Yoshihiro Nakakubo

CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.

Objective Recent studies have demonstrated the importance of tumor immunity for a cancer patients prognosis. In some types of cancer, it has been shown through immunohistochemical analysis that the existence of CD8+ tumor-infiltrating lymphocytes (TILs) is a crucial factor in determining prognosis. In an experimental model, CD4+ lymphocytes together with CD8+ lymphocytes contributed significantly to tumor immunity. Methods Specimens were taken from 80 surgically resected pancreatic adenocarcinomas between 1992 and 1999. Immunohistochemical staining of CD4, CD8, and S100 protein was performed, and the levels of these proteins were determined by microscopic analysis. The percentages of patients in the CD4(+) and CD8(+) groups were 59% (47/80) and 25% (16/80), respectively. When separated into 4 groups, CD4/8(+/+), CD4/8(+/−), CD4/8(−/+) and CD4/8(−/−), the overall survival rate was significantly higher in CD4/8(+/+) patients (13 cases) compared with those in all other groups combined (67 cases; P = 0.0098). CD4/8(+/+) status was negatively correlated with tumor depth and TNM stage. Multivariate analyses showed that CD4/8(+/+) status was an independent favorable prognostic factor. The number of tumor-infiltrating S100 protein positive cells was also significantly higher in the CD4/8(+/+) group than in others (P = 0.0084). Conclusions In pancreatic adenocarcinoma, the presence of CD4+ TILs together with CD8+ TILs serves as a good indicator of the patients outcome after surgical treatment.

High expression of tumor-associated antigen RCAS1 in pancreatic ductal adenocarcinoma is an unfavorable prognostic marker.

RCAS1 (receptor‐binding cancer antigen expressed on SiSo cells) is a recently identified human tumor‐associated antigen expressed on various cancer cells. It is thought that tumor cells evade immune surveillance by expression of RCAS1, which induces apoptotic cell death in receptor‐positive immune cells. The purpose of our study was to investigate the relation between RCAS1 expression and the clinicopathological variables and clinical outcome in patients with pancreatic adenocarcinoma. Immunohistochemical analysis for RCAS1 was performed on paraffin‐embedded specimens of 80 patients (mean age, 62 years) who underwent surgical resection for pancreatic adenocarcinoma. Of the 80 specimens, 77 (96%) were positive for RCAS1. No significant correlation was found between RCAS1 expression and age, gender, depth of invasion, tumor diameter, surgical margin, lymphatic invasion, venous invasion or histopathological grading. Borderline correlations between RCAS1 expression were noted for lymph node metastasis and stage (p = 0.0608 and 0.0934, respectively). RCAS1 expression was very frequently observed and the survival of patients with high RCAS1 expression was significantly shorter than that of those with low expression (p = 0.0012). Multivariate analysis using the Cox regression model indicated that high RCAS1 expression was an independent prognostic factor (risk ratio, 3.090; p = 0.0090). These results suggested that RCAS1 might be a significant tumor marker for pancreatic adenocarcinoma and an unfavorable predictor for prognosis of patients who have undergone surgical resection.

The prognostic significance of RCAS1 expression in squamous cell carcinoma of the oesophagus.

Overexpression of RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) protects cancer cells from immune attack and might be related to poor prognosis in several cancers. We investigated the immunoreactivity of RCAS1 and its correlation with clinicopathological features in 95 patients who underwent surgical resection for oesophageal squamous cell carcinoma. Thirty-two of the 95 (33.7%) cases were strongly positive for RCAS1. RCAS1 showed significant correlations with age and stage grouping. Expression of RCAS1 was associated with shorter postoperative survival. Multivariate analysis indicated that RCAS1 positivity was an independent negative prognostic factor. Our study establishes RCAS1 as a novel prognostic marker for surgically resected oesophageal squamous cell carcinoma.

RCAS1 expression as a prognostic factor after curative surgery for extrahepatic bile duct carcinoma

BackgroundRCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a cancer cell-surface antigen and has been identified as a prognostic factor in several cancers. It is thought that tumor cells escape from immune attack by expressing RCAS1, which induces apoptosis in receptor-positive immune cells. We investigated the relationship between RCAS1 expression and clinicopathologic features and clinical outcome in patients with extrahepatic bile duct carcinoma (EBDC) who underwent curative resection.MethodsRCAS1 expression was determined by immunohistochemistry in 60 patients with EBDC who underwent curative resection from 1992 to 1999. The patients were divided into two groups on the basis of the extent of RCAS1 expression: a low-expression group (immunoreactivity in <25% of cells) and a high-expression group. Expression was correlated with clinicopathologic features and prognosis.ResultsRCAS1 was expressed in 52 (86.7%) of 60 tumors and at a high frequency in all histopathologic stages. High expression of RCAS1 was detected in 46 (76.7%) of 60 cases. No correlation existed between the pattern of RCAS1 expression and any clinicopathologic feature, although high expression did correlate with poor prognosis. High RCAS1 expression was an independent negative predictor for survival.ConclusionsRCAS1 expression predicts poor outcome in resectable EBDC.

Transcriptional targeting of adenovirus vectors with the squamous cell carcinoma-specific antigen-2 promoter for selective apoptosis induction in lung cancer.

Squamous cell carcinoma antigens SCCA1 and SCCA2 are highly homologous serine proteinase inhibitors which have been widely utilized as serological markers for squamous cell cancers, but it has recently been demonstrated that only SCCA2 is truly specific for certain forms of lung cancer. Using a construct containing the 5′-flanking region of the SCCA2 gene between −460 and +0 bp and the luciferase reporter gene, SCCA2 promoter activity was detected in SCCA2-producing SCC cell lines (LK-2, LC-1), but not in SCCA2-nonproducing lung adenocarcinoma cell lines (A549, ABC-1, and RERF-LC-MS) or normal cells (WI-38, SAEC, and NHEK-Adult). Infection with a recombinant adenovirus vector, Ad-SCCA2-DsRed, resulted in cell-specific expression of the SCCA2 promoter-driven DsRed marker gene only in LK-2 and LC-1 cells. The same strategy was used for SCCA2-driven expression of a proapoptotic gene, (KLAKLAK)2, which can cause mitochondrial disruption by triggering mitochondrial permeabilization and swelling, resulting in the release of cytochrome c and induction of apoptosis. Infection with Ad-SCCA2-KLAKLAK2 specifically reduced the growth of the two human lung SCC cell lines compared to the SCCA2 nonproducing cell lines both in vitro and in vivo, suggesting that the SCCA2 promoter had a tumor-specific effect. These results suggest that transduction of SCCA2 promoter-controlled suicide genes by adenoviral vectors can confer transcriptionally targeted cytotoxicity in SCCA2-producing lung SCC cells, and represents a novel strategy for gene transfer specifically targeted to SCC in the lung.

A study of the assessment of axillary lymph nodes before surgery for breast cancer using multidetector-row computed tomography

PurposeSentinel lymph node biopsy (SLNB) is widely used in the detection of breast cancer metastasis, and a retrospective study was conducted to determine whether the preoperative assessment of axillary lymph node metastasis using multidetector-row computed tomography (MDCT) images would contribute to the selection of patients who require SLNB.MethodsSeventy of the 164 patients who underwent surgery of the breast during the period of April 2006 to December 2008 were selected as subjects who: (1) did not undergo preoperative chemotherapy; (2) had undergone MDCT before the surgery; (3) had undergone either SLNB or axillary lymph node removal during the operation; and (4) whose T factor was pathologically T2 or less. The diameter and shape of the largest lymph node that was identified on an MDCT image of the axilla on the affected side were measured and compared with permanent pathological specimens.ResultsSize: The group with lymph node metastasis included 21 subjects with an average diameter of the largest lymph node of 10.3 mm (range, 6–23 mm), and the nonmetastasis group included 49 subjects with that of 7.1 mm (5–13 mm). Shape: Round lymph nodes that internally contained no fat concentration in 24 subjects, and cuneate or round lymph nodes that internally contained a fat concentration in 46 subjects. The observable lymph nodes that were round had a diameter of at least 10 mm, and internally contained no fat concentration (A) were regarded as positive, whereas the cuneate or round lymph nodes that measured less than 8 mm in diameter and internally contained fat concentration (B) were regarded as negative, and both positive predictive value and negative predictive value was 100%.ConclusionsAxilla removal was performed from the beginning in the case of (A) by assessing the size and shape for the presence or absence of axillary lymph node metastasis before surgery using MDCT.