Clinical value of [18F]AlF-NOTA-FAPI-04 PET/CT for assessing early-stage liver fibrosis in adult liver transplantation recipients compared with chronic HBV patients.

AIMS: To investigate the clinical value and performance of [18F]AlF-NOTA-FAPI-04 PET/CT in assessing early-stage liver fibrosis in liver transplantation (LT) recipients. METHODS: A prospective study including 17 LT recipients and 12 chronic Hepatitis B (CHB) patients was conducted. All patients received liver biopsy, transient elastography (TE), and [18F]AlF-NOTA-FAPI-04 PET/CT. On [18F]AlF-NOTA-FAPI-04 PET/CT scans, the liver parenchyma's maximum standardized uptake values (SUVmax) were measured. The receiver operating characteristic (ROC) curve analysis was applied to determine the diagnostic efficacy of [18F]AlF-NOTA-FAPI-04 PET/CT in early-stage liver fibrosis (S1-S2) compared with the diagnostic performance of TE. RESULTS: Among those 29 patients enrolled in this study, 15(51.7%) had fibrosis S0, 10(34.5%) had S1, and 4(13.8%) had S2, respectively. The SUVmax of patients with early-stage liver fibrosis was significantly higher than those without liver fibrosis in LT recipients and CHB patients (P = 0.004, P = 0.02). In LT recipients, a SUVmax cut-off value of 2.0 detected early-stage liver fibrosis with an AUROC of 0.92 (P = 0.006), and a liver stiffness measurements (LSM) score cut-off value of 8.2 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.80 (P = 0.012). In CHB patients, a SUVmax cut-off value of 2.7 detected early-stage liver fibrosis with an AUROC of 0.94 (P < 0.001) and an LSM scores cut-off value of 8.4 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.91 (P < 0.001). CONCLUSION: [18F]AlF-NOTA-FAPI-04 PET/CT could be applied to evaluate early-stage liver fibrosis in LT recipients and CHB patients properly, with the potential additional advantages in monitoring and predicting complications after LT.

Sirolimus improves the prognosis of liver recipients with hepatocellular carcinoma: A single-center experience.

BACKGROUND: Tumor recurrence after liver transplantation (LT) for selective patients diagnosed with hepatocellular carcinoma (HCC) in the setting of cirrhosis is the greatest challenge effecting the prognosis of these patients. The aim of this study was to evaluate the efficacy of sirolimus on the prognosis for these recipients. METHODS: The data from 193 consecutive HCC patients who had undergone LT from January 2015 to December 2019 were retrospectively analyzed. These patients were divided into the sirolimus group [patients took sirolimus combined with calcineurin inhibitors (CNIs) (n = 125)] and non-sirolimus group [patients took CNI-based therapy without sirolimus (n = 68)]. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. The prognostic factors and independent risk factors for RFS and OS were further evaluated. RESULTS: Non-sirolimus was an independent risk factor for RFS (HR = 2.990; 95% CI: 1.050-8.470; P = 0.040) and OS (HR = 3.100; 95% CI: 1.190-8.000; P = 0.020). A higher proportion of patients beyond Hangzhou criteria was divided into the sirolimus group (69.6% vs. 80.9%, P = 0.030). Compared with the non-sirolimus group, the sirolimus group had significantly better RFS (P < 0.001) and OS (P < 0.001). Further subgroup analysis showed similar results. CONCLUSIONS: This study demonstrated that sirolimus significantly decreased HCC recurrence and prolonged RFS and OS in LT patients with different stage of HCC.

Marginal donor liver versus standard donor liver: A single-center observational study.

BACKGROUND: The effectiveness and safety of marginal donor livers remain controversial. This study aimed to investigate the clinical efficacy of marginal donor livers in patients with liver transplantation (LT). METHODS: This study included 199 liver donors (including 16 split donors) and 206 liver recipients from January 1, 2018 to January 27, 2020, with case follow-up until July 31, 2021. Clinical data of donors and recipients were retrospectively analyzed and were divided into the marginal donor and standard donor groups according to the criteria of marginal donor livers. Indices of liver and kidney functions, complications, and survival curves of the two groups were compared. RESULTS: Compared with the standard donor group, the blood creatinine levels were significantly higher in the marginal donor group in the first week after operation (P < 0.05); there were no significant differences in alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels after LT (all P > 0.05); there was no significant difference in the incidence of complications after LT (P > 0.05); there was also no significant difference in the survival curve (P = 0.335). CONCLUSIONS: There were no significant differences in liver and kidney function and survival curve between the standard donor and marginal donor groups. The marginal donor liver appears safe and reliable for LT and may be an important strategy to expand the donor pool and solve the shortage of organs.

Hypoxia inducible factor 1α promotes interleukin-1 receptor antagonist expression during hepatic ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. However, the regulatory mechanism of IL-1ra expression is still unclear. AIM: To identify the mechanism that could protect the liver in the early stage of IRI. METHODS: To screen the key genes in hepatic IRI, we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI. Subsequently, we verified the expression and effect of IL-1ra in hepatic IRI. We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor (HIF)-1α. Finally, to explore the protective mechanism of ischemic preconditioning (IP), we examined the expression of HIF-1α and IL-1ra after IP. RESULTS: We identified IL-1ra as a key regulator in hepatic IRI. The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro. Furthermore, we found that HIF-1α regulated Il-1ra transcription in response to hypoxia. Increased HIF-1α accumulation promoted IL-1ra expression, whereas inhibition of HIF-1α exhibited the opposite effect. We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1α activation. Of note, we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression, which is mediated through HIF-1α. CONCLUSION: We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α. Importantly, IP protects the liver from IRI via the HIF-1α-IL-1ra pathway.

An analysis report on the application of immune checkpoint inhibitors after liver transplantation.

Up to now, a variety of immune checkpoint inhibitors (ICIs) have been proved to have good therapeutic effects in the treatment of hepatocellular carcinoma (HCC). However, the effects of their applications in liver transplant (LT) recipients are still unclear. In this analysis report, the clinical applications and therapeutic effects of ICIs on LT recipients with hepatic tumor recurrence or de novo carcinoma based on eight databases, including PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Infrastructure, Wanfang Data, and CQVIP, were investigated. And the prior treatment, disease response, adverse reactions, and prognosis of patients with malignant tumors after LT and receiving ICI treatments were analyzed. After screening, a total of 28 articles with 47 recipients on the application of ICIs after LT were included. In these patients, their median age was 57 (14-71) years and the main type of tumor after LT was HCC (59.6%). The overall remission rate following ICI treatment was 29.8% (14/47) and the disease progression rate was 68.1% (32/47). Among all these patients, 31.9% (15/47) of patients had immune rejection; the median survival time was 6.5 (0.3-48) months, and the fatality rate was 61.7% (29/47). Considering that the therapeutic effect of ICIs in LT recipients with HCC recurrence or de novo carcinoma is not ideal, ICI treatment should be carefully considered for LT patients, and further research is needed.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

NOD1 activates autophagy to aggravate hepatic ischemia-reperfusion injury in mice.

Hepatic ischemia/reperfusion injury (IRI) is tissue damage resulting from return of the blood supply to the tissue after a period of ischemia or lack of oxygen. Much of the morbidity associated with liver transplantation and major hepatic resections is, in part, due to IRI. Both innate immunity and autophagy play important roles in hepatic IRI. With regard to innate immunity, one factor that plays a key role is NOD1, an intracellular pattern recognition receptor. NOD1 has recently been shown to be associated with autophagy, but the mechanisms involved with this process remain obscure. This relationship between NOD1 and autophagy prompted us to examine the role and potential mechanisms of NOD1 in regulating autophagy as related to hepatic IRI. We found that NOD1 was upregulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. Moreover, levels of Atg5, a critical protein associated with autophagy, were decreased when NOD1 was inhibited by NOD1 small interfering RNA. We conclude that NOD1 appears to exert a pivotal role in hepatic IRI by activating autophagy to aggravate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of NOD1 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.

MiR-27a-5p regulates apoptosis of liver ischemia-reperfusion injury in mice by targeting Bach1.

Ischemia-reperfusion (I/R) injury causes cellular dysfunction and a series of immune or apoptotic reactions. Bach1 is a mammalian transcription factor that represses Hmox1, which encodes heme oxygenase-1 (HO-1) that can degrade heme into free iron, carbon monoxide, and biliverdin, to play an important role in antioxidant, anti-inflammatory, and antiapoptotic activities. MicroRNAs (miRNAs) can be found in a variety of eukaryotic cells and viruses, a class of noncoding small RNAs that are encoded by endogenous genes. The aims of this study were to determine whether miR-27a-5p targets Bach1 and regulates cellular death; the dual-luciferase reporter assay was used to detect this and the results showed that miR-27a-5p significantly decreased the luciferase activity of the Bach1 3'-untranslated region. MiR-27a-5p was increased in mice during hepatic I/R and Bach1 was decreased. By transfecting the AML12 cells with the mimic, inhibitor miR-27a-5p in hypoxia/reoxygenation (H/R) models showed that overexpression of miR-27a-5p decreased Bach1 messenger RNA, upregulated HO-1 expression, and promoted antiapoptotic Bcl-2 and downregulated proapoptotic caspase-3 gene expression. In contrast, the miR-27a-5p inhibitor yielded the opposite results. Meanwhile, transfection with Bach1 small interference RNA obviously upregulated the protein levels of HO-1 and resulted in an increase in Bcl-2 and a decrease in caspase-3 protein levels. Thus, we can conclude that miR-27a-5p is relevant to liver I/R injury and overexpression of miR-27a-5p may alleviate apoptosis in H/R injury by targeting Bach1 in vitro.

Effect of graft size matching on pediatric living-donor liver transplantation at a single center.

We retrospectively analyzed 252 patients with end-stage liver disease who had undergone LDLT from January 2009 to September 2015. Of these, 25 had a GRWR of <2.0% (Group A), 204 had a GRWR of ≥2.0% or <4.0% (Group B), and 23 had a GRWR ≥4.0% (Group C). The three GRWR groups demonstrated similar characteristics, except for recipient age and recipient BMI. The overall 1-, 2-, and 3-year graft survival rates were 95.1%, 93.5%, and 93.5%, respectively. However, among the three groups, graft survival rates at 1 year, 2 years, and 3 years were significantly different (P = .0009). Hepatic artery stenosis/thrombosis was more frequently observed in Group C than in Groups A and B (P = .001). Wound infection was also more frequently observed in Group C than in Group A and B (P = .002). However, intestinal fistula/bile leakage/biliary-enteric anastomotic fistula was more frequently observed in Group A than in Groups B and C (P = .001). In addition, reoperation more frequently occurred in Group A and C than in Group B (P = .001). Recipients with a GRWR between 2.0% and 4.0% had significantly better graft survival rates.

Simultaneous liver, pancreas-duodenum and kidney transplantation in a patient with hepatitis B cirrhosis, uremia and insulin dependent diabetes mellitus.

Simultaneous liver, pancreas-duodenum, and kidney transplantation has been rarely reported in the literature. Here we present a new and more efficient en bloc technique that combines classic orthotopic liver and pancreas-duodenum transplantation and heterotopic kidney transplantation for a male patient aged 44 years who had hepatitis B related cirrhosis, renal failure, and insulin dependent diabetes mellitus (IDDM). A quadruple immunosuppressive regimen including induction with basiliximab and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids was used in the early stage post-transplant. Postoperative recovery was uneventful and the patient was discharged on the 15th postoperative day with normal liver and kidney function. The insulin treatment was completely withdrawn 3 wk after operation, and the blood glucose level remained normal. The case findings support that abdominal organ cluster and kidney transplantation is an effective method for the treatment of end-stage liver disease combined with uremia and IDDM.

Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature.

Mesenchymal hamartomas of the liver (MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography (CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen included intraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg (dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL.

[Middle hepatic treatment algorithm in right lobe living donor liver transplantation for donor recipient safety].

OBJECTIVE: The treatment algorithm of donor middle hepatic vein (MHV) was made depending on the remnant liver volume of the total donor liver volume as calculated by computer tomography, estimated graft-to-recipient weight ratio and also anatomy. The present study was to analyze the influence of this algorithm upon the safety of donors and recipients in right lobe living donor liver transplantation (LDLT) and to provide references for our future clinical practices. METHODS: Data of 73 consecutive LDLT cases, operated and managed by the same surgical team according to the pre-operation MHV treatment algorithm, were analyzed. MHV was harvested in 28 cases and not in 45 cases. Donor and recipient gender, age, weight, operation time, blood loss volume, graft weight, non-hepatic phase, graft cold preservation time, perioperative survival rate and the incidence of small-for-size syndrome were compared, and also the peak post-operative values of ALT, AST, T-bilirubin and D-bilirubin. RESULTS: No donor needed blood transfusion and suffered small-for-size syndrome. One recipient recovered from small-for-size syndrome successfully by medical interventions. One recipient had acute hepatic necrosis at Day 6 post-operation and was converted into cadaveric liver transplantation. At Day 30 post-operation, one recipient died from disseminated infections and respiratory failure, but his liver function was normal. There was significant difference in donor and recipient age, actual GRWR, graft cold preservation time and recipient's ALT peak value between the MHV harvest group and the MHV non-harvest group. CONCLUSION: The MHV treatment algorithm is safe to both donors and recipients.

[Clinical analysis of donor hepatectomy in living donor liver transplantation: report of 74 cases].

OBJECTIVE: To evaluate the living donor selection, donor hepatectomy technique, and surgical complication in living donor liver transplantation. METHODS: From June 2007 to July 2008, 74 consecutive cases living donor hepatectomy were performed by the same surgical team. Seventy-four donors (64 males and 10 females) with a mean age of 29.2 years old passed the donor liver assessment and evaluation program successfully. The hepatectomy procedure types contained right liver resection (n = 72), of which 27 cases harvested the middle hepatic vein and 45 cases not, left liver resection contain middle hepatic vein (n = 1) and left lateral resection (n = 1). RESULTS: Of all the donors, operation time was (6.5 +/- 6.2) hours, the mean blood loss was 300 ml (100 - 500 ml) and didn't accept foreign blood transfusion. The maximum alanine aminotransferase (ALT) level was (229.5 +/- 108.6) U/L, the ALT returned to normal time was (12.7 +/- 4.8) d, the maximum total bilirubin (TB) level was (78.7 +/- 44.3) micromol/L, the TB returned to normal time was (8.8 +/- 2.7) d, and the mean hospital stay time was 14 days (7 - 28 d). The complications included bile leak (n = 1), cut surface hemorrhage (n = 1) and anaphylactoid purpura (n = 1). All the donors returned to normal work and life finally. CONCLUSIONS: Precisely evaluating donor blood vascular and biliary anatomy before operation, keeping the blood vascular and bile duct integrity during operation and monitoring complication to solve it immediately after operation is crucial to ensure donor safety and recovering successfully.

Liver retransplantation for ischemic-type biliary lesions after orthotopic liver transplantation: a clinical report of 66 cases.

BACKGROUND: Ischemic-type biliary lesions (ITBLs) play an extremely important role in influencing the long-term survival and quality of life of recipients after orthotopic liver transplantation (OLT). Some patients can be cured by interventional therapies, however others lose their grafts at last and receive liver retransplantation (re-OLT). The aim of this study was to analyze the data of 66 patients who had received re-OLT at our center because of ITBL and to discuss the treatment of ITBL after OLT. METHODS: We retrospectively analyzed 66 re-OLT cases due to ITBL from September 2001 to February 2007 at our center. The Kaplan-Meier method and the Cox-Mantel test were used to identify factors associated with mortality for univariate analysis and multivariate analysis, respectively. RESULTS: Fifty-five of 66 ITBL cases underwent interventional therapies before re-OLT. The actuarial survival at 1 month and 1 year for these patients was 83% and 74%, respectively. Prognostic factors for mortality in univariate analysis were model of end-stage liver disease score (MELD) >16.5 (Chi(2)=5.856, P=0.016), cold ischemia time >8 hours (Chi(2)=6.539, P=0.011), infections (Chi(2)=5.550, P=0.018) and complications (Chi(2)=12.168, P=0.002) after re-OLT. In the multivariate analysis (Cox regression), the risk factors independently associated with mortality were MELD score >16.5 (RR: 3.140; P=0.035), cold ischemia time >8.2 hours (RR: 0.192; P=0.016) and complications (RR: 3.896, P=0.003). CONCLUSIONS: The incidence of ITBL in China is higher than in other countries. Based on our experience, MELD score, cold ischemia time and complications after re-OLT are risk factors independently associated with mortality in retransplanted ITBL patients.

[Analysis of survival rate and risk factors of liver retransplantation].

OBJECTIVES: To analyze the survival rate of orthotopic liver retransplantation (Re-OLT) and identify the variables predicting the outcome. METHODS: A retrospective analysis of 74 Re-OLT patients from January 1999 to December 2005 was performed. The univariate analysis of Kaplan-Meier model was used to investigate the relativity between the factors and survival rate, and COX regression model was used in multivariate analysis to identify the prognostic factors for survival. RESULTS: The total incidence rate of Re-OLT was 5.7%, and overall patient survival rates at 1 month, 3 month, 1 year and 2 year were 82.4%, 73.8%, 71.9% and 68.5%, respectively. There were 10 factors might influence the survival rate by Kaplan-Meier model, such as the period of Re-OLT, stage of hepatic encephalopathy, prothrombin time, total bilirubin, warm ischemia time, operative surgical procedure, quantity of blood lost during operation, days staying in the intensive care unit (ICU), infection and complications after Re-OLT. And three factors among them were identified as independent prognostic factors for survival by multivariate model: operative surgical procedure, days staying in the ICU and complications after Re-OLT. CONCLUSION: The surgical procedure, duration in ICU and complications after Re-OLT are strong predictors for survival after Re-OLT.

[Clinical study of liver re-transplantation].

OBJECTIVE: To report experiences of liver re-transplantation. METHODS: The cause of re-transplantation, the pre-operative MELD score, timing of re-transplantation, technical considerations, 1 year survival rate and the causes of death of the patients receiving liver re-transplantation in First Central Hospital of Tianjin between January 1999 and December 2005 were retrospectively analyzed. RESULTS: One year survival rate of re-transplantation was 71.6%. The most common cause of hepatic graft failure and subsequent re-transplantation was biliary complications (45.5%). The 1 year survival rate of patients with a MELD score less than 20 was higher than patients with a score of 20 approximately 30 and > 30 (83.8% versus 57.1% and 66.7%). The peri-operative survival rate of patients who received re-transplantation 30 days after the initial transplantation was higher than those who received re-transplantation between 8 to 30 days post the first operation (83.8% versus 41.7%). The main cause of peri-operative death was celiac infections (accounted for 54.2% deaths) in the patients. CONCLUSIONS: Proper indication selection, optimum operation time, right surgical procedure, intensified peri-operative monitoring and infection control are all crucial for the improvement of survival rate in patients receiving liver re-transplantation.