Yo-ichi Yamashita

Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma

Objective: Histone deacetylases (HDACs) play an important role in chromatin remodeling, gene repression and regulating cell cycle progression and differentiation. This study was designed to clarify the role of HDAC1 expression in hepatocellular carcinoma (HCC). Method: The expression of HDAC1 in 47 patients with surgically resected HCC was immunohistochemically examined and analyzed in relation to their clinicopathological factors. The patients were divided into two groups according to the expression status of HDAC1: a high HDAC1 group (n = 25) with more than 20% of positively stained cells and a low HDAC1 group (n = 22) with 20% or fewer positively stained cells. Results: A high HDAC1 expression indicated a higher incidence of cancer cell invasion into the portal vein, a poorer histological differentiation, and a more advanced TNM stage. The survival rates after a surgical resection in low and high HDAC1 patients at 1, 3, 5 and 10 years were 100, 95.5, 81.8 and 60.8% and 88.0, 60.0, 40.0 and 32.0%, respectively (p = 0.008). A multivariate analysis using the Cox regression analysis showed that a high HDAC1 expression was an independent prognostic factor of HCC in patients after hepatic resection (relative risk: 10.1, p = 0.0018). Conclusions: High HDAC1 expression might have an important role in the aggressiveness and cell dedifferentiation, and its expression status may be a useful biomarker for predicting the outcome of the patients with HCC.

Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation.

Backgrounds. Because many patients who did not meet the Milan criteria have survived long after undergoing living donor liver transplantation (LDLT), extended criteria for recipient with hepatocellular carcinoma (HCC) are therefore considered to be necessary. Methods and Results. A total of 90 consecutive adult LDLT recipients with HCC between 1996 and 2007 were reviewed. The recurrence-free survival rates of all 90 patients were 86.0%, 81.3%, and 81.3% at 1, 3, and 5 years, respectively. Fourteen of 90 patients developed a recurrence of tumor after the LDLT. The tumor recurrences were diagnosed within 1 year after the LDLT in 11 (78.6%) patients. In a multivariate analysis, both the tumor size of less than 5 cm (P=0.0202) and the des-gamma-carboxy prothrombin (DCP) level of less than 300 mAU/mL (P=0.0001) were found to be favorable independent factors for the recurrence of HCC after LDLT. Therefore, the authors devised new selection criteria for HCC patients (a tumor size of <5 cm or a DCP of <300 mAU/mL). The 1-, 3-, and 5-year overall or recurrence-free survival rates of the 85 patients who met the new criteria were 92.3%, 85.9%, and 82.7%, or 90.5%, 87.0%, and 87.0%, respectively, which were significantly different from those of the five patients who did not meet the new criteria (P<0.0001). Conclusions. A combination of two factors, namely the tumor size and the DCP level, was found to be useful for expanding the selection of LDLT candidates for HCC.

Donor Risk in Adult-to-Adult Living Donor Liver Transplantation : Impact of Left Lobe Graft

Background. To ensure donor safety in adult-to-adult living donor liver transplantation, we established a selection criterion for donors in which left lobe (LL) was the first choice of graft. Methods. Two hundred six consecutive donors were retrospectively studied. Donors were divided into two groups according to graft type: LL graft (n=137) and right lobe (RL) graft (n=69). Results. Although mean intraoperative blood loss of LL was significantly increased compared with RL, mean peak postoperative total bilirubin levels and duration of hospital stay after surgery were significantly less for LL than RL (P<0.05). No donor died or suffered a life-threatening complication during the study period. The overall complication rate was 34.0%, including biliary complications in 5.3%. The number of biliary complications was four (2.9%) in LL and seven (10.1%) in RL (P<0.05). Logistic regression analysis revealed that only graft type (LL vs. RL) is significantly related to the occurrence of biliary complications (odds ratio 0.11; P=0.0012). The cumulative overall graft survival rates in the recipients with LL were not significantly different from that in the recipients with RL. Conclusions. LL grafting should be considered favorably when selecting donors for adult-to-adult living donor liver transplantation.

The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft

Small‐for‐size (SFS) graft syndrome is one of the major causes of graft loss in living donor liver transplantation (LDLT). We examined whether splenectomy is beneficial for overcoming SFS graft syndrome in LDLT. The patients were classified into two groups: the Sp (−) group (n = 69), in which splenectomy was not performed, and the Sp (+) group (n = 44), in which it was. The incidence of SFS graft syndrome was investigated. Risk factors of SFS graft syndrome were identified by univariate‐ and multivariate analysis. To clarify whether splenectomy is beneficial for patients with a SFS graft, subgroup analysis was performed for patients who had a graft weight‐to‐standard liver weight (GW‐SLW) ratio of 40% or less (n = 50). Thirty‐one of 113 patients developed SFS graft syndrome. A multivariate analysis identified that having a male donor was an independent risk factor of SFS graft syndrome. SFS graft syndrome occurred in 11 of 50 patients with a GW‐SLW ratio <40%, and Sp (−) was an independent risk factor for the occurrence of SFS graft syndrome in patients (P = 0.014). Simultaneous splenectomy is favorable for overcoming SFS graft syndrome in LDLT patients with a GW‐SLW of 40% or less.

The role of macroscopic classification in nodular-type hepatocellular carcinoma

BACKGROUND Little has been reported on the role of macroscopic classification of hepatocellular carcinoma (HCC). We hypothesized that macroscopic classification of HCC might have a strong correlation with long-term prognosis after hepatectomy. METHODS Four hundred and four patients with a macroscopically nodular type of HCC who underwent a hepatectomy were studied. The patients were divided into three groups: single nodular (SN) group (n = 312); single nodular with extranodular growth (SNEG) group (n = 52); and confluent multinodular (CMN) group (n = 40). Clinicopathological variables were compared among the three groups. The patient survival rate was also compared among the three groups. Finally, a multivariate analysis was performed to clarify the independent significant variables of the long-term prognosis. To confirm the consistency of the results in small-size HCC, the same analyses were made using patients whose tumor size was equal to or less than 3 cm in diameter. RESULTS The alpha-fetoprotein value, tumor size, and rate of absolute noncurative operation in the SNEG group were higher than in other groups. The positive rate of both portal vein invasion of cancer cells and intrahepatic metastasis in the SN group was lower than those in other groups. The rate of poorly differentiated histology in the SN group was lower than in the other groups. Patient survival in the SNEG group was worst among the three groups. However, patient survival showed no significant difference between the SN and CMN groups. The multivariate analysis showed that the presence of intrahepatic metastasis, the macroscopic classification of SNEG type, and absolute noncurative operation were independent poor prognostic indicators. The results for patients with small HCCs measuring equal to or less than 3 cm in diameter were quite similar to the results for the other patients. CONCLUSIONS Among the three subtypes of macroscopically nodular type of HCCs, the SNEG type showed higher rates of portal vein invasion of cancer cells, intrahepatic metastasis, and poorly differentiated histology. The patient survival rate in the SNEG type was worst, and the SNEG type was an independent poor prognostic indicator. The macroscopic classification of HCC, especially the SNEG type, helps predict the long-term outcome after hepatectomy.

Graft size, donor age, and patient status are the indicators of early graft function after living donor liver transplantation

No reliable model for predicting early graft function and patient survival after living donor liver transplantation (LDLT) exists. The aim of this study was to establish a new formula for predicting early graft function and prognosis using technetium‐99m galactosyl‐human serum albumin (Tc‐GSA) liver scintigraphy. The ratio of the hepatic uptake ratio of Tc‐GSA to the clearance index of Tc‐GSA (LHL/HH) was determined 7 days after LDLT. There were 22 patients with a ratio greater than 1.3 and 6 patients with a ratio less than 1.3. Graft function on the 14th postoperative day (POD) was compared between the 2 groups. A new formula to predict the LHL/HH score was established as follows: LHL/HH (predictive score) = 0.011 × graft weight (%) − 0.016 × donor age − 0.008 × Model for End‐Stage Liver Disease score − 0.15 × shunt (if present) + 1.757 (r2 = 0.497, P < 0.01). This predicted LHL/HH ratio was compared to the graft function on POD 14 for 110 LDLT patients. The total bilirubin (TB) and prothrombin time international normalized ratio (PT‐INR) in the group with an LHL/HH score ≥ 1.3 were lower than those in the group with an LHL/HH score < 1.3. The TB, PT‐INR, and volume of ascites in the group with a predictive score ≥ 1.3 (n = 86) were lower than those in the group with a score < 1.3 (n = 24). The 6‐month survival probability was improved in the group with a predictive score ≥ 1.3. In conclusion, this preoperative calculated LHL/HH score is correlated with graft function and short‐term prognosis. Thus, this predictive model may allow transplant surgeons to use a living donor left lobe graft with greater confidence. Liver Transpl 14:1007–1013, 2008.

Impact of donor age and recipient status on left‐lobe graft for living donor adult liver transplantation

Donor safety is the priority when performing a living donor adult liver transplantation (LDALT). We herein present our findings using left‐lobe graft in LDALT. Data on 119 recipients who underwent the LDALT, and on 119 donors who underwent extended left lobectomy were reviewed. The recipients were divided into groups above (n = 19) and below (n = 100) 50 years of donor age, into groups above (n = 63) and below (n = 56) 40% of graft size (graft volume/standard liver volume, GV/SLV), and above (n = 25) and below (n = 94) 20 of pre‐operative model for end‐stage liver disease (MELD). Total bilirubin (TB), volume of ascites, prothrombin time international normalized ratio on postoperative day 14 or survival rates were compared. TB (mg/dl) or volume of ascites (ml) of the group in donor age < 50 years was better than that of the group in donor age ≥ 50 years (7.4 vs. 14.7 or 788 vs. 1379, P < 0.001 or P < 0.005, respectively). The graft and patient survival rates of the lower MELD group tended to be better than that of the higher MELD group. LDALT can be safely performed using a left‐lobe graft. However, when using the graft from the donor ≥ 50 years, especially for the recipients with the MELD ≥ 20, the indications should be carefully discussed.

The importance of hepatic resection for hepatocellular carcinoma originating from nonfibrotic liver

BACKGROUND Our study aimed to clarify the characteristics of hepatocellular carcinoma (HCC) in patients with a nonfibrotic liver and the role of surgical resection for HCC in nonfibrotic liver compared with patients with HCC in fibrotic or cirrhotic livers. STUDY DESIGN A total of 516 patients who underwent hepatectomy between April 1985 and June 1999 were classified into two groups: a nonfibrotic liver group (n=65) and a fibrotic liver group (n=451), which included fibrotic or cirrhotic livers. Clinicopathologic variables were then compared between the groups, including disease-free survival rate and patient survival rate. RESULTS Only 8 of 65 patients (12.3%) with a nonfibrotic liver showed a histologically completely normal liver. The numbers of men and patients with alcohol abuse in the nonfibrotic liver group were higher than in the fibrotic liver group. The numbers of patients with positive hepatitis B antigen and positive hepatitis C antibody in the nonfibrotic liver group were lower than in the fibrotic liver group. Results of liver function tests in the nonfibrotic liver group were better than those in the fibrotic liver group. The rates of both portal vein and hepatic vein invasion of cancer cells in the nonfibrotic liver group were higher than in the fibrotic liver group. The tumor size in the nonfibrotic liver group was larger than in the fibrotic liver group. The patient survival and disease-free survival rates in the nonfibrotic liver group were better than in the fibrotic liver group. CONCLUSIONS Hepatic resection can be beneficial for patients with HCC originating from a nonfibrotic liver when compared with fibrotic or cirrhotic patients with HCC.

Clinicopathologic features and postoperative prognosis of multicentric small hepatocellular carcinoma.

BACKGROUND Assessment of clinicopathologic characteristics and postoperative prognoses for patients with multicentric hepatocellular carcinoma (HCC) is important to determine not only a need to operate, but also an appropriate treatment after hepatic resection. STUDY DESIGN Between May 1990 and April 1998, among 116 patients with an initial hepatectomy for HCC measuring 3 cm or less in maximum diameter, 34 patients had multicentric HCC (MC group), and 82 patients had single nodular HCC (SN group). To clarify the clinicopathologic features of patients in the MC group versus the SN group, we compared both the clinicopathologic parameters and the postoperative prognosis after curative hepatectomy between the two groups. RESULTS The percentages of patients positive for hepatitis B surface antigen and hepatitis C virus antibody were not significantly different between the two groups. No differences were noted in pathologic characteristics of the main tumor or tumor markers. On the other hand, in the MC group, the percentage of patients evaluated in a Childs classification as either B or C was significantly higher (p < 0.05) than that of patients in the SN group, indicating that patients with multicentric HCC have a poor hepatic functional reserve. Both survival and disease-free survival of patients in the MC group who underwent a curative hepatectomy did not differ statistically from those in the SN group. CONCLUSIONS Our results indicate that hepatic resection is useful, even for patients with multicentric HCC, if a curative hepatectomy can be performed and liver function can be saved, despite their poor hepatic functional reserve.

CT differentiation between necrotic and nonnecrotic small bowel in closed loop and strangulating obstruction.

AbstractBackground: The purpose of this study was to evaluate computed tomographic (CT) findings for predicting the presence of intestinal necrosis in patients with closed loop and strangulating obstruction of the small bowel. Methods: Twenty-five patients with surgically confirmed closed loop and strangulating obstruction were divided into two groups with (n= 16) and without (n= 9) intestinal necrosis. By using univariate and multivariate statistical procedures, we evaluated the differences in CT findings between the two groups on the basis of the following six findings: bowel dilatation of strangulated loops (bowel dilatation), wall thickening of strangulated intestines (wall thickening), ascites, vascular dilatation of affected mesenteries (vascular dilatation), elevation of mesenteric attenuation (mesenteric attenuation), and radial distribution of the mesenteric vessels (radial distribution). Results: Of the six findings, ascites, vascular dilatation, mesenteric attenuation, and radial distribution provided significant discriminating findings between the two groups on univariate analysis. On multivariate analysis, mesenteric attenuation was the most important discriminative factor, followed by radial distribution and ascites. Using these three parameters, the CT was correlated with the surgical findings in 15 of the 16 patients in the necrosis group (sensitivity = 93.8%) and in eight of the nine patients in the nonnecrosis group (specificity = 88.9%). The overall accuracy was 92.0%. Conclusions: Mesenteric attenuation, radial distribution, and ascites, depicted on CT differentiate well between necrosis and nonnecrosis of the small bowelin patients with closed loop and strangulating obstruction.