Tomohiro Iguchi

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.

Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation

BackgroundPredictive biomarkers for the recurrence of hepatocellular carcinoma (HCC) have great benefit in the selection of treatment options, including liver transplantation (LT), for HCC. The purpose of this study was to identify specific microRNAs (miRs) in exosomes from the serum of patients with recurrent HCC and to validate these molecules as novel biomarkers for HCC recurrence.MethodsWe employed microarray-based expression profiling of miRs derived from exosomes in the serum of HCC patients to identify a biomarker that distinguishes between patients with and without HCC recurrence after LT. This was followed by the validation in a separate cohort of 59 HCC patients who underwent living related LT. The functions and potential gene targets of the recurrence-specific miRs were analysed using a database, clinical samples and HCC cell lines.ResultsWe found that miR-718 showed significantly different expression in the serum exosomes of HCC cases with recurrence after LT compared with those without recurrence. Decreased expression of miR-718 was associated with HCC tumour aggressiveness in the validated cohort series. We identified HOXB8 as a potential target gene of miR-718, and its upregulation was associated with poor prognosis.ConclusionCirculating miRs in serum exosomes have potential as novel biomarkers for predicting HCC recurrence.

Proposal of progression model for intrahepatic cholangiocarcinoma: Clinicopathologic differences between hilar type and peripheral type

It is important to clarify the histologic progression of intrahepatic cholangiocarcinoma (ICC) in consideration of its origin from the intrahepatic large or small biliary ducts. On the basis of the gross and histologic assessment, we classified 87 cases of ICC smaller than 5 cm in diameter into hilar type (H-ICC, n=38) or peripheral type (P-ICC, n=49) to compare their clinical and histologic features. Biliary dysplasia was observed in 65.8% (25/38) of H-ICC cases, whereas hepatitis virus infection and liver cirrhosis were associated with 46.7% (21/45) and 28.6% (14/49) of P-ICC, respectively. The frequency of perineural invasion, lymph node metastasis, and extrahepatic recurrence of H-ICC was significantly higher than that of P-ICC (P<0.0001, 0.0106, and 0.0279, respectively). H-ICC cases showed frequent vascular invasion and intrahepatic metastasis even with small tumor size, compared with P-ICC cases. H-ICC showed large duct involvement within the tumor, and in the cases of large tumor size, intraductal spread was detected in the tumor periphery. P-ICC of small size contained preserved architecture of the portal tracts. The survival of patients with H-ICC was worse than that of patients with P-ICC (P=0.0121). The independent and best prognostic factor by multivariate analysis was intrahepatic metastasis for H-ICC and lymph node metastasis for P-ICC. Our results suggest that ICCs derived from a different level of biliary ducts were related to different premalignant conditions and different tumor progression. Some ICCs arising from the large biliary duct are likely to exhibit an aggressive course even in cases of small tumor size. The recognition of the above events induces the proper therapy.

Rituximab, IVIG, and plasma exchange without graft local infusion treatment: a new protocol in ABO incompatible living donor liver transplantation.

Background. Although graft local infusion (GLI) treatment via the portal vein or the hepatic artery has been the pivotal strategy in ABO incompatible (ABOi) living donor liver transplantation (LDLT) in Japan, the procedure is associated with a high rate of catheter-associated complications. Methods. A new ABOi-LDLT protocol has been implemented using rituximab, intravenous immune globulin (IVIG), plasma exchange (PE), and splenectomy, without using GLI, on four patients, since 2007. Three other patients, treated before 2007, received GLI. Results. Three of the four patients with liver cirrhosis received rituximab over 3 weeks before LDLT, followed by PEs and post-LDLT IVIG, resulting in no rebound elevation of the isoagglutinin titers. The remaining patient, with fulminant hepatitis, received rituximab 3 days before the LDLT, resulting in antibody-mediated rejection, successfully treated by IVIG and PE. All four patients that were treated with the new protocol are alive, 26, 8, 6, and 5 months after ABOi-LDLT with normal liver function. Two of the three other patients with GLI, before 2007, had catheter-associated complications, including one graft loss. Conclusion. The new ABOi-LDLT protocol using rituximab, IVIG, and PE, without the use of GLI, therefore seems to be a safe and an effective treatment modality.

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

Lymph node metastasis via lymphatic vessels is related with an adverse outcome in many tumors. It is unclear whether lymphatic spread needs the development of the new lymphatic vessels or the expression of lymphangiogenetic factor in intrahepatic cholangiocarcinoma. The aim of this study was to assess the role of lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression, and D2-40-positive myofibroblastic cells for lymphatic spread and patient outcome in 88 cases of intrahepatic cholangiocarcinoma. We also assessed VEGF-C expression in 15 cases of metastatic lymph nodes. There was a significant correlation between lower lymphatic vessel density in the tumor center and positive lymphatic invasion (P=0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P=0.0315 and P=0.0360, respectively). Lymphatic invasion was observed higher in the peritumoral area (63%, 24/38) and in the tumor periphery (79%, 30/38) than in the tumor center (27%, 9/38). There was no significant correlation between the proliferative lymphatic vessels and pathologic features; however, lymphatic invasion was significantly associated with VEGF-C expression (P=0.0006), and the VEGF-C expression was seen in 12 of 15 cases (80%) of metastatic lymph node. Nodal metastasis was correlated with D2-40-positive myofibroblasts (P=0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P=0.0131). Our findings suggest that VEGF-C has an important role in lymphatic invasion via the preexisting lymphatic vessels in the tumor margin, and that lymphangiogenesis does not play a direct role in lymphatic metastasis. D2-40-positive myofibroblasts may contribute to lymphatic metastasis.

Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation: Subdivision and comparison with ordinary hepatocellular carcinoma

The morphologic characteristics and biologic behavior of small liver cancers with hepatic and biliary differentiation, and their histogenesis, remain unclear. In this study, 35 cases of hepatocellular carcinoma (HCC) smaller than 3 cm in diameter with biliary differentiation were divided into 3 groups, group 1 [cytokeratin (CK) 19-negative/mucin-negative], group 2 (CK 19-positive/mucin-negative), and group 3 (CK 19-positive/mucin-positive). Sixty-one HCCs without biliary differentiation were used as controls. We compared the histologic features of these tumors and the postoperative outcomes. Three morphologic features of HCCs with biliary differentiation were respectively observed in 40% (14/35), 60% (21/35), and 42.9% (15/35) as follows: (1) cancer cells with intermediate morphology, (2) prominent inflammatory cell infiltrate, (3) desmoplastic stroma; neural cell adhesion molecule and c-kit expression were noted in 25.7%(9/35) and 8.6%(3/35), respectively. Extrahepatic tumor recurrence after surgery occurred in 0% (0/16) of group 1, 33.3% (3/9) of group 2, 40.0% (4/10) of group 3, and 8.2% (5/61) of the ordinary HCCs. The tumor-related survival of group 3 patients was worse than that of patients with ordinary HCCs, but there were no differences between the survival of group 1, or group 2 patients and those with ordinary HCCs. Our results suggest that the biliary differentiation does occur even in small HCC, and a mucin-producing cancer cells indicates aggressive tumor behavior. The combination of intermediate cancer cells, inflammatory cell infiltrate, and desmoplastic stroma is likely to be related to the biliary differentiation of HCC.

Significance of modified Glasgow prognostic score as a useful indicator for prognosis of patients with gastric carcinoma

BACKGROUND The significance of the Glasgow prognostic score (GPS), an inflammation-based prognostic score, as an indicator of aggressiveness in gastric carcinoma has not been investigated fully. METHODS Two hundred thirty-two patients with gastric carcinoma were enrolled. Patients who had both an elevated C-reactive protein (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL) were allocated a traditional GPS (TGPS) of 2. Patients who had one of these abnormal values were allocated a TGPS of 1, and patients who had neither were allocated a TGPS of 0. RESULTS There existed a significant difference between the survival of adjacent groups of patients when examined using the TGPS (P = .05 for TGPS 0 vs 1 and P = .006 for TGPS 1 vs 2). Multivariate analysis based on TGPS demonstrated that TGPS (P = .020) and tumor stage (P = .0007) proved to be independent prognostic indicators for worse prognosis. CONCLUSIONS The preoperative measurement of an inflammation-based prognostic score can demonstrate a strict stratification for the prognosis of patients with gastric carcinoma.

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

Fascin expression in progression and prognosis of hepatocellular carcinoma

Fascin is an actin‐bundling protein and induces membrane protrusions and cell motility after the formation of lamellipodia or filopodia. Fascin expression has been reported to be associated with progression or prognosis in various neoplasms, but the role of fascin in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to investigate the clinicopathological and prognostic relevance of fascin by immunohistochemistry.

Preoperative elevation of serum C-reactive protein as an independent prognostic indicator for gastric cancer

PurposePreoperative elevation of serum C-reactive protein (CRP) is a prognostic indicator for some malignant tumors. We investigated the clinicopathologic importance of an elevated preoperative serum CRP value in gastric carcinoma patients.MethodsWe studied the relationship between the preoperative serum CRP value and clinicopathologic characteristics in 204 patients who underwent curative resection of gastric carcinoma.ResultsThe patients with preoperative CRP elevation had significantly poorer survival than those without CRP elevation (P < 0.0001). According to multivariate analysis, the factors independently associated with an unfavorable prognosis were a high preoperative CRP value (P = 0.024), lymphatic invasion (P = 0.017) and advanced tumor stage (P = 0.016).ConclusionPreoperative serum CRP elevation can be an independent prognostic indicator in patients with gastric carcinoma.