[A Case of Esophageal Cancer with Consciousness Disorder Due to Hyperammonemia during FP Treatment].

Hyperammonemia induced by 5-fluorouracil(5-FU)is known as a rare adverse event, but there are few reports of hyperammonemia occurring during FP(5-FU plus CDDP)treatment for esophageal cancer. We report a case of esophageal cancer with consciousness disorder due to hyperammonemia during FP treatment with an examination of some of the relevant literature. The patient was a man of approximately 70 years of age who was received FP treatment. He showed consciousness disorder on day 4. A blood test showed hyperammonemia(427µg/dL), which was considered to be the cause of his consciousness disorder. He was treated with branched chain amino acid infusion, lactulose and kanamycin and made a full recovery. An operation for esophageal cancer was performed after 3 months and he is currently followed up without recurrence. Hyperammonemia should be considered as a differential diagnosis of consciousness disorder during chemotherapy including 5-FU.

[A Case of Locally Advanced Unresectable Esophageal Cancer Treated with Nivolumab and Ipilimumab Therapy Followed by Surgery].

In cases of unresectable, locally advanced esophageal cancer, conversion surgery may be considered if chemotherapy produces favorable results and surgical resection is indicated. The use of immune checkpoint inhibitors in chemotherapy for esophageal cancer has expanded, and has increased the number of cases in which conversion surgery becomes possible. The patient in the present report had received a diagnosis of Stage Ⅳa esophageal carcinoma, and a prior nephroureterectomy discouraged the administration of platinum-based agents. Nivolumab and ipilimumab were administered as induction chemotherapy. Despite the achievement of stable disease, the patient's esophageal stricture deteriorated, necessitating surgical intervention. The resected specimen revealed that fewer than 50% of malignant cells remained viable and residual cancer cells were noticeably absent, particularly in the enlarged lymph nodes. We herein present the details of this case and discuss the literature concerning surgery following immune checkpoint inhibitor therapy.

[A Case of Gastric Large-Cell Neuroendocrine Carcinoma Combined with Adenocarcinoma in the Cecum].

A 74-year-old man with anemia visited our department. Esophagogastroduodenoscopy showed a type 2 lesion from the angulus to the antrum. Histopathological findings indicated gastric neuroendocrine carcinoma. Colonoscopy showed a type 1 lesion at the cecum. Distal gastrectomy was performed with D1+lymph node dissection, Roux-en-Y reconstruction, and ileocecal resection with D3 lymph node dissection. The patient was pathologically diagnosed with large-cell neuroendocrine carcinoma in the stomach, pT4a(SE), med, INF a>>b-c, ly1-2, v1(SM, EVG), pN0, pM0, pStageⅡB, and adenocarcinoma (tub1>tub2)of the cecum, pT2(MP), ly1(HE), v1(EVG, SM), pN0, pM0, pStageⅠ. Postoperatively, he received oral S-1 as an adjuvant chemotherapy. His postoperative course was uneventful without any recurrence over 18 months.

[A case of gastric arteriovenous fistula causing intraperitoneal hemorrhage].

We report abdominal bleeding caused by an arteriovenous fistula (AVF) of the gastroepiploic artery. A 20-year-old man visited our hospital with epigastric pain and hypovolemic shock. Contrast-enhanced abdominal computed tomography revealed a high-density region within a huge low-density mass. Angiography revealed AVF of the gastroepiploic artery. Therefore, we performed transcatheter arterial embolization using n-butyl-2-cyanoacrylate (Histoacryl(®)) to control the intraperitoneal hemorrhage.

A third glucose uptake bypass in Corynebacterium glutamicum ATCC 31833.

In Corynebacterium glutamicum, the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) has long been the only known glucose uptake system, but we recently found suppressor mutants emerging from a PTS-negative strain of C. glutamicum ATCC 31833 on glucose agar plates, and identified two alternative potential glucose uptake systems, the myo-inositol transporters encoded by iolT1 and iolT2. The expression of either gene renders the PTS-negative strain WTΔptsH capable of growing on glucose. In the present study, we found a suppressor strain that still grew on glucose even after the iolT1 and iolT2 genes were both disrupted under the PTS-negative background. Whole-genome sequencing of the suppressor strain SPH1 identified a G-to-T exchange at 134 bp upstream of the bglF gene encoding an EII component of the ß-glucoside-PTS, which is found in limited wild-type strains of C. glutamicum. Introduction of the mutation into strain WTΔptsH allowed the PTS-negative strain to grow on glucose. Reverse transcription-quantitative PCR analysis revealed that the mutation upregulates the bglF gene by approximately 11-fold. Overexpression of bglF under the gapA promoter in strain WTΔptsH rendered the strain capable of growing on glucose, and deletion of bglF in strain SPH1 abolished the growth again, proving that bglF is responsible for glucose uptake in the suppressor strain. Simultaneous disruption of three glucokinase genes, glk (Cgl2185, NCgl2105), ppgK (Cgl1910, NCgl1835), and Cgl2647 (NCgl2558), in strain SPH1 resulted in no growth on glucose. Plasmid-mediated expression of any of the three genes in the triple-knockout mutant restored the growth on glucose. These results indicate that C. glutamicum ATCC 31833 has an additional non-PTS glucose uptake route consisting of the bglF-specified EII permease and native glucokinases.

A Simple Index to Predict Liver Functional Reserve after Hepatectomy.

BACKGROUND/AIMS: It is difficult to estimate the functional reserve of the liver required for safe hepatectomy in patients with severe chronic liver disease The aim of this study was to retrospectively construct simple model based on routine laboratory data to predict both early liver failure (ELF) and mortality from recurrence-free liver failure (MLF) as an index for late liver failure after hepatectomy. METHODOLOGY: Between 2000 and 2004, 196 consecutive patients underwent curative hepatectomy, and data from 127 minor hepatectomies were included in this study. RESULTS: Mean survival time was [mean (SD)] 1252 (670) days after hepatectomy. ELF and MLF were observed in 29 and 13 patients, respectively. PT%, TB, and direct bilirubin (DB) were the best predictors in patients with both ELF and MLF. PT% alone was the best predictor of ELF and MLF with area under ROC curves of 0.70 and 0.81, respectively. By using a preoperative PT% of ≤ 70, we could accurately predict ELF and MLF in 77% and 87% of patients, respectively. ICG-R15 could not accurately predict both ELF and MLF for any cut-off values. CONCLUSIONS: Unlike ICG-R15, PT% is a simple noninvasive index for estimating liver functional reserve to predict both ELF and MLF.

High resectability of colorectal liver metastases with aggressive chemotherapy in the era of molecular target-based agents.

BACKGROUND/AIMS: Advances in chemotherapy have expanded the resectability of colorectal liver (CRC) metastases. We studied treatment results in CRC patients with liver metastases in the era of molecular target-based agents. METHODOLOGY: Based on data collected retrospectively, we analyzed the demographics, operative and pathological outcomes, and adjuvant chemotherapy, of 91 consecutive CRC patients with liver metastases treated between January, 2008 and June, 2010. RESULTS: Of the 91 patients, 42 (46.2%) underwent liver resection (group 1), 41 underwent only resection of the primary tumor without hepatectomy (group 2), and 8 underwent palliative surgery (group 3). According to multivariate analysis, resection of liver metastases was significantly influenced by the number of metastases and the existence of extrahepatic metastases. Disease-free survival (DFS) differed significantly between patients who received adjuvant therapy and those treated by surgery alone (p<0.001). The regimen (p=0.01) and duration (p<0.0001) of adjuvant chemotherapy also affected DFS. Overall survival after 1 and 3 years was 97.6% and 94.0%, respectively, in group 1, 71.9% and 30.6% in group 2, and 33.3% and 0% in group 3. CONCLUSIONS: Although the observation period was short, our findings suggest that high resectability and effective chemotherapy will prolong the survival of patients with colorectal liver metastases.

Contrast-enhanced intraoperative ultrasound for hepatocellular carcinoma: high sensitivity of diagnosis and therapeutic impact.

BACKGROUND: Postoperative early recurrence is a crucial issue in the treatment of hepatocellular carcinoma (HCC) patients. Some early recurrences seem to occur from minute tumors which were overlooked during both preoperative and intraoperative investigations. Therefore, it is urgently necessary to increase detectability of minute HCCs during operation. If they could be detected and resected during surgery, the prognosis should be improved. The purpose of this study is to investigate the usefulness of contrast-enhanced intraoperative ultrasound (CEIOUS) for the diagnosis and treatment of HCC. METHODS: Institutional ethics committee approval and informed consent were obtained. Fifty-two patients (mean age 65 years; 38 males and 14 females) who underwent liver resection with either preoperative computed tomography during angiography (CTA) or CEIOUS with Sonazoid (perflubutane microbubble contrast agent) were studied. We determined the presence of HCC on the basis of the histopathological findings of resected specimens. RESULTS: The sensitivity of CEIOUS [97.6% (95% CI 91.8-99.4)] was higher than that of CTA [89.4% (95% CI 81.1-94.3)]. The positive predictive values of CEIOUS [91.2% (95% CI 83.6-95.5) and CTA [91.6% (95% CI 83.6-95.9)] were similar. Eight new HCCs from 7 patients, which accounted for 9.4% (8/85) of the total HCCs, were correctly detected and diagnosed by CEIOUS, and we performed an additional partial hepatectomy in 3 of these 7 patients. CONCLUSIONS: CEIOUS with Sonazoid provided increased sensitivity of detection of small HCCs compared with preoperative CTA, thereby leading to a more appropriate surgical procedure and contributing to complete tumor removal.

Pathological complete response and two-year disease-free survival in a primary gastric choriocarcinoma patient with advanced liver metastases treated with germ cell tumor-based chemotherapy: a case report.

Choriocarcinoma is an early metastasizing and highly invasive tumor and characterized as a high-level human chorionic gonadotropin-secreting tumor. It normally arises in the gestational trophoblast, gonads and much less frequently in the stomach. Primary gastric choriocarcinoma appears to have a poor prognosis; especially with liver metastasis, the survival period is expected to be <1 month. This unfavorable clinical outcome is partly due to the lack of defined chemotherapy against primary gastric choriocarcinoma. We herein report a case of a 68-year-old male primary gastric choriocarcinoma patient with advanced liver metastases in which germ cell tumor-based chemotherapy achieved a pathological complete response and 2-year disease-free survival.

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.

Importin-α1 as a novel prognostic target for hepatocellular carcinoma.

BACKGROUND: Perturbations in the nuclear microenvironment, including transport systems, play a critical role in malignant progression, but the nuclear import abnormalities remain unclear in hepatocarcinogenesis. We analyzed the role of importin in hepatocellular carcinoma (HCC). METHODS: Gene expression profiling of the importin family was performed in HCC tissues. The significance of importin protein expression was analyzed in vitro as well as clinicopathologically. RESULTS: According to the microarray profiles, the importin-α1 was dominantly overexpressed in HCC tissues as compared to the adjacent noncancerous tissues. By means of human HCC cell lines, a knockdown of importin-α1 by its siRNA greatly reduced cellular proliferation by 15.2-26.6% (P < 0.005). Immunohistochemical analysis on tissue samples demonstrated cancer-specific overexpression in 36.3% of HCCs. The overexpression of importin-α1 was correlated statistically with high levels of alfa-fetoprotein ( P = 0.0017), the tumor number (P = 0.0116), histological dedifferentiation (P = 0.0054), tumor morphology (P = 0.0433), portal vein invasion (P = 0.0007), hepatic vein invasion (P = 0.0081), Fc (P = 0.0367), Fc-inf (P = 0.0122), and the tumor, node, metastasis stage (P = 0.0026); this resulted in a significantly poorer prognosis in both overall survival (P = 0.0164) and recurrence-free survival (P = 0.0101). Multivariate analysis of recurrence-free survival revealed importin-α1 expression to be a statistically significant factor (P = 0.0361). In addition, early recurrence after curative resection was observed more frequently in the importin-α1-positive group as compared to the negative group (P = 0.0023). The multivariate analysis identified importin-α1 as the only independent predictor of early recurrence after HCC resection (odds ratio = 5.291, P = 0.0191). CONCLUSIONS: Because importin-α1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target.

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: Eggel's 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), α-fetoprotein (P = 0.0424), "lens culinaris agglutinin-reactive fraction of α-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.

Analogy between sphere forming ability and stemness of human hepatoma cells.

Increasing evidence suggests that cancers contain a small subset of cancer-initiating cells, so-called cancer stem cells (CSCs) that are capable of regenerating a tumor after chemoradiation therapy. Sphere forming ability is known to be one of properties of CSCs, but the significance remains unclear. The present study focused on sphere formation of human hepatoma cells in three-dimensional culture in order to evaluate the analogy between sphere forming ability and stemness of cancer cells in vitro. Under three-dimensional culture condition, HepG2, Hep3B and PLC/PRF/5 cells demonstrated the sphere formation while SK-Hep1 and Huh-7 cells did not. The population of G0/G1 phase increased in the spheres compared with the monolayer (67 vs. 38%). In spite of no significant difference in stem cell surface markers (CD44, CD90, CD133, EpCAM and ABCG2), remarkable up-regulation of p27 CDK inhibitor was observed in sphere forming cells. Immunofluorescence analysis revealed the nuclear expression of p27 in the whole of the sphere, but weak expression of p21 only at the peripheral area. The spheres acquired chemoresistance to cisplatin compared with the monolayers (58.9 vs. 16.2 µM in IC50). This model was useful for assessment of the role of cell-cycle quiescence in the stemness and chemoresistance of cancer cells.

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 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.

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.

Influence of risk factors for metabolic syndrome and non-alcoholic fatty liver disease on the progression and prognosis of hepatocellular carcinoma.

BACKGROUND/AIMS: We investigated a relationship between the risk factors for metabolic syndrome, such as obesity, diabetes mellitus, hypertension, and hyperlipidemia, and the pathogenesis and outcome of hepatocellular carcinoma (HCC). METHODOLOGY: One hundred twenty four patients who underwent curative resections for HCC were classified into 3 groups: those patients who were positive for hepatitis B surface antigen (group B), those positive for antibody to hepatitis C virus (group C), and those negative for both of them (non-B non-C) (group NBNC). The preoperative laboratory data, risk factors for metabolic syndrome, history of alcohol abuse, and outcome after surgery were investigated. The presence of non-alcoholic steatohepatitis (NASH) was also evaluated. RESULTS: The incidence of diabetes mellitus, hyperlipidemia, and alcohol abuse, and the serum level of triglyceride were significantly higher in group NBNC than in groups B or C. The risk factors for metabolic syndrome tended to lower the survival rates in group B and C, but not in group NBNC. Three of the 37 non-B non-C patients were associated with NASH. CONCLUSIONS: It is suggested that the pathogenesis of non-B non-C HCC may be more closely associated with the risk factors for metabolic syndrome than that of hepatitis virus related HCC.

Strong association between frequency of intermittent inflow occlusion and transient increase in serum liver enzymes after hepatic resection.

BACKGROUND/AIMS: Although significantly higher serum levels of liver transaminases are commonly observed after hepatic resection, the factors responsible for the increase and the association between the increase and the postoperative course remain unclear. METHODOLOGY: The study population comprised 70 patients who had undergone hepatic resection except hepatectomy with vascular and biliary reconstruction. The relation between the perioperative factors and postoperative aspartic aminotransferase (AST) and alanine aminotransferase (ALT) elevations were analyzed. Outcome parameters, i.e., postoperative total bilirubin level, hospital stay and complications were also analyzed. RESULTS: The average maximum postoperative serum AST and ALT levels were 444.6 IU/L and 390.1 U/L. None of the preoperative factors examined, such as AST, ALT, associated liver disease, Liver Damage Classification, intraoperative hypotension, intraoperative blood loss or types of liver resection, were significantly correlated with liver enzyme elevations. The only factor that was significantly correlated was frequency of intermittent inflow occlusion (p < 0.001). The elevations of AST and ALT were not significantly correlated with length of hospital stay and postoperative serum bilirubin level. ALT also was not correlated to complications, whereas AST was significantly correlated to the frequency of the postoperative complications. CONCLUSIONS: The frequency of intermittent inflow occlusion is the only factor that affects the postoperative enzyme elevation.

Outcomes and recurrence of initially resectable hepatocellular carcinoma meeting milan criteria: Rationale for partial hepatectomy as first strategy.

BACKGROUND: Partial hepatectomy and liver transplantation are considered curative treatments for small hepatocellular carcinoma (HCC) meeting the Milan criteria (solitary tumor <5 cm or up to 3 nodules <3 cm). This study was designed to clarify whether partial hepatectomy can be the first option in patients eligible for both treatments. STUDY DESIGN: All patients (n = 152) underwent curative surgical operation for primary HCC during 2000 to 2005 at our hospital. Eighty-seven patients met Milan criteria and the remaining 65 did not. Outcomes were examined according to Milan criteria. RESULTS: After partial hepatectomy, 3-year survival rate was 89.6% for the group that met Milan criteria, compared with 60.8% for the group that did not (p = 0.0044). Among patients with HCC who initially met the criteria, tumor recurrences were observed in 30 patients; 23 patients met criteria and 7 patients exceeded the criteria at first diagnosis of recurrence. Patients with recurrence within the criteria showed a higher 3-year survival rate compared with patients with recurrence exceeding the criteria (100% versus 19.8%; p < 0.0001). Analysis of clinicopathologic variables to predict mode of recurrence revealed tumor size (p < 0.0001) and lower histologic differentiation (p = 0.0326) as positive factors for recurrence exceeding Milan criteria. CONCLUSIONS: Our results suggest that it is an appropriate strategy to treat HCC patients who meet Milan criteria with partial hepatectomy. It should be noted that approximately one-tenth of patients who initially met Milan criteria experienced postoperative recurrence that exceeded the criteria.