CEACAM1 long cytoplasmic domain isoform is associated with invasion and recurrence of hepatocellular carcinoma.

BACKGROUND: The two isoforms of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), 1 with a long cytoplasmic domain (CEACAM1-L) and 1 with a short (CEACAM1-S), are involved in different signaling pathways. ß2-spectrin (ß2SP) is an adaptor protein that plays critical roles in the proper control of Smad access to activate receptors involved in regulation of TGF-ß signaling. In this study, we examined the association between CEACAM1 isoform balance and hepatocellular carcinoma (HCC) malignant potential and investigated the possibility of a molecular interaction between CEACAM1 and ß2SP. METHODS: Immunohistochemical analysis was carried out with CEACAM1-L or CEACAM1-S antibodies on 154 HCC tissues to correlate with the factors of malignancy. Invasion assay was performed for the effect of CEACAM1 expression on HCC cell lines. Moreover, immunohistochemical analysis and immunoprecipitation analysis were performed to investigate the association between CEACAM1 isoform balance and ß2SP. RESULTS: In immunohistochemical analysis, CEACAM1-L expression dominance was a risk factor for HCC recurrence (p = 0.04) and was significantly associated with a shorter survival compared with CEACAM1-S expression dominance. Invasion assay indicated that CEACAM1-4L-transfected HLF and PLC/PRF/5 cells showed significantly increased invasion (p < 0.0001) and CEACAM1-4S-transfected HLF cells showed significantly decreased invasion. Immunohistochemical analysis of ß2SP suggested that the HCCs with CEACAM1-L-dominant expression were more strongly stained with ß2SP than the HCCs with CEACAM1-S-dominant expression (p = 0.013), and coprecipitation assays indicated that CEACAM1-L could bind to ß2SP. CONCLUSIONS: CEACAM1-L may enhance the HCC invasiveness through an interaction with ß2SP and subsequent effects on TGF-ß signaling.

Hollow spheroids beyond the invasive margin indicate the malignant potential of colorectal cancer.

Objective Tumour budding formed by histologically undifferentiated cancer cells beyond the border of the tumour margin is associated with lymph node metastasis. However, hollow tumour nests, a possible histologically advanced phenotype of tumour budding, have not been discussed. We examined whether hollow spheroids exist beyond the border of the invasive margin and are associated with metastasis and prognosis. Moreover, we suggest that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) isoform balance is associated with hollow spheroid formation. Methods Immunohistochemical analyses with CEACAM1 and M30 as an apoptosis marker were performed to examine the importance of hollow spheroid CEACAM1 expression and central cell apoptosis in hollow spheroid formation. The correlations between the presence of hollow spheroids beyond the invasive margin and the clinicopathological characteristics of 314 patients with colorectal cancer were retrospectively evaluated. A 3D culture with colorectal cancer cells transfected with CEACAM1 cDNA or shRNA was used to determine whether CEACAM1 isoform balance controls colorectal hollow spheroid formation. Results Hollow spheroid formation accompanying central cell apoptosis was confirmed by M30 staining and serial section with CEACAM1 staining. Of the 314 patients, 96 (30.4%) were classified as having hollow spheroids. The presence of hollow spheroids is an independent risk factor for metastases and shorter survival. In 3D culture, CEACAM1 isoform balance modulated hollow spheroid formation of colorectal cancer cells. Conclusions Hollow spheroid formation beyond the border of the tumour margin in colorectal cancer is more important than tumour budding for the prediction of malignant potential.

Combined intraoperative use of contrast-enhanced ultrasonography imaging using a sonazoid and fluorescence navigation system with indocyanine green during anatomical hepatectomy.

PURPOSE: The clear demarcation line is ideal for real-time surgical navigation imaging during hepatectomy. METHODS: The study population was comprised of 22 patients with moderate liver cirrhosis scheduled to undergo an anatomical liver resection for the treatment of hepatocellular carcinoma. This study set out to assess the clinical value of the concomitant intra-operative use of contrast-enhanced intra-operative ultrasound using Sonazoid™, and a fluorescence navigation system (PDE) with ICG, as a novel tool for patients undergoing an anatomical liver resection. RESULTS: Following portal pedicle ligation for anatomical resection, 2 min after injection of ICG, the segments to be resected were detected as a negative-brightness area using PDE fluorescence. Sonazoid™ administration provides a parenchymal transectional line, as the margin of a loss of blood flow shows a hypo-enhanced image, and the resectional line of the parenchyma can be confirmed by CE-IOUS. Although the demarcation line of the liver surface after the portal pedicle ligation was apparent in 17 patients, the resection line using PDE was clearly detected in all 22 patients (p < 0.018). CONCLUSIONS: The combined use of these methods is therefore considered to be useful and safe for surgeons, as an additional tool for performing a liver resection.

Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival.

OBJECTIVE: To determine the importance of the expression pattern of multiple tumor markers for hepatocellular carcinoma (HCC) with regard to the tumor malignancy and patient survival. BACKGROUND: Several studies have indicated that HCC tumor markers, including alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP and des-γ-carboxy prothrombin were predictors of HCC malignancy. However, few reports have shown the relevance of the expression pattern of these 3 tumor markers with regard to patient prognosis. We herein reported the influence of the expression pattern of these 3 tumor markers on HCC malignancy and patient prognosis. METHODS: This retrospective study analyzed 185 patients who underwent hepatectomy for HCC between January 1999 and May 2009. The relationships between clinical parameters and these 3 tumor markers were analyzed. Cox proportional hazards regression analyses were performed to estimate risk factors for recurrence and survival. Furthermore, the relationships between pathological parameters and the expression patterns of the 3 tumor markers were analyzed. RESULTS: From clinical parameters, expression patterns of 3 tumor markers were related to maximum tumor size and macrovascular invasion in image findings. Multivariate analyses revealed independent risk factors for recurrence or survival to be the Child-Pugh score, the presence of multiple tumors, and triple positive tumor marker expression. From pathological findings, microvascular invasion and an Edmondson-Steiner classification of III or IV were related to the expression patterns of the 3 tumor markers. CONCLUSIONS: Triple positive tumor markers for HCC showed poor prognosis and invasive characteristics in pathological findings. Examination of these markers would be useful for predicting the degree of HCC malignancy.

Re-expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is known to be downregulated at the transcriptional level in adenoma and carcinoma. Recent reports have shown that CEACAM1 is overexpressed at protein level in colorectal cancer and correlated with clinical stage. The reason why colorectal cancer cells re-expressed CEACAM1 remains unclear. The aim of our study was to clarify the implication of CEACAM1 re-expression in colorectal cancer. Immunohistochemical analyses were conducted with CEACAM1 long (CEACAM1-L) or short (CEACAM1-S) cytoplasmic domain-specific antibodies on clinical samples from 164 patients with colorectal cancer. The risk factors for metastasis and survival were calculated for clinical implication of CEACAM1 re-expression. Invasion chamber and wound healing assays were performed for the effect of CEACAM1 expression on invasion and migration of colorectal cancer cells. CEACAM1-L and CEACAM1-S stained with greater intensity at the invasion front than at the luminal surface of tumors. Differences between the long and short cytoplasmic isoform expression levels were observed at the invasion front. Multivariate analysis showed that CEACAM1-L dominance was an independent risk factor for lymph node metastasis, hematogenous metastasis and short survival. The Kaplan-Meier evaluation demonstrated that CEACAM1-L dominance was associated with shorter survival time (p < 0.0001). In the invasion chamber and wound healing assays, CEACAM1-L promoted invasion and migration. Re-expression of CEACAM1 is observed at the invasion front of colorectal cancer. CEACAM1-L dominance is associated with metastasis and shorter survival of the patients with colorectal cancer. CEACAM1-L dominance is important for colorectal cancer cells invasion and migration.

Risk factors for postoperative infectious complications after hepatectomy.

BACKGROUND/PURPOSE: This study aimed to clarify the incidence of surgical site infections (SSIs) after hepatectomy. METHODS: The database records of three hundred and eight patients who underwent elective surgical treatment for hepatolithiasis, hepatocellular carcinoma (HCC), and metastatic carcinoma were retrospectively analyzed to determine the occurrence of postoperative infectious complications. The incidences of SSIs, classified as superficial or deep incisional SSIs and organ or space SSIs, and all other infectious complications within 30 days after hepatectomy were evaluated. RESULTS: The incidences of SSIs after a hepatectomy for hepatolithiasis (23.8%) were higher than those after a hepatectomy for HCC (11.3%) (p = 0.034) and after a hepatectomy for metastatic carcinoma (2.7%) (p < 0.001), and the incidence of SSIs after a hepatectomy for HCC was higher than that after a hepatectomy for metastatic carcinoma (p = 0.028). However, there was no significant difference in the incidence of remote site infections between the three groups. The incidence of superficial or deep incisional SSIs after a hepatectomy for hepatolithiasis (11.9%) was higher than that after a hepatectomy for metastatic carcinoma (1.4%) (p < 0.001) and the incidence of superficial or deep incisional SSIs after a hepatectomy for HCC (7.8%) was higher than that after a hepatectomy for metastatic carcinoma (1.4%) (p = 0.050). There was a significant difference in the incidence of space/organ SSIs between the patients with hepatolithiasis (11.9%) and HCC patients (3.6%) (p = 0.029), and between the patients with hepatolithiasis and metastatic carcinoma patients (1.4%) (p < 0.001). The rate of positive bile culture was 36.2% in all patients in this study, and the rates were 83.3, 7.8, and 10.0% for patients with hepatolithiasis, HCC, and metastatic carcinoma, respectively. A significantly higher (p < 0.001) positive bile culture rate was observed in patients with hepatolithiasis as compared with HCC or metastatic carcinoma patients. CONCLUSIONS: Our study suggests the existence of a relationship between postoperative SSIs and bile infection, thus supporting the proposed relationship between post-hepatectomy infection and such variables as liver function, blood sugar control, and nutritional status.

A new prediction model of postoperative complications after major hepatectomy for hepatocellular carcinoma.

BACKGROUND/AIMS: Serum hyaluronic acid (HA) concentrations reflect the degree of hepatic dysfunction and may have potential for predicting postoperative complications in a major hepatectomy for hepatocellular carcinoma (HCC). METHODS: Serum HA concentrations and other conventional liver function tests were measured prior to major hepatectomies in 52 patients. Independent predictors for postoperative complications were analyzed and the discriminant equation was established and validated. RESULTS: Postoperative complications occurred in 17 patients. Serum HA concentrations and the estimated remnant liver volume ratio (remnant Vol%) were recognized as independent predictors for postoperative complications (OR 1.03, 0.85; CI 95% 1.01-1.06, 0.76-0.95; p = 0.006, 0.006; respectively) and produced the discriminant equation: logit = 4.15 + 0.03 x (HA) -0.16 x (remnant Vol%). The value of the area under the curve of a receiver operating characteristic analysis was 0.92. If the cut-off of the logit value was set to 0, then the predictive accuracy was 0.88. The validation accuracy performed by a leave-one-out cross-validation method was 0.83. CONCLUSIONS: The constructed discriminant equation model consisting of the preoperative serum HA concentrations and estimated remnant Vol% could be useful for predicting postoperative complications in a major hepatectomy for HCC.