pinecone/core-2020-05-10-deduplication huggingface dataset:
Liver Transplantation in Patients with Hepatocellular Carcinoma Across Milan Criteria

Milan criteria are the most frequently used limits for liver transplantation (LT)
      in patients with hepatocellular carcinoma (HCC), but our previous experience with
      expanded criteria showed encouraging results. The aim of this study was to
      investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria 
      (1 nodule up to 6 cm or 2-3 nodules up to 5 cm each) could be used to select
      patients with HCC for LT. Eighty-five patients with HCC fulfilling CUN criteria
      were included as candidates for LT. Survival of transplanted HCC patients was
      compared with survival of patients without HCC (n = 180). After the exclusion of 
      2 patients with tumor seeding of the chest wall due to pre-LT tumor biopsy,
      survival and recurrence rates were compared according to tumor staging.
      Twenty-six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had 
      tumor progression on the waiting list. Patients exceeding Milan criteria had a
      higher dropout rate due to tumoral progression. One-, 3-, 5-, 7-, and 10-year
      survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and
      50%, respectively. Survival of patients with HCC was significantly lower than
      that of patients without HCC, but by multivariate analysis, HCC was not
      associated with lower survival. Tumor recurrence and survival rates were similar 
      for patients fulfilling Milan and CUN criteria. Pathological staging showed 55
      patients within Milan criteria, 7 patients exceeding them but within CUN
      criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55
      (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In
      conclusion, following CUN criteria could increase the number of HCC patients who 
      could benefit from LT, without worsening the results. Because of the short number
      of patients in this series, these data need external validation
Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation

The interaction of donor passenger leukocytes and host leukocytes in recipient secondary lymphoid tissues during the early posttransplantation period is crucial in directing host immune reactions toward allograft rejection or acceptance. Responsible T cell clones could be activated through the direct and indirect pathways of allorecognition. We examined the role of the indirect pathway in liver transplantation (LT) tolerance by depleting host antigen-presenting cells (APC) with phagocytic activity [e.g., cluster domain (CD)68+/CD163+ macrophages, CD11c+ dendritic cells (DC)] using liposome-encapsulating clodronate (LP-CL). After Lewis rat cell or liver graft transplantation, Brown Norway (BN) rat recipients pretreated with LP-CL showed a significantly reduced type 1 helper T cell cytokine up-regulation than control-LP-treated recipients. In the LT model, LP-CL treatment and host APC depletion abrogated hepatic tolerance; Lewis liver grafts in LP-CL-treated-BN recipients developed mild allograft rejection, failed to maintain donor major histocompatibility complex (MHC) class II+ leukocytes, and developed chronic rejection in challenged donor heart allografts, while control-LP-treated BN recipients maintained tolerance status and donor MHC class II+ hepatic leukocytes. Furthermore, in the BN to Lewis LT model, LP-CL recipient treatment abrogated spontaneous hepatic allograft acceptance, and graft survival rate was reduced to 43% from 100% in the control-LP group. In conclusion, the study suggests that host cells with phagocytic activity could play significant roles in developing LT tolerance. © 2008 AASLD
Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver

Widespread use of liver transplantation in the treatment of hepatic diseases is restricted by the limited availability of donated organs. One potential solution to this problem would be isolation and propagation of liver progenitor cells or stem cells. Here, we report on the isolation of a novel progenitor cell population from unmanipulated (that is, no prior exposure to chemicals and no injury) adult rat liver. Rat liver cells were cultured following a protocol developed in our laboratory to generate a unique progenitor cell population called liver-derived progenitor cells (LDPCs). LDPCs were analyzed by fluorescence-activated cell sorting, real-time polymerase chain reaction (RT-PCR), immunostaining and microarray gene expression. LDPCs were also differentiated into hepatocytes and biliary epithelium in vitro and examined for mature hepatic markers and urea and albumin production. These analyses showed that, LDPCs expressed stem cell markers such as cluster domain (CD)45, CD34, c-kit, and Thy 1, similar to hematopoietic stem cells, as well as endodermal/hepatic markers such as hepatocyte nuclear factor (HNF)3beta, hematopoietically-expressed homeobox gene-1, c-met, and transthyretin. LDPCs were negative for OV-6, cytokeratins (CKs), albumin, and HNF1alpha. The microarray gene expression profile demonstrated that they showed some similarities to known liver progenitor/stem cells such as oval cells. In addition, LDPCs differentiated into functional hepatocytes in vitro as shown by albumin expression and urea production. In conclusion, LDPCs are a population of unique liver progenitors that can be generated from unmanipulated adult liver, which makes them potentially useful for clinical applications, especially for cell transplantation in the treatment of liver diseases.status: publishe
De novo malignancies following liver transplantation: impact and recommendations

1. De novo malignancy is one of the leading causes of
late mortality after liver transplantation.
2. The risks of skin cancers and lymphoma are more
than 10-fold greater than the risks in an age-matched
and sex-matched general population.
3. Some types of neoplasia, such as lung, head and
neck, and colorectal cancer, are more frequent in liver
transplant recipients than in an age-matched and sexmatched
population. The risks of other frequent malignancies,
such as prostate and breast cancer, do not
seem to be increased.
4. The most important risks for posttransplant malignancy
are Epstein-Barr virus seronegativity (for lymphoma),
sun exposure (for skin cancer), smoking, and
increasing age.
5. Despite the absence of evidence, general recommendations
(such as avoidance of overimmunosuppression,
sunlight protection, and cessation of smoking)
should be given. Screening protocols may help to
detect neoplasia at an early stage of disease
Risk factors of lung, head and neck, esophageal, and kidney and urinary tract       carcinomas after liver transplantation: the effect of smoking withdrawal

Liver transplant recipients have an increased risk of malignancy. Smoking is
      related to some of the most frequent causes of posttransplant malignancy. The
      incidence and risk factors for the development of neoplasia related to smoking
      (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were
      studied in 339 liver transplant recipients. Risk factors for the development of
      smoking-related neoplasia were also studied in 135 patients who had a history of 
      smoking so that it could be determined whether smoking withdrawal was associated 
      with a lower risk of malignancy. After a mean follow-up of 7.5 years, 26 patients
      were diagnosed with 29 smoking-related malignancies. The 5- and 10-year actuarial
      rates were 5% and 13%, respectively. In multivariate analysis, smoking and older 
      age were independently associated with a higher risk of malignancy. In the smoker
      subgroup, the variables related to a higher risk of malignancy were active
      smoking and older age. In conclusion, smoking withdrawal after liver
      transplantation may have a protective effect against the development of
      neoplasia
Organ quality and quality of life after liver transplantation

Not only is there a limited supply of organs for liver transplantation, but the quality of the available organs is not uniform. Risk factors such as donor age and cause of death are known to predict graft failure, but their impact on the recipient's quality of life (QOL) has not been reported. We sent a QOL survey to 299 adults at our institution who had received a liver transplant 1 to 7 years before the study. For the 171 patients (57%) who completed the Medical Outcomes Study Short Form 36 (SF‐36), the mean Physical Composite Score (PCS) and the mean Mental Composite Score (MCS) were 61 and 66, respectively; the highest scores were for the Social Functioning subscale, and the lowest scores were for the Role Functioning/Physical and Energy/Fatigue subscales. The mean donor risk index (DRI) of the organs that the subjects received was 1.4 (range = 0.8‐2.4). There was no correlation between the SF‐36 scores and the DRI [there were changes of −4.8 and −2.8 in the PCS and MCS per unit increase in the DRI ( P  = 0.4 and 0.6, respectively)], even though we controlled for potential confounders such as age, sex, hospitalization before transplantation, the Model for End‐Stage Liver Disease score at transplantation, years since transplantation, previous transplantation, and the Charlson comorbidity index. In conclusion, we found no association between organ quality and QOL after liver transplantation. If this finding is confirmed in prospective, multicenter studies, it will be useful in counseling patients about the decision to accept or not accept high‐risk organ offers. Liver Transpl, 2011. © 2011 AASLD
Relationship between sleep problems and health‐related quality of life among pediatric liver transplant recipients

Among adult liver transplant recipients (LTRs), sleep disturbances and fatigue are common. Sleep problems following pediatric liver transplantation may contribute to daytime fatigue and lower health‐related quality of life (HRQOL). The aim of this cross‐sectional study was to determine the impact of sleep problems on the HRQOL of pediatric LTRs using validated measures. Participants included 47 LTRs. Mean age of the LTRs was 10.9 ± 4.6 years, and mean time since transplantation was 6.2 ± 3.9 years. The primary indication for transplantation was biliary atresia (51%). According to parent reports, pediatric transplant recipients had symptoms of sleep‐disordered breathing, excessive daytime sleepiness, daytime behavior problems, and restless legs; 40.4% of parents and 43.8% of children reported significantly lower total HRQOL for the recipients. Age, time since transplantation, and health status were not significantly related to the quality of life. Hierarchical regression analyses revealed that the sleep‐disordered breathing subscale of the Pediatric Sleep Questionnaire accounted for significant variance in parent‐proxy reports on the Pediatric Quality of Life (PedsQL) summary scales measuring children's psychosocial health ( R  2  = 0.36,  P  < 0.001), physical health ( R  2  = 0.19,  P  = 0.004), and total HRQOL ( R  2  = 0.35,  P  < 0.001). Also, the sleep‐disordered breathing subscale accounted for significant variance in the child self‐reported school functioning scale ( R  2  = 0.18,  P  = 0.03). Clinically significant sleep problems were more common among children with low total HRQOL. In conclusion, sleep problems were common in this cohort of pediatric LTRs and predicted significant variance in HRQOL. Prospective larger scale studies are needed to assess factors that contribute to sleep difficulties and low HRQOL in this population. The detection and treatment of significant sleep problems may benefit the HRQOL of pediatric LTRs. Liver Transpl 18:707–715, 2012. © 2012 AASLD
Monitoring of liver grafts with microdialysis catheters

List of papers. The papers are removed from the thesis due to publisher restrictions.

I. Haugaa H, Thorgersen EB, Pharo A, Boberg KM, Foss A, Line PD, Sanengen T, Almaas R, Grindheim G, Pischke SE, Mollnes TE, Tønnessen TI: Early bedside detection of ischemia and rejection in liver transplants by microdialysis. Liver Transpl. 2012; 18: 839-49 <a href="http://dx.doi.org/10.1002/lt.23425">doi:10.1002/lt.23425</a>

II. Haugaa H, Thorgersen EB, Pharo A, Boberg KM, Foss A, Line PD, Sanengen T, Almaas R, Grindheim G, Waelgaard L, Pischke SE, Mollnes TE, Tønnessen TI: Inflammatory markers sampled by microdialysis catheters distinguish rejection from ischemia in liver grafts. Liver Transpl. 2012 Dec;18(12):1421-9. <a href="http://dx.doi.org/10.1002/lt.23503">doi:10.1002/lt.23503</a>

III. Haugaa H, Almaas R, Thorgersen EB, Foss A, Line PD, Sanengen T, Bergmann GB, Ohlin P, Grindheim G, Wælgaard L, Pischke SE, Mollnes TE, Tønnessen TI. Clinical Experience with Microdialysis Catheters in pediatric Liver Transplants. Liver Transpl. 2013 Mar;19(3):305-14. <a href="http://dx.doi.org/10.1002/lt.23578">doi:10.1002/lt.23578</a
Case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation

A recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) can lead to accelerated allograft injury and fibrosis. The aim of this article is to report the first ever use of daclatasvir (DCV; also known as BMS‐790052), a potent orally administered nonstructural 5A replication complex inhibitor, in combination with peginterferon α (PEG‐IFNα) and ribavirin in an LT recipient. A 49‐year‐old female developed a severe recurrent HCV genotype 1b infection 4 months after transplantation with severe cholestasis on biopsy, an HCV RNA level of 10,000,000 IU/mL, an alkaline phosphatase level of 1525 IU/mL, and a total bilirubin level of 8.4 mg/dL. Despite partial virological suppression with PEG‐IFNα and ribavirin, progressive allograft failure ensued and culminated in retransplantation at 9 months. Three months after the second transplant, DCV (20 mg/day), PEG‐IFNα2a (180 μg/week), and ribavirin (800 mg/day) were prescribed for early recurrent cholestatic HCV. Serum HCV RNA became undetectable at week 3 of treatment and remained undetectable during 24 weeks of triple therapy and during the posttreatment follow‐up. DCV was well tolerated, and the trough drug levels were within the targeted range throughout the treatment. The cyclosporine trough levels were also stable during and after therapy. In conclusion, the lack of anticipated drug‐drug interactions between DCV and calcineurin inhibitors and the potent antiviral efficacy of DCV make this agent (in combination with PEG‐IFN and ribavirin) an attractive antiviral regimen worthy of further study in LT recipients with recurrent HCV. Liver Transpl, 2012. © 2012 AASLD
Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion

Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver. Liver Transpl 18:1198-1208, 2012. (c) 2012 AASLD.Spanish Ministry of Science and Innovation [BFU2009-07410]Agency for the Innovation and Internationalization of Catalan Enterprise [VALTEC08-2-0033]Agency for the Support and Evaluation of Graduate Education (Brazilian Ministry of Education)Spanish Society for Liver Transplantation Foundatio
Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation.

Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether complement component 4d (C4d) immunostaining would be useful for diagnosing AMR, we compared the results of C4d immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C4d endothelial staining (identifiable with a 4× objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C4d positivity. In the ABO-C cases, C4d positivity in late biopsy samples (≥30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P = 0.01) and with the presence of donor-specific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity > 5000 according to the Luminex single-antigen bead assay (P = 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C4d positivity. During the 2-year follow-up, neither C4d positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C4d positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C4d-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C4d endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C4d positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated
Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model.

Excessive portal flow to a small remnant liver or small-for-size graft is a primary factor of small-for-size syndrome. We demonstrated that olprinone (OLP), a phosphodiesterase III inhibitor, had a hepatoprotective effect in a rat extended hepatectomy model and a small-for-size liver transplantation model through a modification of the portal venous pressure (PVP). To identify the appropriate dose and duration of treatment for clinical applications, we conducted experiments with a swine partial hepatectomy model. Twenty microminipigs were divided into 4 groups that received the following treatments: (A) saline (control group), (B) OLP at 0.3 μg/kg/minute (preoperative and postoperative administration), (C) OLP at 0.1 μg/kg/minute (preoperative administration), and (D) OLP at 0.3 μg/kg/minute (preoperative administration). The pigs underwent 70% partial hepatectomy. Hemodynamic changes, including changes in PVP, were examined. Liver biopsy was performed 1 and 3 hours after hepatectomy. Blood samples were collected until postoperative day 7 (POD7). In comparison with group A, PVP elevations, periportal edema, and sinusoidal hemorrhaging were attenuated after left Glisson's ligation in groups C and D. Pretreatment with OLP in groups C and D preserved the microstructure of sinusoids and improved the prothrombin activity 1 and 3 hours after hepatectomy. These animals showed better recovery of the remnant liver volume and the plasma disappearance rate of indocyanine green on POD7. In contrast, group B showed exacerbation of liver damage. Measurements of the serum OLP concentration showed that 10 ng/mL OLP was appropriate for a hepatoprotective effect. In conclusion, pretreatment with OLP shows hepatoprotective effects in a swine partial hepatectomy model. OLP may have the potential to ameliorate patients' outcomes after hepatectomy or liver transplantation
Intestinal ischemic preconditioning ameliorates hepatic ischemia/reperfusion injury in rats: role of heme oxygenase 1 in the second window of protection.

Preconditioning by brief ischemia protects not only the concerned organ but also other distant organs against subsequent lethal damage; this is called remote ischemic preconditioning (RIPC). This study was designed to investigate the impact of intestinal RIPC on hepatic ischemia/reperfusion injury (IRI) with a special interest in heme oxygenase 1 (HO-1) induction in the second window of protection (SWOP). Male Wistar rats were randomly assigned to 1 of 2 groups: an RIPC group or a sham group. Before hepatic IRI, either intestinal RIPC, consisting of 2 cycles of 4-minute superior mesenteric artery clamping separated by 11 minutes of declamping (RIPC group), or a sham procedure (sham group) was performed. After 48 hours of recovery, the rats were exposed to 30 minutes of total hepatic IRI. Transaminase releases and proinflammatory cytokines were determined at several time points after reperfusion. Histopathological analysis and animal survival were also investigated. Intestinal RIPC significantly lowered transaminase release (alanine aminotransferase at 2 hours: 873.3 ± 176.4 IU/L for the RIPC group versus 3378.7 ± 871.1 IU/L for the sham group, P < .001) as well as proinflammatory cytokine production (tumor necrosis factor α at 2 hours: 930 ± 42 versus 387 ± 17 pg/μL, P < .001). The morphological integrity of the liver and the ileum was maintained significantly better with intestinal RIPC; this reached statistical significance not only in Suzuki's liver injury score (3.5 ± 0.2 versus 0.7 ± 0.5, P = .007) but also in Park's score for intestinal damage (4.0 ± 0.4 versus 2.0 ± 0.2, P = .007). Animal survival was also markedly improved (83.1% versus 15.4%, P < .001). As a mechanism underlying this protection, HO-1 was substantially induced in liver tissue, especially in hepatocytes, with remarkable up-regulation of bradykinin in the portal blood, whereas HO-1 protein induction in enterocytes was not significant. In conclusion, intestinal RIPC remarkably attenuates hepatic IRI in the SWOP, presumably by HO-1 induction in hepatocytes