relationship Between Model for End-Stage Liver Disease and Survival Without a Liver Transplant.

Scores from the Model for End-Stage Liver Disease (MELD), which are used to prioritize candidates for deceased donor livers, are widely acknowledged to be negatively correlated with the 90-day survival rate without a liver transplant. However, inconsistent and outdated estimates of survival probabilities by MELD preclude useful applications of the MELD score. Using data from all prevalent liver waitlist candidates from 2016 to 2019, we estimated 3-day, 7-day, 14-day, 30-day, and 90-day without-transplant survival probabilities (with confidence intervals) for each MELD score and status 1A. We used an adjusted Kaplan-Meier model to avoid unrealistic assumptions and multiple observations per person instead of just the observation at listing. We found that 90-day without-transplant survival has improved over the last decade, with survival rates increasing >10% (in absolute terms) for some MELD scores. We demonstrated that MELD correctly prioritizes candidates in terms of without-transplant survival probability but that status 1A candidates' short-term without-transplant survival is higher than that of MELD 40 candidates and lower than that of MELD 39 candidates. Our primary result is the updated survival functions themselves. We calculated without-transplant survival probabilities for each MELD score (and status 1A). The survival function is an invaluable tool for many applications in liver transplantation: awarding of exception points, calculating the relative demand for deceased donor livers in different geographic areas, calibrating the pediatric end-stage liver disease score, and deciding whether to accept an offered liver.

Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure

Hepatectomy is an effective therapeutic strategy for many benign and malignant liver diseases, while the complexity of liver anatomy and the difficulty of operation lead to complications after hepatectomy. Among them, post-hepatectomy liver failure (PHLF) is the main factor threatening the life of patients. At present, liver transplantation is an effective approach for PHLF. However, the application of liver transplantation has been largely limited due to the shortage of donors and the high cost of such operation. Therefore, it is urgently necessary to develop a new treatment for PHLF. Mesenchymal stem cells (MSCs) have become a new treatment regimen for liver diseases because of their easy access and low immunogenicity. Our study found that there were some subtle connections between MSCs and liver lipid metabolism in the PHLF model. We used MSC transplantation to treat PHLF induced by 90% hepatectomy. MSC transplantation could restore the mitochondrial function, promote the β-oxidation of fatty acid (FA), and reduce the lipid accumulation of hepatocytes. In addition, interleukin 10 (IL-10), a cytokine with immunoregulatory function, had an important role in lipid metabolism. We also found that MSCs transplantation activated the mammalian target of rapamycin (mTOR) pathway. Therefore, we explored the relationship between mitochondrial damage and lipid metabolism abnormality or PHLF. MSCs improved mitochondrial function and corrected abnormal lipid metabolism by affecting the mTOR pathway in the treatment of PHLF. Collectively, MSC transplantation could be used as a potential treatment for PHLF.

Surgical Aspects of Liver Transplantation and Domino Liver Transplantation in Maple Syrup Urine Disease: Analysis of 15 Donor-Recipient Pairs.

Liver transplantation (LT) has been shown to be a feasible treatment in patients with severe forms of maple syrup urine disease (MSUD). Because of a sufficient extrahepatic enzyme activity in non-MSUD individuals, the organ of MSUD patients can be used as a domino graft. We performed a retrospective data collection of all LTs for MSUD carried out at the University Medical Center Hamburg-Eppendorf (2016-2018). Moreover, data from all consecutive domino LTs of the MSUD grafts either transplanted at our institution or allocated to other transplant centers were analyzed. During the study period, 15 LTs in MSUD patients were performed (12 children, 3 adults; median age, 10.9years; range, 0.3-26.1years). Biliary complications occurred in 20%, and 13.3% suffered from bleeding complications. No further surgical problems occurred. At present, all MSUD patients are alive with a well-functioning liver graft and on an unrestricted diet. In total, 14 consecutive domino LTs were performed. No surgical complications requiring intervention occurred. One patient died because of HCC relapse, and all other patients are alive with good liver graft function. In conclusion, the use of MSUD livers as domino grafts is safe and allows application of LT in MSUD patients without net extraction of a liver graft from the limited donor pool.

Remnant vital tissue following locoregional therapy for hepatocellular carcinoma: another player in the game.

The applicability of liver transplantation (LT) as a curative option for patients with hepatocellular carcinoma (HCC) is limited by organ shortage. In addition to tumor size and number, other variables, particularly those that are surrogates of tumor biology should be incorporated into the allocation policies to improve the estimation of post-LT benefit. In this issue of Transplant International, Manzia etal. analyze the role of remnant vital tissue (RVT) of the target lesion after locoregional therapies (LRT) in predicting post-LT HCC recurrence This article is protected by copyright. All rights reserved.

Liver perfusion devices: how close are we to widespread application?

Ex-situ liver machine perfusion has been the focus of increasing interest over the past decade as a means to improve the quality of livers for transplantation and the applicability of liver transplantation in general. The present review aims to evaluate the experimental basis for liver machine perfusion and the significance of recent reports on its clinical application. Although liver machine perfusion has been studied experimentally over a range of temperatures, clinical liver transplant work that has been performed to date has been done using either hypothermic machine perfusion (0-12 °C), HMP or normothermic machine perfusion (35-38 °C, NMP). Both HMP and NMP have been studied clinically in the context of phase I trials demonstrating the feasibility of their application. It has also been shown through a small number of cases that NMP may serve as a useful means to evaluate initially discarded livers to determine viability for subsequent transplantation. Although initial clinical results are promising, higher level evidence is still needed to justify more widespread application of machine perfusion in human liver transplantation.

Umbilical cord mesenchymal stem cells and their association with liver fibrosis

At present, the most effective therapeutic method for end-stage liver fibrosis is liver transplantation. However, the application of liver transplantation is limited by a shortage of liver donors, a high incidence rate of surgical complications, graft-versus-host disease, and high medical costs. Umbilical cord mesenchymal stem cell (UC-MSC) transplantation may become a promising method for the treatment of liver diseases. UC-MSCs are adult stem cells which exhibit multipotential differentiation and can differentiate into hepatic parenchymal cells. Due to their functions including immune regulation and secretion of trophic factors, UC-MSCs can inhibit immune response, promote hepatocyte regeneration, alleviate the progression of liver fibrosis, and improve liver function. In addition, compared with bone marrow mesenchymal stem cells, UC-MSCs have abundant sources, noninvasive collection, and high safety and thus they are attracting more and more attention. This article reviews the characteristics of UC-MSCs and their mechanism of action in the treatment of liver fibrosis, as well as risks of UC-MSCs therapy.

Can we prevent ischemic-type biliary lesions in donation after circulatory determination of death liver transplantation?

The pool of livers for transplantation consists of an increasingly greater proportion of marginal grafts, in particular those arising through donation after circulatory determination of death (DCD). However, a primary factor limiting the use of marginal livers, and, thereby, the applicability of liver transplantation in general, is concern over the subsequent development of ischemic-type biliary lesion (ITBL). ITBL is a devastating complication of liver transplantation; in its most severe forms, recipients suffer frequent infectious complications that require repeated invasive biliary procedures and ultimately result in either retransplantation or death. In the present review article, we discuss our current understanding of ITBL pathogenesis as it pertains to DCD, in particular. We discuss the most relevant theories regarding its development and provide a comprehensive overview of the most promising strategies we have available today to prevent the appearance of ITBL, strategies that may, furthermore, allow us to transplant a greater proportion of marginal livers in the future. Liver Transplantation 22 1025-1033 2016 AASLD.

Application of hyperbaric oxygen in liver transplantation.

In recent years, hyperbaric oxygen (HBO) has been used in the treatment of a lot of diseases such as decompression sickness, arterial gas embolism, carbon dioxide poisoning, soft tissue infection, refractory osteomyelitis, and problematic wound, but little is known about its application in liver transplantation. Although several studies have been conducted to investigate the protective effects of HBO on liver transplantation and liver preservation, there are still some controversies on this issue, especially its immunomodulatory effect. In this short review, we briefly summarize the findings supporting the application of HBO during liver transplantation (including donors and recipients).

Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis

Background & Aims: Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. Methods: Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. Results: Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) =0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR=0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. Conclusions: For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible.

Application of contrast-enhanced ultrasound after liver transplantation: Current status and perspectives.

Liver transplantation is an effective treatment for patients with end-stage liver disease. Accurate imaging evaluation of the transplanted patient is critical for ensuring that the limited donor liver is functioning appropriately. Ultrasound contrast agents (UCAs), in combination with contrast-specific imaging techniques, are increasingly accepted in clinical use for the assessment of the hepatic vasculature, bile ducts and liver parenchyma in pre-, intra- and post-transplant patients. We describe UCAs, their technical requirements, the recommended clinical indications, image interpretation and the limitations for contrast-enhanced ultrasound applications in liver transplantation.

Long-term results of biliary atresia in the era of liver transplantation

The purpose of this study was to analyze the survival of patients with biliary atresia (BA) after Kasai operation and liver transplantation (LT) and to analyze the factors affecting survival. Seventy-two patients diagnosed with BA were operated on between April 1995 and December 2009 and retrospectively analyzed. Out of the 72 patients, 59 received Kasai operation and 13 received LT without prior Kasai operation. Twenty-seven patients received LT after Kasai operation. Survival with native liver was 39 % at 10 years. With the application of LT, overall 10-year survival for patients with BA was 94.9 %. Among patients alive with native livers after Kasai operation, 14 patients (58.3 %) have at least one complication associated with biliary cirrhosis and portal hypertension. Age at which Kasai operation was performed (60 days) and postoperative normalization of bilirubin were independent risk factors for survival with the native liver, according to multivariate analysis (HR 2.90, p = 0.033 and HR 9.89, p = 0.002). Survival of BA patients has greatly increased in the era of LT. However, many patients surviving with native livers after Kasai operation continue to have signs of biliary cirrhosis and abnormal liver function.

A clinical study on the anatomy of hepatic veins and its applications in liver transplantation: a report on 248 patients

Objective To investigate the anatomy and the variations of hepatic veins draining into the inferior vena cava (IVC),and to classify the surgical techniques of piggyback liver transplantation (PBLT) based on the anatomy of the hepatic veins.Method 248 PBLT were preformed in our hospital from May 2000 to Aug.2007.The anatomy of the hepatic veins were noted on resection of the recipient livers.The anatomy of the 3 major hepatic veins (HV) and the short hepatic veins (SHV) draining into IVC was recorded.Results Of the 248 recipient livers,the left and middle hepatic veins joined as a single trunk in 142 patients (type Ⅰ,57.2％); the right and middle hepatic vein joined as a single trunk in 54 patients (type Ⅱ,21.7％) ; three hepatic veins joined as single trunk in 14 patients (type Ⅲ,5.6％); the left,right and middle hepatic veins were all separate in 34 patients (16 patients in the same horizontal plane,type ⅣA,6％; 18 patients in different horizontal planes type ⅣB,7％); and there were no major hepatic veins but only short hepatic veins which drained into IVC in 4 patients (type Ⅴ,1.6％).Conclusions In patients who had type Ⅰ,Ⅱ or Ⅲhepatic vein anatomy,a classical piggyback liver transplantation (CPBLT) could be carried out.In nearly half of the type Ⅳ (type ⅣA) patients who had the hepatic veins draining into the IVC in the same horizontal plane,CPBLT could also be performed on these patients.For the type ⅣB and type V patients,ameliorative piggyback liver transplantation (APBLT) with an end to-side or a side-to-side cavo-caval anastomosis only could be carried out.The study showed that the classification of hepatic vein anatomy can help us to choose the type of PBLT. Key words: Hepatic vein; Classification; Liver transplantation technology

Complications and Long-Term Results of Salvage Cystectomy After Failed Bladder Sparing Therapy for Muscle Invasive Bladder Cancer

Radical cystectomy has been the standard treatment for muscle invasive bladder cancer. Combined modality therapy involving transurethral bladder tumor resection, external beam radiation and chemotherapy is an effective alternative to cystectomy in selected patients. Salvage cystectomy is reserved for those in whom combined modality therapy fails. We characterized complications associated with salvage cystectomy. From 1986 to 2007 of 348 patients undergoing bladder sparing therapy 102 (29%) underwent salvage cystectomy, 91 of whom were treated at Massachusetts General Hospital after receiving combined modality therapy for T2-T4aNxM0 bladder cancer. Patients underwent transurethral bladder tumor resection followed by chemoradiation (40 Gy). Early assessment was performed by cystoscopy/re-biopsy. Patients with complete response continued with consolidation chemoradiation (total dose 64 Gy). Immediate salvage cystectomy (50 of 91) was performed for persistent disease, while delayed salvage cystectomy (41 of 91) was performed for an invasive recurrence. Complications were classified using the Clavien system. Median patient age was 69.4 years (range 27.5 to 88.9) and median living patient followup was 12 years (range 0 to 23). Of the patients 99% (90 of 91) underwent ileal diversion. Complications of any grade within 90 days occurred in 69% (63 of 91) of patients and 16% (15 of 91) experienced major complications within 90 days. Of the patients 21% (19 of 91) required hospital readmission within 90 days. The 90-day mortality rate was 2.2% (2 of 91). Significant cardiovascular/hematological complications (pulmonary embolism, myocardial infarction, deep vein thrombosis, transfusion) within 90 days were more common in the immediate than in the delayed cystectomy group (37% vs 15%, p = 0.02). Tissue healing complications (fascial dehiscence, wound infection, ureteral stricture, anastomotic stricture, stoma/loop revisions) were more common in the delayed than in the immediate cystectomy group (35% vs 12%, p = 0.05). Salvage cystectomy is associated with acceptable morbidity, although complication rates are slightly higher than for other cystectomy series. Immediate cystectomies have more cardiovascular/hematological complications while delayed cystectomies have more tissue healing complications.

Milan criteria in liver transplantation for hepatocellular carcinoma: An evidence-based analysis of 15 years of experience

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third most common cause of cancer-related deaths; the number of new cases per year is approaching 750,000. The magnitude of the incidence of HCC has discouraged any attempts to apply liver transplantation (LT) as the prevailing curative therapy for HCC worldwide because of the limited sources of donated organs (deceased and living donors) and the poor access to sophisticated health care systems in some geographical areas. If these limitations continue to prevail throughout the world, any attempt to significantly reduce HCC-related mortality rates through the application of LT will be delusional. International experiences have confirmed, however, the potential of LT to definitively cure HCC because it presents a unique opportunity to remove both the tumor (HCC is associated with 695,000 deaths per year) and the underlying cirrhosis. Despite its limited access, LT has become the standard of care for patients with small HCCs and the main driving force for alternative strategies offered to patients with intermediate HCCs. In 1996, a prospective cohort study defined restrictive selection criteria that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. Since then, these selection criteria have become universally known as the Milan criteria (MC) in recognition of their origin. Ever since their adoption in clinical practice, the MC have helped doctors to single out early-stage HCC as a prognostic category of cancer presentation that is amenable to curative treatments. After their implementation, the favorable posttransplant outcomes that were observed in cohort series were so convincing that the MC immediately became the standard of care for early HCC, and further validation by randomized controlled trials (RCTs) was prevented. After the passage of approximately a decade, researchers began to challenge the MC with other proposals designed to capture those patients not meeting the MC who could achieve similar posttransplant survival rates through the expansion of the accepted tumor limits for transplant eligibility. None of these expanded criteria have become the new reference standard for selecting LT candidates with HCC; any broadening of the selection criteria for transplantation is inevitably hampered by severe