Overexpression of NKX6.1 is closely associated with progressive features and predicts unfavorable prognosis in human primary hepatocellular carcinoma.

The homeobox gene NKX6.1 was recently identified in cervical tumors. This study was designed to explore the clinical and prognostic significance of NKX6.1 further in patients with primary hepatocellular carcinoma (HCC). The expression levels of NKX6.1 were examined using real-time PCR, Western blotting, and immunohistochemistry in HCC cell lines and HCC tissues. The invasion capability of cell lines following silencing or overexpression of NKX6.1 was investigated by Transwell assay. Cells proliferation was tested by MTT assays. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to NKX6.1 expression. Correlation between NKX6.1 immunohistochemical staining, clinicopathologic parameters, and follow-up data of HCC patients was analyzed statistically. NKX6.1 expression was higher in HCC tissues compared to the adjacent noncancerous tissue. NKX6.1 overexpression was significantly correlated with tumor size, tumor differentiation, clinical stage, metastasis, and relapse. Kaplan-Meier analysis revealed that NKX6.1 overexpression was related to unfavorable 5-year disease-free survival and overall survival. Importantly, multivariate analysis indicated that NKX6.1 overexpression was an independent unfavorable marker for overall survival. Moreover, a significant relationship was observed between NKX6.1 and EMT marker expression levels, and NKX6.1 knockdown inhibited cell invasion, and overexpression of NKX6.1 promotes cell proliferation in vitro. NKX6.1 is upregulated in HCC and is a reliable prognostic marker for patients with HCC.

Low expression of BARX2 in human primary hepatocellular carcinoma correlates with metastasis and predicts poor prognosis.

AIM: The homeobox gene Barx2 was recently identified as a regulator of ovarian and breast cancer; however, the expression level of BARX2 and its significance in hepatocellular carcinoma (HCC) remain unknown. METHODS: Protein and mRNA expression levels of Barx2 were examined using Western blotting and real-time PCR respectively, in paired HCC tissue and matched adjacent non-cancerous tissue from 12 patients. The expression levels of epithelial-mesenchymal transition (EMT) markers were also detected in relation to BARX2 expression. Lastly, immunohistochemistry for BARX2 was also performed on a tissue microarray containing 231 HCC tissue samples. RESULTS: We observed that BARX2 expression was lower in HCC tissues compared to matching adjacent non-cancerous tissue. The low expression level of BARX2 was significantly correlated with metrics of tumor size, tumor differentiation, clinical stage, metastasis and relapse. Furthermore, the patients with low BARX2 expression had adverse survival outcomes. Importantly, multivariate Cox regression analysis revealed that low BARX2 expression was an independent marker for lower overall survival (P = 0.007). Moreover, a significant negative relationship was observed between the expression of BARX2 and markers of EMT. CONCLUSION: These findings provide evidence that the low expression level of BARX2 in HCC is significantly correlated with tumor metastasis, and that BARX2 may be an independent prognostic biomarker for patients with HCC.

Bilateral pulmonary artery aneurysms, coronary artery aneurysm, and ventricular pseudoaneurysm in Behçet disease.

Massive hemoptysis in Behçet disease (BD) is rare but often fatal. This report presents a 28-year-old man with recurrent massive hemoptysis. He was diagnosed with bilateral multiple pulmonary artery aneurysms (PAAs), coronary artery aneurysm, and ventricular pseudoaneurysm from BD. The patient underwent emergency right lower lobectomy with no obvious complications. No hemoptysis recurred during an 18-month follow-up. This report also reviews the occurrence of PAAs in BD, with an emphasis on the treatment approaches.

The value of contrast-enhanced transrectal ultrasound in predicting the nature of prostate diseases and the Gleason score of prostate cancer by a subjective blood flow grading scale.

OBJECTIVES: To investigate the value of contrast-enhanced transrectal ultrasound (CETRUS) in predicting the nature of prostate diseases and prostate cancer Gleason score. METHODS: 106 patients suspected of prostate cancer were evaluated with CETRUS followed by systematic biopsy. Prostate blood flow of CETRUS was graded using a subjective 5-point scale. The relationships between ultrasound findings and biopsy outcomes, as well as prostate cancer Gleason score were analyzed. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of CETRUS. RESULTS: Biopsy revealed prostate cancer in 43 of 106 patients. The proportions of malignant histology in the groups with CETRUS scores of 1-5 were 0% (0/10), 8.3% (2/24), 31.7% (13/41), 88.9% (16/18) and 92.3% (12/13), respectively. The rate of prostate cancer with a Gleason score ≥7 in the groups with a CETRUS score of 2-5 were 0% (0/2), 15.4% (2/13), 37.5% (6/16) and 91.7% (11/12), respectively. The blood flow grading scale correlated with pathological outcomes and Gleason score significantly (r = 0.66, p < 0.001; and r = 0.61, p < 0.001, respectively). ROC analysis showed the area under the ROC curve to be 0.87. CONCLUSIONS: CETRUS-based blood flow grading scale is a reliable tool for predicting the pathological outcome of prostate diseases and prostate cancer Gleason score noninvasively.

Identification and validation of AIB1 and EIF5A2 for noninvasive detection of bladder cancer in urine samples.

We previously demonstrated that amplified in breast cancer 1 (AIB1) and eukaryotic initiation factor 2 (EIF5A2) overexpression was an independent predictor of poor clinical outcomes for patients with bladder cancer (BCa). In this study, we evaluated the usefulness of AIB1 and EIF5A2 alone and in combination with nuclear matrix protein 22 (NMP22) as noninvasive diagnostic tests for BCa. Using urine samples from 135 patients (training set, controls [n = 50] and BCa [n = 85]), we detected the AIB1, EIF5A2, and NMP22 concentrations using enzyme-linked immunosorbent assay. We applied multivariate logistic regression analysis to build a model based on the three biomarkers for BCa diagnosis. The diagnostic accuracy of the three biomarkers and the model were assessed and compared by the area under the curve (AUC) of the receiver operating characteristic. We validated the diagnostic accuracy of these biomarkers and the model in an independent validation cohort of 210 patients. In the training set, urinary concentrations of AIB1, EIF5A2, and NMP22 were significantly elevated in BCa. The AUCs of AIB1, EIF5A2, NMP22, and the model were 0.846, 0.761, 0.794, and 0.919, respectively. The model had the highest diagnostic accuracy when compared with AIB1, EIF5A2, or NMP22 (p < 0.05 for all). The model had 92% sensitivity and 92% specificity. We obtained similar results in the independent validation cohort. AIB1 and EIF5A2 show promise for the noninvasive detection of BCa. The model based on AIB1, EIF5A2, and NMP22 outperformed each of the three individual biomarkers for detecting BCa.

Prognostic significances of tumor-infiltrating S-100 positive dendritic cells and lymphocytes in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: To investigate the prognostic significances of dendritic cells and lymphocytes infiltration in hepatocellular carcinoma. METHODOLOGY: The clinicopathological and follow-up data of 44 patients with hepatocellular carcinoma, who underwent curative resection of tumor in our hospital from January 1995 to July 1996, were collected. Immunohistochemical staining was employed to detect the S-100 positive dendritic cells in the tumor tissue, and lymphocytes infiltration was evaluated simultaneously. The relationship of the tumor-infiltrating dendritic cells and lymphocytes to the postoperative recurrence-free time and survival rate was analyzed. RESULTS: Either the tumor-infiltrating dendritic cells or the tumor-infiltrating lymphocytes alone had no significant relationship to the postoperative recurrence-free time and survival rate. By taking into consideration both tumor-infiltrating dendritic cells and lymphocytes simultaneously, the patients were classified into two groups. Group A included patients having dendritic cell counts > or = 20 cells/10 high power fields together with positive lymphocytes infiltration (n = 17), and group B consisted of patients having dendritic cell count > or = 20 cells/10 high power fields but with negative lymphocytes infiltration or dendritic cell count < 20 cells/10 high power fields with either positive or negative lymphocytes infiltration (n = 27). There were no significant differences in clinicopathological features between two groups. The recurrence-free time was markedly longer in group A as compared with group B, with a median time of 21.6 months for group A and 4.1 months for group B (P < 0.05). The 1-, 3-, 4-year survival rates were significantly greater in group A than those in group B, being 83.5% vs. 42.2%, 61.8% vs. 28.4% and 48.7% vs. 23.0%, respectively (P < 0.01). CONCLUSIONS: Marked infiltration of dendritic cells together with lymphocytes in tumor tissue was closely related to the improved clinical prognosis in patients with hepatocellular carcinoma, and represented as an independent prognostic factor.

Sorafenib enhances the chemotherapeutic efficacy of S-1 against hepatocellular carcinoma through downregulation of transcription factor E2F-1.

PURPOSE: Sorafenib and S-1 (one mixed formulation containing 5-FU prodrug and dihydropyrimidine dehydrogenase inhibitor) were two effective agents against hepatocellular carcinoma (HCC), but whether they had synergistic effects remained unclear. The present study aimed at evaluating their synergistic effects against HCC and its mechanisms. METHODS: Inhibitory effects of sorafenib, 5-FU and their combination on HCC cells PLC/PRF/5 and SK-HEP-1 were evaluated. Expressions of transcription factor E2F-1 and its downstream thymidylate synthetase (TS) in the treated cells were determined using real-time PCR and Western blot. In vivo anti-tumoral efficacy of S-1 plus sorafenib on HCC was evaluated in NOD/SCID mice. E2F-1 and TS expressions in tumors were determined by immunohistochemical staining. RESULTS: Sorafenib inhibited growth of HCC cells in dose-dependent manner, with IC50 of 5.4 ± 0.3 µmol/L for PLC/PRF/5 and 5.3 ± 0.5 µmol/L for SK-HEP-1. Sorafenib (1 µmol/L) enhanced inhibitory efficacy of 5-FU on HCC cells in vitro, dropping IC50 of 5-FU from 167.7 ± 12.1 to 105.4 ± 8.4 µmol/L for PLC/PRF/5 and 115 ± 10.2 to 82 ± 7.4 µmol/L for SK-HEP-1 (both p < 0.01). Sorafenib downregulated E2F-1 and TS expressions on HCC cells, and its combination with 5-FU yielded a synergistic downregulation of TS expression on HCC cells. In NOD/SCID mice with subcutaneously inoculated HCC, sorafenib combined with S-1 yielded greater inhibition on tumor growth and remarkable TS suppression when compared with sorafenib or S-1 alone (all p < 0.05). CONCLUSIONS: Sorafenib enhanced therapeutic efficacy of 5-FU/S-1 against HCC through downregulation of E2F-1 and TS expressions. Sorafenib combined with S-1 might represent as valuable therapeutic regimen against HCC.

Overexpression of YKL-40 is an independent prognostic marker in gastric cancer.

YKL-40 is a growth factor for connective tissue cells and a migration factor for endothelial cells. Elevated serum level of YKL-40 has been associated with poor prognosis in many cancers. However, the status of YKL-40 expression and its clinical/prognostic significance in gastric cancer are unclear. In this study, the expression of YKL-40 was studied by immunohistochemistry in gastric cancer tissue microarray containing 172 primary gastric cancer cases and 70 adjacent nonneoplastic mucosa specimens. The correlations between YKL-40 expression and clinicopathologic features, as well as activation of PI3K/Akt pathways were addressed. Expression of YKL-40 was significantly higher in gastric cancer tissues than that in adjacent nonneoplastic tissues. Overexpression YKL-40 was found in 28.4% of gastric cancers and was significantly associated with tumor invasion (P = .007) and lymph node metastasis (P = .009). For survival study, overexpression of YKL-40 was significantly associated with worse outcome (P = .001). When known clinical variables were added to a multivariate analysis, TNM stage, tumor size, and overexpression of YKL-40 emerged as independent prognostic factors. Further study indicated that the oncogenic function of YKL-40 might be through the activation of Akt pathway. These results suggest that overexpression of YKL-40 is correlated with the aggressive behavior of tumor cells, which could be used as an independent molecular marker for the predicting poor prognosis of patients with gastric cancer.

[Infiltration length of gastric cancer on giant sections].

BACKGROUND & OBJECTIVE: The resection boundary for gastric cancer is controversial. The study was designed to investigate gastric wall infiltration length of gastric cancer. METHODS: A total of 105 patients with gastric cancer who underwent gastrectomy at Cancer Center of Sun Yat-sen University from Apr. 2002 to Feb. 2004 were eligible. During gastrectomy, gastric wall lengths of 18 patients before traction (L1), after traction (L2), and after isolation (L3) were measured. Longitudinal specimen along the center of gastric cancer was fixed to measure the lengths of proximal and distal margins to the cancer. Giant section was observed under microscope to calculate the true infiltration length in proximal and distal margins according to the principle of the length changing uniformity. RESULTS: In the 18 specimens, L2 was significantly longer than L1 and L3 (P < 0.05); no significant difference was showed between L1 and L3 (P > 0.05). The infiltration length of localized gastric cancer, including early stage cancer, Borrmann I type cancer, and Borrmann II type cancer, was less than 2 cmû that of invasive gastric cancer, including Borrmann III type cancer and Borrmann IV type cancer, was less than 5 cm. CONCLUSION: The resection length for localized gastric cancer is at least 2 cm to tumor margin, and for invasive gastric cancer is at least 5 cm to tumor margin.