Elevated CA19-9 Is Associated With Increased Mortality In A Prospective Cohort Of Hepatocellular Carcinoma Patients.

OBJECTIVES: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. CA19-9 is a glycoprotein that predicts poor prognosis in pancreatic and biliary malignancies. We evaluated it as a prognostic biomarker for patients with HCC. METHODS: We prospectively enrolled 145 patients with HCC, diagnosed using American Association for Study of Liver Diseases criteria, between October 2008 and November 2012. We examined whether baseline serum CA19-9 levels predicted overall survival. We also examined immunostains of hepatic resections and explants of patients with elevated and normal serum CA19-9. RESULTS: In a cohort of predominantly hepatitis C and B patients, CA19-9 ≥100 U/ml was associated with a 2.7-fold increased mortality (hazard ratio (HR): 2.72; 95% confidence interval (CI): 1.52-4.88, P<0.001). It remained a significant predictor (HR: 2.58; 95% CI: 1.41-4.72, P=0.002) in a multivariable model adjusted for Child-Pugh score, alpha-fetoprotein, Barcelona Clinic Liver Cancer stage, and Model for End-Stage Liver Disease. CA19-9 immunohistochemistry performed on a subset of liver resection and explant specimens showed increased CA19-9 immunostaining of non-tumor liver parenchyma in patients with elevated serum CA19-9. It also showed staining of native and reactive bile ducts, and of progenitor-like cells at the periphery of cirrhotic nodules. CONCLUSIONS: Elevated serum CA19-9 ≥100 U/ml is an independent predictor of poor overall survival in this hypothesis-generating study. The unfavorable prognosis seen with elevated serum levels may be related to progenitor-like cells in the non-tumor liver.

Risks of diabetic nephropathy with variation in hemoglobin A1c and fasting plasma glucose.

BACKGROUND: This study examined whether annual variation in glycosylated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), as represented by the coefficient of variation (CV), can predict diabetic nephropathy independently of mean FPG, mean HbA1c, and other risk factors in patients with type 2 diabetes. METHODS: A computerized database of patients with type 2 diabetes aged ≥30 years and free of diabetic nephropathy (n = 3220) who were enrolled in the Diabetes Care Management Program of China Medical University Hospital before 2007 was used in a time-dependent Cox proportional hazards regression model. RESULTS: The incidence rates of diabetic nephropathy were 16.11, 22.95, and 28.86 per 1000 person-years in the first, second, and third tertiles of baseline HbA1c-CV, respectively; the corresponding incidence rates for FPG-CV were 9.46, 21.23, and 37.51 per 1000 person-years, respectively. After multivariate adjustment, the corresponding hazard ratios for the second and third tertiles versus the first tertile of annual HbA1c-CV were 1.18 (95% confidence interval [CI], 0.88-1.58) and 1.58 (95% CI, 1.19-2.11), respectively, and 1.55 (95% CI, 0.99-2.41) and 4.75 (95% CI, 3.22-7.01) for FPG-CV, respectively. The risks of diabetic nephropathy for HbA1c-CV and FPG-CV stratified according to age, gender, renal function, and hypertension status were provided. CONCLUSIONS: Annual FPG and HbA1c variations have a strong association with diabetic nephropathy in patients with type 2 diabetes. Whether intervention for reducing glucose variation should be administered needs to be examined in a future study.

Percentage of body fat assessment using bioelectrical impedance analysis and dual-energy X-ray absorptiometry in a weight loss program for obese or overweight Chinese adults.

The current study aimed to compare the estimates of body fat percentage (%BF) by performing bioelectrical impedance analysis (BIA) and dual energy X-ray absorptiometry (DXA) in a sample of obese or overweight Chinese adults who participated in a weight-loss randomized control trial stratified by gender to determine whether or not BIA is a valid measurement tool. Among 189 adults [73 males, 116 females; age = 41 to 74 years; mean body mass index (BMI) = 27.3 kg/m(2)], assessments of %BF at the baseline and six months from the baseline were conducted by performing BIA and DXA. Bland-Altman analyses and multiple regression analyses were used to assess the relationships between %BFBIA and %BFDXA. Compared with DXA, BIA underestimated %BF [in males: 4.6, -2.4 to 11.7 (mean biases, 95% limit of agreement) at the baseline, 1.4, -7.4 to 10.2 at the endpoint, and 3.2, -4.8 to 11.3 in changes; in females: 5.1, -2.4 to 12.7; 2.2, -6.1 to 10.4; and 3.0, -4.8 to 10.7, respectively]. For males and females, %BFDXA proved to be a significant predictor of the difference between DXA and BIA at the baseline, the endpoint, and in changes when BMI and age were considered (in males: p<0.01 and R (2) = 23.1%, 24.1%, 20.7%, respectively; for females: p<0.001 and R (2) = 40.4%, 48.8%, 25.4%, respectively). The current study suggests that BIA provides a relatively accurate prediction of %BF in individuals with normal weight, overweight, or obesity after the end of weight-loss program, but less accurate prediction of %BF in obese individuals at baseline or weight change during the weight-loss intervention program.

Combined effects of peroxisome proliferator-activated receptor alpha and apolipoprotein E polymorphisms on risk of breast cancer in a Taiwanese population.

BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARA) and apolipoprotein E (APOE) proteins are reported to be correlated with lipid metabolism, cardiovascular disease, and breast cancer. METHODS: We screened APOE and PPARA (S24F and V227A) polymorphisms in 306 breast cancer patients and 300 noncancer controls and determined the relationship between their genetic polymorphisms and breast cancer risk. Interactions with clinical characteristics were also examined. RESULTS: We found that the risk of breast cancer was associated with APOE genotypes (P = 0.014) but not with PPARA S24F or V227A genotypes. The combined effects of F24/APOE genotypes (P = 0.003) on breast cancer risk were more significant than the individual effect of APOE genotypes (P = 0.014). F24/ε4 carriers had a higher tendency to develop breast cancer than F24/ε3 carriers (P = 0.013), and this effect is stronger than with individual ε4 carriers (P = 0.029). In addition, both F24/ε4 and V227/ε4 carriers were significantly enriched in the human epidermal growth factor receptor 2/neu negative status. CONCLUSIONS: These findings suggest that the APOE ε4 genotype plays a major role in the prediction of breast cancer, but the PPARA F24 mutation enhances this outcome. The combined effects of F24/ε4 genotypes are positively associated with risk of breast cancer.

AKT serine/threonine protein kinase modulates bufalin-triggered intrinsic pathway of apoptosis in CAL 27 human oral cancer cells.

Bufalin has been reported to induce apoptosis in a variety of cancers but little is demonstrated in oral squamous cell carcinoma (OSCC) cells. The present study investigated the inhibition of proliferation, cell cycle arrest and apoptotic effects of bufalin in CAL 27 human oral cancer cells. Bufalin inhibited the growth of CAL 27 cells in a concentration-dependent manner and an IC50 value of bufalin was about 125 nM for 24 h treatment using the MTT assay. Moreover, the cell cycle distribution was arrested at the G0/G1 phase in CAL 27 cells after bufalin exposure. Upon bufalin stimulation, the expression of Bcl-2 was significantly decreased while that of cytochrome c, Apaf-1 and AIF was increased compared to the control group by western blot analysis. An increase in the expression of the active form of caspases was found in bufalin-treated cells, and the caspase activities were also elevated. Bufalin-triggered apoptosis was blocked by specific inhibitors of caspase-9 (z-LEHD-fmk) and caspase-3 (z-DEVD-fmk), respectively. In contrast, CAL 27 cells overexpressing constitutively active AKT (CAL 27/CA-AKT) were exposed to bufalin at different concentrations, and cell growth remained unchanged. Bufalin exhibited minimal apoptotic effects on CAL 27/CA-AKT cells. Taken together, bufalin induced G0/G1 phase arrest and provoked the intrinsic apoptotic pathway via AKT activation in CAL 27 cells. Our data suggest that bufalin could be potentially efficacious in the treatment of oral cancer in the future.

Mental disorder as a risk factor for dog bites and post-bite cellulitis.

OBJECTIVES: Patients with mental disorders are at an increased risk for sustaining traumatic injury. No study has evaluated the association between mental disorders and the injury of dog bite. We conducted case-control studies to investigate whether people with mental disorders are at elevated risks of dog bite and post-bite cellulitis. METHODS: Using insurance data of 2000-2007, we compared 4660 patients with dog bites and 18,640 controls without the events for the association with mental disorders and other covariates. Amongst those with dog bites, a nested case-control study was performed to compare 286 patients with post-bite cellulites and rest of 4374 patients for factors associated with the infection. RESULTS: Young children, the older adults, and people with low socioeconomic status were at an elevated risk of sustaining the dog bite. In separate logistic regression models adjusting for socio-demographic variables, the results showed that patients with concomitant psychotic and non-psychotic mental disorders were associated with increased risks of dog bites (adjusted odds ratio [OR]=1.51, 95% confidence interval [CI]: 1.32-1.74) and of post-bite cellulitis (OR=2.13, 95% CI 1.46-3.10). CONCLUSIONS: Individuals with mental disorders are likely at an elevated risk for serious dog bites and post-bite cellulitis.

HER2 codon 655 G-allele is associated with reductions in plasma high-density lipoprotein levels in breast cancer patients treated with tamoxifen.

BACKGROUND: Retrospective studies have revealed that overexpression of the epidermal growth factor receptor ErbB-2 (HER2) reduced the efficacy of tamoxifen therapy, which is associated with an increased risk for cardiovascular events. The aim of this study was to evaluate the effects of the HER2 I655V polymorphism (ATC/isoleucine to GTC/valine) on lipid profiles after tamoxifen treatment. METHODS: Thirty-four women diagnosed with breast cancer were recruited in the study and followed up for 6 months. The presence of the HER2 I655V polymorphism and fasting plasma lipid profiles before and after tamoxifen treatment were determined for each subject for the duration of the study. RESULTS: In response to tamoxifen therapy, we found that plasma total cholesterol (TC, P = 0.041), low-density lipoprotein-cholesterol (LDL-C, P < 0.001), and high-density lipoprotein-cholesterol (HDL-C, P = 0.012) levels decreased significantly in the A-allele (AA genotype) carriers compared with the baseline measurements. Plasma LDL-C (P < 0.001) and HDL-C (P < 0.001) levels decreased significantly, and the TC/HDL-C (P = 0.027) ratio increased significantly in the G-allele (AG/GG genotypes) carriers. According to the repeated-measures analysis, G-allele carriers had a lower ratio of LDL-C/HDL-C than A-allele carriers did (P = 0.016). Notably, G-allele carriers had a greater reduction in HDL-C concentration than A-allele carriers (P = 0.039; G-allele, -12.4 ± 6.8 mg/dL vs A-allele, -5.6 ± 9.5 mg/dL). CONCLUSIONS: This study shows that the HER2 codon 655 G-allele was associated with a larger reduction in plasma HDL-C levels in breast cancer patients under tamoxifen therapy. Therefore, we suggest that the polymorphism of HER2 655 codon should be considered for the prevention of cardiovascular events in breast cancer patients after tamoxifen therapy.

Prospective validation of American Diabetes Association risk tool for predicting pre-diabetes and diabetes in Taiwan-Taichung community health study.

BACKGROUND: A simple diabetes risk tool that does not require laboratory tests would be beneficial in screening individuals at higher risk. Few studies have evaluated the ability of these tools to identify new cases of pre-diabetes. This study aimed to assess the ability of the American Diabetes Association Risk Tool (ADART) to predict the 3-year incidence of pre-diabetes and diabetes in Taiwanese. METHODS: This was a 3-year prospective study of 1021 residents with normoglycemia at baseline, gathered from a random sample of residents aged 40-88 years in a metropolitan city in Taiwan. The areas under the curve (AUCs) of three models were compared: ADART only, ADART plus lifestyle behaviors at baseline, and ADART plus lifestyle behaviors and biomarkers at baseline. The performance of ADART was compared with that of 16 tools that had been reported in the literature. RESULTS: The AUCs and their 95% confidence intervals (CIs) were 0.60 (0.54-0.66) for men and 0.72 (0.66-0.77) for women in model 1; 0.62 (0.56-0.68) for men and 0.74 (0.68-0.80) for women in model 2; and 0.64 (0.58-0.71) for men and 0.75 (0.69-0.80) for women in model 3. The AUCs of these three models were all above 0.7 in women, but not in men. No significant difference in either women or men (p = 0.268 and 0.156, respectively) was observed in the AUC of these three models. Compared to 16 tools published in the literature, ADART had the second largest AUC in both men and women. CONCLUSIONS: ADART is a good screening tool for predicting the three-year incidence of pre-diabetes and diabetes in females of a Taiwanese population. The performance of ADART in men was similar to the results with other tools published in the literature. Its performance was one of the best among the tools reported in the literature.

Reduced health-related quality of life in elders with frailty: a cross-sectional study of community-dwelling elders in Taiwan.

PURPOSE: Exploring the domains and degrees of health-related quality of life (HRQOL) that are affected by the frailty of elders will help clinicians understand the impact of frailty. This association has not been investigated in community-dwelling elders. Therefore, we examined the domains and degree of HRQOL of elders with frailty in the community in Taiwan. METHODS: A total of 933 subjects aged 65 years and over were recruited in 2009 from a metropolitan city in Taiwan. Using an adoption of the Fried criteria, frailty was defined by five components: shrinking, weakness, poor endurance and energy, slowness, and low physical activity level. HRQOL was assessed by the short form 36 (SF-36). The multiple linear regression model was used to test the independent effects of frailty on HRQOL. RESULTS: After multivariate adjustment, elders without frailty reported significantly better health than did the pre-frail and frail elders on all scales, and the pre-frail elders reported better health than did the frail elders for all scales except the scales of role limitation due to physical and emotional problems and the Mental Component Summary (MCS). The significantly negative differences between frail and robust elders ranged from 3.58 points for the MCS to 22.92 points for the physical functioning scale. The magnitude of the effects of frail components was largest for poor endurance and energy, and next was for slowness. The percentages of the variations of these 10 scales explained by all factors in the models ranged from 11.1% (scale of role limitation due to emotional problems) to 49.1% (scale of bodily pain). CONCLUSIONS: Our study demonstrates that the disabilities in physical health inherent in frailty are linked to a reduction in HRQOL. Such an association between clinical measures and a generic measure of the HRQOL may offer clinicians new information to understand frailty and to conceptualize it within the broader context of disability.

Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients.

ErbB2 (HER2/neu) is overexpressed in about 25-30% of breast malignancies, and up-regulation of ErbB2 in breast cancer patients is associated with poor prognosis. It is known that the carboxyl terminus of heat shock cognate 70 interacting protein (CHIP) efficiently down-regulates ErbB2 in vitro. Human tumourous imaginal disc 1 (Tid1, DnaJa3), a co-chaperone of heat shock protein 70 (Hsp70), also suppresses ErbB2 expression in breast cancer cell lines. However, the intracellular interactions among Tid1, CHIP, and ErbB2 remain elusive, and the utilization of Tid1 and CHIP as breast cancer biomarkers has never been proposed. Herein, we analysed the expression and correlations among Tid1, CHIP, and ErbB2 in a total of 183 breast cancer histology sections, including 30 fresh tissue specimens, using immunohistochemistry (IHC) and immunoblotting assay. A computerized image analysis system was used for IHC scoring and determining relative immunoblot intensity. The immunohistochemical expression of Tid1 and CHIP were positively correlated with each other but were both inversely correlated to that of ErbB2. Odds ratio analyses showed that lower expression of Tid1 has a relatively higher risk of unfavourable tumour grade, later pathological stage, larger tumour size, and microscopic features of a more malignant histology including lymphovascular invasion, stromal inflammatory response, and tumour necrosis. Expression of CHIP displayed similar characteristics. Furthermore, expression of Tid1 and/or CHIP increases patients' 10-year overall and disease-free survival rate. Empirically, we also demonstrated that Tid1, CHIP, and ErbB2 interacted with each other through immunofluorescence or co-immunoprecipitation analyses. Functionally, Tid1 and CHIP acted synergistically to degrade ErbB2 in vitro. Conversely, Tid1 cannot compensate for the loss of proteolytic function noted in CHIP mutations for degradation of ErbB2. Overall, our data suggest that Tid1 and CHIP play pivotal roles in affecting the levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival.

Reliability and validity of the Taiwan (Mandarin Chinese) version of the chronic respiratory questionnaire.

PURPOSE: The chronic respiratory disease questionnaire (CRQ) has been validated and proved useful in assessing therapies for pulmonary diseases. We translated the CRQ into a Taiwan (Mandarin Chinese) version and surveyed its validity and reliability. METHODS: The CRQ includes 20 items divided into four domains: dyspnea, fatigue, emotional function, and mastery. We followed a forward-back translation procedure to create the Taiwan version. A cross-sectional survey was conducted among outpatients with chronic obstructive pulmonary disease. Participants underwent tests including the CRQ, the medical outcomes study short form (SF-36), the St. George respiratory questionnaire (SGRQ), lung function tests (LFTs), and a graded exercise test (GET). We used Cronbach's alpha to evaluate the internal consistency of the CRQ, intraclass coefficient for test-retest reliability, and Spearman's correlation for validity. RESULTS: Thirty-six men and 4 women (mean age 67.9 ± 9.9 years) were recruited. Evidence of good internal consistency, test-retest reliability, convergent, discriminant, concurrent, and construct validity of the CRQ was shown. Spearman's correlation showed moderate-to-strong correlation between the CRQ scores and scores of the SGRQ, subscales of the SF-36, and the results of LFTs and GET. CONCLUSIONS: The Taiwan version of the CRQ shows good validity, internal consistency, and test-retest reliability.

Apolipoprotein E4 allele influences the response of plasma triglyceride levels to tamoxifen in breast cancer patients.

BACKGROUND: Apolipoprotein E4 (APOE4) allele is an important risk factor for breast cancer and affects clearance of chylomicron remnants. Tamoxifen therapy increases serum triglyceride levels and sometimes inducing severe hypertriglyceridemia in breast cancer patients. METHODS: Thirty-three women with breast cancer were recruited to examine the APOE polymorphism and fasting plasma lipid profiles before and after tamoxifen treatment for 6 months. RESULTS: We found that plasma lipid profiles changed in accordance with the APOE4 allele after tamoxifen treatment for 6 months. Especially plasma triglyceride levels significantly decreased in the APOE4-positive patients (p=0.025), while there was no change in APOE4-negative patients (p=0.189). The total plasma cholesterol levels were reduced in APOE-4 positive patients after 6-month tamoxifen treatment (p=0.014). The levels of plasma low density lipoprotein cholesterol and high density lipoprotein cholesterol significantly decreased in both APOE4-negative and APOE4-positive patients. CONCLUSIONS: These findings indicate that the effects of tamoxifen on plasma triglyceride levels are modified by APOE polymorphism. Breast cancer patients with APOE4 allele have low plasma triglyceride levels when receiving tamoxifen therapy. Therefore, we suggest that APOE gene polymorphism is a critical validation before tamoxifen treatment in breast cancer patients.

Seroprevalence and sources of Toxoplasma infection among indigenous and immigrant pregnant women in Taiwan.

Investigation on seroprevalence and risk factors of Toxoplasma gondii infections among indigenous and immigrant pregnant women in Mid-Taiwan showed that anti Taxoplasma-specific IgG antibody counts were significantly higher in indigenes (40.6%) than in immigrants (18.2%), with an odds ratio of OR=3.34 (95% CI: 1.93-4.80). The titre of Taxoplasma-specific IgG was also significantly higher in indigenes than in immigrants (P<0.001). Differences of living styles for Toxoplasma infection between the two groups were drinking untreated water (OR=2.34, 95% CI: 1.36-4.02), consumption of raw/undercooked meats (OR=10.11 95% CI: 4.92-20.78), especially raw/undercooked pork (P=0.000), or raw/undercooked viscera (OR=9.16, 95% CI: 2.97-27.94), contact with cats (OR=5.69, 95% CI: 2.83-11.47), or soil (OR=2.55 95% CI: 1.72-3.80). Differences of risk factors for Toxoplasma infection in terms of positive IgG in the two groups were consumption of raw/undercooked meats (P=0.005) especially raw/undercooked pork (P=0.004), and contact with cats (P=0.013) or soil (P=0.028). It is concluded that seroprevalence of Toxoplasma infection is higher in indigenous pregnant women and related to their living styles. To prevent congenital toxoplasmosis, health education seems required.

Hepatoprotective effect of Phyllanthus in Taiwan on acute liver damage induced by carbon tetrachloride.

The effect of oral administration of Phyllanthus methanolic extracts (PME) (i.e. P. acidus, P. emblica, P. myrtifolius, P. multiflorus, P. amarus, P. debilis, P. embergeri, P. hookeri, P. tenellus, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria) or gallic acid (GA) on the progression of acute liver damage induced by CCl(4) in rats was examined by morphological and biochemical methods. P. acidus, P. urinaria L.s. urinaria, GA at a dose of 0.5 g/kg, and P. emblica, P. urinaria L.s. nudicarpus at a dose of 1.0 g/kg attenuated CCl(4)-induced increase in serum glutamate-oxalate-transaminase (GOT). P. acidus, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria, GA at a dose of 0.5 g/kg, and P. emblica, P. amarus, P. hookeri, P. tenellus at a dose of 1.0 g/kg attenuated CCl(4)-induced increase in serum glutamate-pyruvate-transaminase (GPT). Concurrently, P. acidus, P. multiflorus, P. embergeri, P. hookeri, P. tenellus and P. urinaria L.s. urinaria elevated the activity of liver reduced glutathione peroxidase (GSH-Px). Since the protective effects of P. acidus, P. emblica, P. myrtifolius, P. embergeri, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria and GA correlate with a reduction in liver infiltration and focal necrosis observed using histological methods, these data demonstrate that P. acidus and P. urinaria L.s. urinaria are hepatoprotective and antioxidant agents.

Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan.

Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimer's disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (xi(2) = 8.652, p = 0.013). Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197-2.664). In addition, the epsilon4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111-0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE epsilon4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.