Kefei Chen

Salvage Liver Transplantation for Recurrent Hepatocellular Carcinoma within UCSF Criteria after Liver Resection

Background Salvage liver transplantation (SLT) is restricted to patients who develop hepatocellular carcinoma (HCC) recurrence within Milan criteria (MC). Little is known about outcomes for SLT in patients with recurrent HCC within University of California San Francisco (UCSF) criteria after liver resection (LR). Methods Between January 2001 and December 2011, 380 patients with HCC meeting UCSF criteria, 200 of which were resected (LR group) from a perspective of SLT in case of recurrence, and 180 directly underwent LT (PLT). We compared patient characteristics, perioperative and long-term outcomes between SLT and PLT groups. We also assessed the outcome of LR and PLT groups. Results Among the 200 patients in LR group, 86 (43%) developed HCC recurrence and 15/86 (17%) of these patients presented HCC recurrence outside UCSF criteria. Only 39 of the 86 patients underwent SLT, a transplantation rate of 45% of patients with HCC recurrence. Compared with PLT group, LR group showed lower overall survival rate (P = 0.005) and higher recurrence rate (P = 0.006). Although intraoperative blood loss and required blood transfusion were more frequent in SLT group, the perioperative mortality and posttransplant complications were similar in SLT and PLT groups. The overall survival and recurrence rates did not significantly differ between the two groups. When stratifying by graft type in the SLT group, overall survival and recurrence rates did not significantly differ between deceased donor LT (DDLT) and living donor LT (LDLT) groups. In the subgroup analysis by MC, similar results were observed between patients with recurrent HCC meeting MC and patients with recurrent HCC beyond MC but within UCSF criteria. Conclusion Our single institution experience demonstrated that prior hepatectomy and SLT for recurrent HCC within UCSF criteria was feasible and SLT could achieve the same outcome as PLT.

Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution's experience with 398 consecutive patients.

BACKGROUND Surgical resection is an important curative treatment for hepatocellular carcinoma (HCC); however, some patients experience an unexpected recurrence even after hepatectomy. The present study aimed to investigate risk factors and predictive criteria for early and late recurrence of HCC after resection. METHODS A retrospective analysis of 398 Chinese patients who received curative resection for HCC was conducted. Patients were divided into three groups: without recurrence, early recurrence, and late recurrence. Prognostic factors and predictive criteria for early and late recurrence were statistically analyzed. RESULTS The cumulative recurrence-free survival rates at 1, 2, 3, 4, and 5 years were 75.5%, 58.2%, 54.1%, 40.5%, and 28.7%, respectively. The distribution of the time to recurrence suggested that recurrence could be divided into early phase (before 2 years; n=164) and late phase (after 2 years; n=83). Coxs multivariate proportional hazard model analysis revealed that multiplicity of tumors (P=0.004) and venous infiltration (P=0.002) were independent risk factors associated with early recurrence. In contrast, indocyanine green retention rate at 15 minutes (P=0.007), serum albumin level (P=0.045), and HBeAg status (P=0.028) proved to be significant independent adverse prognostic factors for late recurrence. Patients with at least 1 of the 2 early recurrence risk factors (multiplicity of tumors ≥ 2 and venous infiltration) or with 2 or more late recurrence risk factors are often susceptible to recurrence (P=1.36e-4 and 1.0e-6, respectively). CONCLUSIONS Early and late recurrences correlate with different risk factors and predictive criteria. Early recurrence primarily results from intrahepatic metastases, while late recurrence may be multicentric in origin.

Epidermal Growth Factor +61 G/A Polymorphism and the Risk of Hepatocellular Carcinoma in a Chinese Population

BACKGROUND Chronic hepatitis B virus (HBV) infection is a risk factor of hepatocellular carcinoma (HCC) in China. Epidermal growth factor (EGF) plays an important role in tumorigenesis. The association between EGF +61 G/A polymorphism and the risk of HCC is still controversial and ambiguous. AIM The objective of this study was to investigate the association between EGF +61 G/A polymorphism and the risk of HCC in a Chinese population. METHODS A hospital-based case-control study was designed in a Chinese population. EGF +61 G/A polymorphisms were determined in 120 chronic HBV-infected HCC patients, 120 chronic HBV-infected cirrhotic patients, and 120 healthy controls. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS EGF +61 GG (odds ratio=2.76, 95% confidence interval=1.03, 7.38; p=0.04) and G allele frequencies (odds ratio=1.59, 95% confidence interval=1.08, 2.34; p=0.02) in the HCC group were higher than those in the cirrhosis group. EGF +61 A and G allele frequencies in healthy subjects were 28.8% and 71.2%. No relationship between EGF +61 G/A gene polymorphism and HCC risk was found among our recruited HCC patients and healthy controls. CONCLUSION This study suggests that EGF +61 GG genotype is associated with a higher risk of chronic HBV-infected HCC in the Chinese population.

Interleukin-10-819 Promoter Polymorphism Associated with Gastric Cancer among Asians

Studies investigating the association between interleukin-10-819 promoter polymorphism and gastric cancer risk report conflicting results. This study aimed to summarize quantitatively the evidence for such a relationship. Two investigators independently searched the Medline (January 1966 – January 2009) and Embase (January 1980 – January 2009) databases for eligible studies to be included in a meta-analysis. Six case-control studies, which included 681 gastric cancer cases and 1621 control subjects were selected. Combined results for all studies showed that there was no significant difference in genotype distribution (TT, TC or CC) between gastric cancer patients and control subjects. When stratifying for race, results were similar except that Asian patients with gastric cancer had a significantly lower frequency of TT and a higher frequency of TC than Asian control subjects. When stratifying by location and Laurens classification of gastric cancer, there was no significant difference in genotype distribution between patients with gastric cancer and control subjects. This meta-analysis suggests that the interleukin-10-819 promoter polymorphism may be associated with gastric cancer in Asians.

BORIS, Brother of the Regulator of Imprinted Sites, Is Aberrantly Expressed in Hepatocellular Carcinoma

BACKGROUND The brother of the regulator of imprinted sites (BORIS) is a novel member of the cancer testis antigen gene family, which are normally expressed only in spermatocytes, but abnormally activated in different malignancies. AIM The aim of this study was to explore the expression of BORIS in hepatocellular carcinoma (HCC) and its correlation with the clinicopathologic features and prognosis of HCC. METHODS We investigated BORIS expression in HCC cell lines and 105 primary HCC clinical surgical specimens using real-time polymerase chain reaction and Western blot analysis. We further examined the correlation of BORIS with a liver stem cell marker (CD90) in HCC tissues by histochemical double staining. The correlation of BORIS with clinicopathologic features and prognosis of HCC was analyzed using patient data. RESULTS The expression of BORIS was found in SMMC-7721, BEL-7402, and Huh-7, but not in hep-G2 cells. The expression rate of BORIS was significantly higher in the HCC tissues than in the adjacent noncancerous tissues (p=0.000). BORIS expression was correlated with the tumor size (p=0.000), CD90 expression (p=0.000), and satellite nodule (p=0.000). Kaplan-Meier survival curves showed that patients with positive expression of BORIS had lower overall survival rate (p=0.003). CONCLUSIONS Our data indicate that BORIS may be an auxiliary diagnosis index and a novel favorable prognostic indicator of HCC.

Analysis of DNA Methylation in Plasma for Monitoring Hepatocarcinogenesis

AIM To explore whether the aberrant DNA methylation status in plasma could be used as a biomarker for hepatocellular carcinoma (HCC) screening among high-risk individuals. METHODS The promoter methylation status of ELF, RASSF1A, p16, and GSTP1 was investigated by methylation-specific polymerase chain reaction (PCR) in 34 paired HCC and nontumor liver tissue from HCC patients and 10 tissues from patients with liver cirrhosis (LC). Plasma samples from 31 HCC patients, 10 LC patients as well as 7 patients with benign hepatic conditions were also collected and characterized using the same method. RESULTS Among liver specimens, HCC tissues displayed a significantly higher methylation frequency of each gene compared with nontumor tissue (p<0.05). Moreover, the frequency was much higher in tumor tissues than in nontumor tissue, when the data from two or three genes were combined (p=0.001 and p<0.001, respectively). Among plasma samples, either the frequency of at least one methylated gene (p<0.001) or the average number of methylated genes (p<0.05) demonstrated a stepwise increase in patients with benign lesions, LC, and HCC. Furthermore, when positive results, that is, plasma methylation status of at least one gene were combined with the elevated AFP400 level (serum alpha-fetoprotein [AFP] level at a cutoff of 400 ng/mL), the diagnostic sensitivity of HCC could increase to 93.55%. CONCLUSIONS These results suggested that the methylation of tumor suppressor genes may participate in the development and progression of HCC. Additionally, it may be useful to combine the plasma DNA methylation status of a panel of gene markers and the serum AFP for HCC screening.

Adult-to-adult living donor liver transplantation for acute liver failure in China

AIM To investigate the long-term outcome of recipients and donors of adult-to-adult living-donor liver transplantation (AALDLT) for acute liver failure (ALF). METHODS Between January 2005 and March 2010, 170 living donor liver transplantations were performed at West China Hospital of Sichuan University. All living liver donor was voluntary and provided informed consent. Twenty ALF patients underwent AALDLT for rapid deterioration of liver function. ALF was defined based on the criteria of the American Association for the Study of Liver Diseases, including evidence of coagulation abnormality [international normalized ratio (INR) ≥ 1.5] and degree of mental alteration without pre-existing cirrhosis and with an illness of < 26 wk duration. We reviewed the clinical indications, operative procedure and prognosis of AALDTL performed on patients with ALF and corresponding living donors. The potential factors of recipient with ALF and corresponding donor outcome were respectively investigated using multivariate analysis. Survival rates after operation were analyzed using the Kaplan-Meier method. Receiver operator characteristic (ROC) curve analysis was undertaken to identify the threshold of potential risk factors. RESULTS The causes of ALF were hepatitis B (n = 18), drug-induced (n = 1) and indeterminate (n = 1). The score of the model for end-stage liver disease was 37.1 ± 8.6, and the waiting duration of recipients was 5 ± 4 d. The graft types included right lobe (n = 17) and dual graft (n = 3). The mean graft weight was 623.3 ± 111.3 g, which corresponded to graft-to-recipient weight ratio of 0.95% ± 0.14%. The segment Vor VIII hepatic vein was reconstructed in 11 right-lobe grafts. The 1-year and 3-year recipients survival and graft survival rates were 65% (13 of 20). Postoperative results of total bilirubin, INR and creatinine showed obvious improvements in the survived patients. However, the creatinine level of the deaths was increased postoperatively and became more aggravated compared with the level of the survived recipients. Multivariate analysis showed that waiting duration was independently correlated with increased mortality (P = 0.014). Furthermore, ROC curve revealed the cut-off value of waiting time was 5 d (P = 0.011, area under the curve = 0.791) for determining the mortality. The short-term creatinine level with different recipients waiting duration was described. The recipients with waiting duration ≥ 5 d showed the worse renal function and higher mortality than those with waiting duration < 5 d (66.7% vs 9.1%, P = 0.017). In addition, all donors had no residual morbidity. Furthermore, univariate analysis did not show that short assessment time induced the high morbidity (P = 0.573). CONCLUSION Timely AALDLT for patients with ALF greatly improves the recipient survival. However, further systemic review is needed to investigate the optimal treatment strategy for ALF.

Second Hepatectomy Improves Survival in Patients With Microvascular Invasive Hepatocellular Carcinoma Meeting the Milan Criteria.

AbstractMicrovascular invasion (MVI) is a strong risk factor for patients with hepatocellular carcinoma (HCC) meeting the Milan criteria and who have received curative hepatectomy. The relevance of a second hepatectomy in patients with MVI-positive recurrent HCC remains controversial.We had 329 cases of HCC hepatectomy meeting the Milan criteria and compared data on patient demographics, liver function, and tumor pathology between MVI-positive and MVI-negative group. We analyzed potential risk factors of overall survival (OS) and disease-free survival (DFS). Furthermore, newly developed pathological features following the second hepatectomy were also analyzed.The median OS and DFS were significantly superior in the MVI-negative group than in the MVI-positive group, 61 (10–81) versus 49 (11–82) months (P < 0.01) and 41 (7–75) versus 13 (3–69) months (P < 0.01), respectively. The presence of MVI and a total tumor diameter >3 cm were independent risk factors associated with both OS and DFS. Overall survival was significantly improved by a second hepatectomy in the MVI-positive group compared with the original MVI-positive group, 60 (26–82) versus 49 (11–82) months, respectively. This was now comparable to the MVI-negative group, 60 (26–82) versus 61 (10–81) months (P = 0.72). A second hepatectomy was consistently associated with better survival in the MVI-negative group as compared to the MVI-positive group.A second hepatectomy improves survival in patients with MVI HCC meeting the Milan criteria. The biology of MVI may change following a second hepatectomy. The absence of MVI is a good prognostic sign for patients undergoing second hepatectomy.

Evaluation outcomes of donors in living donor liver transplantation: a single-center analysis of 132 donors

BACKGROUND Donor safety has always been a major concern, and potential risk to the donor must be balanced against recipient benefit. However, lack of a standardized and uniform evaluation of perioperative complications is a serious limitation of the evaluation of donor morbidity. This study was designed to evaluate the outcomes of donors in adult living donor liver transplantation (LDLT) using the newer Clavien classification system in a single center in China. METHODS We prospectively analyzed the outcomes of 132 consecutive living liver donors from 2005 to 2008 using the newer Clavien classification system. The preoperative, intraoperative and postoperative data of the donors were collected and analyzed. Ordinal regression was used to analyze the ordered grades of complications. RESULTS Ninety-four (71.2%) of the donors developed postoperative complications of grade I (n=45, 34.1%), grade II (n=39, 29.5%) and grade III (n=10, 7.6%). There was no death or grade IV morbidity. Hepatic functional impairment and pleural effusion were the most frequent morbidities for living donors. Fifty-three donors (40.1%) developed hepatic functional impairment of grade I (n=40, 31.1%) and grade II (n=13, 10.0%). The ICU stay (7.8+/-1.8 days) and length of hospital stay (17.7+/-4.6 days) were significantly longer in donors with grade III than others. Furthermore, ordinal logistic regression revealed that donors older age (>40 years) and right hepatectomy were associated with morbidity. In addition, only preoperative total bilirubin (within the normal range) and postoperative nadir serum phosphorus were independently associated with hepatic functional impairment. The receiver operator characteristic curve revealed that preoperative total bilirubin >18.0 μmol/L and postoperative nadir of serum phosphorus <1 mg/dL may lead to more severe hepatic functional impairment. CONCLUSIONS Despite the fact that donors are relatively safe to undergo hepatectomy, many living donors still experience postoperative morbidity. Meticulous technical and preoperative donor evaluation and treatment are sure to reduce the incidence of complications.

Hepatectomy-Related Hypophosphatemia May Predict Donor Liver Dysfunction in Live-Donor Liver Transplantation

BACKGROUND Hypophosphatemia after living-donor liver donation was recently reported to not be linked to donor morbidity. However, few studies have examined the relationship between hypophosphatemia and hepatic function after hepatectomy in live liver donors. In this study, we investigated the relationship between postoperative hypophosphatemia and hepatic function in living donors after hepatectomy. METHODS We collected data from 102 live-donor hemihepatectomy cases. The severity of hypophosphatemia was categorized as mild (1.5-2.5 mg/dL), moderate (1.1-1.5 mg/dL), or severe (<1.0 mg/dL). We compared complications among the groups and factors possibly related to the postoperative nadir phosphorus levels. RESULTS One hundred cases (98%) developed mild (n = 56), moderate (n = 25), or severe (n = 19), hypophosphatemia. Serum phosphate levels began to fall on postoperative day (POD) 2, reaching a nadir (1.89 ± 0.72 mg/dL) on POD 3. There was a significant difference in the incidence of postoperative liver dysfunction among the 3 groups (P = .027). Moreover, a correlation was identified between the incidence and the hypophosphatemia severity (r = 0.549; P = .023). The nadir phosphorous level significantly and negatively correlated with the peak of total bilirubin (P = .001) and international normalized ratio (P = .004). Patients with intravenous phosphorus replacement showed better hepatic function and a lower incidence of hepatic dysfunction among the severely hypophosphatemic group. CONCLUSION Hypophosphatemia was predictive of hepatic dysfunction after hepatectomy in living donors. Phosphorus replacement may improve recovery of hepatic function among living liver donors.