Pin Wen Lin

Prognostic Significance of Co-expression of RON and MET Receptors in Node-Negative Breast Cancer Patients

Purpose: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration, cell dissociation, and matrix invasion. Cross-linking experiments show that RON and MET form a noncovalent complex on the cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression patterns in node-negative breast cancer. Experimental Design: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T1-2N0M0 breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after at least a 10-year follow-up. Results: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET. In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON−/MET+ tumors resulted in a large risk increase for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON−/MET− tumors, was only 11.8% in patients with RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON−/MET+ and RON+/MET− tumors. Conclusions: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.

Expression of S100A4 and Met: Potential Predictors for Metastasis and Survival in Early-Stage Breast Cancer

Background: To formulate individually tailored therapy for patients with early-stage breast cancer, it is necessary to identify biomarkers for predicting metastasis and survival. Methods: A homogeneous cohort of 92 T1-2N0M0 breast carcinoma patients with a long-term follow-up were divided into two groups: the metastasis group (n = 41) and the disease-free group (n = 51). We evaluated the ability of risk discrimination of six biomarkers, including S100A4, Met, bcl-2, p53, survivin, and HER-2/neu, in early-stage breast cancer. Results: In multiple logistic regression analysis, only S100A4 expression (odds ratio = 5.37, p = 0.008) and Met expression (odds ratio = 6.91, p = 0.002) were independent predictors of distant relapse. Multivariate Cox models showed S100A4 and Met expressions were associated with 10-year disease-free survival (DFS) (risk ratio 3.2 and 4.0, respectively); however, tumor size and histological grade were not significant predictors. The 10-year DFS of T1-2N0M0 patients was 55.4%. T1-2N0M0 patients with S100A4-positive tumors had a significantly worse 10-year DFS than those with S100A4-negative tumors (29.0 vs. 68.9 %, p = 0.001). The 10-year DFS in T1-2N0M0 patients with Met-negative tumors was 82.4 vs. 39.7% if Met expression was positive (p = 0.0002). S100A4, but not Met, was still a significant predictor of 10-year DFS in T1N0M0 breast carcinoma patients (p = 0.02). For the T2N0M0 subgroup, both S100A4 and Met were significantly correlated with survival. The 10-year DFS of T2N0M0 patients with S100A4-negative and Met-negative tumors was 92.3%; in those with S100A4-positive and Met-positive tumors, however, it was only 11.8%. Conclusions: S100A4 expression is an indicator of a poor prognosis for T1N0M0 breast cancer. In addition, the combination of S100A4 and Met expression gives the best risk group discrimination in the T2N0M0 subgroup. S100A4 expression appears to be an earlier step in the metastatic progression compared to Met expression in early-stage breast carcinoma.

Evaluation of predictive value of CLIP, Okuda, TNM and JIS staging systems for hepatocellular carcinoma patients undergoing surgery.

Background:  An accurate staging system is required to assess hepatocellular carcinoma (HCC) patients in order to benefit from hepatic resection before surgery. Cancer of the Liver Italian Program (CLIP) score was considered to be better than the Okuda staging system to predict survival. Japan Integrated Staging Score (JIS score) includes tumor, nodes, metastases (TNM) stage and Child–Pugh grade as a new staging system for HCC. The purpose of the present paper was to compare the CLIP, Okuda, TNM and JIS staging systems for HCC patients undergoing surgery.

Role of Somatostatin in the Prevention of Pancreatic Stump-related Morbidity following Elective Pancreaticoduodenectomy in High-risk Patients and Elimination of Surgeon-related Factors: Prospective, Randomized, Controlled Trial

A prospective, randomized, controlled trial was performed to determine the efficacy of somatostatin in the prevention of pancreatic stump-related complications with elimination of surgeon-related factors in high-risk patients undergoing panceaticoduodenectomy. From August 1997 to December 2000, 54 patients, 28 men and 26 women, with age ranged from 32 to 89 years, were randomly assigned to somatostatin group (n = 27) or placebo group (n = 27). Ninety-four percent of the patients had pancreatic and periampullary lesions; 6% had secondary lesion involving the duodenum such as local recurrent colon carcinoma and renal cell carcinoma. These patients received either standard pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy. An experienced surgeon performed all operations in same fashion to minimize the surgical factor. A transanastomotic tube was inserted into the pancreatic duct for diversion of pancreatic juice in the pancreaticojejunostomy for a 3-weeks period postoperatively. Intravenous infusion of somatostatin was given at a dose of 250μg/hr in the somastotatin group and normal saline was given to the control group for 7 days postoperatively. There was one perioperative death in each group, resulting in a 3.7% mortality rate. In the somastotatin group, as compared to the placebo group, the incidence of overall morbidity and pancreatic stump related complications were significantly lower with a mean decrease of 50% pancreatic juice output and a slightly shorter duration of hospital stays. In conclusion, after excluding surgeon related factor, prophylactic use of somatostatin reduces the incidence and severity of pancreatic stump related complications in high-risk patients having pancreaticoduodenectomy via decreased secretion of pancreatic exocrine.

Predictors for Patterns of Failure after Pancreaticoduodenectomy in Ampullary Cancer

BackgroundAmpullary cancer has the best prognosis in periampullary malignancy but unpredicted early recurrence after resection is frequent. The current study tried to find the predictors for recurrence to be used as determinative for postoperative adjuvant therapy.MethodsInformation was collected from patients who underwent pancreaticoduodenectomy with regional lymphadenectomy for ampullary cancer in high-volume hospitals between January 1989 and April 2005. Recurrence patterns and survival rates were calculated and predictors were identified.ResultsA total of 135 eligible patients were included. The 30-day operative mortality was 3%. Median followup for relapse-free patients was 52 months. Disease recurred in 57 (42%) patients, including 31 liver metastases, 26 locoregional recurrences, 9 peritoneal carcinomatoses, 7 bone metastases, and 6 other sites. Pancreatic invasion (P = 0.04) and tumor size (P = 0.05) were the predictors for locoregional recurrence, while lymph node metastasis was the sole predictor for liver metastasis (P = 0.01). The 5-year disease-specific survival rate was 45.7%; 77.7% for stage I, 28.5% for stage II, and 16.5% for stage III; and 63.7% for node-negative versus 19.1% for node-positive patients. Pancreatic invasion and lymph node involvement were both predictors for survival of patients with ampullary cancer.ConclusionPancreaticoduodenectomy with regional lymphadenectomy is adequate for early-stage ampullary cancer but a dismal outcome can be predicted in patients with lymph node metastasis and pancreatic invasion. Lymph node metastasis and pancreatic invasion can be used to guide individualized, risk-oriented adjuvant therapy.

Identification of a pre-S2 mutant in hepatocytes expressing a novel marginal pattern of surface antigen in advanced diseases of chronic hepatitis B virus infection

Background and Aims : The expression of hepatitis B viral (HBV) antigens in liver tissue reflects the replicative status of chronic HBV infection. We have previously recognized a novel marginal pattern of hepatitis B surface antigen (HBsAg) in hepatocytes, which usually clusters in groups and emerges at the late non‐replicative phase. This study was designed to investigate whether the marginal‐type HBsAg represented the gene product of a specific HBV‐surface mutant.

Incisional Hernia after Laparotomy: Prospective Randomized Comparison between Early-absorbable and Late-absorbable Suture Materials

Abstract. Incisional hernia is a serious postoperative complication of laparotomy. Selecting an appropriate suture material may lessen such morbidity. This study undertook a prospective, randomized comparison of early-absorbable polyglactin 910 suture versus late-absorbable polydioxanone loop suture for fascial closure after abdominal surgery. A series of 340 consecutive patients undergoing elective laparotomy were randomized to have fascial closure with either polyglactin 910 suture or polydioxanone loop suture between October 1993 and August 1996. A 2-year follow-up revealed that 23 patients had died, and the overall mortality rate was 6.8% (23/340). Ten (10/340, 2.9%) patients, including seven with polyglactin 910 suture and three with polydioxanone loop suture, developed incisional hernias. The early postoperative evaluation revealed an incidence of wound infection of 4.1% (14/340). The development of incisional hernia was not secondary to postoperative wound infection in this study. Among these 340 patients, 192 had malignant diseases and 148 had nonmalignant ones. Fascial closure with polyglactin 910 suture was associated with more incisional hernias than that with polydioxanone loop suture, with marginal significance for patients in the malignant group (4.7% versus 0%, p= 0.07) but not in the nonmalignant group (2.6% versus 4.2%, p= 0.67). In conclusion, abdominal closure with a late-absorbable polydioxanone loop suture may be beneficial to patients with a malignant disease for preventing incisional hernia.

Estrogen receptor-α polymorphism in a Taiwanese clinical breast cancer population: a case–control study

IntroductionReceptor-mediated estrogen activation participates in the development and progression of breast cancer. Estrogen receptor (ER)-α polymorphism has been found to be associated with breast cancer and clinical features of the disease in Caucasians. Epidemiologic studies have revealed that age–incidence patterns of breast cancer in Asians differ from those in Caucasians. Genomic data for ER-α in either population is therefore of value in the clinical setting for that ethnic group.MethodsA case–control study was conducted to establish a database of ER-α polymorphisms in a Taiwanese population in order to compare Western and Taiwanese (Asian) distributions and to evaluate ER-α polymorphism as an indicator of clinical outcome. The ER-α gene was scanned in a Taiwanese clinical breast cancer group (189 patients) and in healthy individuals (177 healthy control individuals). PCR single-strand conformation polymorphism technology was employed and real-time PCR melting curve analysis was performed.ResultsThree sites of silent single nucleotide polymorphism (SNPs) were found, as reported previously in Western studies, but at significantly different frequencies. Among the three SNPs, the frequency of allele 1 (TCT → TCC) in codon 10 was significantly lower in breast cancer patients (32.0%) than in control individuals (40.4%; P = 0.018). We found that allele 1 (ACG → ACA) in codon 594 was less common in breast cancer patients with a family history of breast cancer (5.9%) than in those without such a history (19.6%; P = 0.049). Individually, both allele 1 in codon 325 (CCC → CCG) and allele 1 in codon 594 exhibited a reverse association with the occurrence of lymph node metastasis. Furthermore, incorporation of both SNP markers further increased predictive accuracy.ConclusionsOur data suggest that ER-α polymorphisms are correlated with various aspects of breast cancer in Taiwan. ER-α genotype, as determined during presurgical evaluation, might represent a surrogate marker for predicting breast cancer lymph node metastasis.

Hepatitis B Virus X Protein Upregulates mTOR Signaling through IKKβ to Increase Cell Proliferation and VEGF Production in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), a major cause of cancer-related death in Southeast Asia, is frequently associated with hepatitis B virus (HBV) infection. HBV X protein (HBx), encoded by a viral non-structural gene, is a multifunctional regulator in HBV-associated tumor development. We investigated novel signaling pathways underlying HBx-induced liver tumorigenesis and found that the signaling pathway involving IκB kinase β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1), was upregulated when HBx was overexpressed in hepatoma cells. HBx-induced S6K1 activation was reversed by IKKβ inhibitor Bay 11-7082 or silencing IKKβ expression using siRNA. HBx upregulated cell proliferation and vascular endothelial growth factor (VEGF) production, and these HBx-upregulated phenotypes were abolished by treatment with IKKβ inhibitor Bay 11-7082 or mTOR inhibitor rapamycin. The association of HBx-modulated IKKβ/mTOR/S6K1 signaling with liver tumorigenesis was verified in a HBx transgenic mouse model in which pIKKβ, pS6K1, and VEGF expression was found to be higher in cancerous than non-cancerous liver tissues. Furthermore, we also found that pIKKβ levels were strongly correlated with pTSC1 and pS6K1 levels in HBV-associated hepatoma tissue specimens taken from 95 patients, and that higher pIKKβ, pTSC1, and pS6K1 levels were correlated with a poor prognosis in these patients. Taken together, our findings demonstrate that HBx deregulates TSC1/mTOR signaling through IKKβ, which is crucially linked to HBV-associated HCC development.

A clustered ground‐glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery

The recurrence of hepatocellular carcinoma (HCC) after hepatectomy is a serious event. It has been demonstrated that different ground‐glass hepatocyte (GGH) patterns harbor specific hepatitis B virus (HBV) pre‐S deletion mutants and represent preneoplastic lesions in chronic HBV infection. In the current study, the authors investigated whether a specific GGH pattern in nontumorous liver tissues was associated with the recurrence of HBV‐related HCC after surgery.