Viral activity and outcome of hepatitis B surface antigen-positive grafts in deceased liver transplantation.

Indications of liver transplantation are extensive, but deceased donation does not meet the demand. Hepatitis B surface antigen (HBsAg)-positive grafts used to be discarded in the past. The aim of this study was to examine viral activity and outcome of HBsAg-positive deceased grafts transplanted to HBsAg-positive recipients. Eleven HBsAg-positive deceased grafts were transplanted to HBsAg-positive patients with acute liver failure (3 patients), hepatocellular carcinoma (6 patients) and repeatedly bleeding varices (2 patients). Postoperatively, hepatitis B virus (HBV) infection was treated by a combination of antiviral nucleoside and nucleotide analogues. HBV DNA and HBsAg were measured periodically. The median (interquartile) model of end-stage liver disease score for the recipients was 19 (16-32) with a range from 11 to 40. HBV DNA was detected in 6 patients with a range from 61 to 1083 IU/mL before transplantation. After transplantation, HBV DNA was detected in 4 patients in the first month and 2 patients in the 6th month and became undetectable for all patients at end of the first year. The quantitative HBsAg ranged from 0.86 to 241.1 IU/mL at 6 months and 0.34 to 238.5 IU/mL at 24 months (P = .135). Three of the patients died in the early phase, and the other patients were followed up for 40.0 ± 19.2 months with normal liver function. In conclusion, HBsAg-positive deceased liver grafts function well with minimal viral activity under treatment of combined antiviral nucleoside and nucleotide analogues. Use of HBsAg-positive deceased grafts is feasible and increases the donor pool to rescue dying patients.

Efficacy and safety of colesevelam in combination with pioglitazone in patients with type 2 diabetes mellitus.

Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulin-based regimens. We evaluated colesevelam's effects in subjects on stable pioglitazone-based therapy. This 24-week multicenter, double-blind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control [HbA1c ≥ 58 mmol/mol (7.5%) and ≤ 80 mmol/mol (9.5%)] on pioglitazone (30 or 45 mg) with or without 1-2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c [least-squares mean treatment difference, - 3.5 mmol/mol (- 0.32%); p < 0.001] and fasting plasma glucose (- 14.7 mg/dl; p<0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7%) (40% vs. 25%; p<0.001) or HbA1c < 53 mmol/mol (7.0%) (21% vs. 13%; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, - 6.5%), LDL-cholesterol (- 16.4%), non-HDL-cholesterol (- 9.8%), apolipoprotein B (- 8.8%), and total LDL particle concentration, and increased apolipoprotein A1 (+3.4%) and triglycerides (median treatment difference, + 11.3%) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.

The glucose and lipid effects of colesevelam as monotherapy in drug-naïve type 2 diabetes.

Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥7.5% and ≤9.5%) with diet and exercise alone were randomized to receive colesevelam 3.75 g/day (n=176) or placebo (n=181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (-2.92 mmol/mol [0.3%]; p=0.01) and fasting plasma glucose (-10.3 mg/dl; p=0.04) at week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (-11.2%; p<0.0001), total cholesterol (-5.1%; p=0.0005), non-high-density lipoprotein cholesterol (-7.4%; p=0.0001), and apolipoprotein B (-6.5%; p=0.0001) and increased apolipoprotein A-I (+ 2.4%; p=0.04), and triglycerides (+ 9.7%; p=0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved.ClinicalTrials.gov identifier: NCT00789737.

"Left at right" adult liver transplantation: the feasibility of heterotopic implantation of left liver graft.

Left liver grafts have been widely utilized in adult liver transplantation (LT) and yielded acceptable results. However, the conventional orthotopic implantation of a left liver graft imposes the potential risk of perioperative vascular complications. We report herein an alternative modified technique for adult left liver LT and evaluate its feasibility in LT. In this study, 10 recipients had their left liver graft rotated 180°, and heterotopically implanted at the right subphrenic space, which we termed "left at right" liver transplantation (LAR-LT). The sequence of vascular and biliary reconstruction was performed as standard techniques, and no perioperative vascular complications related to LAR-LT were encountered. There were two mortalities in this series, one due to a small-for-size graft dysfunction and the other due to postoperative internal hemorrhage. Two recipients had biliary strictures that were successfully managed by percutaneous biliary dilatation and Roux-en-Y hepaticojejunostomy. The clinical characteristics and outcomes of patients undergoing LAR-LT were also compared with patients undergoing conventional orthotopic left liver LT (n = 14). Although the results showed no significant difference between the two groups, according to our experience, the satisfactory outcome and easier technical reconstruction suggest that the LAR-LT modification could be a feasible alternative to left liver LT.

A 26-week, placebo- and pioglitazone-controlled monotherapy study of rivoglitazone in subjects with type 2 diabetes mellitus.

AIMS: To evaluate the efficacy and safety of rivoglitazone, a peroxisome proliferator-activated receptor γ agonist in the thiazolidinedione class, in subjects with suboptimally controlled type 2 diabetes mellitus (T2DM). METHODS: Subjects aged ≥18 years with T2DM and haemoglobin A1c (HbA1c) >7.0% and ≤8.5%, who were treatment naïve or receiving a non-thiazolidinedione antidiabetes monotherapy, entered a 2-week washout and single-blind placebo run-in period and were then randomized 2 : 4 : 11 : 11 to double-blind treatment with placebo, rivoglitazone 1.0 mg/day, rivoglitazone 1.5 mg/day, or pioglitazone 45 mg/day, for 26 weeks. RESULTS: A total of 1912 subjects received placebo (n = 137), rivoglitazone 1.0 mg (n = 274), rivoglitazone 1.5 mg (n = 750) or pioglitazone (n = 751). Rivoglitazone 1.5 mg was statistically superior (p = 0.0339) and rivoglitazone 1.0 mg was non-inferior (p = 0.0339) to pioglitazone in reducing HbA1c from baseline (changes of -0.7%, -0.4% and -0.6%, respectively). Rivoglitazone also significantly reduced fasting plasma glucose from baseline (p < 0.0001). Rivoglitazone significantly improved estimates of insulin sensitivity, high-density lipoprotein cholesterol levels, and other metabolic and inflammatory biomarkers. Rivoglitazone was generally well tolerated at both doses, with treatment-emergent adverse event (TEAE) rates similar to pioglitazone. The most common drug-related TEAEs were peripheral oedema (active, 5.2-6.2%; placebo 0.7%), increased weight (active, 1.6-3.1%; placebo, 0%) and pitting oedema (active, 1.3-2.2%; placebo, 0%). CONCLUSIONS: In subjects with suboptimally controlled T2DM, rivoglitazone 1.5 mg was associated with statistically superior glycaemic control to pioglitazone 45 mg, while rivoglitazone 1.0 mg was non-inferior; the safety profiles of the two drugs appeared similar.

Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus.

AIM: Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. METHODS: In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A(1c) (HbA(1c)) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of (3) H-labelled glucose followed by a 2-step hyperinsulinemic-euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA(1c) and fasting plasma glucose (FPG) levels were evaluated pre- and post-treatment. RESULTS: Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC(g)) but not incremental AUC(g). At week 12, neither total AUC(g) nor incremental AUC(g) were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC(i)) and incremental AUC(i) did not differ between groups. Both HbA(1c) and FPG improved with colesevelam, but treatment differences were not significant. CONCLUSIONS: Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.

Indicators and outcome of liver transplantation in acute liver decompensation after flares of hepatitis B.

Non-cirrhotic patients having acute liver decompensation in flares of hepatitis B can recover spontaneously or die without liver transplantation. Criteria for identifying patients in need of liver transplantation are lacking. Fifty-one non-cirrhotic patients having acute liver decompensation in flares of hepatitis B were retrospectively reviewed. The patients were divided into three groups: group A patients (n=18) recovered from acute liver decompensation spontaneously; group B patients (n=22) died of acute liver failure; and group C patients (n=11) had liver transplantation. Model of end-stage liver disease (MELD) scores were evaluated to identify the criteria for liver transplantation. The cut-off point of MELD scores for liver transplantation was evaluated by receiver operating characteristic (ROC) curve. Comparing group A and B patients, MELD score was an independent factor to predict prognosis. By analysing ROC curve, a MELD score>30 was the most optimal cut-off point to indicate liver transplantation; however, the false positive rate was 11.1%. By weekly measurement of MELD scores, subsequent increase in MELD scores could help to avoid false positives. Moreover, a MELD score>34 yielded 0% false positive rate and indicated the necessity of definite liver transplantation. For group C patients, ten of 11 patients were saved by liver transplantation. In conclusion, for the patients having acute liver decompensation in flares of hepatitis B, liver transplantation is definitely indicated by MELD scores>34. Liver transplantation is also indicated if the MELD score increases in the subsequent 1-2 weeks. Liver transplantation has a good outcome if performed on time.

Flexible and individualized treatment to achieve sustained viral response for recurrent hepatitis C in liver transplant recipients.

Hepatitis C recurrence after liver transplantation is universal and is a major cause of long-term graft failure. Improving the effectiveness of recurrent hepatitis C treatment is extremely important. We studied 35 anti-hepatitis C virus (HCV)-positive patients who underwent liver transplantation. Among the 35 patients, 25 patients had recurrent hepatitis C and received antiviral treatment. HCV RNA load after liver transplantation was increased by 3.68-fold. The antiviral treatment regimen comprised pegylated-interferon (180 µg) every 2 weeks and ribavirin at a dose of 200-400 mg every day. The treatment duration was flexible and individualized, and depended on viral response to treatment. The dosage of tacrolimus was decreased gradually to minimize immunocompromise. Median (interquartile) serum level of tacrolimus was 6.9 (6-8.9) ng/mL at initiation of treatment and 3.8 (3.6-5) ng/mL at the end of treatment. One patient (4.0%) was withdrawn from the study, and three patients (12%) died of infection during treatment. At end of treatment, 18 of 25 patients (72%) were negative for serum HCV RNA. After an additional 6 months following the end of treatment, 16 of the 25 patients (64%) had sustained viral response (SVR) and only two patients had HCV relapse. The 1-year, 3-year and 5-year survival rates were 91.4%, 84.5% and 84.5% for all patients and 88.0%, 82.8% and 82.8% for the 25 patients who received antiviral therapy. In conclusion, recurrent HCV infection is an important issue in liver transplantation. The flexible regimen of antiviral therapy and individualized immunosuppressive agents that was applied in this study achieved a SVR rate of 64%.

Germline organization of the murine T cell receptor beta-chain genes.

The complete germline organization of the beta-chain genes of the murine T cell receptor was elucidated in order to obtain the structural basis for understanding the mechanisms of somatic DNA rearrangements. Twenty of the 22 known variable (V beta) genes are clustered within 250 kilobases of DNA 5' to the constant region (C beta) genes. These V beta genes share the same transcriptional orientation as the diversity (D beta), joining (J beta), and C beta genes, which implies that chromosomal deletion is the mechanism for most V beta to D beta-J beta rearrangements. Within this V beta cluster, the distance between the most proximal V beta gene and the D beta-J beta-C beta cluster is 320 kilobases, as determined by field-inversion gel electrophoresis. The large distance between V beta and D beta, relative to that between D beta and J beta, may have significant implications for the ordered rearrangement of the T cell receptor beta-chain genes.

T-cell receptor beta-chain expression: dependence on relatively few variable region genes.

Fifteen independently isolated complementary DNA clones that contain T-cell receptor (TCR) V beta genes were sequenced and found to represent 11 different V beta genes. When compared with known sequences, 14 different V beta genes could be defined from a total of 25 complementary DNA's; 11 clones therefore involved repeated usage of previously identified V beta's. Based on these data, we calculate a maximum likelihood estimate of the number of expressed germline V beta genes to be 18 with an upper 95 percent confidence bound of 30 genes. Southern blot analysis has shown that most of these genes belong to single element subfamilies which show very limited interstrain polymorphism. The TCR beta-chain diversity appears to be generated from a limited V beta gene pool primarily by extensive variability at the variable-diversity-joining (V-D-J) junctional site, with no evidence for the involvement of somatic hypermutation.

Potential benefits of early addition of rosiglitazone in combination with glimepiride in the treatment of type 2 diabetes.

AIM: To assess the efficacy and tolerability of early combination therapy with rosiglitazone (RSG) and glimepiride (GLIM) vs. GLIM monotherapy in patients with type 2 diabetes mellitus (T2DM). METHODS: Strategies for the addition of RSG in combination with GLIM were evaluated with data from two randomized, double-blind, placebo (PBO)-controlled studies. Study A - addition of RSG (4 or 8 mg) or PBO to continued GLIM 3 mg once daily; study B - addition of low-dose RSG (4 mg) prior to uptitration of GLIM (from 2 to 4 mg) vs. continued uptitration of GLIM (from 2 to 8 mg). RESULTS: Study A reported significant reductions in fasting plasma glucose (FPG) from baseline to week 26 with the addition of both 4 and 8 mg RSG to GLIM 3 mg [-21 mg/dl (-1.2 mmol/l), p = 0.0019 and -43 mg/dl (-2.4 mmol/l), p < 0.0001, respectively] and in haemoglobin A(1c) (HbA(1c)) (-0.63%, p = 0.00015 and -1.17%, p < 0.0001, respectively) from a baseline of 8.2 and 8.1%, respectively. At the end of the study, target HbA(1c) <7.0% was achieved in 43 and 68% of patients in the RSG 4 mg + GLIM and RSG 8 mg + GLIM groups, respectively, compared with 32% in the PBO + GLIM (GLIM alone) group. In study B, addition of RSG to GLIM reduced mean FPG and HbA(1c) levels at week 24 from baseline [-28 mg/dl (-1.5 mmol/l), p < 0.0001, and -0.68%, p < 0.0001, respectively]. There were no significant changes with GLIM monotherapy in either study. Favourable effects of RSG + GLIM on insulin sensitivity, beta-cell function and cardiovascular disease biomarkers were also observed. All treatments were similarly well tolerated. CONCLUSIONS: Early addition of RSG to GLIM is an effective and well-tolerated treatment option to improve glycaemic control in sulphonylurea-treated patients with T2DM.

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes.

AIM: This study assessed the efficacy and safety of two different dosing regimens of fixed-dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug-naive subjects with type 2 diabetes mellitus (T2DM). METHODS: Drug-naive subjects (n = 901) were enrolled into this 28-week, double-blind, parallel-group study if their glycosylated haemoglobin A(1c) (HbA(1c)) was >7.5% but

Suspect the donor with potential infection in the adult deceased donor liver transplantation.

INTRODUCTION: Liver transplantation is the treatment of choice for end-stage liver disease. However, the shortage of donors is still the major problem in most Asian countries. Using extended donor criteria may maximize the deceased donor pool, but some high-risk donors may show adverse recipient outcomes due to preexisting infection. MATERIALS AND METHODS: This study included deceased donor liver transplant patients from June 2002 through June 2007. We retrospectively reviewed the clinical manifestations of donors and recipients. The donors showed no definite infection at the time the organs were matched to the recipients. Routine sputum, urine, blood, and bile cultures were obtained from the donor during the perioperative period. According to the final reports of the cultures, the recipients divided into two groups: donor infection (DI) and no donor infection (NDI). RESULTS: This study included 59 donor and 72 recipients, including 34 who received a graft from a donor with a positive culture (47.2%) finally, defined as the DI groups, and 38 recipients (52.8%) as the NDI group. Most of them had positive sputum cultures, followed by urine cultures. Staphylococcus aureus was the most common pathogen. Using a stepwise logistical regression model to analyze the significant donor characteristics, donor admission to the intensive care unit (ICU) for 7 days or longer (P < or = .0001), previous cardiopulmonary cerebral resuscitation (CPCR) (P = .036), and inotropic agents (P = .022) were the only three independent factors to predict donor infection. To compare the outcomes between DI and NDI groups, the days of recipient ICU or hospital admission, the 1-week or 1-month mortality rate, and the overall survival showed no significant difference between both groups. However, the hospital mortality rate was mildly higher in the DI group (P = .050). CONCLUSION: Donors with prolonged ICU admissions, rescue by CPCR, and use of inotropic agents carried an high risk of potential infections. Our data did not show a significant increase in adverse outcomes if the recipient received a graft from a potentially infected donor. However, there may be an increased risk of hospital mortality. We should be careful in using these potentially infected donors in selective recipients.

Endoscopic management of biliary complications after adult right-lobe living donor liver transplantation without initial biliary decompression.

OBJECTIVES: We sought to examine biliary complications in adult right-lobe living donor liver transplantation (LDLT) with duct-to-duct anastomosis (RL-LDLT-DD), evaluating the efficacy of endoscopic retrograde cholangiography (ERC) in the diagnosis and management of biliary complications following LDLT. METHODS: Ninety adult RL-LDLT-DD were performed from June 2004 to August 2007, including 21 (23.3%) cases of biliary complications. RESULTS: The endoscopic retrograde cholangiopancreatiography (ERCP) findings were stricture only (n = 8), stricture plus leakage (n = 9), and leakage only (n = 4). In the overall 13 cases of leakage, nine patients recovered after treatment by stent or endoscopic nasobiliary drainage. The time to resolution was 3.0 +/- 1.3 months with 2.2 +/- 1.3 endoscopic examinations. All bile duct complications were treated by ERC first. Among 17 cases with stricture, seven cases were successfully treated by endoscopy and three cases by percutaneous transhepatic cholangiography plus stent (PTCS). In the other seven cases, the treatment was still ongoing in five cases and two subjects died during treatment. The mean time to stricture resolution 7.2 +/- 3.3 months with 3.9 +/- 1.4 endoscopic examinations. The results of 21 cases were 5/21 mortalities (23.8%), successful ERC treatment in 9/21; (42.9%), successful PTCS treatment in 3/21 (14.3%), and ongoing ERC treatment in 5/21, (23.8%), including one case with successful ERC treatment who died of lung infection postoperatively. During follow-up (13.1 +/- 9.9 months), there was no recurrence in the stricture or leak. CONCLUSIONS: When compared with the literature, RL-LDLT-DD without biliary drainage does not increase the incidence of biliary complications. From our study, ERC and PTC play a complementary roles in the treatment of bile duct complications.

Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression.

Loss-of-function mutations of p16(INK4a) have been identified in a large number of human tumors. An established biochemical function of p16 is its ability to specifically inhibit cyclin D-dependent kinases in vitro, and this inhibition is believed to be the cause of the p16-mediated G1 cell cycle arrest after reintroduction of p16 into p16-deficient tumor cells. However, a mutant of Cdk4, Cdk4(N158), designed to specifically inhibit cyclin D-dependent kinases through dominant negative interference, was unable to arrest the cell cycle of the same cells (S. van den Heuvel and E. Harlow, Science 262:2050-2054, 1993). In this study, we determined functional differences between p16 and Cdk4(N158). We show that p16 and Cdk4(N158) inhibit the kinase activity of cellular cyclin D1 complexes through different mechanisms. p16 dissociated cyclin D1-Cdk4 complexes with the release of bound p27(KIP1), while Cdk4(N158) formed complexes with cyclin D1 and p27. In cells induced to overexpress p16, a higher portion of cellular p27 formed complexes with cyclin E-Cdk2, and Cdk2-associated kinase activities were correspondingly inhibited. Cells engineered to express moderately elevated levels of cyclin E became resistant to p16-mediated growth suppression. These results demonstrate that inhibition of cyclin D-dependent kinase activity may not be sufficient to cause G1 arrest in actively proliferating tumor cells. Inhibition of cyclin E-dependent kinases is required in p16-mediated growth suppression.

Human and yeast cdk-activating kinases (CAKs) display distinct substrate specificities.

Cell cycle progression is controlled by the sequential functions of cyclin-dependent kinases (cdks). Cdk activation requires phosphorylation of a key residue (on sites equivalent to Thr-160 in human cdk2) carried out by the cdk-activating kinase (CAK). Human CAK has been identified as a p40(MO15)/cyclin H/MAT1 complex that also functions as part of transcription factor IIH (TFIIH) where it phosphorylates multiple transcriptional components including the C-terminal domain (CTD) of the large subunit of RNA polymerase II. In contrast, CAK from budding yeast consists of a single polypeptide (Cak1p), is not a component of TFIIH, and lacks CTD kinase activity. Here we report that Cak1p and p40(MO15) have strikingly different substrate specificities. Cak1p preferentially phosphorylated monomeric cdks, whereas p40(MO15) preferentially phosphorylated cdk/cyclin complexes. Furthermore, p40(MO15) only phosphorylated cdk6 bound to cyclin D3, whereas Cak1p recognized monomeric cdk6 and cdk6 bound to cyclin D1, D2, or D3. We also found that cdk inhibitors, including p21(CIP1), p27(KIP1), p57(KIP2), p16(INK4a), and p18(INK4c), could block phosphorylation by p40(MO15) but not phosphorylation by Cak1p. Our results demonstrate that although both Cak1p and p40(MO15) activate cdks by phosphorylating the same residue, the structural mechanisms underlying the enzyme-substrate recognition differ greatly. Structural and physiological implications of these findings will be discussed.

Difficult Situation of Pancreas Transplantation in the Setting of Scarce Organ Donation.

BACKGROUND: Currently, pancreas transplantation has been a promising strategy to restore long-term normoglycemia as well as to improve life quality for patients with insulin-dependent diabetes mellitus (DM). However, the discrepancy between the number of organs needed and the number donated for transplantation is always enormous. Under a setting of scarce organ donations, we examined our limited experience of pancreas transplantation. METHODS: A retrospective review of pancreas transplantations was performed with the use of data from the Taiwan Organ Registry and Sharing Center and the Ministry of Health and Welfare. Pancreas transplantations in the Organ Transplantation Institute of Chang Gung Memorial Hospital also were reviewed. RESULTS: At present, there are 5 medical centers approved for pancreas transplantation in Taiwan. Overall, a total of 156 pancreas transplantations were performed from 2005 to the end of 2016; only 9 of them were performed in the Organ Transplantation Institute of Chang Gung Memorial Hospital. Although the number of organ donations is rising, pancreas transplantation numbers remain low. More than 20 pancreas transplantations were performed in 2016, yet there remained a total of 111 patients registered on the wait list for pancreas transplantation at the end of this study. Thus the gap between organ donation and transplantation is still vast. CONCLUSIONS: With continuing improvements in Taiwanese health policies and public education regarding organ transplantation, organ donation rates have risen steadily in recent years. Moreover, quality control and continuing evolution in organ transplantation is crucial to ameliorate the difficult situation of pancreas transplantation and other solid organ transplantation in the context of low levels of donation.

Pre-Transplantation Immune Cell Distribution and Early Post-Transplant Fungal Infection Are the Main Risk Factors of Liver Transplantation Recipients in Lower Model of End-Stage Liver Disease.

BACKGROUND: The prognosis of patients after liver transplantation (LTx) with high Model of End-Stage Liver Disease (MELD) score (>30) is predicted, but patients with lower MELD scores (<30) have no conclusive studies of pre- and post-transplant risk factors that influence the long-term outcome. METHODS: This retrospective study reviewed 268 recipients with MELD score <30, from 2008 to 2013 in our institution, for evaluation of pre-transplant risk factors including patients' clinical background data, pre-transplant lymphocyte subpopulation, and early post-transplant infection complication as predictors for long-term survival after LTx. RESULTS: The post-transplant patients' survival estimates were 90.7%, 85.1%, and 83.6% at 1, 3, and 5 years, respectively. In multivariate analysis, age >55years, presence of ascites, cluster of differentiation (CD)3 < 93.2 (count/µL), CD4/CD8 <2.4, fungal infection, and more than one site of fungal colonization significantly influenced survival (P = .0003, P = .002, P = .04, P = .004, P < .0001, and P > .0001, respectively). We also noticed that these five factors accumulatively influence the long-term survival rate; this means that in the presence of any two risk factors, the 5-year survival can still be 88.4%, whereas in the presence of any three risk factors, the survival rate dropped to only 57.1%. CONCLUSIONS: Older patients in the presence of pre-transplant low immune cell number and ascites in association with post-transplant fungal infection are the independent risk factors in MELD scores <30 LTx groups for long-term survival. Patients in these groups with any of the three factors had inferior long-term survival results.

Application of CD8+ Cells Count as a Guide of Immunosuppressive Regimen Introduction for Very Sick Patients Undergoing Liver Transplantation.

BACKGROUND: Immunosuppression (IS) protocols should be individualized according to the individual recipient's immunity to minimize adverse effects. The aim of this study was to determine whether preoperative levels of CD8+ T lymphocytes could be used as a guide for the introduction of IS. METHODS: Sixteen adult liver transplantations in our institute were retrospectively analyzed. The immunosuppressive agents were temporarily withheld for 8 patients with a lower (<10%) preoperative percentage of CD8+ cells after transplant (classified as group A). In this group, postoperative immunosuppressive agents had never been used until acute rejection was suspected. Another 8 patients receiving classic IS were classified as group B. We collected their demographic features and analyzed the clinical courses. RESULTS: The postoperative IS-free period of group A was 5 to 120 days (median, 31 days). Our data showed an inverse correlation between CD8+ levels and the severity of liver disease. Although the IS-free protocol did not present a lower incidence of infection-related events, most of them were effectively treated with antibiotics. The 1-, 3-, and 5-year overall patient survival rates were not different between those with a short-term IS-free period and those with regular IS (87.5% vs 100%, 75% vs 100%, and 62.5% vs 87.5%; P = .468). No patient died of graft failure due to acute rejection. CONCLUSIONS: Postoperative immunosuppressive agents can be safely withheld for a period of time to preserve proper immune responses against infections in very sick recipients guided by using the CD8+ levels.

Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era.

AIMS: Surgical treatment for early-stage hepatocellular carcinoma (HCC) is toward transplantation. However, liver resection remains the major surgical treatment for HCC in Asia. This study is to examine the results of liver resection when liver transplantation became an option of treatment for early-stage HCC. METHODS: In this retrospective cohort study, 1639 patients with resectable HCC were reviewed and divided into two groups. In the 1st period (2002-2005), all 679 patients received liver resection. In the 2nd period (2006-2010), 916 patients had liver resection and 44 patients jointed liver transplantation program. The results of treatment in these two periods were analyzed. RESULTS: The characteristics of tumors were the most important factors of tumor recurrence after liver resection. Liver function reserve, characteristics of tumors, and surgeons' endeavor were all independent factors for overall survival after liver resection. When the patients with oligo-nodular tumors or portal hypertension with low platelet count had liver transplantation rather than liver resection in the 2nd period, the survival rates in the 2nd period were improved. When the patients in the 1st period with low platelet count (≤105 × 10(3)/uL) were subtracted, the 5-year survival rate of the patients with one-segmentectomy for small-sized HCC in the 1st period was similar to those in the 2nd period and transplant patients. CONCLUSIONS: The outcomes of liver resection were improved while liver transplantation was performed for the patients with suspicious portal hypertension. Platelet count, 105 × 10(3)/uL, could be a watershed for early stage HCC patients to undergo liver resection or liver transplantation.