Tsuyoshi Sano

Lymph Node Metastasis from Hilar Cholangiocarcinoma: Audit of 110 Patients Who Underwent Regional and Paraaortic Node Dissection

ObjectiveTo assess the status of the regional and paraaortic lymph nodes in hilar cholangiocarcinoma and to clarify the efficacy of systematic extended lymphadenectomy. Summary Background DataThere have been no studies in which regional and paraaortic lymphadenectomies for hilar cholangiocarcinoma have been routinely performed. Therefore, the metastasis rates to the regional and paraaortic nodes, the mode of lymphatic spread, and the effect of extended lymph node dissection on survival remain unknown. MethodsThis study involved 110 patients who underwent surgical resection for hilar cholangiocarcinoma with lymph node dissection including both the regional and paraaortic nodes. A total of 2,652 nodes retrieved from the surgical specimens were examined microscopically. ResultsOf the 110 patients, 52 (47.3%) had no involved nodes, 39 (35.5%) had regional lymph node metastases, and 19 (17.3%) had regional and paraaortic node metastases. The incidence of positive nodes was significantly higher in the patients with pT3 disease than in those with pT2 disease. The pericholedochal nodes were most commonly involved (42.7%), followed by the periportal nodes (30.9%), the common hepatic nodes (27.3%), and the posterior pancreaticoduodenal nodes (14.5%). The celiac and superior mesenteric nodes were rarely involved. The 3-year and 5-year survival rates were 55.4% and 30.5% for the 52 patients without involved nodes, 31.8% and 14.7% for the 39 patients with regional node metastases, and 12.3% and 12.3% for the 19 patients with paraaortic node metastases, respectively. Of the 19 patients with positive paraaortic nodes, 7 had no macroscopic evidence of paraaortic disease on intraoperative inspection. The survival in this group was significantly better than in the remaining 12 patients. ConclusionThe paraaortic nodes and the regional nodes are frequently involved in advanced hilar cholangiocarcinoma. Whether extended lymph node dissection provides a survival benefit requires further study. However, the fact that long-term survival is possible despite pN2 or pM1 disease encourages the authors to perform an aggressive surgical procedure with extended lymph node dissection in selected patients with hilar cholangiocarcinoma.

One Hundred Two Consecutive Hepatobiliary Resections for Perihilar Cholangiocarcinoma With Zero Mortality

Objective:To analyze the short-term surgical outcome of hepatobiliary resections for perihilar cholangiocarcinoma in the last 5 years. Summary Background Data:Hepatobiliary resection for perihilar cholangiocarcinoma remains a technically demanding procedure, calling for a high level of expertise in biliary and hepatic surgery, and is still associated with significant morbidity or mortality. Methods:Between 2000 and 2004, we surgically treated 102 consecutive patients with perihilar cholangiocarcinoma with a management strategy consisting of preoperative biliary drainage, portal vein embolization (for right-sided and extended left-sided resections), and major hepatobiliary resection. The data on all of the patients were analyzed retrospectively to identify the factors that might significantly affect the postoperative mortality and morbidity. Results:There were no cases of in-hospital mortality or postoperative liver failure. Major complications were encountered in 7 patients (6.9%), and the overall morbidity rate was 50%. Reoperation was required in 2 patients (2%). The overall median length of postoperative hospital stay was 26 days (range, 13–119 days). Univariate analysis in relation to the postoperative morbidity showed significant differences in the preoperative occurrence of segmental cholangitis or cholecystitis (P = 0.015), the severity of postoperative hyperbilirubinemia (P < 0.001), and the total amount of fresh frozen plasma administered (P = 0.002). Multivariate analysis revealed a single independent significant predictive factor for postoperative morbidity, namely, preoperative cholangitis or cholecystitis (odds ratio, 9.08; 95% confidence interval, 1.05–78.56, P = 0.045). Conclusions:Our experience indicates that hepatobiliary resections for perihilar cholangiocarcinoma can be conducted safely, without a single case of postoperative liver failure or mortality. Occurrence of preoperative cholangitis or cholecystitis is a significant indicator for morbidity of major hepatobiliary resection.

Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas

Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs.

Therapeutic value of lymph node dissection during hepatectomy in patients with intrahepatic cholangiocellular carcinoma with negative lymph node involvement.

BACKGROUND Routine and radical lymph node dissection is a clinical concern for improving the surgical outcome in patients with intrahepatic cholangiocarcinoma (ICC). The therapeutic value of the procedure during hepatectomy has, however, not been evaluated. METHODS Between January 1990 and December 2004, 104 patients with ICC undergoing macroscopic curative resections were investigated retrospectively with special reference to lymph node status. The role of lymph node dissection was evaluated according to macroscopic type: mass-forming (MF) type (n = 68) and MF plus periductal infiltration (PI) type (n = 36) of ICC. RESULTS Lymph node involvement and intrahepatic metastases were an independent, unfavorable prognostic factor in the MF type of ICC. Negative lymph node involvement provided a favorable survival rate in the 41 patients without intrahepatic metastases (P < .0001). Among the 29 patients without lymph node involvement and intrahepatic metastases, there was no difference according to the use of lymph node dissection (P = .8071). Also, no difference was seen with lymph node involvement in the 24 patients with the MF plus PI type of ICC who had no intrahepatic metastases (P = .6620). CONCLUSION For purpose of diagnostic staging and exclusion of positive regional lymph nodes, lymph node dissections might be useful in patients with the MF type and the MF plus PI type of ICC; however, routine use of lymph node dissection in patients with the MF type of ICC is not recommended, because no difference in survival was observed in the patients with negative lymph node metastases, irrespective of the use of lymph node dissection.

A long‐term follow‐up and management study of hepatocellular carcinoma patients surviving for 10 years or longer after curative hepatectomy

The aims of the current study were to elucidate the clinicopathologic characteristics and disease recurrence patterns of patients with hepatocellular carcinoma (HCC) who survived for 10 years or longer after undergoing an initial hepatectomy.

Preoperative evaluation of invasive and noninvasive intraductal papillary-mucinous neoplasms of the pancreas: clinical, radiological, and pathological analysis of 123 cases.

Objective: We aimed to investigate preoperative findings that are useful to distinguish intraductal papillary-mucinous neoplasm (IPMN) subtypes. Methods: One hundred twenty-three patients who underwent pancreatectomy for IPMN were analyzed clinicopathologically and radiologically. Invasive IPM carcinomas (IPMCs) were subdivided into early-stage nonaggressive (minimally invasive IPMC [MI-IPMC]) and more advanced and aggressive (invasive carcinoma originating in IPMC [IC-IPMC]) subtypes according to our recently proposed pathological criteria. Results: The lesions consisted of 27 IPMNs with low-grade dysplasia, 14 IPMNs with moderate dysplasia, 21 IPMNs with high-grade dysplasia, 30 MI-IPMCs, and 31 IC-IPMCs. Multidetector-row computed tomography detected a component of invasive carcinoma in IC-IPMC with 86% sensitivity and 100% specificity. In patients with IPMNs other than IC-IPMC, multivariate analysis demonstrated 3 significant predictive factors of malignancy: IPMN size (>40 mm), IPMN duct type (main pancreatic duct or mixed type), and the presence of a mural nodule or thick septum. The diagnostic score obtained using these 3 factors showed a strong correlation with the presence of malignancy. Conclusions: For preoperative evaluation of patients with IPMN, it is recommended to rule out IC-IPMC using multidetector-row computed tomography and then to categorize IPMN other than IC-IPMC according to malignant potential based on the diagnostic score.

Prognostic Value of Tumor Architecture, Tumor-Associated Vascular Characteristics, and Expression of Angiogenic Molecules in Pancreatic Endocrine Tumors

Purpose: It is difficult to predict the biological behavior of pancreatic endocrine tumors (PETs). Our aim was to evaluate the prognostic significance of certain variables in PETs. Experimental Design: The following variables were examined in 37 patients with PETs and then compared with other clinicopathologic characteristics: histologic tumor structure; microvessel density (MVD) measured by three different methods, including a unique method involving calculation of solid area MVD; endothelial proliferation; and the immunohistochemical expression of vascular endothelial growth factor-A and CXC chemokine CXCL-12. Intratumoral vascular structures were analyzed by double immunofluorescence using 30-μm-thick sections. Results: The presence of focal and intensive solid growth of tumor cells (large solid nests; P = 0.003), low solid area MVD (P = 0.002), a high endothelial cell proliferation index (EPI; P = 0.005), and high expression of CXCL-12 in PET cells (P = 0.018) were significant unfavorable prognostic indicators. The predominant structure of the overall tumor histology and the expression of vascular endothelial growth factor-A did not separate aggressive PETs. In areas of focal solid growth, tumor-associated blood vessels had obviously low MVD and high EPI, and their structures were poorly formed with highly abnormal features, in comparison with other areas. High expression of CXCL-12 in tumor cells was significantly associated with variables representing tumor growth, hematogenous tumor spread, low MVD, high EPI, and the presence of large solid nests. Conclusions: This study has provided novel findings on the prognostic features of tumor architecture and tumor-associated angiogenesis in PETs. CXCL-12 is the first candidate molecule in association with neoangiogenesis in PETs.

Clinical Implications of Combined Portal Vein Resection as a Palliative Procedure in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Head Carcinoma

BackgroundThe clinical implications of combined portal vein resections are controversial.MethodsOne-hundred and forty-nine consecutive patients underwent macroscopically curative pancreatectomies for pancreatic head carcinoma between January 1, 1996 and December 31, 2004. Portal vein resection was performed in 86 patients (58%). Data on surgical mortality, morbidity, perioperative outcome, pathological factors, initial recurrence site, and survival were retrospectively compared between the patients with and without portal vein resection.ResultsThe incidence of postoperative pancreatic fistula was lower among patients who underwent portal vein resection. The median survival period was 14 months for the portal vein resection group and 35 months for the non-portal vein resection group, respectively. Combined portal vein resection was a significant predictor of poor survival using a multivariate analysis. Portal vein resection was strongly associated with larger tumor size, the degree of retropancreatic tissue invasion, the presence of extrapancreatic nerve plexus invasion, lymph node metastases, and positive cancer infiltration at the surgical margins.ConclusionsPortal vein resection at the time of pancreaticoduodenectomy can be safely performed. However, most of patients requiring portal vein resection do not achieve a potentially curative resection or a favorable survival term. As a result, the aggressive application and the strict selection of portal vein resection might reduce the incidence of positive surgical margins, enabling long-term survival in patients who do not require portal vein resection.

Bacteremia after hepatectomy: an analysis of a single-center, 10-year experience with 407 patients

Background and aims. Septic complications after hepatectomy remain a difficult problem. Intra-abdominal sources of postoperative infections are well described in the literature. However, no studies have examined the cause and outcome of bacteremia after hepatectomy. This study evaluated the incidence and outcome of bloodstream infections, bacteremia, after hepatectomy and determined the risk factors associated with the development of this serious complication. Patients and methods. Records were retrospectively reviewed of 407 patients who underwent an elective first hepatectomy at Nagoya University Hospital between January 1990 and December 1999. The incidence, cause, outcome, and possible risk factors for bacteremia were examined. Results. A total of 403 blood cultures were performed after hepatectomy in 188 patients (46%), and bacteremia was confirmed in 46 (11%). The incidence was significantly different between patients with obstructive jaundice and those without (24% vs. 4%). Multivariate analysis identified four significant independent variables: operative time, age, obstructive jaundice, and large-scale hepatectomy. The most common bacteria isolated were Staphylococci, followed by Enterococci, Klebsiella pneumoniae, and Enterobacter. A probable source of bacteremia was identified in 21 (46%) of the 46 patients. Patients with bacteremia had higher morbidity and mortality rates than patients without bacteremia, and the incidence of organ failure was five to ten times that of patients without bacteremia; the mortality rate was 43% (20/46). Conclusions. Postoperative bacteremia is a common complication of hepatectomy to resect biliary tract carcinoma, especially in older patients with obstructive jaundice undergoing major hepatectomy. In addition, for more than half of patients with bacteremia, no clear source of the infection is identified. Thus blood cultures are mandatory in high-risk patients who spike a fever after hepatectomy to identify the correct pathogen and its antibiotic susceptibility.

Hepatitis Virus Infection Affects DNA Methylation in Mice With Humanized Livers

BACKGROUND & AIMS Cells of tumors associated with chronic inflammation frequently have altered patterns of DNA methylation, including hepatocellular carcinomas. Chronic hepatitis has also been associated with aberrant DNA methylation, but little is known about their relationship. METHODS Pyrosequencing was used to determine the methylation status of cultured Huh7.5.1 hepatoma cells after hepatitis C virus (HCV) infection. We also studied mice with severe combined immunodeficiency carrying the urokinase-type plasminogen activator transgene controlled by an albumin promoter (urokinase-type plasminogen activator/severe combined immunodeficient mice), in which up to 85% of hepatocytes were replaced by human hepatocytes (chimeric mice). Mice were given intravenous injections of hepatitis B virus (HBV) or HCV, liver tissues were collected, and DNA methylation profiles were determined at different time points after infection. We also compared methylation patterns between paired samples of hepatocellular carcinomas and adjacent nontumor liver tissues from patients. RESULTS No reproducible changes in DNA methylation were observed after infection of Huh7.5.1 cells with HCV. Livers from HBV- and HCV-infected mice had genome-wide, time-dependent changes in DNA methylation, compared with uninfected urokinase-type plasminogen activator/severe combined immunodeficient mice. There were changes in 160 ± 63 genes in HBV-infected and 237 ± 110 genes in HCV-infected mice. Methylation of 149 common genes increased in HBV- and HCV-infected mice; methylation of some of these genes also increased in hepatocellular carcinoma samples from patients compared with nontumor tissues. Expression of Ifng, which is expressed by natural killer cells, increased significantly in chimeric livers, in concordance with induction of DNA methylation, after infection with HBV or HCV. Induction of Ifng was reduced after administration of an inhibitor of natural killer cell function (anti-asialo GM1). CONCLUSIONS In chimeric mice with humanized livers, infection with HBV and HCV appears to activate a natural kill cell-dependent innate immune response. This contributes to the induction and accumulation of aberrant DNA methylation in human hepatocytes.