Norio Noguchi

Surgical Strategies for Hepatocellular Carcinoma with Special Reference to Anatomical Hepatic Resection and Intraoperative Contrast-Enhanced Ultrasonography

Here we described our strategies to attain a better prognosis for hepatocellular carcinoma (HCC) patients by surgery. Among a variety of attempts conducted to date, we focused on anatomical resection and intraoperative contrast-enhanced ultrasonography. There are still controversies with respect to the significance of anatomical resection. We analyzed the significance of this surgical procedure in 207 patients without macrovascular invasion. These patients underwent either anatomical resection or non-anatomical resection. We found that the patients with anatomical resection had higher recurrence-free survival rate than those with non-anatomical resection. Univariable analysis showed that liver damage, the serum level of α-fetoprotein, tumor number, surgical margin, and type of surgery (anatomical or non-anatomical resection) were significant predictive factors for intrahepatic recurrence. Multivariable analysis revealed that multiple tumors, α-fetoprotein, and non-anatomical resection were independent risk factors for recurrence. We conclude that anatomical resection is a recommendable surgical procedure in patients without macrovascular invasion. A recent innovation is the development of contrast-enhanced ultrasonography. Then we have applied this to liver surgery intraoperatively. We confirm that vascular images contribute to a precise diagnosis and the detection of small portal tumor thrombi, and that Kupffer images are useful to discover the minute tumors. In addition, by clarifying the relationship between tumors and the vascular architecture, real-time 3-dimensional images using Kupffer imaging are a promising guide during the surgical procedures, although further development is needed.

Laparoscopic and Thoracoscopic Partial Hepatectomy for Hepatocellular Carcinoma

Several trials have been reported examining laparoscopic liver resections for the treatment of various kinds of liver tumors. However, there are no detailed reports on the use of laparoscopic (LH) and thoracoscopic (TH) hepatectomy for the treatment of hepatocellular carcinoma (HCC). Eleven laparoscopic and thoracoscopic partial liver resections were attempted for treating HCC. The indications for performing a laparoscopic or thoracoscopic partial hepatectomy were as follows: (1) the tumor was located on the surface of the liver; (2) the tumor was less than 3 cm in diameter; and (3) the tumor was not located adjacent to any large vessels. A TH was performed if the tumor was located in segment 8; an LH was performed if the tumor was located in segment 3, 4, or 5. Hand-assisted operations were performed in two patients. The mean operating time was 186.1 ± 44.0 minutes (range 130–310 minutes). The operative blood loss was 218.3 ± 197.6 ml (range 20–650 ml). The mean postoperative hospital stay was 11.3 ± 5.7 days (range 7–26 days). Two patients experienced postoperative complications (wound infection and ascites). No local recurrences have occurred to date. The overall 5-year survival rate and disease-free 5-year survival rate were 75.0% and 38.2%, respectively. Laparoscopic and thoracoscopic hepatic resections are less invasive than conventional surgical techniques and are useful for treating HCC in select patients.

The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma

BACKGROUND & AIMS We previously identified that high Aurora B expression was associated with hepatocellular carcinoma (HCC) recurrence due to tumor dissemination. In this preclinical study, a novel inhibitor of Aurora B kinase was evaluated as a treatment for human HCC. METHODS AZD1152 is a selective inhibitor of Aurora B kinase. Twelve human HCC cell lines were analyzed for Aurora B kinase expression and the in vitro effects of AZD1152. The in vivo effects of AZD1152 were analyzed in a subcutaneous xenograft model and a novel orthotopic liver xenograft model. RESULTS Aurora B kinase expression varied among the human HCC cell lines and was found to correlate with inhibition of cell proliferation, accumulation of 4N DNA, and the proportion of polyploid cells following administration of AZD1152-hydroxyquinazoline-pyrazol-anilide (AZD1152-HQPA). AZD1152-HQPA suppressed histone H3 phosphorylation and induced cell death in a dose-dependent manner. Growth of subcutaneous human HCC xenografts was inhibited by AZD1152 administration. In an orthotopic hepatoma model, treatment with AZD1152 significantly decelerated tumor growth and increased survival. Pharmacobiological analysis revealed that AZD1152 induced the rapid suppression of phosphohistone H3, followed by cellular apoptosis in the liver tumors but not in the normal tissues of the orthotopic models. CONCLUSIONS Our preclinical studies indicate that AZD1152 is a promising novel therapeutic approach for the treatment of HCC.

Gene expression signature of the gross morphology in hepatocellular carcinoma.

Objective:To evaluate the gene expression signature of hepatocellular carcinoma (HCC) in relation to the gross morphology. Background:Eggels nodular type of HCC is morphologically subclassified into the single nodular (SN) type, the single nodular type with extranodular growth (SNEG), and the confluent multinodular (CM) type, but their biomolecular differences remain unclear. Methods:The clinicopathological characteristics and genome-wide gene expressions were analyzed in 275 patients with nodular-type HCC (124 SN-type, 91 SNEG-type, and 60 CM-type) who received curative hepatectomy. Results:Significantly poor prognosis was recognized in CM types in overall survival (P = 0.0020) and recurrence-free survival (P = 0.0066). Analysis of the genome-wide expression patterns revealed significant difference of CM-type HCC from either SN- or SNEG-type HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC. Immunohistochemical studies confirmed the specific expression of EpCAM in HCC cancer cells of CM type. In multivariate analysis, the gross morphology of CM type was significantly associated with EpCAM expression (P = 0.0092), &agr;-fetoprotein (P = 0.0424), “lens culinaris agglutinin-reactive fraction of &agr;-fetoprotein” level (P = 0.0288), and the portal vein invasion (P = 0.0150). Furthermore, EpCAM was predictive for poor prognosis in overall and recurrence-free survivals of patients with CM-type HCC (P = 0.0082 and P = 0.0043, respectively). Conclusion:Our studies suggest that the distinct signature of gene expression is closely related to morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC.

Resection of a cancer developing in the remnant pancreas after a pancreaticoduodenectomy for pancreas head cancer

We report a rare case of a curative resection performed on a carcinoma developing in the remnant pancreas at 3 years 7 months after a pancreaticoduodenectomy for pancreatic cancer. A 63-year-old man underwent a pancreaticoduodenectomy for pancreatic cancer on November 1999. Because the celiac trunk was occluded by atherosclerosis, an aortohepatic bypass with a saphenous vein graft was performed simultaneously. In May 2003, tumor marker levels increased, and a tumor was detected in the remnant pancreas on computed tomography. There were no findings such as invasion into the surrounding tissue or distant metastasis, and therefore we removed the remnant pancreas in July 2003. Histopathologically, the tumor consisted of a well-differentiated tubular adenocarcinoma and was limited to the pancreas. Moreover, the anastomotic site of the pancreaticojejunostomy was negative for cancer, and some foci of papillary hyperplasia and goblet cell metaplasia of the pancreatic ductal epithelium, which was thought to be the precursor of the pancreatic cancer, were seen. These findings suggested that the tumor was a second primary cancer developing in the remnant pancreas. This case provided suggestive evidence for the development of pancreatic cancer, and the surgical procedure for a pancreaticoduodenectomy with occlusion of the celiac trunk is discussed.

Hepatocellular carcinoma with osteoclast-like giant cells: Possibility of osteoclastogenesis by hepatocyte-derived cells

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast‐like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast‐like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate‐resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease‐9, in osteoclast‐like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor‐kappa B (RANK) in the giant cells and receptor activator of nuclear factor‐kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte‐derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast‐like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.

Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: A prospective, multicenter study†‡

The prediction of cancer recurrence holds the key to improvement of the postoperative prognosis of patients. In this study, the recurrence of early‐stage hepatocellular carcinoma (HCC) after curative hepatectomy was analyzed by the genome‐wide gene‐expression profiling on cancer tissue and the noncancerous liver tissue. Using the training set of 78 cases, the cytochrome P450 1A2 (CYP1A2) gene in noncancerous liver tissue was identified as the predictive candidate for postoperative recurrence (hazard ratio [HR], 0.447; 95% confidence interval [CI], 0.249‐0.808; P = 0.010). Multivariate analysis revealed the statistically significant advantage of CYP1A2 down‐regulation to predict recurrence (odds ratio, 0.534; 95% CI, 0.276‐0.916; P = 0.036), and the expression of CYP1A2 protein was confirmed immunohistochemically. An independently multi‐institutional cohort of 211 patients, using tissue microarrays, validated that loss of expression of CYP1A2 in noncancerous liver tissue as the only predictive factor of recurrence after curative hepatectomy for early‐stage HCC (HR, 0.480; 95% CI, 0.256‐0.902; P = 0.038). Gene set‐enrichment analysis revealed close association of CYP1A2 down‐regulation with oxidative stress pathways in liver tissue (P < 0.001, false discovery rate [FDR] = 0.042; P = 0.006, FDR = 0.035). Our results indicate these pathways as the molecular targets to prevent recurrence, as well as the potential prediction of the super high‐risk population of HCC using liver tissue. (HEPATOLOGY 2011;54:1273–1281)

Surgical Contribution to Recurrence-Free Survival in Patients with Macrovascular–Invasion−Negative Hepatocellular Carcinoma

BACKGROUND Macroscopic vascular invasion (MVI) is a well-known indicator of recurrence of hepatocellular carcinoma (HCC) even after curative hepatectomy, but the clinicopathologic and molecular features of the recurrence remain unclear in MVI-negative HCC. STUDY DESIGN Two hundred seven consecutive patients with confirmed primary MVI-negative HCC were retrospectively assessed after curative resection, with special emphasis on the importance of anatomically systematized hepatectomy. HCC tissues were also analyzed for genome-wide gene expression profile of each tumor using a microarray technique. RESULTS Univariant analysis of HCC recurrence revealed multiple tumors (p < 0.001), moderate to poor differentiation (p = 0.044), Child-Pugh B/C (p = 0.047), alpha-fetoprotein elevation (p = 0.007), and nonanatomic hepatectomy (p = 0.010) as risk factors. According to Cox hazard multivariant analysis, multiple tumors (p = 0.002), alpha-fetoprotein elevation (p < 0.001), and nonanatomic hepatectomy (p = 0.002) were identified as independent factors of the recurrence. In the recurrent cases after anatomic hepatectomy for HCC, local recurrence was significantly infrequent compared with those after nonanatomic hepatectomy (p < 0.001). Network expression analysis using cDNA microarray revealed distinct signaling pathways of epithelial-mesenchymal transitions are associated with recurrence after anatomically systematized hepatectomy. CONCLUSIONS Anatomically systematized hepatectomy might contribute to recurrence-free survival of HCC patients of HCC without MVI. Local recurrence could be mostly averted by anatomic hepatectomy, although specific epithelial-mesenchymal transitions signaling might regulate the biologic aggressiveness of HCC.

Liver metastasis from rectal cancer with prominent intrabile duct growth.

Intrabiliary growth of liver metastases from colorectal cancer has rarely been studied. A surgically resected case of a metastatic liver tumor with prominent intrabiliary growth derived  from  rectal  cancer  is  reported.  The  patient  was  a 62‐year‐old man who had received a low anterior resection for rectal cancer in March 2000. He was re‐admitted due to obstructive jaundice in January 2003, and was diagnosed with hepatic malignancy in segment II of the liver with an intrabiliary tumor extending from the intrahepatic bile duct of segment II to the common hepatic duct. He underwent a left hepatectomy, a partial resection of segment VI, and an extrahepatic bile duct resection with reconstruction of the biliary tract. In the resected specimen, there were whitish tumors of 3 cm and 1.5 cm in diameter in segments II and VI, respectively, and an intrabiliary tumor originating from the main tumor in segment II extended to the common hepatic duct. Both the liver tumors and the intrabiliary tumor consisted of a well‐ to moderately differentiated adenocarcinoma, which showed the same histological features as the rectal cancer. The immunohistochemical findings strongly supported that these tumors, including the intrabiliary growth, were liver metastasis from the rectal cancer. The intrabiliary invasion and growth of metastatic liver tumors has generally been overlooked, notwithstanding their frequently observed biological behavior. The present case is informative, and further investigation into this type of metastatic liver tumor may be warranted.

Gene-expression phenotypes for vascular invasiveness of hepatocellular carcinomas.

BACKGROUND Gross vascular invasion is a well-established prognostic indicator in hepatocellular carcinoma (HCC), but the biological significance of microscopic invasion remains unclear. METHODS Curatively resected primary HCCs were classified retrospectively into 3 groups: HCCs without vascular invasion (V0), HCCs with microvascular invasion (V1), and HCCs with macrovascular invasion (V2). Microarray profiling of patients with V0, V1, and V2 using Jonckheere-Terpstra (JT) tests and Wilcoxon rank sum tests was performed. RESULTS Distinct patterns of gene expression were demonstrated between V0 and V2 groups; less (L) and highly (H) invasive phenotypes, respectively. It is noteworthy that 2 dendrograms by the hierarchical clustering provided exactly the same assignment results for V1 cases that were thus separated into L and H gene-expression phenotypes. Marked differences were found in overall (P < .001) and tumor-free survival (P < .001) between L and H gene-expression phenotypes. Multivariate analyses indicated that the phenotypes of the patterns of gene expression, rather than the clinicopathologic markers of vascular invasion, were independent predictors of tumor recurrence (P = .031). Using the gene-expression patterns identified by both JT and Wilcoxon rank sum test analyses, other V1 cases validated these differences in tumor-free survivals between gene-expression phenotypes within the group (P = .039). CONCLUSION Gene profiling suggested that microvascular invasiveness consisted of a classable mixture of 2 distinct phenotypes. Thus, gene-array analyses may have clinical benefit, because they may in fact be more predictive than other clinical factors.