Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.

Comparison of the long-term outcomes of patients with hepatocellular carcinoma within the Milan criteria treated by ablation, resection, or transplantation.

BACKGROUND: Liver transplantation (LT), resection (LR), and ablation (LA) are three curative-intent treatment options for patients with early hepatocellular carcinoma (HCC). We aimed to develop a prognostic calculator to compare the long-term outcomes following each of these therapies. METHODS: A total of 976 patients with HCC within the Milan criteria who underwent LT, LR, and LA between 2009 and 2019 from four institutions were evaluated. Multistate competing risks prediction models for recurrence-free survival (RFS), recurrence within the Milan criteria (RWM), and HCC-specific survival (HSS) were derived to develop a prognostic calculator. RESULTS: During a median follow-up of 51 months, 420 (43%) patients developed recurrence. In the multivariate analysis, larger tumor size, multinodularity, older age, male, higher alpha-fetoprotein (AFP), higher albumin-bilirubin (ALBI) grade, and the presence of portal hypertension were significantly associated with higher recurrence and decreased survival rates. The RFS and HSS were both significantly higher among patients treated by LT than by LR or LA and significantly higher between patients treated by LR than by LA (all p < 0.001). For multinodular HCC ≤3 cm, although LT had better RFS and HSS than LR or LA, LA was noninferior to LR. An online prognostic calculator was then developed based on the preoperative clinical factors that were independently associated with outcomes to evaluate RFS, RWM, and HSS at different time intervals for all three treatment options. CONCLUSIONS: Although LT resulted in the best recurrence and survival outcomes, LR and LA also offered durable long-term alternatives. This prognostic calculator is a useful tool for clinicians to guide an informed and personalized discussion with patients based on their tumor biology and liver function.

Suture ligation for submucosal hemostasis during hand-sewn side-to-side duodeno-ileostomy in simultaneous pancreas and kidney transplantation.

BACKGROUND: Enteric anastomotic (EA) bleeding is a potentially life-threatening surgical complication associated with enteric anastomosis during simultaneous pancreas and kidney transplantation (SPKT). AIM: To investigate whether suture ligation (SL) for submucosal hemostasis during hand-sewn enteric anastomosis could decrease the morbidity of early EA bleeding in SPKT. METHODS: We compared the outcomes of 134 patients classified into SL (n = 44) and no SL (NSL) groups (n = 90). This study adheres to the declarations of Istanbul and Helsinki and all donors were neither paid nor coerced. RESULTS: During the first postoperative week, the EA bleeding rate in the SL group was lower than that in the NSL group (2.27% vs 15.56%; P = 0.021); no relationship was found between EA bleeding and donor age, mean pancreatic cold ischemia time, platelet count, prothrombin time international normalized rate, activated partial thromboplastin time, and thrombin time. Anastomotic leakage was observed in one case in the SL group at postoperative day (POD) 14 and in one case at POD 16 in the NSL group (P = 0.754). No significant difference was found between the two groups in the patient survival, pancreas graft survival, or kidney graft survival. CONCLUSION: SL for submucosal hemostasis during hand-sewn enteric anastomosis in SPKT can decrease the morbidity of early EA bleeding without increasing the anastomotic leakage rate.

[Supergenes:Generalists in Gene Expression].

In eukaryote cells,transcription from genome DNA is a key process of gene expression.The transcription products contain not only messenger RNAs that code proteins,but also various types of non-coding RNAs.During transcription,some of the gene loci produce more than one kind of RNA molecule,including coding RNAs and more often non-coding RNAs.These gene loci that generate several kinds of RNA molecules are named supergenes.According to the transcription pattern,supergenes are divided into three types,known as types Ⅰ,Ⅱ and Ⅲ.In this review,we summarize the transcription pattern of each type of supergene,and exposit the role of these genes in cells.

Simultaneous partial splenectomy during liver transplantation for advanced cirrhosis patients combined with severe splenomegaly and hypersplenism.

BACKGROUND: The most effective treatment for advanced cirrhosis and portal hypertension is liver transplantation (LT). However, splenomegaly and hypersplenism can persist even after LT in patients with massive splenomegaly. AIM: To examine the feasibility of performing partial splenectomy during LT in patients with advanced cirrhosis combined with severe splenomegaly and hypersplenism. METHODS: Between October 2015 and February 2019, 762 orthotopic LTs were performed for patients with end-stage liver diseases in Tianjin First Center Hospital. Eighty-four cases had advanced cirrhosis combined with severe splenomegaly and hypersplenism. Among these patients, 41 received partial splenectomy during LT (PSLT group), and 43 received only LT (LT group). Patient characteristics, intraoperative parameters, and postoperative outcomes were retrospectively analyzed and compared between the two groups. RESULTS: The incidence of postoperative hypersplenism (2/41, 4.8%) and recurrent ascites (1/41, 2.4%) in the PSLT group was significantly lower than that in the LT group (22/43, 51.2%; 8/43, 18.6%, respectively). Seventeen patients (17/43, 39.5%) in the LT group required two-stage splenic embolization, and further splenectomy was required in 6 of them. The operation time and intraoperative blood loss in the PSLT group (8.6 ± 1.3 h; 640.8 ± 347.3 mL) were relatively increased compared with the LT group (6.8 ± 0.9 h; 349.4 ± 116.1 mL). The incidence of postoperative bleeding, pulmonary infection, thrombosis and splenic arterial steal syndrome in the PSLT group was not different to that in the LT group, respectively. CONCLUSION: Simultaneous PSLT is an effective treatment and should be performed in patients with advanced cirrhosis combined with severe splenomegaly and hypersplenism to prevent postoperative persistent hypersplenism.

Clinical progress of auxiliary liver transplantation.

After half a century of development, auxiliary liver transplantation (ALT) technology gradually matured and major indications of ALT have been gradually expanded. This review summarized the history of ALT and introduced indications for ALT which including metabolic liver disease, fulminant hepatic failure, highly sensitized kidney transplantation, prevention of hepatic resection of small hepatic syndrome, etc.; at the same time, the hot issues related to ALT were discussed, including the regulation of hepatic portal blood flow of transplanted liver and residual liver, how to treat the graft liver and remaining liver on second stage. Additionally, the expansion of indications for ALT which included the implementation of ALT for patients with liver cancer and ALT for patients with liver cirrhosis was discussed. It was believed that ALT can greatly alleviate the contradiction of insufficient source of graft liver.

Heme oxygenase-1-modified bone marrow mesenchymal stem cells combined with normothermic machine perfusion to protect donation after circulatory death liver grafts.

BACKGROUND: Donation after circulatory death (DCD) liver grafts have a poor prognosis after transplantation. We investigated whether the outcome of DCD donor organs can be improved by heme oxygenase 1 (HO-1)-modified bone marrow-derived mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP), and explored its underlying mechanisms. METHODS: BMMSCs were isolated, cultured, and transduced with the HO-1 gene. An NMP system was established. DCD rat livers were obtained, preserved by different methods, and the recipients were divided into 5 groups: sham operation, static cold storage (SCS), NMP, BMMSCs combined with NMP, and HO-1/BMMSCs combined with NMP (HBP) groups. Rats were sacrificed at 1, 7, and 14 days after surgery; their blood and liver tissue samples were collected; and liver enzyme and cytokine levels, liver histology, high-mobility group box 1 (HMGB1) levels in monocytes and liver tissues, and expression of Toll-like receptor 4 (TLR4) pathway-related molecules were evaluated. RESULTS: After liver transplantation, the SCS group showed significantly increased transaminase levels, liver tissue damage, and shorter survival time. The HBP group showed lower transaminase levels, intact liver morphology, prolonged survival time, and decreased serum and liver proinflammatory cytokine levels. In the NMP and SCS groups, HMGB1 expression in the serum, monocytes, and liver tissues and TLR4 pathway-related molecule expression were significantly decreased. CONCLUSIONS: HO-1/BMMSCs combined with NMP exerted protective effects on DCD donor liver and significantly improved recipient prognosis. The effect of HO-1/BMMSCs was greater than that of BMMSCs and was mediated via HMGB1 expression and TLR4 pathway inhibition.

CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction.

During the process of human islet isolation a cascade of stressful events are triggered and negatively influence islet yield, viability, and function, including the production of proinflammatory cytokines and activation of apoptosis. Carbon monoxide-releasing molecule 2 (CORM-2) is a donor of carbon monoxide (CO) and can release CO spontaneously. Accumulating studies suggest that CORM-2 exerts cytoprotective and anti-inflammatory properties. However, the effect of CORM-2 on islet isolation is still unclear. In this study, we found that CORM-2 pretreatment significantly decreased the expression of critical inflammatory genes, including tissue factor, intercellular adhesion molecule-1, chemokine (C-C motif) ligand 2, C-X-C motif chemokine 10, Toll-like receptor 4, interleukin-1ß, interleukin-6, and tumor necrosis factor-α (TNF-α). The isolated islets of the CORM-2 pretreatment group showed reduced apoptotic rate, improved viability, and higher glucose-stimulated insulin secretion, and functional gene expression in comparison to control group. Importantly, CORM-2 pretreatment prevented the impairment caused by TNF-α, evidenced by the improved glucose-stimulated index and transplantation outcomes. The present study demonstrated the anti-inflammatory property of CORM-2 during human islet isolation, and we suggest that CORM-2 pretreatment is an appealing treatment to mitigate inflammation-mediated islet dysfunction during isolation and culture ex vivo and to preserve long-term islet survival and function.

Bone marrow mesenchymal stem cells combine with normothermic machine perfusion to improve rat donor liver quality-the important role of hepatic microcirculation in donation after circulatory death.

Donation after circulatory death (DCD) can expand the donor pool effectively. A gap remains in outcome between DCD livers and living donor livers, warranting improved DCD liver quality and urgent resolution. Bone marrow mesenchymal stem cells (BMMSCs) can regulate immunity, participate in the anti-inflammatory response, and secrete cytokines. We investigated the effect of BMMSCs combined with normothermic machine perfusion (NMP) on DCD liver quality, and the role of microcirculation therein. Rat thoracic aortas were clipped to obtain DCD livers, and a rat NMP system was established. The DCD livers were grouped by preservation method: normal, static cold storage (SCS), NMP (P), and BMMSCs plus NMP (BP); storage time was up to 8 h. Liver function in outflow perfusate was detected by biochemical methods; liver tissue histopathology was observed by hematoxylin-eosin staining; hepatocyte ultrastructure was observed by transmission electron microscopy; hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling; liver microcirculation-related indicators were detected by immunofluorescence, immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay. Compared with SCS, P and BP significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis, and repaired hepatocyte mitochondrial damage after 6 h in vitro. BP also significantly inhibited intrahepatic macrophage activation and intercellular adhesion, improved endothelial damage, and significantly improved endothelin 1-nitric oxide balance and microcirculation perfusion. In conclusion, BP can improve DCD liver microcirculation and quality. The mechanism may be the improvement of improve hepatic sinusoidal endothelial injury and microcirculation perfusion by inhibiting macrophage activation and intercellular adhesion.

Normothermic Machine Perfusion Combined with Bone Marrow Mesenchymal Stem Cells Improves the Oxidative Stress Response and Mitochondrial Function in Rat Donation After Circulatory Death Livers.

There is a need to improve the quality of donor liver from donation after circulatory death (DCD). The purpose of this study was to investigate the effects and mechanism of normothermic machine perfusion (NMP) combined with bone marrow mesenchymal stem cells (BMMSCs) on the oxidative stress and mitochondrial function in DCD livers. DCD livers were obtained, a rat NMP system was established, and BMMSCs were extracted and identified. The DCD livers were grouped by their preservation method: Normal, static cold storage (SCS), NMP (P), and NMP combined with BMMSCs (PB), and the preservation time was up to 8 h. An IAR20 cell oxidative stress injury model was established in vitro by simulating DCD oxidative stress injury and coculturing with BMMSCs for 6 h. Compared with SCS group, after 6 h in vitro, the PB and P groups had significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis and oxidative stress, improved hepatocyte mitochondrial damage, and increased mitochondrial membrane potential. These indicators were significantly better in the PB group than in the P group. BMMSCs significantly inhibited reactive oxygen species release from the IAR20 cell oxidative stress model in vitro, ameliorated mitochondrial damage, and increased mitochondrial membrane potential level. BMMSCs also downregulated the JUN N-terminal kinase-nuclear factor kappa B (JNK-NF-κB) signaling pathway significantly in the IAR20 cell oxidative stress model and promoted AMP-activated protein kinase (AMPK) activation. We verified that NMP combined with BMMSCs also played the same role in the PB group. NMP combined with BMMSCs could improve liver quality by relieving oxidative stress injury and improving mitochondrial function in rat DCD livers. The mechanism of protective role might involve inhibiting the JNK-NF-κB pathway to reduce oxidative stress and promote AMPK activation, thereby reducing mitochondrial damage and increase mitochondrial function.

Complex liver retransplantation to treat graft loss due to long-term biliary tract complication after liver transplantation: A case report.

BACKGROUND: Loss of graft function after liver transplantation (LT) inevitably requires liver retransplant. Retransplantation of the liver (ReLT) remains controversial because of inferior outcomes compared with the primary orthotopic LT (OLT). Meanwhile, if accompanied by vascular complications such as arterial and portal vein (PV) stenosis or thrombosis, it will increase difficulties of surgery. We hereby introduce our center's experience in ReLT through a complicated case of ReLT. CASE SUMMARY: We report a patient who suffered from hepatitis B-associated cirrhosis and underwent LT in December 2012. Early postoperative recovery was uneventful. Four months after LT, the patient's bilirubin increased significantly and he was diagnosed with an ischemic-type biliary lesion caused by hepatic artery occlusion. The patient underwent percutaneous transhepatic cholangial drainage and repeatedly replaced intrahepatic biliary drainage tube regularly for 5 years. The patient developed progressive deterioration of liver function and underwent liver re-transplant in January 2019. The operation was performed in a classic OLT manner without venous bypass. Both the hepatic artery and PV were occluded and could not be used for anastomosis. The donor PV was anastomosed with the recipient's left renal vein. The donor hepatic artery was connected to the recipient's abdominal aorta. The bile duct reconstruction was performed in an end-to-end manner. The postoperative process was very uneventful and the patient was discharged 1 mo after retransplantation. CONCLUSION: With the development of surgical techniques, portal thrombosis and arterial occlusion are no longer contraindications for ReLT.

Study of the protective effect on damaged intestinal epithelial cells of rat multilineage-differentiating stress-enduring (Muse) cells.

In this study, we determined whether multilineage-differentiating stress-enduring (Muse) cells exist in rat bone marrow and elucidated their effects on protection against the injury of intestinal epithelial cells associated with inflammation. Rat Muse cells were separated from bone marrow mesenchymal stem cells (BMMSCs) by trypsin-incubation stress. The group of cells maintained the characteristics of BMMSCs; however, there were high positive expression levels of stage-specific embryonic antigen-3 (SSEA-3; 75.6 ± 2.8%) and stage-specific embryonic antigen-1 (SSEA-1; 74.8 ± 3.1%), as well as specific antigens including Nanog, POU class 5 homeobox 1 (OCT 3/4), and SRY-box 2 (SOX 2). After inducing differentiation, α-fetoprotein (endodermal), α-smooth muscle actin and neurofilament medium polypeptide (ectodermal) were positive in Muse cells. Injuries of intestinal epithelial crypt cell-6 (IEC-6) and colorectal adenocarcinoma 2 (Caco-2) cells as models were induced by tumor necrosis factor-α stimulation in vitro. Muse cells exhibited significant protective effects on the proliferation and intestinal barrier structure, the underlying mechanisms of which were related to reduced levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ), and the restoration of transforming growth factor-ß (TGF-ß) and IL-10 in the inflammation microenvironment. In summary, there were minimal levels of pluripotent stem cells in rat bone marrow, which exhibit similar properties to human Muse cells. Rat Muse cells could provide protection against damage to intestinal epithelial cells depending on their anti-inflammatory and immune regulatory functionality. Their functional impact was more obvious than that of BMMSCs.

Long non-coding RNA highly up-regulated in liver cancer promotes exosome secretion.

BACKGROUND: Highly upregulated in liver cancer (HULC) is a long non-coding RNA (lncRNA) which has recently been identified as a key regulator in hepatocellular carcinoma (HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown. AIM: To explore the mechanism by which HULC promotes the secretion of exosomes from HCC cells. METHODS: Serum and liver tissue samples were collected from 30 patients with HCC who had not received chemotherapy, radiotherapy, or immunotherapy before surgery. HULC expression in serum exosomes and liver cancer tissues of patients was measured, and compared with the data obtained from healthy controls and tumor adjacent tissues. The effect of HULC upregulation in HCC cell lines and the relationship between HULC and other RNAs were studied using qPCR and dual-luciferase reporter assays. Nanoparticle tracking analysis was performed to detect the quantity of exosomes. RESULTS: HULC expression in serum exosomes of patients with HCC was higher than that in serum exosomes of healthy controls, and HULC levels were higher in liver cancer tissues than in tumor adjacent tissues. The expression of HULC in serum exosomes and liver cancer tissues correlated with the tumor-node-metastasis (TNM) classification, and HULC expression in tissues correlated with that in serum exosomes. Upregulation of HULC promoted HCC cell growth and invasion and repressed apoptosis. Notably, it also facilitated the secretion of exosomes from HCC cells. Moreover, qPCR assays showed that HULC repressed microRNA-372-3p (miR-372-3p) expression. We also identified Rab11a as a downstream target of miR-372-3p. Dual-luciferase reporter assays suggested that miR-372-3p could directly bind both HULC and Rab11a. CONCLUSION: Our findings illustrate the importance of the HULC/miR-372-3p/Rab11a axis in HCC and provide new insights into the molecular mechanism regulating the secretion of exosomes from HCC cells.

Efficacy and Safety of Mizoribine Combined With Tacrolimus in Living Donor Kidney Transplant Recipients: 3-Year Results by a Chinese Single Center Study.

BACKGROUND: Mizoribine (MZR) was effective and safe for living Chinese donor kidney transplantation (LDKT) on tacrolimus-based treatment 1 year after transplantation. We investigated whether MZR was effective and safe for LDKT on tacrolimus-based treatment with long follow-up periods. METHODS: We compared 22 LDKT recipients who were administered MZR, tacrolimus, and corticosteroids with a control group (n = 20) treated with mycophenolate mofetil (MMF), tacrolimus, and corticosteroids. Primary efficacy endpoints were 3-year patient survival, 3-year graft survival, and acute rejection (AR) rate within 3 years after transplantation. RESULTS: The 3-year patient and graft survival rates for the MZR and MMF groups were 100%. The AR rate after transplantation was 18.2% for the MZR group and 10.0% for the MMF group; the difference was not significant (P = .665). There was no significant difference in serum creatinine levels, glomerular filtration rates (eGFR), serum urate levels, blood urea nitrogen, and cystatin C levels 12, 24, and 36 months after transplantation. No significant differences in the CD3, CD4, CD8, CD4/CD8, and CD45 were observed between the 2 groups 12, 24, and 36 months after transplantation. There were no significant differences in adverse events among the MZR or the MMF group, whereas the prevalence of gastrointestinal symptoms were significantly lower in the MZR treatment group (P = .003), especially acid reflux (P = .007). Compared with the MMF group, the MZR group should lighten the burden on patients. CONCLUSION: MZR with tacrolimus and corticosteroids provides satisfactory immunosuppression and higher safety for Chinese LDKT over a 3-year follow-up.

Hyperuricemia in Living Donor Kidney Transplantation Patients During Mizoribine Administration Caused Mainly by Changes in Kidney Function.

BACKGROUND: Although mizoribine (MZR) is used as an immunosuppressant after renal transplantation, the occurrence of hyperuricemia has been reported. The onset of hyperuricemia is often observed within the first several months after surgery. Since MZR is a renal excretion-type drug excreted as an unchanged drug from the kidneys, MZR blood concentrations may rise due to the influence of renal function. We investigated whether the onset of hyperuricemia after MZR administration was associated with the direct effect of a change in renal function. METHODS: Serum uric acid (serum UA), serum creatinine (sCr), serum ß2-microglobulin (serum ß2-MG), and serum cystatin C (serum Cys-C) were measured for about 3 months in 22 subjects. Correlation coefficients were calculated using the change rates of serum UA and sCr (Δ serum UA, Δ sCr), serum UA and serum ß2-MG (Δ serum UA, Δ serum ß2-MG), and serum UA and serum Cys-C (Δ serum UA, Δ serum Cys-C) at the onset of hyperuricemia. RESULTS: The correlation coefficients between Δ serum UA and Δ sCr, Δ serum UA and Δ serum ß2-MG, and Δ serum UA and Δ serum Cys-C were 0.723 (P < .001), 0.863 (P < .001) and 0.548 (P < .001), respectively. Further, serum UA and sCr level reached their highest peak on the same day after MZR administration, and the behavior was mostly consistent. CONCLUSION: It was suggested that hyperuricemia occurred about 3 months after MZR administration due mainly to temporary changes in kidney function.

Normothermic Machine Perfusion Protects Against Liver Ischemia-Reperfusion Injury During Reduced-Size Liver Transplantation in Pigs.

BACKGROUND Normothermic machine perfusion (NMP) preservation is superior to cold preservation during reduced-size liver transplantation (RSLT) in pigs. However, the mechanism of this protective effect has not been explained. We aimed to compare the effects of NMP preservation with that of cold preservation (CS) in protecting against ischemia-reperfusion injury (IRI) during RSLT in pigs. MATERIAL AND METHODS Twenty-four healthy Bama miniature pigs were randomized into 2 groups: 1) the NMP group in which donor livers harvested without warm ischemia time and cardiac activity were connected to the NMP system to reduce liver size under normothermic conditions, and 2) the CS group in which donor livers harvested without warm ischemia time and cardiac activity were perfused using the University of Wisconsin (UW) solution and then preserved in the 0-4°C UW solution to reduce liver size under cold conditions. Livers were then transplanted without veno-venous bypass. Amounts of bile secretion for the NMP groups were recorded hourly. The serological indices were measured. Expressions of cytochrome C, caspase 3, and NF-κB p65 in liver tissue were observed. RESULTS The levels of bile secretions were gradually diminished from 16.50±2.66 mL/h before splitting to 6.35±1.24 mL/h after splitting. With the exception of TNF-α on postoperative day 2, overall, levels of TNF-α, IL-1, IL-6, and MDA were significantly lower in the NMP group versus CS group for all 5 days postoperatively. Finally, cytochrome C, caspase 3, and NF-κB p65 expressions were all significantly suppressed in the NMP group as compared with the CS group. CONCLUSIONS MP preservation is superior to cold preservation in protecting against liver IRI during RSLT in pigs.

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.

Development and Assessment of Normothermic Machine Perfusion Preservation for Extracorporeal Splitting of Pig Liver.

BACKGROUND Studies have shown that normothermic machine perfusion (NMP) exerts a significant protective role for donations after cardiac death (DCD) livers and verified the effects of NMP in preservation, repair, and preoperative assessment of human donor livers. The objective of this study was to verify the effectiveness and stability of NMP system by splitting pig livers in perfusion preservation. MATERIAL AND METHODS Four healthy Ba-Ma miniature pigs were used. The livers were harvested, and then connected to the NMP system to split the livers. The indexes during the splitting were recorded, the serological indices were measured, and routine pathological examination of liver tissue were observed. RESULTS With splitting, the portal vein pressure and the hepatic artery pressure were not significantly changed. The flow in the portal vein and hepatic artery reduced respectively from 455±107.55 mmHg, 180.75±59.46 mmHg before splitting to 392.5±125.27 mmHg and 126.25±6.99 mmHg after splitting. The liver preservation temperature was controlled to 38.83±0.24 to 38.93±0.43°C during splitting. At the beginning of perfusion preservation, the alanine aminotransferase(ALT), lactate dehydrogenase(LDH), and alkaline phosphatase (ALP) were lower than the baseline level; ALT and LDH gradually increased with splitting, whereas ALP was maintained in a lower level in the splitting. At the beginning of perfusion preservation, aspartate aminotransferase(AST) was comparable with the baseline value, and it was gradually increased with splitting. The cell structure in the liver before NMP preservation and after splitting did not show significant changes. CONCLUSIONS The NMP device developed in this study can be used for donor liver preservation and splitting, without causing significant liver damage.