Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity.

Lenvatinib is a multitargeted tyrosine kinase inhibitor capable of promoting apoptosis, suppressing angiogenesis, inhibiting tumor cell proliferation, and modulating the immune response. In multiple cancer types, lenvatinib has presented manageable safety and is currently approved as an effective first-line therapy. However, with the gradual increase in lenvatinib application, the inevitable progression of resistance to lenvatinib is becoming more prevalent. A series of recent researches have reported the mechanisms underlying the development of lenvatinib resistance in tumor therapy, which are related to the regulation of cell death or proliferation, histological transformation, metabolism, transport processes, and epigenetics. In this review, we aim to outline recent discoveries achieved in terms of the mechanisms and potential predictive biomarkers of lenvatinib resistance as well as to summarize untapped approaches available for improving the therapeutic efficacy of lenvatinib in patients with various types of cancers.

Association of phenotypic transformation of circulating tumor cells and early recurrence in patients with hepatocellular carcinoma following liver transplantation.

BACKGROUND: CTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. METHODS: Retrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. RESULTS: During the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). CONCLUSION: CanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.

CEUS detection of biliary ischaemia during the first 4 weeks after liver transplantation predicts non-anastomotic biliary stricture.

BACKGROUND: Biliary ischaemia is an important factor in the pathogenesis of non-anastomotic biliary stricture (NAS) after liver transplantation (LT). Contrast-enhanced ultrasound (CEUS) can be used to detect biliary ischaemia, but no study has examined the utility of CEUS in predicting NAS. OBJECTIVE: To evaluate whether repeated CEUS as a non-invasive method of biliary ischaemia can identify NAS. METHODS: Consecutive LT patients who underwent CEUS examinations at 1-4 weeks after LT from September 2012 to December 2015 at our institution were included. The CEUS images and clinical data were analysed. RESULTS: Among 116 eligible LT patients, 39 (33.6%) were diagnosed with NAS within 1 year after LT. The patients with NAS had a significantly higher CEUS score at weeks 2-4 (all P < 0.05) and a higher slope of CEUS score progression (0.480 vs -0.044, P < 0.001). The accuracy of CEUS in identifying NAS improved over time after LT, reaching its maximum at week 4, with a sensitivity of 66.7%, a specificity of 87.9%, a positive predictive value (PPV) of 75.9%, a negative predictive value (NPV) of 82.3%, and an accuracy of 80.2%in the full cohort when a CEUS score≥3 was used as the cut-off. Multivariate analysis identified gamma-glutamyl transpeptidase (GGT), alanine transaminase (ALT) and the CEUS score at week 4 as independent predictors of NAS. In the task of identifying NAS, an NAS score combining the above 3 variables at week 4 showed areas under the receiver operating characteristic curve of 0.88 (95%CI, 0.78-0.99) in the estimation group (n = 60) and 0.82 (95%CI, 0.69-0.96) in the validation group (n = 56). An NAS score cut-off of 0.396 identified 87.2%of NAS cases in the estimation group, with a PPV of 93.3%; and 75.0%of NAS cases in the validation group, with a PPV of 58.8%. CONCLUSIONS: CEUS examination during the first 4 weeks is useful in assessing the risk of NAS within 1 year after LT. In particular, an NAS score combining the CEUS score, GGT level, and ALT level at week 4 can be used to accurately predict the risk of NAS in LT patients.

Effect of Hepatic Artery Spasm on a Rat Model of Hepatic Ischemia-Reperfusion Injury.

OBJECTIVES: To investigate hemodynamic changes in the hepatic artery after hepatic ischemia-reperfusion injury (IRI) in rats via ultrasound (US) imaging and to discuss the protective effect of phentolamine (PHT) pretreatment on hepatic IRI. METHODS: Fifty rats were randomly divided into 3 groups: a sham operation group (n = 10), a control ischemia-reperfusion group (n = 20), and a PHT pretreatment group (n = 20). Color Doppler flow imaging and contrast-enhanced US examinations were performed in each group at 30 minutes (n = 10) and 90 minutes (n = 10) after reperfusion. Blood samples were obtained to analyze serum alanine aminotransferase and aspartate aminotransferase levels, and liver tissue specimens were collected for pathologic analysis. RESULTS: Using US, we found that hepatic artery resistance at 30 minutes after reperfusion in the control group was higher than that in the sham group (mean resistive index [RI] ± SD, 0.65 ± 0.09 versus 0.50 ± 0.09; P < .01), which was higher at 30 than 90 minutes (RI, 0.65 ± 0.09 versus 0.50 ± 0.08; P < .01) after reperfusion in the control group. However, the hepatic artery resistance and liver microcirculation in the PHT group were better than those in the control group at 30 minutes after reperfusion (RI, 0.54 ± 0.09 versus 0.65 ± 0.09; P < .05; time to peak, 31.94 ± 2.02 versus 48.34 ± 4.74 seconds; P < .01). Compared to the control group, the aspartate aminotransferase and alanine aminotransferase levels were significantly lower at 30 minutes after reperfusion in the PHT group (P < .05). A pathologic examination revealed a smaller hepatic artery diameter and a depressed vessel wall in the control group. CONCLUSIONS: The hepatic artery can undergo a transient spasm during the hepatic IRI process, which can exacerbate liver damage. Phentolamine treatment can alleviate hepatic artery spasms, improve liver perfusion, and reduce liver injury by ameliorating the hepatic microcirculation.

Better prognosis of hepatic resection combined with antiviral therapy for HBV-related hepatocellular carcinoma with BCLC Stage B/C.

BACKGROUND: Whether hepatic resection (HR) could be performed for patients with Barcelona Clinic Liver Cancer (BCLC) B/C stage hepatocellular carcinoma (HCC) is controversial, and the safety and clinical value of HR combined with antiviral therapy for hepatitis B virus (HBV)-related HCC with BCLC-B/C stage remain to be investigated. METHODS: We retrospectively evaluated 126 patients with BCLC stage B/C HCC who underwent HR. These patients were divided into the antiviral group (Group A, n = 86) and the control group (Group B, n = 40). The operative indications and prognosis of 126 patients were analyzed. RESULTS: The 1-year, 3-year, and 5-year disease-free survival (DFS) rates for Group A and Group B were 55.4%, 36.1%, 33.7% and 53.8%, 28.2%, 23.1%, respectively. The corresponding overall survival (OS) rates for the two groups were 89.2%, 61.4%, 45.8% and 82.1%, 48.7%, 33.3%, respectively. The DFS and OS for Group A were better than for Group B (p = 0.013, and p = 0.038, respectively). Antiviral therapy was an independent protective factor of late tumor recurrence [hazard ratio (HR) = 0.391, 95% confidence interval (CI): 0.190-0.806, p = 0.011] but not of early tumor recurrence. CONCLUSION: It is safe and feasible to perform HR combined with antiviral therapy for HBV-related HCC with BCLC stage B/C.

Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation.

BACKGROUND AIMS: Ischemic-type biliary lesions are severe, graft-threatening complications after orthotopic liver transplantation, and a novel and efficient therapeutic strategy is urgently needed. Due to the immunosuppressive and regenerative properties, mesenchymal stromal cells (MSCs) could be an interesting candidate. METHODS: We initiated safety and efficacy of human umbilical cord-derived MSC (UC-MSC) transfusions for patients with ischemic-type biliary lesions after liver transplantation. From January 2013 to June 2014, 12 ischemic-type biliary lesions patients were recruited as the MSCs group in this phase I, prospective, single-center clinical study. Patients in this group received six doses of UC-MSCs (about 1.0 × 106 MSCs per kilogram body weight through peripheral intravenous infusion). The traditional therapeutic protocol was applied during October 2003 to December 2012 in 70 ischemic-type biliary lesions patients who were treated as the control group. Liver function tests, the need for interventional therapies and graft survival rate were chosen to evaluate the therapeutic efficacy of MSC treatment. Adverse events were closely monitored up to 2 years after MSC transfusions. RESULTS: No significant MSC-related adverse events were observed during the trial. Compared with baseline, the levels of total bilirubin, γ-glutamyl transferase and alkaline phosphatase were decreased after UC-MSC treatment at week 20 and week 48. Interventional therapies were performed in 64.3% (45/70) of patients in the control group and 33.3% (4/12) of patients in the MSCs groups. MSC therapy significantly decreased the need for interventional therapies (P = 0.046). The 1- and 2-year graft survival rates were higher in the MSCs group (100% and 83.3%, respectively) than in the control group (72.9% and 68.6%, respectively). CONCLUSIONS: The UC-MSC transfusions are clinically safe and short-term favorable, which may become a novel treatment for patients with ischemic-type biliary lesions after liver transplantation.

Survival analysis of sirolimus-based immunosuppression in liver transplantation in patients with hepatocellular carcinoma.

AIM: To investigate the effect of a sirolimus-based immunosuppressive protocol on tumor recurrence and survival after liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. METHODS: We retrospectively analyzed 142 HCC patients who underwent LT in our hospital from January 2006 to January 2012. The patients were divided into the sirolimus (SRL) group (62 cases) and non-sirolimus (control) group (80 cases). Disease-free survival (DFS) and tumor-bearing survival after tumor recurrence were compared using the Kaplan-Meier method. RESULTS: No significant difference in DFS was observed between the two groups. Furthermore, DFS showed no significant differences in the subgroups of patients who met the Milan criteria, exceeded the Milan criteria but met the University of California, San Francisco (UCSF) criteria, or exceeded the UCSF criteria between the two groups. In the control group, 21 patients who were administered SRL after tumor recurrence had a median tumor-bearing survival time of 12months (3-34months), while 14 patients who did not experience a change in their immunosuppressive protocol after tumor recurrence had a median tumor-bearing survival time of 8months (6-22months). There was a significant difference in the tumor-bearing survival time between these patients (P=0.039). CONCLUSIONS: Not all HCC patients benefited from the sirolimus-based immunosuppressive protocol after LT. However, sirolimus may prolong the survival time of patients after tumor recurrence.

Contrast-enhanced sonography for quantitative assessment of portal hypertension in patients with liver cirrhosis.

OBJECTIVES: The clinical utility of contrast-enhanced sonography in portal hypertension remains unclear. We explored the feasibility of using contrast-enhanced sonography for noninvasive assessment of portal venous pressure. METHODS: Twenty healthy individuals (control group; 9 men; mean age, 46.4 years) and 18 patients with portal hypertension (15 men; mean age, 46.2 years) were enrolled in this study. The portal hypertension group included patients who underwent splenectomy and pericardial blood vessel disarticulation at our hospital from October 2010 to March 2011. One week before surgery, patients with portal hypertension underwent preoperative liver contrast-enhanced sonography. Two-dimensional, Doppler, and contrast-enhanced sonographic parameters were compared between the groups. Portal venous pressure was measured intraoperatively by portal vein puncture in the portal hypertension group, and its relationship with the other parameters was analyzed. RESULTS: The 2-dimensional, Doppler, and contrast-enhanced sonographic parameters differed between the groups (P < .01). Portal venous pressure was inversely correlated with the area under the portal vein/hepatic artery time-intensity curve ratio (Qp/Qa), portal vein/hepatic artery strength ratio (Ip/Ia), and portal vein/hepatic artery wash-in perfusion slope ratio (ßp/ßa), with correlation coefficients of -0.701, -0.625, and -0.494, respectively. CONCLUSIONS: Measurement of the liver contrast-enhanced sonographic parameters Qp/Qa, Ip/Ia, and ßp/ßa could be used as a new quantitative method for noninvasively assessing portal venous pressure.

New diagnosis and therapy model for ischemic-type biliary lesions following liver transplantation--a retrospective cohort study.

Ischemic-type biliary lesions (ITBLs) are a major cause of graft loss and mortality after orthotopic liver transplantation (OLT). Impaired blood supply to the bile ducts may cause focal or extensive damage, resulting in intra- or extrahepatic bile duct strictures or dilatations that can be detected by ultrasonography, computed tomography, magnetic resonance cholangiopancreatography, and cholangiography. However, the radiographic changes occur at an advanced stage, after the optimal period for therapeutic intervention. Endoscopic retrograde cholangio-pancreatography (ERCP) and percutaneous transhepatic cholangiodrainage (PTCD) are the gold standard methods of detecting ITBLs, but these procedures cannot be used for continuous monitoring. Traditional methods of follow-up and diagnosis result in delayed diagnosis and treatment of ITBLs. Our center has used the early diagnosis and intervention model (EDIM) for the diagnosis and treatment of ITBLs since February 2008. This model mainly involves preventive medication to protect the epithelial cellular membrane of the bile ducts, regular testing of liver function, and weekly monitor of contrast-enhanced ultrasonography (CEUS) to detect ischemic changes to the bile ducts. If the liver enzyme levels become abnormal or CEUS shows low or no enhancement of the wall of the hilar bile duct during the arterial phase, early ERCP and PTCD are performed to confirm the diagnosis and to maintain biliary drainage. Compared with patients treated by the traditional model used prior to February 2008, patients in the EDIM group had a lower incidence of biliary tract infection (28.6% vs. 48.6%, P = 0.04), longer survival time of liver grafts (24±9.6 months vs. 17±12.3 months, P = 0.02), and better outcomes after treatment of ITBLs.

Bone marrow mesenchymal stem cells ameliorate hepatic ischemia/reperfusion injuries via inactivation of the MEK/ERK signaling pathway in rats.

BACKGROUND: Primary graft dysfunction or nonfunction after liver transplantation, which is usually caused by ischemia/reperfusion injury (IRI), is a serious clinical problem. Although bone marrow mesenchymal stem cells (MSCs) have shown great potential in cell therapy for IRI in several organs, the mechanism(s) by which MSCs offer protection is unclear. METHODS: In the present study, we injected MSCs systemically via the tail vein in the rat model of 70% hepatic IRI and measured the biochemical and pathologic alterations to evaluate the therapeutic effect of MSC transplantation. Concurrently, H(2)O(2) was used in vitro to mimic oxidative injury and to induce apoptosis in the human normal liver cell line LO2 to evaluate the protective effects of mesenchymal stem cell conditioned medium (MSC-CM) on LO2 cells. RESULTS: The systemic infusion of MSCs led to a significant prevention of liver enzyme release and an improvement in the histology of the acutely injured liver. In vitro assays demonstrated that MSC-CM promoted hepatocyte proliferation and had a direct inhibitory effect on hepatocyte apoptosis induced by H(2)O(2). In addition, we demonstrated that the prevention of MEK/ERK pathway activation played a pivotal role in the protection. CONCLUSIONS: These data suggest that MSC may represent a potential therapeutic strategy to alleviate hepatic ischemia/reperfusion injuries after liver transplantation via inactivation of the MEK/ERK signaling pathway.

[Effects of CD40LIg gene-modified bone marrow mesenchymal stem cells on liver graft rejection in rats].

OBJECTIVE: To study the effects of cluster of differentiation 40 ligand immunoglobulin (CD40LIg) gene-modified bone marrow mesenchymal stem cells (MSCs) on liver graft rejection in rats. METHODS: The orthotopic liver transplantation models were established with DA rats as the donors and Lewis rats as the recipient. MSCs infected with the recombinant adenoviruses containing CD40LIg gene were infused into the liver graft after transplantation. The liver function, survival of the recipient rats and the morphological changes of the liver grafts were observed after the transplantation. The serum levels of the cytokines interferon-γ (INF-γ) and interleukin-2 (IL-2) in the recipient rats were quantified by ELISA. RESULTS: The survival of the recipient rats receiving transplantation of genetically modified MSCs (group D) was significantly prolonged compared with that of the control group (group A), MSCs group (group B) and gene transfection group (group C); the survival of groups B and C were significantly longer than that of group A (F=7.615, P<0.05). The level of serum alanine aminotransferase, total bilirubin, IL-2 and INF-γ were significantly higher in group A than in the other 3 groups (F=8.738, P<0.05). HE staining of the liver grafts showed severe acute rejection in group A, mild acute graft rejection in groups B and group C, but no rejection in group D. CONCLUSION: CD40LIg gene-modified MSCs can prolong the survival of the recipient rats and suppress graft rejection following liver transplantation.

Prognostic factors for late mortality after liver transplantation for benign end-stage liver disease.

BACKGROUND: There are increasing numbers of patients who survive more than one year after liver transplantation. Many studies have focused on the early mortality of these patients. However, the factors affecting long-term survival are not fully understood. This study aims to evaluate prognostic factors predicting long-term survival and to explore measures for improving the survival outcomes of patients who underwent liver transplantation for benign end-stage liver diseases. METHODS: The causes of late death after liver transplantation and potential prognostic factors were retrospectively analyzed for 221 consecutive patients who underwent liver transplantation from October 2003 to June 2008. Twenty-seven variables were assessed using the Kaplan-Meier method, and those variables found to be univariately significant at P < 0.10 were entered into a backward step-down Cox proportional hazard regression analysis to identify the independent prognostic factors influencing the recipients' long-term survival. RESULTS: Twenty-eight recipients died one year after liver transplantation. The major causes of late mortality were infectious complications, biliary complications, and Hepatitis B virus recurrence/reinfection. After Cox analysis, the five remaining co-variables were: age, ABO blood group, cold ischemia time, post-infection region, and biliary complications. CONCLUSIONS: The major causes of late mortality were infection, biliary complications and Hepatitis B virus recurrence/reinfection. Five variables (Age, ABO blood group, cold ischemia time, infection, and biliary complications) had significant impacts on patient survival.

[Risk factors predicting late mortality after liver transplantation for benign end-stage liver disease].

OBJECTIVES: To find out the risk factors predicting long-term survival, and to explore the measures for further improving the survival outcome of whom underwent liver transplantation (LT) for benign end-stage liver disease. METHODS: The common causes of late death after LT and risk factors were retrospectively analyzed in 221 consecutive patients, who underwent LT from October 2003 to June 2007 and survived more than one year. Twenty-six potential risk factors were assessed by the Kaplan-Meier method, and those variables found to be univariately significant at P < 0.10 were entered into a backward step down Cox proportional hazard regression analysis to screen the independent risk factors influencing the recipient's long-term survival. RESULTS: There were 28 recipients died one year later after LT during the follow-up period. The major causes of late mortality were related to infectious complications 5.0% (11/221), biliary complications 3.6% (8/221) and HBV recurrence/reinfection 1.4% (3/221). After Cox proportional hazard regression analysis, 5 covariables finally retained in the formula were: age (RR = 2.325, P = 0.009), ABO blood group (RR = 2.206, P = 0.015), cold ischemia time (RR = 3.001, P = 0.000), post-infection region (RR = 1.665, P = 0.007) and biliary complications (RR = 2.655, P = 0.004). CONCLUSION: Age (≥ 60 years), ABO blood group (incompatible), cold ischemia time (> 12 h), infectious complications (lung infection) and biliary complications (diffuse biliary stricture) significantly impact patient's survival time.

Liver transplantation for end-stage alcoholic liver disease: a single-center experience from mainland China.

There has been a gradual increase in the number of patients with end-stage alcoholic liver disease (ALD) undergoing liver transplantation (LT) in mainland China. However, few studies have focused on the post-transplant outcomes of this population. The aim of this study was to evaluate the efficacy of LT in patients with ALD, mainly focusing on survival rates, complications, and alcohol recidivism. The results were retrospectively analyzed from 20 patients, who underwent LT for ALD from December 2003 to September 2007 at Liver Transplant Center of Third Affiliated Hospital of Sun Yat-sen University. The 1-, 2-, and 3-year survival rates of the ALD group and non-ALD group were 90.0, 80.0, 80.0% and 90.3, 84.7, 79.8%, respectively. There was no significant difference in 1-, 2-, and 3-year survival rates between these two groups (P=.909). No significant difference was observed in complications such as pulmonary infection (50.0 vs. 31.9%, P=.137), biliary complications (15.0 vs. 27.4%, P=.297), hepatic arterial complications (10.0 vs. 6.9%, P=.641), and rejection (15.0 vs. 8.1%, P=.394) after LT between the ALD group and non-ALD group. There was only one person who resumed mild, intermittent drinking after LT. End-stage ALD is a good indication for LT, with similar results in non-ALD patients. The major cause of death in ALD patients after LT was infectious complications. More attention is needed for the prophylaxis of infectious complications after LT.

Hepatic artery complications after orthotopic liver transplantation: interventional treatment or retransplantation?

BACKGROUND: The main therapeutic treatments for hepatic artery complications after orthotopic liver transplantation (OLT) include thrombolysis, percutaneous transluminal angioplasty, stent placement, and liver retransplantation. The prognosis of hepatic artery complications after OLT is not only related to the type, extent, and timing but also closely associated with the selection and timing of the therapeutic methods. However, there is no consensus of opinion regarding the treatment of these complications. The aim of this study was to determine optimal treatment for hepatic artery complications after OLT. METHODS: The clinical data of 25 patients diagnosed with hepatic artery thrombosis (HAT) and hepatic artery stenosis (HAS) between October 2003 and March 2007 were retrospectively reviewed. Treatments included liver retransplantation and interventions which contain thrombolysis, percutaneous transluminal angioplasty and stent placement. RESULTS: Among five patients with HAT, 3 were treated with thrombolysis. One recovered, one died after thrombolysis and another one died of multi-organ failure after retransplantation because of recurrent HAT. The remaining 2 patients underwent successful retransplantation and have survived after that. Among 12 patients presented with HAS within 1 month postoperatively, 2 patients underwent retransplantation due to irreversible liver failure and another 10 patients were treated with interventions. The liver function failed to improve in 3 patients and retransplantations were performed in 4 patients after stent placement because of ischemic cholangitis. Among 6 patients undergoing liver retransplantations, two died of intracranial hemorrhage and infection respectively. Eight patients presented with HAS after 1 month postoperatively, 5 patients were treated with interventional management and recovered after stent placement. Among another 3 patients presented with HAS, 2 patients' liver function was stable and one patient received late liver retransplantation due to ischemic bile duct lesion. CONCLUSIONS: Individualized therapeutic regimens should be adopted in treating hepatic artery complications after OLT, according to postoperative periods, types and whether ischemic bile duct lesion exists or not. Liver retransplantation is the best treatment for patients with hepatic artery thrombosis. Interventional treatments of late HAS without irreversible liver failure or bile duct ischemia are appropriate, whereas retransplantation is recommended for early HAS.

[Long-term survival after liver transplantation for benign end-stage liver disease in adults].

OBJECTIVE: To evaluate the long-term survival rates of the adults with benign end-stage liver disease (BELD) after liver transplantation (LT) and the causes of death. METHODS: The common causes of late death (after more than 1 year) after LT were retrospectively analyzed in 203 consecutive patients with BELD who underwent LT from Oct. 2003 to May.2006. RESULTS: The 1, 2 and 3-year survival rates were 88.7%, 85.5%, and 81.2% respectively. The 2-year and 3-year survival rates of the patients with HBV-related liver disease were 88.4% and 84.5% respectively, not significantly different from those of patients with non-HBV-related liver disease (75.6% and 64.0% respectively, P = 0.144). 165 recipients survived for more than 1 year and 21 recipients died during the period between 12 and 48 months after LT with a mean of (22.7 +/- 6.6) months. The common causes of late death included related to infectious complications (4.8%, 8/165), biliary tract complications (3.6%, 6/165), HBV re-infection (1.8%, 3/165), chronic rejection (1.2%, 2/165), renal functional lesion (0.6%, 1/165), and hepatic arterial complication (0.6%1/165). CONCLUSION: Satisfactory long-term survival can be achieved in most adult recipients with BELD after LT and the major causes that influence the long-term survival are infectious complications, biliary tract complications, and HBV re-infection. Prevention of these complications, rational use of immunosuppressant, and regular follow-up are essential to improve long-term survival.

Prophylaxis of hepatitis B recurrence in post-liver transplantation patients with lamivudine-resistant YMDD mutant.

BACKGROUND: The most frequently used therapy for post-transplantation recurrence of hepatitis B virus (HBV) infection is lamivudine, but this drug is associated with a high resistance rate due to YMDD mutant. In preliminary reports, adefovir dipivoxil (ADV) has been shown to have activity against lamivudine-resistant strains of HBV. However, clinical experience in treatment of HBV infection after liver transplantation (LT) is still not entirely clear. This study was aimed to evaluate the prophylactic efficacy of ADV plus hepatitis B immunoglobulin (HBIG) in patients with YMDD mutant before LT. METHODS: From March 2004 to March 2006, 16 patients with chronic hepatitis B had lamivudine-resistant YMDD mutants detected prior to liver transplantation and received treatment with ADV plus additional intramuscular HBIG after LT as prophylaxis against graft reinfection. Tests for liver function, serum HBsAg, anti-HBs (HBIG), HBeAg, anti-HBc, anti-HBe, HBV-DNA, and creatinine were assessed pre- or post-liver transplantation. RESULTS: The median follow-up of these patients post-liver transplantation was 19.4 months. Fifteen patients survived and one patient died of recurrence of hepatocellular carcinoma (HCC). There was significant difference (10.98% vs. 2.26%, P < 0.05) in YMDD mutant rate between the patients with HBV-DNA over 10(6) copies/ml and those with HBV-DNA less than 10(6) copies/ml. Fifteen patients (93.8%) had undetectable HBV-DNA at 4 weeks and 1 (6.3%) at 6 months after LT. No hepatitis B recurrence was detected by persistent testing of HBsAg, HBeAg, and HBV-DNA and no increase of serum creatinine level associated with ADV was observed in any of the patients. CONCLUSION: ADV combined with intramuscular HBIG can effectively prevent patients with pre-transplantation YMDD mutant from HBV recurrence after LT.

[Excitatory postsynaptic potential evoked by stimulation of the ventrolateral region of the cerebellum in crucian carp Mauthner cell].

In the present experiments, the characteristics of the electrical responses to stimulation of the cerebellum in crucian carp Mauthner cell were explored with microeletrode intracellular recording technique. A composite excitatory postsynaptic potential (cerebellum-evoked EPSP) could be induced from the soma, the ventral dendrite and the proximal end of the lateral dendrite in crucian carp Mauthner cell (M-cell) on either side by stimulation of the ventrolateral region of the cerebellum. The cerebellum-evoked EPSP presented characteristics of relatively short latency (0.63+/-0.09 ms), longer duration (5.49+/-1.13 ms), graded amplitude and dependence on stimulation frequency. Stimulation of the cerebellum with higher intensity always activated the M-cell orthodromically. Multiple intracellular recordings showed that the cerebellum-evoked EPSP originated in the distal end of the ventral dendrite. The results suggest that the cerebellum-M-cell pathway is probably composed of a group of neuron chains with different numbers of synaptic relays projecting to the distal end of the ventral dendrite in order of length of the chains.