Does response rate of chemotherapy with molecular target agents correlate with the conversion rate and survival in patients with unresectable colorectal liver metastases?: A systematic review.

PURPOSE: This study aimed to evaluate whether the response rate of chemotherapy with molecular target agents correlates with the conversion rate, R0 resection rate, and survival in patients with initially unresectable colorectal liver metastases (CRLM). METHODS: We reviewed the literature of prospective, controlled trials of systemic chemotherapy for patients with unresectable liver-only CRLM, including resectable extrahepatic metastases. Pearson's correlation coefficients were calculated. RESULTS: A total of 26 patient groups from 18 studies were reviewed. The response rate was significantly correlated with the conversion rate (r = 0.66) and R0 resection rate (r = 0.43) in overall patients. In subgroup analysis, only the conversion rate in patients with chemotherapy only (r = 0.75) and anti-EGFR therapy (r = 0.78) were significantly strongly correlated with the response rate. A non-significant strong trend toward correlation between response and conversion rates was observed in patients with bevacizumab (r = 0.73, p = 0.10). The regression line in the scatter plot of patients using bevacizumab showed a less steep slope. This indicated that conversion rates were relatively less affected by response rates under anti-VEGF therapy compared with the other patient groups. The response rate in chemotherapy-only patients was significantly correlated with median progression-free survival (r = 0.61) and overall survival (r = 0.66). CONCLUSIONS: Chemotherapy without molecular target agents and with anti-EGFR agents shows similar results of correlation between response and conversion/R0 resection rates. Under anti-VEGF therapy, conversion would be expected, even with a relatively lower response rate.

Salvage living-donor liver transplantation for liver failure following definitive radiation therapy for recurrent hepatocellular carcinoma: a case report.

A 57-year-old man with a history of hepatitis B virus infection was referred to our hospital for living-donor liver transplantation (LDLT). Five years earlier, right lobectomy had been performed for solitary hepatocellular carcinoma (HCC) with bile duct tumor thrombus in segments 5 and 6 in the liver. Two years later, transarterial chemoembolization and radiofrequency ablation were performed for recurrent HCC. Two years after those local therapies, another recurrent HCC was treated with transhepatic arterial infusion chemotherapy with cisplatin and conventional radiation therapy (RT) with 60 Gy in 20 fractions, because the tumor was contiguous to the trunk of the portal vein. After the completion of RT, symptoms due to liver failure and severe infection caused by multiple liver abscesses developed despite the administration of antibiotics and percutaneous transhepatic cholangiodrainage. Therefore, LDLT was performed with the use of a right lobe graft donated by his wife. Vascular anastomosis was successfully performed with the use of normal procedures. The patient recovered uneventfully, and has since been doing well for 34 months, with no evidence of vascular complications. However, the degree of injury to the anastomotic vessels caused by definitive RT before LDLT remains unclear, whereas the safety and efficacy of some forms of RT as a bridge to deceased-donor LT have been reported. Salvage LDLT is effective for patients with liver failure after multidisciplinary treatment including radiation, while carefully taking radiation-induced vessel injury as a potential late complication into consideration, especially in LDLT cases.

Prediction of the remnant liver hypertrophy ratio after preoperative portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) is considered to improve the safety of major hepatectomy. Various conditions might affect remnant liver hypertrophy after PVE. The aim of the present study was to clarify the factors that affect remnant liver hypertrophy and to establish a prediction formula for the hypertrophy ratio. METHODS: Fifty-nine patients who underwent preoperative PVE for cholangiocarcinoma (39 patients), metastatic carcinoma (10 patients), hepatocellular carcinoma (8 patients), and other diseases (2 patients) were enrolled in this study. For the prediction of the hypertrophy ratio, a formula with stepwise multiple regression analysis was set up. The following parameters were used: age, gender, future liver remnant ratio to total liver (FLR%), plasma disappearance rate of indocyanine green (ICGK), platelet count, prothrombin activity, serum albumin, serum total bilirubin at the time of PVE and the maximum value before PVE (Max Bil), as well as a history of cholangitis, diabetes mellitus, and chemotherapy. RESULTS: The mean hypertrophy ratio was 28.8%. The 5 parameters detected as predictive factors were age (p = 0.015), FLR% (p < 0.001), ICGK (p = 0.112), Max Bil (p < 0.001), and history of chemotherapy (p = 0.007). The following prediction formula was established: 101.6 - 0.78 × age - 0.88 × FLR% + 128 × ICGK - 1.48 × Max Bil (mg/dl) - 21.2 × chemotherapy. The value obtained using this formula significantly correlated with the actual value (r = 0.72, p < 0.001). A 10-fold cross validation also showed significant correlation (r = 0.62, p < 0.001), and a hypertrophy ratio <20% was predictable with a sensitivity of 100% and a specificity of 90.9%. Moreover, technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy showed a significantly smaller increase in the uptake ratio of the remnant liver in patients with prediction values <20% than in those with values ≥20% (6.8 vs. 20.8%, p = 0.030). CONCLUSIONS: The prediction formula can prognosticate the hypertrophy ratio after PVE, which may provide a new therapeutic strategy for major hepatectomy.

Effect of maintenance therapy with low-dose peginterferon for recurrent hepatitis C after living donor liver transplantation.

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n =17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were -0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

Uptake of gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid in metastatic adrenal tumour from hepatocellular carcinoma.

We present the case of a metastatic adrenal tumour from hepatocellular carcinoma (HCC) showing the uptake of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) on MRI. To our knowledge, this is the first case of metastatic HCC in which Gd-EOB-DTPA uptake was shown on MRI and this finding facilitated the accurate pre-operative diagnosis of a metastatic adrenal tumour.

Coupled regulation of interleukin-12 receptor beta-1 of CD8+ central memory and CCR7-negative memory T cells in an early alloimmunity in liver transplant recipients.

This study investigated how CD8(+) T cell subsets respond to allo- and infectious immunity after living donor liver transplantation (LDLT). Early alloimmunity: 56 recipients were classified into three types according to the post-transplant course; type I demonstrated uneventful post-transplant course, type II developed severe sepsis leading to multiple organ dysfunction syndrome or retransplantation and type III with acute rejection. In 23 type I recipients, the interleukin (IL)-12 receptor beta-1 (R beta 1)(+) cells of central memory T cells (Il-12R beta 1(+) T(CM)) were increased above the pretransplant level. In 16 type II recipients, IL-12R beta 1(+) T(CM) was decreased markedly below the pretransplant level on postoperative day (POD) 5. In 17 type III recipients, IL-12R beta 1(+) T(CM) was decreased for a more prolonged period until POD 10. Along with down-regulation of IL-12R beta 1(+) T(CM), the IL-12R beta 1(+) cells of CCR7-negative subsets (CNS) as well as perforin, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha decreased gradually, resulting in the down-regulation of effectors and cytotoxicity. The down-regulation of IL-12R beta 1(+) T(CM) was suggested to be due to the recruitment of alloantigen-primed T cells into the graft, and then their entry into the secondary lymphoid organ, resulting in graft destruction. Infectious immunity: immunocompetent memory T cells with the capacity to enhance effectors and cytotoxicity were generated in response to post-transplant infection along with both up-regulation of the IL-12R beta 1(+) T(CM) and an increase in the CNS showing the highest level of IL-12R beta 1(+) cells. In conclusion, this work demonstrated that the IL-12R beta 1(+) cells of T(CM) and CNS are regulated in a tightly coupled manner and that expression levels of IL-12R beta 1(+) T(CM) play a crucial role in controlling allo- and infectious immunity.

A history of smoking is inversely correlated with the incidence of gemcitabine-induced neutropenia.

BACKGROUND: Smoking may affect the efficacy of chemotherapy and the incidence of adverse events. We investigated the correlation between smoking history and gemcitabine-induced neutropenia. PATIENTS AND METHODS: Data on smoking history and incidence of grade 3-4 neutropenia were retrospectively gathered for 103 chemo-naive patients treated with gemcitabine monotherapy (59 patients with pancreatic, 41 with hepatobiliary and three with other cancers). RESULTS: There was a significantly higher incidence of grade 3-4 neutropenia among patients without a history of smoking (55.7%) than among those with a history of smoking (including current and ex-smokers; 23.6%) [odds ratio (OR) 0.244, 95% confidence interval (CI) 0.105-0.569; P < 0.001]. After adjustment for age, gender, platelet and baseline neutrophil counts, history of surgery for primary cancer, creatinine concentration, hemoglobin concentration, aspartate aminotransferase concentration, alanine aminotransferase concentration and total bilirubin concentration, logistic regression analysis identified a history of smoking as an independent inverse predictor of gemcitabine-induced neutropenia (OR 0.188, 95% CI 0.057-0.618; P = 0.006). CONCLUSION: Patients without a history of smoking may be at higher risk of developing gemcitabine-induced neutropenia. The mechanism underlying this phenomenon is unclear at this point.

Nuclear factor {kappa}B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury.

BACKGROUND: In hepatic ischaemia/reperfusion injury, activated liver macrophages (Kupffer cells) are dominantly regulated by a transcription factor, nuclear factor kappaB (NFkappaB), with respect to expression of inflammatory cytokines, acute phase response proteins, and cell adhesion molecules. AIMS: We assessed whether inactivation of NFkappaB in the liver could attenuate total hepatic warm ischaemia/reperfusion injury. METHODS: We studied rats with hepatic overexpression of inhibitor kappaBalpha super-repressor (IkappaBalpha SR) caused by a transgene introduced using an adenoviral vector. Hepatic ischaemia/reperfusion injury was induced under warm conditions by total occlusion of hepatoduodenal ligament structures for 20 minutes, followed by reperfusion. Controls included uninfected and control virus (AdLacZ) infected rats. RESULTS: IkappaBalpha SR was overexpressed in Kupffer cells as well as in hepatocytes, blocking nuclear translocation of NFkappaB (p65) into the nucleus after reperfusion. Gene transfection with IkappaBalpha SR, but not with LacZ, markedly attenuated ischaemia/reperfusion injury, suppressing inducible nitric oxide synthase and nitrotyrosine expression in the liver. Moreover, no remarkable hepatocyte apoptosis was detected under IkappaBalpha SR overexpression. CONCLUSIONS: Adenoviral transfer of the IkappaBalpha SR gene in the liver ameliorates short term warm ischaemia/reperfusion injury, possibly through attenuation of hepatic macrophage activation.

Akt protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NK-kappa B activation.

To determine the role of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappa B) in protecting hepatocytes from tumor necrosis factor-alpha (TNF-alpha)- and Fas-mediated apoptosis, we pretreated primary cultures of mouse hepatocytes with pharmacological and adenovirus-mediated inhibitors of the PI3K/Akt and NF-kappa B pathways followed by treatment with TNF-alpha or Jo2, an anti-Fas antibody. Jo2 and, to a lesser extent, TNF-alpha phosphorylate Akt. The PI3K inhibitor LY-294002 blocks TNF-alpha- and Fas-mediated Akt phosphorylation. LY-294002 pretreatment reduces NF-kappa B binding activity and transcriptional activity and NF-kappa B-responsive gene expression by TNF-alpha or Jo2. LY-294002 promotes apoptosis after TNF-alpha or Jo2. The expression of dominant-negative Akt blocks NF-kappa B activation and sensitizes hepatocytes to TNF-alpha- and Fas-mediated apoptosis. The expression of constitutively active Akt rescues LY-294002-pretreated cells from TNF-alpha- and Fas-mediated apoptosis. Active Akt induces NF-kappa B transcriptional activity but not NF-kappa B binding activity or I kappa B degradation. Furthermore, LY-294002 pretreatment blocks TNF-alpha- and Jo2-induced Bcl-xL levels in hepatocytes, with no effect on the phosphorylation levels of Bad. Bcl-xL overexpression protects hepatocytes from Fas- but not TNF-alpha-induced apoptosis after sensitization by actinomycin D or the I kappa B superrepressor. Together, the PI3K/Akt pathway has a protective role in Fas-mediated apoptosis, which requires NF-kappa B activation, partially through the subsequent induction of Bcl-xL.

Dominant-negative TAK1 induces c-Myc and G(0) exit in liver.

Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a serine/threonine kinase, is reported to function in the signaling pathways of TGF-beta, interleukin 1, and ceramide. However, the physiological role of TAK1 in vivo is largely unknown. To assess the function of TAK1 in vivo, dominant-negative TAK1 (dnTAK1) was expressed in the rat liver by adenoviral gene transfer. dnTAK1 expression abrogated c-Jun NH(2)-terminal kinase and c-Jun but not nuclear factor (NF)-kappaB or SMAD activation after partial hepatectomy (PH). Expression of dnTAK1 or TAM-67, a dominant-negative c-Jun, induced G(0) exit in quiescent liver and accelerated cell cycle progression after PH. Finally, dnTAK1 and TAM-67 induced c-myc expression in the liver before and after PH, suggesting that G(0) exit induced by dnTAK1 and TAM-67 is mediated by c-myc induction.

NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis.

BACKGROUND AND AIMS: Hepatocyte apoptosis is induced by tumor necrosis factor alpha (TNF-alpha) and Fas ligand. Although nuclear factor-kappaB (NF-kappaB) activation protects hepatocytes from TNF-alpha-mediated apoptosis, the NF-kappaB responsive genes that protect hepatocytes are unknown. Our aim was to study the role of NF-kappaB activation and inducible nitric oxide synthases (iNOSs) in TNF-alpha- and Fas-mediated apoptosis in hepatocytes. METHODS: Primary cultures of hepatocytes from wild-type and iNOS knockout mice were treated with TNF-alpha, the Fas agonistic antibody Jo2, a nitric oxide (NO) donor (S-nitroso-N-acetylpenicillamine), an NO inhibitor (N(G)-methyl-L-arginine acetate), and/or adenovirus-expressing NF-kappaB inhibitors. RESULTS: The IkappaB superrepressor and a dominant-negative form of IkappaB kinase beta (IKKbeta) inhibited NF-kappaB binding activity by TNF-alpha or Jo2 and sensitized hepatocytes to TNF-alpha- and Jo2-mediated apoptosis. TNF-alpha and Jo2 induced iNOS messenger RNA and protein levels through the induction of NF-kappaB. S-nitroso-N-acetylpenicillamine inhibited Bid cleavage, the mitochondrial permeability transition, cytochrome c release, and caspase-8 and -3 activity, and reduced TNF-alpha- and Fas-mediated death in hepatocytes expressing IkappaB superrepressor. N(G)-methyl-L-arginine acetate partially sensitized hepatocytes to TNF-alpha- and Fas-mediated cell killing. TNF-alpha alone or Jo2 alone induced moderate cell death in hepatocytes from iNOS(-)/(-) mice. CONCLUSIONS: NO protects hepatocytes from TNF-alpha- and Fas-mediated apoptosis. Endogenous iNOS, which is activated by NF-kappaB via IKKbeta, provides partial protection from apoptosis.

The mitochondrial permeability transition augments Fas-induced apoptosis in mouse hepatocytes.

Tumor necrosis factor-alpha receptor 1 and Fas recruit overlapping signaling pathways. To clarify the differences between tumor necrosis factor alpha (TNFalpha) and Fas pathways in hepatocyte apoptosis, primary mouse hepatocytes were treated with TNFalpha or an agonist anti-Fas antibody after infection with an adenovirus expressing an IkappaB superrepressor (Ad5IkappaB). Treatment with TNFalpha induced apoptosis in Ad5IkappaB-infected mouse hepatocytes, as we previously reported for rat hepatocytes. Ad5IkappaB plus anti-Fas antibody or actinomycin D plus anti-Fas antibody rapidly induced apoptosis, whereas anti-Fas antibody alone produced little cytotoxicity. The proteasome inhibitor (MG-132) and a dominant-negative mutant of nuclear factor-kappaB-inducing kinase also promoted TNFalpha- and Fas-mediated apoptosis. Expression of either crmA or a dominant-negative mutant of the Fas-associated death domain protein prevented TNFalpha- and Fas-mediated apoptosis. In addition, the caspase inhibitors, DEVD-cho and IETD-fmk, inhibited TNFalpha- and Fas-mediated apoptosis. In Ad5IkappaB-infected hepatocytes, caspases-3 and -8 were activated within 2 h after treatment with anti-Fas antibody or within 6 h after TNFalpha treatment. Confocal microscopy demonstrated onset of the mitochondrial permeability transition (MPT) and mitochondrial depolarization by 2-3 h after anti-Fas antibody treatment and 8-10 h after TNFalpha treatment, followed by cytochrome c release. The combination of the MPT inhibitors, cyclosporin A, and trifluoperazine, protected Ad5IkappaB-infected hepatocytes from TNFalpha-mediated apoptosis. After anti-Fas antibody, cyclosporin A and trifluoperazine decreased cytochrome c release but did not prevent caspase-3 activation and cell-death. In conclusion, nuclear factor-kappaB activation protects mouse hepatocytes against both TNFalpha- and Fas-mediated apoptosis. TNFalpha and Fas recruit similar but nonidentical, pathways signaling apoptosis. The MPT is obligatory for TNFalpha-induced apoptosis. In Fas-mediated apoptosis, the MPT accelerates the apoptogenic events but is not obligatory for them.

Gene transfer to the rat biliary tract with the HVJ-cationic liposome method.

BACKGROUND/AIMS: The ability to transfer foreign genes into the biliary tract would be useful for the treatment of biliary tract diseases, including cancer, cystic fibrosis and other genetic diseases. To introduce a foreign gene precisely into the rat biliary epithelial cells, we developed a new technique, inserting a polyethylene catheter into the common bile duct through the papilla of Vater by use of a fusigenic cationic liposome with hemagglutinating virus of Japan (HVJ-cationic liposome). METHODS: Transfection efficiency was estimated with the use of FITC-oligonucleotides (FITC-ODNs) and cDNA of beta-galactosidase (pCAG-lacZ). RESULTS: FITC-ODNs encapsulated in HVJ-cationic liposome were effectively transfected into cell nuclei of human cholangiocellular carcinoma in vitro after a 30-min incubation as compared with the simple application of naked FITC-ODNs. After in vivo injection of FITC-ODNs using the HVJ-cationic liposome method through the papilla of Vater, fluorescence accumulation was observed only in the epithelial cells of the biliary tract, but not in the parenchymal cells of the liver. Beta-galactosidase expression was observed in the biliary epithelial cells 3 days after the transfection of pCAG-lacZ and was also detected at 14 days, but not at 28 days, without obvious cytotoxicity. CONCLUSIONS: HVJ-cationic liposome-mediated gene transfer to the biliary tract via the papilla of Vater is a minimally-invasive and an effective gene-delivery method for site-specific targeting to the epithelial cells of the biliary tract, which could be applied to the treatment of human biliary tract diseases.

Perioperative changes in hepatic function as assessed by asialoglycoprotein receptor indices by technetium 99m galactosyl human serum albumin.

BACKGROUND/AIMS: Perioperative changes in intrinsic hepatocyte function and functional volume were investigated. METHODOLOGY: 52 cases of liver cancer, including hepatocellular carcinoma, cholangiocellular carcinoma and metastatic carcinoma were studied. There were diagnoses of liver cirrhosis, liver fibrosis and normal liver in 20, 23 and 9 cases, respectively. Hepatic resection of subsegment, one segment, two segments and three segments were performed in 11, 6, 23 and 4 cases, respectively, while 8 cases were diagnosed as inoperable. Assessments were performed before and 4 weeks after hepatectomy with asialoglycoprotein (ASGP) receptor indices, i.e., technetium-99m-galactosyl human serum albumin (TcGSA) uptake by the liver, TcGSA retention in the blood and functional volume as measured by single emission computed tomography (SPECT) with TcGSA as a probe. RESULTS: The hyperbolic relationship between galactosyl human serum albumin (GSA) uptake by the liver and GSA retention in the blood, both of which were independent of functional volume, shifted to the right after hepatectomy. The number of conventional liver function tests correlating to the GSA uptake increased after hepatectomy. By contrast, none of the pre-operative and post-operative tests were correlated with functional volume. Post-operative decrease in intrinsic hepatocyte function can be minimized by selection of mode of hepatic resection. CONCLUSIONS: These results indicate that GSA uptake by the liver can reveal information regarding intrinsic liver function which deteriorates and becomes a decisive factor after hepatectomy.

Suppression of proliferative cholangitis in a rat model with direct adenovirus-mediated retinoblastoma gene transfer to the biliary tract.

Proliferative cholangitis (PC) associated with hepatolithiasis develops the stricture of main bile ducts, and is the main cause of residual and/or recurrent stones after repeated treatments for hepatolithiasis. The aim of this study was to inhibit PC using the cytostatic gene therapy with direct adenovirus-mediated retinoblastoma (Rb) gene transfer to the biliary tract. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. The adenovirus vector encoding a nonphosphorylatable, constitutively active form of retinoblastoma gene product (AdRb) was administered directly into the biliary tract. The adenovirus vector encoding beta-galactosidase (AdlacZ) was also given as a control. The bile duct wall thickness and 5'-bromodeoxyuridine (BrdU) labeling index were compared among uninfected, AdlacZ-infected, and AdRb-infected PC rats. The Rb expression in the bile duct was detected using reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemical study. AdRb-infected bile ducts showed inhibition of the epithelial and fibrous tissue proliferation and the peribiliary gland hyperplasia, resulting in a significant reduction of wall thickness compared with uninfected and AdlacZ-infected ones. The BrdU labeling index was 4.87% +/- 3.06% in the AdRb-infected bile ducts, while those of uninfected and AdlacZ-infected ones were 15.48% +/- 4.61% and 11.72% +/- 1.23%, respectively (P < .05). In conclusion, our cytostatic gene therapy approach using direct Rb gene transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrences following treatments against hepatolithiasis.

The beneficial effect of phosphocreatine accumulation in the creatine kinase transgenic mouse liver in endotoxin-induced hepatic cell death.

Purpose. The purpose of this study was to investigate the relationship between hepatic energy status and liver injury during sepsis, using transgenic mice which express creatine kinase in the liver catalyzing the phosphocreatine/creatine system. Methods. Creatine kinase transgenic mice were fed with normal rodent chow or chow containing 10% creatine for 5 days. Lipopolysaccharide (0.2 mg/kg) combined with d-galactosamine (600 mg/kg) was administered intraperitoneally. Results. Eighty percent of the creatine-fed transgenic mice had survived at 48 h post-d-galactosamine and lipopolysaccharide administration, compared with none of the normally fed transgenic mice. Hepatic phosphocreatine and ATP levels in the normally fed transgenic mice were significantly lower than those in the creatine-fed transgenic mice before and after lipopolysaccharide combined with d-galactosamine was administered. Massive hepatic hemorrhagic necrosis with apoptosis was seen in response to d-galactosamine and lipopolysaccharide in normally fed transgenic mice. These results are consistent with a significant increase in serum aminotransferase at 8 h. In contrast, there were faint necrotic changes in the liver with minimal cellular infiltration in creatine-fed transgenic mice. Conclusions. Maintenance of hepatic ATP levels protects from sepsis-induced liver injury and mortality.

Hepatic preservation with histidine-tryptophan-ketoglutarate solution in living-related and cadaveric liver transplantation.

1. Living-related liver transplantation has some advantages in the evaluation of novel clinical protocols, since many complicated factors affecting initial graft function are almost uniform in grafts obtained from healthy donors. 2. To compare histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solution in terms of tissue oxygenation in living-related liver transplantation, oxygen saturation of haemoglobin (SO2) in hepatic tissue and its heterogeneity (CV, coefficient of variation) were measured by near-infrared spectroscopy. The HTK and UW groups consisted of 15 and 49 successful transplants respectively, in which no statistical differences in background were observed. 3. In the HTK group, hepatic SO2 after portal vein reflow was higher (P < 0.01) than that in the UW group, as was that after hepatic artery reflow (P < 0.05). In the UW group, hepatic SO2 remained at the lower level at the end of the operation. 4. Furthermore, the increase in CV after portal vein reflow was normalized after hepatic artery reflow in the HTK group. However, the CV remained at a high level at the end of the operation in the UW group. 5. Postoperative peak aspartate aminotransferase level in the HTK group was lower than that in the UW group (P < 0.05). 6. In cadaveric liver transplantation, higher hepatic SO2 and lower CV of hepatic SO2 in the early phase after reperfusion compared with the UW group (n = 18) were also observed in the HTK group (n = 30) (P < 0.05). 7. In conclusion, recovery of tissue oxygenation and its heterogeneity after reperfusion in HTK-preserved livers were more rapid and homogeneous than in UW-preserved livers in living-related liver transplantation. Accordingly, HTK solution may be a potential alternative to UW solution.

Prostaglandin E1 resuscitates hepatic organic anion transport independent of its hemodynamic effect after warm ischemia.

Prostaglandin E1 (PGE1) is a promising agent against ischemic liver damage, but direct evidence of the benefit to intrinsic hepatocyte function has been lacking. We demonstrate here that organic anion transport can be supported by treatment with PGE1 even at a lower dose which does not affect hepatic microcirculation in rabbits with liver inflow occlusion. Near-infrared spectroscopy was applied to directly measure hepatic clearance of indocyanine green (ICG), an exogenous organic anion, and to estimate microcirculation as measured by oxygen saturation and the content of hemoglobin in the sinusoid. Also, morphological changes in microtubules, the cytoskeleton which is known to be associated with organic anion transport, and energy status, as measured by adenine nucleotide levels, were observed. ICG removal rate in hepatocytes decreased significantly from 0.100 +/- 0.018 to 0.027 +/- 0.019 min-1 (mean +/- SD, P < 0.01) by 60-min warm ischemia, whereas the value increased to 0.082 +/- 0.030 min-1 (P < 0.05) when PGE1 was given at a dose of 0.05 microgram/kg/min. The treated livers also showed early reorganization of microtubules, as well as amelioration of ATP resynthesis after reperfusion. However, there were no significant differences in intraoperative changes in oxygen saturation and the content of hemoglobin in the sinusoid between PGE1-treated and untreated groups, indicating that the influence of PGE1 at this dose on hemodynamic changes is not considerable. These results indicate that PGE1 resuscitates an inherent hepatocyte function of organic anion transport on reperfusion after warm ischemia and suggest that the benefit could be attributed solely to direct action on hepatocytes.

Postoperative monitoring of the oxygenation state of the graft liver in cases with hepatopulmonary syndrome.

Postoperative changes in the oxygen saturation of hemoglobin in the graft liver (graft SO2) were monitored by near-infrared spectroscopy in four cases complicated by hepatopulmonary syndrome. A plastic cylinder was placed in the abdominal wall, and optical measurements of the graft liver were obtained through this window. Our findings were as follows; (1) graft SO2 decreased after abdominal wall closure, and decreased further 1 day after surgery. (2) Graft SO2 was maintained despite severe hypoxemia, with partial pressure of oxygen in arterial blood as low as 50 mmHg. High hematocrit was beneficial for oxygenating the graft. (3) Graft livers could tolerate hypoxia with a graft SO2 as low as 20%. (4) It may be useful to monitor graft SO2 during the critical period after transplantation for the assessment of graft function.