Naoto Gotohda

Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma

The relationship between overexpression of glypican (GPC)‐3 that is specific for hepatocellular carcinoma (HCC) and the prognosis has not yet been clarified. We attempted to determine the expression profile of GPC3 in association with the clinicopathological factors by immunohistochemical analysis in HCC patients and investigated the potential prognostic value of GPC3 by comparing the survival rate between the GPC3‐positive and GPC3‐negative HCC patients. Primary HCC tissue samples (n = 107) obtained from patients who had undergone hepatectomy between 2000 and 2001 were analyzed. GPC3 expression was less frequently observed in well‐differentiated HCC than in moderately and poorly differentiated HCC, the difference in the frequency being statistically significant. GPC3‐positive HCC patients had a significantly lower 5‐year survival rate than the GPC3‐negative HCC patients (54.5 vs 87.7%, P = 0.031). Among 80 of the 107 (74.6%) patients with initial treatment who underwent hepatectomy, none of GPC3‐negative HCC patients (n = 16, 20.0%) died during the follow‐up period. No deaths were noted in the GPC3‐negative HCC patients among the 71 (88.7%) patients with moderately and poorly differentiated HCC. Multivariate analysis identified GPC3 expression (P = 0.034) as an independent prognostic factor for the overall survival. We showed that GPC3 expression is correlated with a poor prognosis in HCC patients. (Cancer Sci 2009)

Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-γ ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers α-fetoprotein and/or des-γ-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination. Clin Cancer Res; 18(13); 3686–96. ©2012 AACR.

Long-term and perioperative outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma with propensity score matching: A multi-institutional Japanese study

The aim of this study was to compare the long‐term outcomes and perioperative outcomes of laparoscopic liver resection (LLR) with those of open liver resection (OLR) for hepatocellular carcinoma (HCC) between well‐matched patient groups.

Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head.

Tumor‐associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumor‐associated macrophages can be affected by cancer‐related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM‐related factors and the clinical impact of TAMs. CD68 (a pan‐macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease‐free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02411.x, 2012)

Clinicopathological Features and Prognostic Factors of Adenocarcinoma of the Esophagogastric Junction According to Siewert Classification: Experiences at a Single Institution in Japan

BackgroundTreatment strategy for adenocarcinoma of the esophagogastric junction (AEG) remains controversial. The aims of this study are to evaluate results of surgery for AEG, to clarify clinicopathological differences according to the Siewert classification, and to define prognostic factors.MethodsWe retrospectively analyzed 179 consecutive patients with Siewert type I, II, and III AEG who underwent curative (R0) resection at the National Cancer Center Hospital East between January 1993 and December 2008.ResultsPatients with AEG were divided according to tumor: 10 type I (5.6%), 107 type II (59.8%), and 62 type III (34.6%). Larger, deeper tumors and nodal metastasis were more common in type III than type II tumors. No significant differences were seen in 5-year survival rates among the three types: type I (51.4%), type II (51.8%), and type III (62.6%). Multivariate analysis showed that depth of tumor and mediastinal lymph node metastasis were independent prognostic indicators. The recurrence rate for patients with mediastinal lymph node metastasis was 87.5%. The risk factors for mediastinal lymph node metastasis were length of esophageal invasion and histopathological grade.ConclusionsMediastinal lymph node metastasis and tumor depth were significant and independent factors for poor prognosis after R0 resection for AEG. Esophageal invasion and histopathological grade were significant and independent factors for mediastinal lymph node metastasis.

Detail histologic analysis of nerve plexus invasion in invasive ductal carcinoma of the pancreas and its prognostic impact

Nerve plexus invasion is regarded as one of the most important prognostic factors in invasive ductal carcinoma (IDC) of the pancreas, though nerve plexus invasion has not been evaluated in terms of prognostic impact on the basis of detailed histologic investigation. The purpose of this study was to precisely examine morphologic characteristics of nerve plexus invasion and analyze its prognostic predictive power compared with the well-known prognostic parameters of pancreatic IDCs. The outcome and histologic features of 75 patients with pancreatic IDC in the pancreas head were investigated, and 422 lesions of nerve plexus invasion were evaluated. Tumor cells invading nerve plexus showed a duct-forming differentiated feature and predominantly existed in the perineurium and perineural space. Multivariate analyses revealed that the important prognostic factors, in addition to invasive tumor size and tumor necrosis, were at long distances from nerve plexus invasion to pancreatic capsule and perineural invasion in nerve plexus invasion.

Long-term and perioperative outcomes of laparoscopic versus open liver resection for colorectal liver metastases with propensity score matching: A multi-institutional Japanese study

The aim of the present study was to clarify the surgical outcome and long‐term prognosis of laparoscopic liver resection (LLR) compared with conventional open liver resection (OLR) in patients with colorectal liver metastases (CRLM).

Evaluation of the prognostic factors and significance of lymph node status in invasive ductal carcinoma of the body or tail of the pancreas.

Objective: We evaluated prognostic indicators for distal pancreatectomy with regional lymph node dissection in pancreatic body or tail carcinoma. Methods: Between 1993 and 2008, 50 patients with ductal carcinoma of the body or tail of the pancreas who underwent distal pancreatectomy with regional lymph node dissection were retrospectively analyzed. Clinicopathological factors associated with patient survival were evaluated. Results: No in-hospital deaths occurred among the study patients. The overall 5-year survival rate was 19.3%, and median survival was 22.6 months. Univariate analysis revealed that lymph node metastasis, intrapancreatic neural infiltration, peripancreatic nerve plexus infiltration, and tumor differentiation affected patient survival significantly. Multivariate analysis validated lymph node metastasis as an independent prognostic factor. Moreover, the lymph nodes attached to the pancreas were the most frequent metastatic nodes, and the number of metastasis in the lymph nodes attached to the pancreas was significantly associated with survival after surgical resection. Conclusions: Lymph node metastasis was a significant and independent prognostic factor for the surgically resected pancreatic body or tail carcinoma. Furthermore, the lymph nodes attached to the pancreas were the most frequent metastatic nodes, and these lymph nodes were potential indicators predicting both tumor extension and survival after surgery for pancreatic body or tail carcinoma.

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemo-embolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pre-treatment and post-treatment by an interferon-γ enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P=0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC.

Surgical outcome of solid pseudopapillary tumor of the pancreas.

BACKGROUND/PURPOSE The best surgical treatment for solid pseudopapillary tumor of the pancreas is a matter of debate. METHODS Fourteen patients with solid pseudopapillary tumor of the pancreas who underwent surgical resection, including enucleation, between June 1996 and January 2007 were retrospectively analyzed to evaluate the effect of the treatment. RESULTS The mean age of the patients was 39 years (range, 15 to 59 years). The mean size of the tumor was 4.4 cm (range, 2.0 to 12 cm). Ten tumors (71%) had a well-defined capsule, and 6 tumors (43%) extended beyond the pancreas. Eight of the 14 tumors (57%) had a cystic component, and calcification was observed in 6 tumors (43%). The frequency of microscopic venous invasion, lymphatic invasion, and nerve invasion was 29% (4 of 14), 0%, and 21% (3 of 14), respectively. No lymph node involvement or liver metastasis was observed. Six patients underwent positron emission tomography with 2-deoxy-2-[(18)F] fluoro-D-glucose (FDG), and stronger FDG accumulation compared with the surrounding pancreatic parenchyma was observed in 5 of the 6 patients. The median standardized uptake value (SUV) was 6.3 (range, 0.9 to 42.8). Distal pancreatectomy (n = 5), subtotal stomach-preserving pancreatoduodenectomy (n = 3), local resection (n = 3), enucleation (n = 2), and duodenum-preserving pancreatic head resection (n = 1) were performed. Overall morbidity and mortality rates were 43% and 0%, respectively. All patients were still alive without recurrent disease after a median follow-up of 46 months. CONCLUSIONS Patients with solid pseudopapillary tumor of the pancreas had a favorable outcome after surgical treatment, including enucleation.