Tatsuya Orimo

Proteomic Profiling Reveals the Prognostic Value of Adenomatous Polyposis Coli-End-Binding Protein 1 in Hepatocellular Carcinoma

Histological differentiation is a major pathological parameter associated with poor prognosis in patients with hepatocellular carcinoma (HCC) and the molecular signature underlying HCC differentiation may involve key proteins potentially affecting the malignant characters of HCC. To develop prognostic biomarkers for HCC, we examined the global protein expression profiles of 45 surgically resected tissues, including 27 HCCs with different degree of histological differentiation, 11 adjacent nontumor tissues, and seven normal liver tissues. Unsupervised classification grouped the 45 samples according to their histological classification based on the protein expression profiles created by laser microdissection and two‐dimensional difference gel electrophoresis (2D‐DIGE). Statistical analysis and mass spectrometry identified 26 proteins with differential expression, of which 14 were functionally linked to c‐Myc, AP‐1, HIF1A, hepatocyte nuclear factor 4 alpha, or the Ras superfamily (RhoA, CDC42, and Rac1). Among the proteins identified, we focused on APC‐binding protein EB1 (EB1) because it was dominantly expressed in poorly differentiated HCCs, which generally correlate with the poor prognosis in patients with HCC. In addition, EB1 is controlled by c‐Myc, RhoA, and CDC42, which have all been linked to HCC malignancy. Immunohistochemistry in a further 145 HCC cases revealed that EB1 significantly correlated with the degree of histological differentiation (P < 0.001), and univariate and multivariate analyses indicated that EB1 is an independent prognostic factor for recurrence (hazard ratio, 2.740; 95% confidence interval, 1.771–4.239; P < 0.001) and survival (hazard ratio, 2.256; 95% confidence interval, 1.337–3.807; P = 0.002) of patients with HCC after curative surgery. Conclusion: Proteomic profiling revealed the molecular signature behind the progression of HCC, and the prognostic value of EB1 in HCC. (HEPATOLOGY 2008;48:1851‐1863.)

Multiplication of alpha‐fetoprotein and protein induced by vitamin K absence‐II is a powerful predictor of prognosis and recurrence in hepatocellular carcinoma patients after a hepatectomy

To evaluate the oncological implications of multiplication of α‐fetoprotein (AFP) and protein induced by vitamin K absence or antagonists‐II (PIVKA‐II) in patients with hepatocellular carcinoma (HCC).

Hand-assisted laparoscopic splenectomy for sclerosing angiomatoid nodular transformation of the spleen complicated by chronic disseminated intravascular coagulation: A case report

A 36‐year‐old man who presented with a nosebleed and anemia was referred to our hospital. Laboratory test results showed platelet depletion, decreased levels of fibrinogen, and increased fibrinogen degeneration products. CT showed a 13‐cm splenic tumor. T2‐weighted MRI revealed a high‐intensity mass. We preoperatively diagnosed splenic hemangioma with chronic disseminated intravascular coagulation and scheduled an operation to relieve the disseminated intravascular coagulation. We also performed hand‐assisted laparoscopic splenectomy to ensure easy handling of the splenomegaly. The resected specimen microscopically consisted of hemorrhages and hemangiomatous lesions, and multiple angiomatoid nodules were scattered and separated by fibrocollagenous stroma with inflammatory cells. Three types of vessels (capillaries, sinusoids and small veins) were contained in the angiomatoid nodules, and the pathological diagnosis was sclerosing angiomatoid nodular transformation. The results of this case suggest that we should consider sclerosing angiomatoid nodular transformation in the differential diagnosis of patients with splenic tumors, as sclerosing angiomatoid nodular transformation with hemangiomatous features may cause coagulation disorders for which splenectomy should be performed.

Fatty acid-binding protein 5 function in hepatocellular carcinoma through induction of epithelial-mesenchymal transition

Hepatocellular carcinoma (HCC) is a highly prevalent cancer with poor prognosis. The correlation between overexpression of fatty acid‐binding protein 5 (FABP5) and malignant potential of tumor growth and metastasis in several cancers has been previously reported. However, the correlation between FABP5 expression and HCC malignant behavior remains unknown. We compared FABP5 expression and patient characteristics in paired HCC and adjacent noncancerous liver tissues from 243 patients who underwent surgical resection of primary HCC. Cell proliferation, invasion, and migration assays were performed in HCC cell lines overexpressing FABP5 or downregulated for FABP5. Tumor growths were monitored in xenograft model, and liver and lung metastasis models were established. In the 243 HCC patients, FABP5‐positive staining (n = 139/243, 57.2%) was associated with poor prognosis and recurrence (P < 0.0001) and showed positive correlation with distant metastasis, tumor size and vascular invasion (P < 0.05). Cell proliferation, invasion, and migration in vitro were enhanced by upregulation of FABP5 and decreased by downregulation of FABP5 in HCC cell lines. Similar results in tumor formation and metastasis were obtained through in vivo analyses. PCR array results revealed upregulation of SNAI1 in FABP5‐overexpressing HepG2 cells. Western blot analysis showed significantly increased expression of E‐cadherin and ZO‐1 and decreased SNAI1 expression and nuclear translocation of β‐catenin by knockdown of FABP5. We revealed a significant role for FABP5 in HCC progression and metastasis through the induction of epithelial‐to‐mesenchymal transition. FABP5 may be a potential novel prognostic biomarker and new therapeutic target for HCC.

Hepatectomy for hepatocellular carcinoma with portal vein tumor thrombus

Despite surgical removal of tumors with portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) patients, early recurrence tends to occur, and overall survival (OS) periods remain extremely short. The role that hepatectomy may play in long-term survival for HCC with PVTT has not been established. The operative mortality of hepatectomy for HCC with PVTT has also not been reviewed. Hence, we reviewed recent literature to assess these parameters. The OS of patients who received hepatectomy in conjunction with multidisciplinary treatment tended to be superior to that of patients who did not. Multidisciplinary treatments included the following: preoperative radiotherapy on PVTT; preoperative transarterial chemoembolization (TACE); subcutaneous administration of interferon-alpha (IFN-α) and intra-arterial infusion of 5-fluorouracil (5-FU) with infusion chemotherapy in the affected hepatic artery; cisplatin, doxorubicin and 5-FU locally administered in the portal vein; and subcutaneous injection of IFN-α, adjuvant chemotherapy (5-FU + Adriamycin) administration via the portal vein with postoperative TACE, percutaneous isolated hepatic perfusion and hepatic artery infusion and/or portal vein chemotherapy. The highest reported rate of operative mortality was 9.3%. In conclusion, hepatectomy for patients affected by HCC with PVTT is safe, has low mortality and might prolong survival in conjunction with multidisciplinary treatment.

Huge hepatocellular carcinoma greater than 10 cm in diameter worsens prognosis by causing distant recurrence after curative resection

This study aimed to evaluate the impact of huge (≥10 cm) hepatocellular carcinoma (HCC) to the recurrence pattern and the prognosis after hepatectomy.

Clear cell sarcoma of the esophagus: report of a case

We report a rare case of clear cell sarcoma of the esophagus and review the literature regarding clear cell sarcomas of the gastrointestinal tract. A 57-year-old male was admitted with dysphagia during swallowing. Preoperative imaging studies, including upper gastrointestinal endoscopy and endoscopic ultrasonography, showed that the tumor was located between the mucosa and the muscularis propria of the lower esophagus. We performed subtotal esophagectomy with gastric tube reconstruction. Pathological findings of the tumor showed mixed spindle cells and oval cells. Immunohistochemical staining showed that the tumor cells were positive for S-100, vimentin and neuron-specific enolase and negative for α-smooth muscle actin, myoglobin and c-kit. Fluorescence in situ hybridization using a Ewing sarcoma breakpoint region 1 probe showed split signals in a small percentage of cells. We finally diagnosed the patient with clear cell sarcoma of the esophagus.

Pancreatoduodenectomy for circumportal pancreas accompanying the retroportal pancreatic duct: a case report and review of the literature

Circumportal pancreas (CP) is an extremely rare pancreatic fusion anomaly which is usually asymptomatic. This report presents the case of a patient with a tumor in the head of a CP and the retroportal accessory pancreatic duct in the pancreatic tissue behind the portal vein. A 53-year-old male was diagnosed with a nonfunctioning neuroendocrine tumor of the pancreas and resection of the tumor was scheduled. The patient was revealed to have CP on preoperative computed tomography and endoscopic retrograde cholangiopancreatography, which showed the pancreatic tissue encircling the portal vein and the retroportal accessory pancreatic duct. The patient safely underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreaticogastrostomy.

R0 Resection for Locally Advanced Pancreatic Cancer with Low-dose Gemcitabine with Wide Irradiation Area as Neoadjuvant Chemoradiotherapy

Background: Local antitumor efficacy and the outcome of neoadjuvant chemoradiotherapy (NACRT) with low-dose gemcitabine and wide irradiation area for borderline resectable and unresectable pancreatic cancer were evaluated. Patients and Methods: Thirty-four cases of borderline resectable and unresectable pancreatic cancer were recruited. Three-dimensional conformal radiotherapy to the pancreatic bed and the region scheduled for lymph node dissection was performed to a total dose of 50.4 Gy28 fractions with gemcitabine at a dose of 150 mg/m2 weekly. Clinical and pathological results were examined. Results: Twenty-seven patients (79.4%) completed the protocol. Grade 3/4 leucopenia (n=10), and grade 3 anorexia (n=1) occurred. Seven cases were excluded (two refused treatment; five had progressive disease), 20 underwent laparotomy, and 16 resected (47.1%) cases achieved R0 resection. Median survival time, and 3-year and 5-year survival rates were 39.0 months, and 56.3% and 28.1% in resected cases, respectively. Conclusion: NACRT with low-dose gemcitabine and wide irradiation area achieved 100% R0 resection and acceptable prognosis.

Curative resection of pancreatic ductal adenocarcinoma developing in the remnant pancreas 13 years after distal pancreatectomy for intraductal papillary mucinous neoplasms: A case report

Intraductal papillary mucinous neoplasms (IPMNs) are characterized by the papillary proliferation of atypical mucinous epithelial cells in the pancreatic ductal system. There are two recurrence patterns following resection of IPMNs: Metachronous multifocal occurrence of IPMNs, and distinct pancreatic ductal adenocarcinoma (PDAC) in the remnant pancreas. Several recent studies investigated the development of distinct PDAC during follow-up evaluation of IPMNs and the incidence rate ranged from 4.5 to 8%. Thus, IMPNs may be a good predictor for the early detection of PDAC during observation or after the resection of IPMNs. We herein report the rare case of a patient who underwent resection of PDAC that developed in the remnant pancreas 13 years after distal pancreatectomy with splenectomy for IPMNs. PDAC may develop in the remnant pancreas after pancreatectomy for IPMNs; thus, careful long-term follow-up with periodic surveillance, at least every 6 months, is warranted.