Second and third hepatectomies for recurrent hepatocellular carcinoma are justified.

BACKGROUND: Liver resection is the main curative treatment for hepatocellular carcinoma (HCC), but recurrence rates are high. The remnant liver is the most common site of recurrence, but the role of repeat hepatectomy in the treatment of recurrent HCC is controversial. METHODS: Patients who underwent curative hepatectomy for HCC and subsequent repeat hepatectomy for recurrent HCC between 1990 and 2007 were reviewed retrospectively. Clinicopathological characteristics, and early- and long-term outcomes of patients who had a first, second, third and fourth hepatectomy were compared. RESULTS: Some 1177 patients underwent a first hepatectomy for HCC, and 149, 35 and eight patients respectively had a second, third and fourth hepatectomies for recurrence. There were no significant differences in early postoperative outcomes after first and repeat hepatectomies. Five-year disease-free and overall survival rates after first, second and third hepatectomies were 43.6, 31.8 and 33.8 per cent (P = 0.772), and 52.4, 56.4 and 59.4 per cent (P = 0.879), respectively. Patients undergoing second and third hepatectomies for recurrence had better survival rates than those who did not have a repeat hepatectomy, but not those after fourth hepatectomy. CONCLUSION: Second and third hepatectomies seem justified for hepatic recurrence of HCC. The role of fourth hepatectomy needs further investigation.

Liver resection for hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Although liver resection is now a safe procedure, its role for hepatocellular carcinoma (HCC) in patients with cirrhosis remains controversial. METHODS: This study compared the results of liver resection for HCC in patients with cirrhosis over two time intervals. One hundred and sixty-one patients had resection during period 1 (1991-1996) and 265 in period 2 (1997-2002). Early and long-term results after liver resection in the two periods were compared, and clinicopathological characteristics that influenced survival were identified. RESULTS: Tumour size was smaller, indocyanine green retention rate was higher, patients were older and a greater proportion of patients were asymptomatic in period 2 than period 1. Operative blood loss, need for blood transfusion, operative mortality rate, postoperative hospital stay and total hospital costs were significantly reduced in period 2. The 5-year disease-free survival rates were 28.2 and 33.9 per cent in periods 1 and 2 respectively (P = 0.042), and 5-year overall survival rates were 45.9 and 61.2 per cent (P < 0.001). Multivariate analysis identified serum alpha-fetoprotein level, need for blood transfusion and Union Internacional Contra la Cancrum tumour node metastasis stage as independent determinants of disease-free and overall survival. CONCLUSION: The results of liver resection for HCC in patients with cirrhosis improved over time. Liver resection remains a good treatment option in selected patients with HCC arising from a cirrhotic liver.

Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis.

BACKGROUND: Hepatic stellate cells (HSCs) are a major fibrogenic cell type that contributes to collagen accumulation during chronic liver disease. With increasing interest in developing antifibrotic therapies, there is a need for cell lines that preserve the in vivo phenotype of human HSCs to elucidate pathways of human hepatic fibrosis. We established and characterised two human HSC cell lines termed LX-1 and LX-2, and compared their features with those of primary human stellate cells. METHODS AND RESULTS: LX-1 and LX-2 were generated by either SV40 T antigen immortalisation (LX-1) or spontaneous immortalisation in low serum conditions (LX-2). Both lines express alpha smooth muscle actin, vimentin, and glial fibrillary acid protein, as visualised by immunocytochemistry. Similar to primary HSCs, both lines express key receptors regulating hepatic fibrosis, including platelet derived growth factor receptor beta (betaPDGF-R), obese receptor long form (Ob-RL), and discoidin domain receptor 2 (DDR2), and also proteins involved in matrix remodelling; matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinase (TIMP)-2, and MT1-MMP, as determined by western analyses. LX-2 have reduced expression of TIMP-1. LX-2, but not LX-1, proliferate in response to PDGF. Both lines express mRNAs for alpha1(I) procollagen and HSP47. Transforming growth factor beta1 stimulation increased their alpha1(I) procollagen mRNA expression, as determined by quantitative reverse transcription-polymerase chain reaction. LX-2, but not LX-1, cells are highly transfectable. Both lines had a retinoid phenotype typical of stellate cells. Microarray analyses showed strong similarity in gene expression between primary HSCs and either LX-1 (98.4%) or LX-2 (98.7%), with expression of multiple neuronal genes. CONCLUSIONS: LX-1 and LX-2 human HSC lines provide valuable new tools in the study of liver disease. Both lines retain key features of HSCs. Two unique advantages of LX-2 are their viability in serum free media and high transfectability.

Liver resection for hepatocellular carcinoma in patients with end-stage renal failure.

BACKGROUND AND OBJECTIVES: Surgical resection remains the main option for curing hepatocellular carcinoma (HCC). However, liver resection in patients with end-stage renal disease (ESRD) is risky. The aim of this study is to clarify the role of liver resection for treating HCC in patients with ESRD. METHODS: A retrospective review was carried out on 468 patients who underwent liver resection for HCC between 1989 and 1999. The clinicopathological characteristics and operative results of 12 patients who had ESRD (ESRD group) were compared with those of the other 456 patients who did not have ESRD (non-ESRD group). In the ESRD group, heparin-free hemodialysis using the periodic saline-rinse method was performed during the perioperative period. RESULTS: The ESRD group had lower hemoglobin and a higher serum creatinine levels. Other patient background and tumor pathological characteristics were comparable between the two groups as well. The operative morbidity and mortality between the two groups were also similar. The 5-year disease-free survival rates for ESRD and non-ESRD groups were 35.0 and 34.2% (P = 0.31), respectively, while the 5-year actuarial survival rates were 67.8 and 53.3% (P = 0.54), respectively. CONCLUSION: With improving techniques and knowledge of dialysis, liver resection for HCC is justified in selected patients with ESRD.

KLF6, a candidate tumor suppressor gene mutated in prostate cancer.

Kruppel-like factor 6 (KLF6) is a zinc finger transcription factor of unknown function. Here, we show that the KLF6 gene is mutated in a subset of human prostate cancer. Loss-of-heterozygosity analysis revealed that one KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirm that whereas wild-type KLF6 up-regulates p21 (WAF1/CIP1) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Our data suggest that KLF6 is a tumor suppressor gene involved in human prostate cancer.

DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells.

Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.

Transcriptional regulation in hepatic stellate cells.

Modulation of gene expression through altered transcription regulates stellate cell behavior in normal liver and following hepatic injury. Transcription factors are generally classified according to conserved motifs within either the activation- or DNA- binding domains of the molecules. Transcriptional activity in stellate cells represents a delicate fine tuning of multiple inputs. Activities of these transcription factors are modified by their intracellular localization, rate and pathway of degradation, oligomerization, and interactions with heterologous factors and chromatin, as well as by posttranslational modifications, including phosphorylation, glycosylation, and acetylation. General paradigms of transcriptional control are increasingly being validated in hepatic stellate cells, particularly involving the transcription factors CCAAT/enhancer-binding proteins, c-myb, CREB, nuclear factor kappaB, peroxisome proliferator-activated receptor, and Kruppel-like zinc finger factors. Although there are no simple rules that govern mechanisms of transcriptional regulation in stellate cells, continued advances will yield new insights into their role in normal liver homeostasis and in the response to injury.

Management of acute pancreatitis: results of a 15-year experience in Taiwan.

In the past two decades, there have been great changes regarding the policy for treating acute pancreatitis. The aim of this study was to examine the chronological changes in the management of acute pancreatitis in a tertiary referral center. A retrospective review was carried out of the management approaches for acute pancreatitis in the 15 years since 1984. The patients were divided into groups according to the admission date, representing two periods: period 1, from 1984 through 1992; and period 2, from 1993 through 1999. Decision-making for treating acute pancreatitis was based mainly on Beger's criteria. The background features and treatment outcome were compared between the two periods. The severity of pancreatitis was based on the Atlanta classification system. Octreotide was available from January 1993. No differences could be found between the two periods regarding the patients' background characteristics or severity of pancreatitis. Patients in period 2 had a longer interval between the onset of pancreatitis and surgery, and a lower incidence of pancreatectomy. Although the surgical morbidity, mortality, and reoperation rates were not significantly different between the two periods, more patients with severe acute pancreatitis in period 2 received nonsurgical treatment, and a lower mortality rate was also noted. With improvements in critical care, increasing experience, and better surgical techniques, even patients with severe acute pancreatitis can be treated by nonsurgical means. However, aggressive surgical intervention is necessary for patients who have signs of infected necrosis and whose disease is not controllable by conservative methods.

Comparison of the UICC/AJCC 1992 and 1997 pN categories for gastric cancer patients after surgery.

BACKGROUND/AIMS: UICC/AJCC 1997 classification changes pN category. We evaluated its prognostic impact. METHODOLOGY: A total of 710 patients who underwent a > or = D2 gastrectomy were recruited. Among them, the data of 319 patients who had involved regional lymph nodes and no evidence of distant metastases were used for comparing the 1992 and 1997 pN categories. RESULTS: For 1997 category, 201 patients (64%) were pN1, 75 (23.5%) pN2, and 43 (13.5%) pN3. For 1992 category, 143 patients (44.8%) were pN1, and 147(46.1%) pN2. 29 patients (9.1%) with lymph node metastasis to the hepatoduodenal ligament were distant metastasis. The 1997 pN category was a more powerful prognostic discriminant (relative risk: 2.086) than the 1992 category. Compared to the 1992 stage classification, the 1997 one had a skewed distribution of patients with marked shift of patients of stage IIIA (105-126 patients), IIIB (116-58 patients), and IV (100-122 patients). The survival difference between stage IIIA and IIIB for the 1997 stage classification is narrower than for 1992. CONCLUSIONS: The 1997 pN category allows for estimation of prognosis superior to the 1992 category.

Improving operative safety for cirrhotic liver resection.

BACKGROUND: Liver resection in a patient with cirrhosis carries increased risk. The purposes of this study were to review the results of cirrhotic liver resection in the past decade and to propose safe strategies for cirrhotic liver resection. METHODS: Based on the date of operation, 359 cirrhotic liver resections in 329 patients were divided into two intervals: period 1, from September 1989 to December 1994, and period 2, from January 1995 to December 1999. The patient backgrounds, operative procedures and early postoperative results were compared between the two periods. The factors that influenced surgical morbidity were analysed. RESULTS: In period 2, patient age was higher and the amounts of blood loss and blood transfused were lower. Although postoperative morbidity rates were similar, blood transfusion requirement, postoperative hospital stay and mortality rate were significantly reduced in period 2. No death occurred in 154 consecutive cirrhotic liver resections in the last 38 months of the study. Prothrombin activity and operative time were independent factors that influenced postoperative morbidity. CONCLUSION: With improving perioperative assessment and operative techniques, most complications after cirrhotic liver resection can be treated with a low mortality rate. However, more care should be taken if prothrombin activity is low or there is a long operating time.

An appraisal of liver and portal vein resection for hepatocellular carcinoma with tumor thrombi extending to portal bifurcation.

BACKGROUND: The role of surgical resection for hepatocellular carcinoma with tumor thrombi involving the major portal vein is controversial because of a high operative risk and poor prognosis. Previously, a resection was performed only when the tumor thrombi were limited to the first branch of the portal vein without extension to the portal bifurcation. HYPOTHESIS: Concomitant liver and portal vein resection may be beneficial in patients with hepatocellular carcinoma with tumor thrombi extending to portal bifurcation. DESIGN: Retrospective review. SETTING: University hospital, tertiary referral center. PATIENTS: Among 368 patients with hepatocellular carcinoma who underwent a curative resection, portal vein involvement occurred in 112 patients. Fifteen of the 112 patients underwent a concomitant liver and portal vein resection owing to extension of tumor thrombi to the portal bifurcation (group 1). The remaining 97 patients did not need portal vein resection (group 2). INTERVENTION: Surgical indications, procedures, and results of pathological examination of resected specimens were assessed in patients in group 1. The clinicopathological characteristics, operative morbidity and mortality, and operative results were compared between the 2 groups. MAIN OUTCOME MEASURES: Disease-free and actuarial survival rates. RESULTS: Intramural tumor infiltration was found at the site of thrombi adhesion to the portal vein cuff in 11 of 15 patients in group 1. Owing to patient selection bias, patients in group 1 were significantly younger and had better liver function and greater resected liver weight. The operative time, postoperative hospitalization, operative blood loss, amount of blood transfusion, and operative morbidity and mortality did not differ significantly between the 2 groups. The 5-year disease-free survival rates of groups 1 and 2 were 21.6% and 20.4% (P =.19), respectively, while the actuarial survival rates were 26. 4% and 28.5% (P =.33), respectively. CONCLUSION: Liver resection with partial resection of the portal vein is justified in selected patients with hepatocellular carcinoma with tumor thrombi extending to portal bifurcation.

Surgical treatment for recurrent hepatocellular carcinoma with tumor thrombi in right atrium: using cardiopulmonary bypass and deep hypothermic circulatory arrest.

Tumor in the right atrium creates a life-threatening condition and should be removed immediately. A cirrhotic patient who had recurrent hepatocellular carcinoma (HCC) over remnant liver with tumor thrombi extending to inferior vena cava (IVC) and right atrium presented with impending congestive heart failure. The recurrent tumor and its thrombi were successfully resected en-bloc using cardiopulmonary bypass and hypothermic circulatory arrest. Although the patient's disease-free and actual survival time were only 6 months and 14 months, respectively, he was rescued from heart failure. This aggressive surgical strategy creates further possibility to treat such advanced HCC cases. Further investigations regarding adjuvant therapies in these circumstances, however, are necessary.

Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex.

Hepatic stellate cell activation is a complex process. Paradoxes and controversies include the origin(s) of hepatic stellate cells, the regulation of membrane receptor signaling and transcription, and the fate of the cells once liver injury resolves. Major themes have emerged, including the dominance of autocrine signaling and the identification of counterregulatory stimuli that oppose key features of activated cells. Advances in analytical methods including proteomics and gene array, coupled with powerful bioinformatics, promise to revolutionize how we view cellular responses. Our understanding of stellate cell activation is likely to benefit from these advances, unearthing modes of regulating cellular behavior that are not even conceivable on the basis of current paradigms.

Surgical mortality, survival, and quality of life after resection for gastric cancer in the elderly.

Although there were some studies on clinicopathologic characteristics, operative morbidity, and mortality in elderly patients with gastric cancer, no reports have specifically focused on survival and quality of life after resection. A total of 433 patients aged >/= 65 years (1987-1994) who underwent gastric resection for gastric adenocarcinoma were studied. Two groups were considered: patients aged 65 to 74 years and those > 74 years. Most of the patients (78.1%) had advanced diseases, and nearly half (41. 3%) had associated chronic disease(s). Resections with curative intention were performed in 362 patients (83.6%). The overall operative morbidity rate was 21.7% and mortality rate 5.1%. Although operative procedures were similar in both groups, patients aged >74 years had a higher mortality rate than those aged 65 to 74 years (10. 1% vs. 3.5%; p = 0.034). Age and extent of gastric resection were two independent factors negatively affecting mortality. The cumulative survival rates for patients who underwent curative resection were 86.2%, 72.4%, 67.2%, 62.9%, and 60.0% at 1, 2, 3, 4, and 5 years, respectively. Nearly all patients (96%) after surgery had normal work and daily activities. Some patients appeared to lack energy (16%) or experienced a period of anxiety or depression. There was no statistical difference in survival and quality of life assessed by the Spitzer index after curative resection between the two groups. Therefore resection with curative intention can be performed for the elderly with acceptable morbidity and mortality rates, possible long-term survival, and good quality of life, but a limited operation should be considered in the very elderly patients.

Hepatitis viral status in patients undergoing liver resection for hepatocellular carcinoma.

BACKGROUND: Hepatitis B and C viruses are the main causative agents of hepatocellular carcinoma (HCC). The influence of hepatitis viral status on liver resection for HCC remains undetermined. METHODS: Patients who underwent curative resection for HCC were divided into four groups: group 1, seronegative for hepatitis B surface antigen (HBsAg) and antihepatitis C antibody (HCVAb); group 2, seropositive for HBsAg only; group 3, seropositive for HCVAb only; and group 4, seropositive for HBsAg and HCVAb. The clinicopathological characteristics and surgical results of the four groups were compared. Resection of HCC was determined according to liver functional reserve and tumour extent. RESULTS: There were 40, 131, 70 and 20 patients in groups 1, 2, 3 and 4 respectively. Due to patient selection bias, there were significant differences in some background features, resectional extent and pathological characteristics among the four groups. Postoperative morbidity and mortality, as well as the Union Internacional Contra la Cancrum tumour node metastasis stages, did not differ. Patients in group 1 had a higher disease-free survival rate than those in group 2 (P = 0. 02). The actuarial survival rates of patients in groups 2 and 4 were lower than those of groups 1 and 3. CONCLUSION: With careful patient selection, the hepatitis viral status does not influence the surgical risks of hepatectomy for HCC. After liver resection for HCC, the long-term survival rate of patients seronegative for HBsAg is greater than that of patients seropositive for HBsAg.

Characterization of the enzymatic properties of the first and second domains of metallocarboxypeptidase D.

Carboxypeptidase D (CPD) contains three domains with homology to other metallocarboxypeptidases. To further characterize the various domains, we constructed a series of point mutants with a critical active site Glu of duck CPD converted to Gln. The proteins were expressed in the baculovirus system, purified to homogeneity, and characterized. Point mutations within both the first and second domains eliminated enzyme activity, indicating that the third domain is inactive toward dansyl-Phe-Ala-Arg. CPD removed only the C-terminal Lys or Arg from peptides, with the first domain more efficient toward Arg and the second domain more efficient toward Lys. Peptides containing Pro in the penultimate position were poorly cleaved by either domain. Cleavage of a peptide with Ala in the penultimate position was most efficient, with the relative order Ala >/= Met > Ser, Phe > Tyr > Trp > Thr >/= Gln, Asp, Leu, Gly >> Pro for CPD with both domains active. There were only minor differences between the first and the second domains regarding the influence of the penultimate amino acid. The first domain was optimally active at pH 6.3-7.5, whereas the second domain was optimally active at pH 5. 0-6.5. Thus, the first and second carboxypeptidase domains have complementary enzyme activities. Furthermore, the finding that CPD with both domains active shows a broad activity to a wide range of substrates is consistent with a role for this enzyme in the processing of many proteins that transit the secretory pathway.

Development of a new prognostic system and validation of APACHE II for surgical ICU mortality: a multicenter study in Taiwan.

BACKGROUND: To develop and to validate a new prognostic prediction system for patients admitted to the surgical intensive care unit (ICU), and to compare its performance with the Acute Physiology and Chronic Health Evaluation (APACHE) II system. METHODS: The database was derived from three surgical ICUs in three hospitals. For each patient, demographic data, diagnosis, APACHE II score and hospital survival data were collected. The accuracy in outcome prediction of the APACHE II was assessed by means of receiver operating characteristic (ROC) analysis. The new prognostic system was developed by using a multiple logistic regression in the developmental data set and validated with the validation data set. RESULTS: A total of 1,248 patients were included from three ICUs. The area under the ROC curve was 0.74 for the APACHE II score. The new prognostic system includes 18 variables. Goodness-of-fit tests indicated that the model performed well in the developmental and validation samples (p = 0.235 in the developmental data set and p = 0.297 in the validation set). The area under the ROC curve was 0.84 in the developmental sample and 0.77 in the validation sample for the new prognostic score. The area under the ROC curve was 0.71 in the validation sample for the APACHE II score. CONCLUSIONS: Although APACHE II correlates with mortality for surgical ICU patients in Taiwan, its accuracy is not as good as in the original study. Mortality prediction performance improved with the use of the new, local scoring system.

Factors affecting morbidity, mortality and survival after pancreaticoduodenectomy for carcinoma of the ampulla of Vater.

BACKGROUND/AIMS: The aim of this paper is to reevaluate the factors responsible for hospital morbidity, mortality and post-operative survival following pancreaticoduodenectomy for ampullary cancer. METHODOLOGY: Peri-operative data on 132 patients undergoing pancreaticoduodenectomy for ampullary cancer were correlated with post-operative morbidity, mortality and long-term survival. RESULTS: Three factors were found to correlate well with post-operative morbidity; however, only intraabdominal or wound sepsis was an independently significant variable. Four parameters correlated well with hospital mortality, while multivariate analysis revealed age > 75 y/o, positive blood culture and albumin < or = 3.0 g% to be independently significant in predicting post-operative mortality. Univariate analysis identified seven significant factors: 1) age < or = 75 y/o, 2) hematocrit > 30%, 3) blood urea nitrogen < 20 mg%, 4) earlier TNM staging, 5) smaller tumor size, 6) negative nodal status and 7) well-differentiated tumors, which were associated with longer survival. However, multivariate analysis disclosed nodal status and hematocrit to be the two most significant independent variables. CONCLUSIONS: Although radical resection for ampullary cancer can be performed with a low mortality in recent years, the justification for performing this major operation in a patient over 75 years of age should be reevaluated for prohibitively high mortality (10x) and shorter survival (median 6.0 months). Pre-operative nutritional support and careful surgical technique to prevent post-operative sepsis are mandatory to reduce operative morbidity and mortality. Correction of anemia and adequate lymph node dissection will clarify the patient's survival benefit following this operation.

Peri-anhepatic phase oxygen kinetics in porcine liver transplantation.

BACKGROUND: We applied a liver transplantation animal model to examine the relationship between oxygen delivery and consumption. The presence of pathologic flow-dependent oxygen consumption was investigated during and after the anhepatic phase. The effect of venous-to-venous bypass on oxygen kinetics was evaluated. METHODS: Twelve pigs were randomly divided into two groups. The non-bypass group consisted of six pigs that were subjected to clamping of the hepatic artery, portal vein, and the superior and inferior vena cava to produce an anhepatic phase. The bypass group consisted of six pigs that underwent vascular clamping and liver transplantation with venous bypass. Hemodynamics, oxygen delivery index (DO2) and oxygen consumption index (VO2) were recorded during the peri-anhepatic phase. Best-fit regression lines were calculated for DO2 vs VO2. RESULTS: In the pigs without venous bypass, the blood pressure, cardiac index and VO2 dropped significantly after vascular clamping and lactic acidosis developed. In pigs with venous bypass, vascular clamping induced a significant decline of cardiac output and DO2 but VO2 was maintained by a compensatory increase in oxygen extraction ratio. DO2 and VO2 after the release of vascular clamping increased significantly higher than that before vascular clamping. The O2 supply-dependent regression line was drawn from the points below critical oxygen delivery with a slope of 0.232 (95% CI = 0.110-0.354, r2 = 0.50, p = 0.010). The pathologic supply-dependent line was drawn from the points with supranormal DO2 and VO2 with a slope of 0.185 (95% CI = 0.050-0.333, r2 = 0.510, p = 0.029). The slope of the supply-independent line was 0.0089 (95% CI = -0.030-0.050, r2 < 0.009, p = 0.12). CONCLUSIONS: Oxygen delivery dropped below the critical level and flow-dependent oxygen consumption developed during the anhepatic phase without venous bypass. Venous-to-venous bypass is necessary to maintain a critical DO2 and stable hemodynamics during porcine liver transplantation. Pathologic flow-dependent oxygen consumption developed after the anhepatic phase.