OLT Group Research Articles

Exosome is involved in liver graft protection after remote ischemia reperfusion conditioning

BackgroundRemote ischemic perconditioning (RIPerC) has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury (IRI). This study investigated the role of exosomes in RIPerC of liver grafts in rats. MethodsTwenty-five rats (including 10 donors) were randomly divided into five groups (n = 5 each group): five rats were used as sham-operated controls (Sham), ten rats were for orthotopic liver transplantation (OLT, 5 donors and 5 recipients) and ten rats were for OLT + RIPerC (5 donors and 5 recipients). Liver architecture and function were evaluated. ResultsCompared to the OLT group, the OLT + RIPerC group exhibited significantly improved liver graft histopathology and liver function (P < 0.05). Furthermore, the number of exosomes and the level of P-Akt were increased in the OLT + RIPerC group. ConclusionsRIPerC effectively improves graft architecture and function, and this protective effect may be related to the increased number of exosomes. The upregulation of P-Akt may be involved in underlying mechanisms.

Clinical outcome associated with neoadjuvant chemoradiation and orthotopic liver transplantation versus definitive chemoradiation in 49 patients with unresectable, hilar, or extrahepatic cholangiocarcinoma.

494 Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P &lt; 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P &lt; 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P &lt; 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.

Investigation of factors related to the occurrence of osteochondral lesions of the talus by 3D bone morphology of the ankle.

The aims of this study were to evaluate the morphology of the ankle in patients with an osteochondral lesion of the talus using 3D CT, and to investigate factors that predispose to this condition. The study involved 19 patients (19 ankles) who underwent surgery for a medial osteochondral lesion (OLT group) and a control group of 19 healthy patients (19 ankles) without ankle pathology. The mean age was significantly lower in the OLT group than in the control group (27.0 vs 38.9 years; p = 0.02). There were 13 men and six women in each group. 3D CT models of the ankle were made based on Digital Imaging and Communications in Medicine (DICOM) data. The medial malleolar articular and tibial plafond surface, and the medial and lateral surface area of the trochlea of the talus were defined. The tibial axis-medial malleolus (TMM) angle, the medial malleolar surface area and volume (MMA and MMV) and the anterior opening angle of the talus were measured. The mean TMM angle was significantly larger in the OLT group (34.2°, sd 4.4°) than in the control group (29.2°, sd 4.8°; p = 0.002). The mean MMA and MMV were significantly smaller in the OLT group than in the control group (219.8 mm2, sd 42.4) vs (280.5 mm2, sd 38.2), and (2119.9 mm3, sd 562.5) vs (2646.4 mm3, sd 631.4; p < 0.01 and p = 0.01, respectively). The mean anterior opening angle of the talus was significantly larger in the OLT group than in the control group (15.4°, sd 3.9°) vs (10.2°, sd 3.6°; p < 0.001). 3D CT measurements showed that, in patients with a medial osteochondral lesion of the talus, the medial malleolus opens distally, the MMA and MMV are small, and the anterior opening angle of the talus is large. This suggests that abnormal morphology of the ankle predisposes to the development of osteochondral lesions of the talus. Cite this article: Bone Joint J 2018;100-B:1487-90.

Optimized postconditioning algorithm protects liver graft after liver transplantation in rats

BackgroundIschemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism. MethodsThirty Sprague–Dawley rats were randomly divided into 3 groups: the sham group (n = 5), standard orthotopic liver transplantation group (OLT, n = 5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). PostC group was then subdivided into 4 groups according to the different time intervals: (10 s × 3, 10 s × 6, 30 s × 3, 60 s × 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated. ResultsCompared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10 s × 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10 s × 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated. ConclusionsPostC algorithm, especially 10 s × 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway.

The impact of exposure to liver transplantation anesthesia on the ability to treat intraoperative hyperkalemia: a simulation experience.

The objective of this study was to assess whether resident exposure to liver transplantation anesthesia results in improved patient care during a simulated critical care scenario. Our hypothesis was that anesthesia residents exposed to liver transplantation anesthesia care would be able to identify and treat a simulated hyperkalemic crisis after reperfusion more appropriately than residents who have not been involved in liver transplantation anesthesia care. Participation in liver transplantation anesthesia is not a mandatory component of the curriculum of anesthesiology training programs in the United States. It is unclear whether exposure to liver transplantation anesthesia is beneficial for skill set development. A high-fidelity human patient simulation scenario was developed. Times for administration of epinephrine, calcium chloride, and secondary hyperkalemia treatment were recorded. A total of 25 residents with similar training levels participated: 13 residents had previous liver transplantation experience (OLT), whereas 12 residents had not been previously exposed to liver transplantations (non-OLT). The OLT group performed better in recognizing and treating the hyperkalemic crisis than the non-OLT group. Pharmacologic therapy for hyperkalemia was given earlier (OLT 53.3 ± 27.0 seconds versus non-OLT 148 ± 104.1 seconds; P < 0.01) and hemodynamics restored quicker (OLT 87.9 ± 24.9 seconds versus non-OLT 219.9 ± 87.1 seconds; P < 0.01). Simulation-based assessment of clinical skills is a useful tool for evaluating anesthesia resident performance during an intraoperative crisis situation related to liver transplantations. Previous liver transplantation experience improves the anesthesia resident's ability to recognize and treat hyperkalemic cardiac arrest.

Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model.

BackgroundRemote ischemic conditioning (RIC) is a known manual conditioning to decrease ischemic reperfusion injury (IRI) but not increase ischemic time. Here we tried to establish a rat RIC model of liver transplantation (LT), optimize the applicable protocols and investigate the protective mechanism.MethodsThe RIC model was developed by a standard tourniquet. Sprague-Dawley rats were assigned randomly to the sham operated control (N), standard rat liver transplantation (OLT) and RIC groups. According to the different protocols, RIC group was divided into 3 subgroups （10min×3, n = 6; 5min×3, n = 6; 1min×3, n = 6）respectively. Serum transaminases (ALT, AST), creatine kinase (CK), histopathologic changes, malondialdehyde (MDA), myeloperoxidase (MPO) and expressions of p-Akt were evaluated.ResultsCompared with the OLT group, the grafts subjected to RIC 5min*3 algorithm showed significant reduction of morphological damage and improved the graft function. Also, production of reactive oxygen species (MDA) and neutrophil accumulation (MPO) were markedly depressed and p-Akt was upregulated.ConclusionIn conclusion, we successfully established a novel model of RIC in rat LT, the optimal RIC 5min*3 algorithm seemed to be more efficient to alleviate IRI of the liver graft in both functional and morphological categories, which due to its antioxidative, anti-inflammation activities and activating PI3K Akt pathway.

Influence of Selected Factors on Survival After Liver Retransplantation

Objective The aim of this study was to examine the survival of adult liver retransplant recipients depending on selected factors: time from the primary transplantation, cold ischemia time, indications for retransplantation, patient age and United Network for Organ Sharing (UNOS) status. Patients and Methods Between December 1989 and March 2011, we performed 43 orthotopic liver retransplantations (re-OLTs) among patients aged 20–62 years including 24 women and 19 men. The cold ischemia time was 250–820 minutes. UNOS status before re-OLT: UNOS 1 (n = 19; 44%) UNOS 2A (n = 15; 35%), and UNOS 2B (n = 4; 9%). The time from OLT to re-OLT was 1–2, 146 days. The indications for re-OLT were arterial thrombosis (n = 14; 33%), anastomotic biliary complication (n = 3; 7%), recurrence of the original disease (n = 9; 21%), hepatic vein thrombosis (n = 1; 2%), primary nonfunction (PNF) dysfunction (n = 2; [5%] /6 [14%]), de novo hepatitis C cirrhosis (n = 2; 5%) and other etiologies (n = 6; 14%). Results The 6-year survival among the primary OLT group was 80% compared with 58% among the re-OLT group ( P = .0001). One-year survivals in the re-OLT group according to UNOS status 1, 2A, and 2B were 47%, 60%, and 75%, respectively ( P = .475). There was a low negative correlation between survival time and time between OLT and re-OLT. There was a low positive correlation between survival time and cold ischemia time. There was a low negative correlation between survival time and patient age. Conclusions There was a significant difference in survival between OLT and re-OLT. There was a correlation between survival time and time to re-OLTx; a shorter time corresponded to longer survival. There was a poor correlation between survival time and patient age. UNOS status before re-OLT and indication for re-OLTx influenced survival.

Indoleamine2, 3-dioxygenase enzyme activity detected by in vivo liver microdialysis after rat ortho topic liver transplantation

Objective To observe the activity of indoleamine 2, 3-dioxygenase (IDO) enzyme in vivo after rat liver transplantation, and the effects of liver transplantation rejection on IDO enzyme activity.Methods Ten SD rats were subjected to othotopic liver transplantations respectively in allogenic OLT group (SD→SD) and heterogenic OLT group (Wistar→SD). In the other 10 SD rats, the blood supply to the liver was obstructed for 15 min for simulating the anhepatic period in the OLT group ( sham group). An in vivo rat liver microdialysis-HPLC system was established on the day I after OLT. The concentrations of kynurenine and tryptophan in dialysate samples were continuously monitored quantitatively and reproducibly for more than 2 weeks in the same animal. Results The average concentrations of tryptophan in dialysate were 97. 14, 85.71, 53.07 nmol/L respectively in the sham, allogenic OLT and heterogenic OLT groups respectively. The concentrations of kynurenine were 3.46, 14. 58, 46.79 nmoL/L in the sham, allogenic OLT and heterogenic OLT groups respectively. The concentration of kynurenine was increased significantly on the day 7 after surgery in heterogeneic OLT group (70. 75 nmol/L). Conclusion The transplantation surgery can induce the activity of IDO enzyme in vivo and accelerate the metabolism of tryptophan in the liver allografts. Key words: Liver transplantation; Acute rejection; Immune tolerance; Tryptophane; Indoleamine 2,3-dioxygenase

Orthotopic liver transplantation as a rescue operation for recurrent hepatocellular carcinoma after partial hepatectomy

To compare post-orthotopic liver transplantation (OLT) survival between patients with recurrent hepatocellular carcinoma (HCC) after partial hepatectomy and those who received de novo OLT for HCC and to assess the risk factors associated with post-OLT mortality. From July 2003 to August 2005, 77 consecutive HCC patients underwent OLT, including 15 patients with recurrent HCC after partial hepatectomy for tumor resection (the rescue OLT group) and 62 patients with de novo OLT for HCC (the de novo OLT group). Thirty-three demographic, clinical, histological, laboratory, intra-operative and post-operative variables were analyzed. Survival was calculated by the Kaplan-Meier method. Univariable and multivariable analyses were also performed. The median age of the patients was 49.0 years. The median follow-up was 20 mo. Three patients (20.0%) in the rescue OLT group and 15 patients (24.2%) in the de novo OLT group died during the follow-up period (P = 0.73). The 30-day mortality of OLT was 6.7% for the rescue OLT group vs 1.6% for the de novo OLT group (P = 0.27). Cox proportional hazards model showed that pre-OLT hyperbilirubinemia, the requirement of post-OLT transfusion, the size of the tumor, and family history of HCC were significantly associated with a higher hazard for mortality. There are no significant differences in survival/mortality rates between OLT as de novo therapy and OLT as a rescue therapy for patients with hcc. Pre-OLT hyperbilirubinemia, post-OLT requirement of transfusion, large tumor size and family history of HCC are associated with a poor survival outcome.

Liver Transplantation for Klatskin’s Tumor: Contraindicated, Palliative, or Indicated?

Objective Surgical resection is the only potential curative treatment for Klatskin’s tumor. In the cases of Bismuth type IV, some authors have suggested performing liver transplantation (OLT). Our aim was to present our experience in the management of Klatskin’s tumor, with special reference to patients undergoing OLT. Patients and methods Between May 1988 and December 2006, 66 patients were treated in our department for Klatskin’s tumor, including 43 men and 23 women of overall mean age 66 years (range = 38 to 88). Twenty patients (group 1) were in operable and 46 patients underwent resection surgery (group 2), including 13 tumors considered unresectable (group 2a), with OLT contraindicated for disseminated tumor; tumor resection was possible in 23 cases (group 2b) and the remaining 10 patients who were surgically unresectable but with nondisseminated neoplasm (by staging laparotomy) underwent OLT (group 2c). The mean waiting time for OLT was 2 months (range = 1 to 4 months). Results The mean survival rates of the group 1 and 2a patients was 6 ± 2 months and 8 ± 2 months, respectively. Of the 23 resected patients, the 1-, 3-, and 5-year survivals were 84%, 59%, and 40%. The 1-, 3-, and 5-year survival of OLT was 80%, 60%, and 37%, respectively. Among the 10 transplanted patients, six died due to tumor recurrence at 46, 43, 19, 16, 12, and 12 months. The remaining four patients are alive and tumor-free at 120, 89, 68, and 29 months, respectively. Conclusions A more accurate preoperative staging, perhaps by systematic use of pre-OLT laparotomy, and the use of adjuvant, and most importantly neoadjuvant therapy may improve the results of OLT in Klatskin’s tumor.

Superiority of Transplantation Versus Resection for the Treatment of Small Hepatocellular Carcinoma

The best therapy for hepatocellular carcinoma (HCC) is still debated. Hepatic resection (HR) is the treatment of choice for single HCC in Child A patients, whereas liver transplantation (OLT) is usually reserved for Child B and C patients with multiple nodules. The aim of this study was to compare HR and OLT for HCC within the Milan criteria on an intention-to-treat basis. Forty-eight patients were treated by OLT and 38 by HR. Three- and 5-year patient survival rates were significantly higher ( P = .0057) in the OLT group (79% and 74%) than after HR (61% and 26%). The 3- and 5-year disease-free survival rate was better ( P = .0005) for OLT (74% and 74%) versus HR (41% and 11%). The probability of HCC recurrences after resection was greater ( P = .0002) than after transplantation, achieving 31% and 76% for HR and 2% and 2% for OLT at 3 and 5 years after surgery. The median waiting list time was 118 days; two patients dropped out for HCC progression. We concluded that OLT is superior to HR for small HCC in cirrhotic patients assuming that OLT can be performed within 6 to 10 months after listing to reduce dropouts due to tumor progression.

Molecular Adsorbent Recirculating System in Liver Transplantation: Safety and Efficacy

We assessed the safety and clinical efficacy of the Molecular Adsorbent Recirculating System (MARS) in liver failure patients admitted to our intensive care unit (ICU) from May 2000 to February 2006. Of 28 adult patients with bilirubin >15 mg/dL and hepatic encephalopathy (HE) grade ≥2 or hepato-renal syndrome, 22 patients were included in the study, because 6 patients were older than 65 years of age or showed recent alcohol abuse or extrahepatic malignancy. Patients were assigned to 2 groups according to whether MARS therapy was associated with a transplantation procedure: 11 patients received MARS therapy and liver transplantation (OLT group) and 11 patients received MARS therapy alone (non-OLT group). Five of 11 patients in the OLT group were listed for transplantation and 6 patients with graft failure for retransplantation. The patients in the OLT and non-OLT groups were similar in MELD, SOFA, and SAPS scores. All patients were stable and free from complications. MARS significantly reduced bilirubin, bile acids, and blood urea nitrogen (BUN) levels in both groups ( P < .05), whereas a significant decrease in ammonia level was observed in the OLT group. Patient survival rates at 3 and 6 months in the OLT group were 91% and 73%, respectively, and in the non-OLT group, 9% and 9%, respectively ( P < .001). MARS was safe and well tolerated, improving biochemical parameters, neurological function, and pruritus. In terms of survival, the use of MARS alone was not effective due to the high rate of multiple organ failure. Nevertheless, the association of MARS with a transplant/retransplantation procedure was highly effective.

Hepatocellular carcinoma: strategy for optimizing surgical resection, transplantation and palliation.

In December 1997, a prospective study with informed consent was initiated to test a neoadjuvant treatment of transcatheter hepatic arterial chemo-embolization (TACE) and thermal or chemical ablation followed by transcatheter hepatic arterial chemo-infusion (TACI) in patients with hepatocellular carcinoma (HCC) referred for transplantation (OLT) and for resection. Patients were staged with American Liver Tumor Study Group-modified tumour-node-metastasis (TNM) staging classification using serial 3-6 month physical exam, alphafetoprotein (AFP), abdominal enhanced MRI, chest CT and bone scan. Sixty-five patients with HCC, out of 508 patients referred for OLT, were divided into five clinical groups and an incidental HCC patient group (n = 8), diagnosed on post-transplant explant pathology. The key focus of study was safety, site of HCC recurrence and tumour free survival. One hundred and thirty three ablation, infusion procedures were performed with an overall 24.8% morbidity, including two septic deaths. There were 13 (21.6%) HCC recurrences in 60 patients having one or more ablative treatments with only 23% hepatic HCC recurrences at 43 months of study. Eighteen HCC patients were listed for OLT (Group 3), with 12 patients transplanted after 29-424 d waiting. Two patients were removed from the OLT list due to HCC metastases, waiting a mean of 145 d. Two patients, post-OLT, had their TNM score upgraded from T2, T3 to T4. No Group 3 post-OLT patient has died or had HCC recurrence at mean follow-up of 27 +/- 15 months. No incidental HCC group post-OLT patient has died or had HCC recurrence at mean follow-up of 24 +/- 14 months. This neoadjuvant protocol is safe and effective in reducing HCC recurrence prior to and after OLT and resection.

THE INDUCTION OF IMMEDIATE EARLY GENES IN POSTISCHEMIC AND TRANSPLANTED LIVERS IN RATS Its Relation to Organ Survival

The protein products of the immediate early genes (IEG)s have been proposed to play an important role in long-term tissue plasticity such as cell repair or programmed cell death. The expression of liver IEGs was studied following liver ischemia (LI) or OLT in rats. In LI, 60 min of warm ischemia was induced in shunted rats (shunt LI group; 100% survival) and nonshunted rats (nonshunted LI group; poor survival). In OLT, donor livers were transplanted into the recipients within 1 hr (fresh liver OLT group; 100% survival) or after 24 hr of storage using University of Wisconsin solution (preserved liver OLT group; poor survival). Using both models, IEG mRNAs (c-fos and c-jun) were analyzed by Northern blot hybridization at various times before and after reperfusion. The expression of liver IEGs was not induced by warm ischemia and cold preservation alone. Reperfusion of livers following warm ischemia or cold preservation resulted in a distinctly different pattern of gene expression in viable and nonviable livers. In shunted LI and fresh liver OLT groups (viable), c-fos and c-jun mRNAs increased markedly to a peak value within 1-2 hr of reperfusion, returning to basal level by 3 hr. In nonviable livers, the level of these mRNAs was detected continuously at 3 hr of reperfusion in the nonshunted LI model and also at 6 hr after reperfusion in the preserved liver OLT group. Our data suggest that a protracted pattern of expression of c-fos and c-jun in the liver at the early stage of reperfusion might be correlated with the severity of liver transplant-related insults and subsequent graft failure.