Limited sorafenib anticancer effects on primary cultured hepatocellular carcinoma cells with high NANOG expression.

Cancer stem cell is considered as an important cause to exacerbate the prognosis. NANOG and POU5F1 are markers for cancer stem cells. The associations between NANOG and POU5F1 expressions with the sorafenib anticancer effects in primary cultured hepatocellular carcinoma (HCC) cells were investigated. Eight primary cultured HCC parent cell lines and 13 subgroups established by flow cytometric sorting using NANOG and POU5F1 as targets were investigated with clinically achievable sorafenib plasma concentrations (5 and 10 µg/mL). Sorafenib showed obvious downregulation of RAF/MEK/ERK signaling pathways and dose-dependent anti-proliferative effects only on s003 parent cell line, which showed the lowest expression of NANOG among all tested cell lines except one downregulated NANOG with upregulated POU5F1 s020 subgroup. Sorafenib also inhibited proliferation in this s020 subgroup but promoted proliferation in its parent cell line. For the only one downregulated NANOG alone s015 subgroup, sorafenib which had no influence on its parent cell line inhibited proliferation in this subgroup. Only the above three cell lines could demonstrate sorafenib antiproliferative effects. On the contrary, sorafenib promoted proliferation in three (s003, s015, s071) out of four upregulated NANOG alone subgroups. On the other hand, Sorafenib showed diverse influence on proliferation among four upregulated POU5F1 alone subgroups. In conclusion, NANOG rather than POU5F1 expression is a critical marker for the anticancer effects of sorafenib on HCC. The sorafenib anticancer effects on HCC cells with high NANOG expression were limited. Sorafenib should be combined with other drug able to target cancer cells with high NANOG expression.

Association between secondhand smoke and peripheral arterial disease: a meta-analysis of cross-sectional studies.

PURPOSE: The association between secondhand smoke (SHS) and peripheral arterial disease (PAD) was inconsistent and the studies were relatively scarce, hence, we conducted a meta-analysis of the association between SHS and PAD. MATERIALS AND METHODS: We systematically searched three electronic databases (PubMed, EMBASE, and Web of Science), and calculated the pooled prevalence risk ratio (RR) and estimated standard error by random effect model from the meta-analysis. Furthermore, we performed a subgroup meta-analysis according to the location of SHS exposure. RESULTS: We initially identified 502 articles from the electronic database, and 6 articles, cross-sectional data from 4 cross-sectional studies and 2 prospective cohort studies, were included in the meta-analysis. Among these six articles, two studies showed a significant correlation between SHS exposure and PAD, whereas no study showed a negative correlation between SHS exposure and PAD. In the meta-analysis, pooled prevalence showed a significant association between SHS exposure and PAD (RR = 1.23; 95% confidence interval [CI] 1.08-1.41; z = 3.02, p = 0.003). In the subgroup analysis based on location of SHS exposure, the prevalence RR of PAD at home was 1.30 (95% CI 1.14-1.49, Z-3.99, p < 0.0001). The prevalence RR in the subgroup of SHS exposure at work was not significant (RR = 0.89; 95% CI 0.55-1.44; z = 0.48, p = 0.63). CONCLUSION: Exposure to SHS was significantly and positively associated with PAD. Moreover, we found a significant association between exposure to SHS and PAD at home, but the association was not significant at work.

Regorafenib for Taiwanese patients with unresectable hepatocellular carcinoma after sorafenib failure: Impact of alpha-fetoprotein levels.

BACKGROUND AND AIMS: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. METHODS: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. RESULTS: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml. CONCLUSIONS: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response.

Significant amelioration of hepatitis C virus infection in a hyperendemic area: longitudinal evidence from the COMPACT Study in Taiwan.

OBJECTIVES: Hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma worldwide. Tzukuan, located in the southwestern area of Taiwan, is an HCV hyperendemic area (>30%). This study aimed to assess the changing epidemiological characteristics of HCV infection and to evaluate the long-term outcomes after the implementation of public health strategies for two decades. DESIGN: A population-based retrospective cohort study. SETTING: A comprehensive care programme was implemented, namely COMPACT Study, in Tzukuan since 1997. PARTICIPANTS: A total of 10 714 residents participated the screening. OUTCOME MEASURES: The HCV status, demographic and clinical profiles of the participants were recorded and validated annually from 2000 through 2019. RESULTS: The HCV infection prevalence rates were 21.1% (1076/5099) in 2000-2004, 18.8% (239/1269) in 2005-2009, 14.1% (292/2071) in 2010-2014 and 10.3% (234/2275) in 2015-2019 (p for trend test <0.0001). Among them, 1614 underwent repeated tests during the follow-up period. The annual incidence rates were 0.54% in 2005-2009, 0.4% in 2010-2014 and 0.22% in 2015-2019, respectively (p=0.01). In addition to old age, lower education level was a major risk factor for HCV infection across different periods. HCV infection prevalence rate among those illiterates reached 40.9%, followed by 28.5% in those with elementary school level, and <10% in those with high school or higher levels. The major risk factor has shifted from iatrogenic exposure in 2000-2009 to household transmission after 2010. CONCLUSIONS: HCV infection has been decreasing and the epidemiological features are changing in the hyperendemic area by continuing education, prevention and treatment strategies.

Potential of novel colchicine dosage schedule for the palliative treatment of advanced hepatocellular carcinoma.

Previous in vitro and in vivo experiments had demonstrated dose-dependent anti-cancer effects of clinical plasma colchicine concentrations on hepatocellular carcinoma (HCC) cells. This phase IIa trial was to evaluate the potential efficiency and safety of our novel colchicine dosage schedule for the palliative treatment of advanced HCC. The dosage schedule started from oral intake of 1 mg colchicine three times per day for 4 days and discontinuation in the following 3 days (one cycle). The treatment cycle was repeated and the dosage was adjusted ranging from 3 to 1.5 mg/day according to the condition of the participant. The control group was originated from chart review of 86 HCC patients treated by sorafenib for more than 2 months. Fifteen participants signed the inform consent. Two participants were excluded due to screening failure in one and less than four treatment cycles in another. For severe adverse events, the colchicine group demonstrated higher incidence of biliary tract obstruction (p = 0.0184) than the sorafenib group. Comparison grade 1 or 2 adverse events between two groups, the colchicine group had higher incidence of diarrhea (p = 0) and the sorafenib group had higher incidence of palmar-plantar erythrodysesthesia syndrome (p = 0.0045). There was no significant difference in mortality, median survival, and overall survival between two groups (all p > 0.2). In conclusion, our novel colchicine dosage schedule is clinically feasible and has the potential to be applied in the palliative treatment of advanced HCC especially based on the cost-effectiveness consideration.

The prognostic factors between different viral etiologies among advanced hepatocellular carcinoma patients receiving sorafenib treatment.

Sorafenib is currently the first-line therapy for advanced hepatocellular carcinoma (aHCC) patients. However, the outcomes and prognostic factors of sorafenib therapy have not been well investigated. We aimed to investigate the pretreatment factors and outcomes among Taiwanese aHCC patients receiving sorafenib treatment. A total of 347 patients with aHCC and well-compensated liver cirrhosis (Child-Pugh A) status receiving sorafenib were consecutively enrolled from March 2013 through December 2016. Pre-treatment clinical data and viral hepatitis markers were collected and analyzed with their outcomes. The primary endpoint of the study was overall survival. The factors associated with overall survival were also investigated. The median overall survival of all the patients was 238 days (range, 9-1504 days) with a 1-year overall survival of 43.2%. Positive hepatitis B surface antigen and absence of portal vein thrombosis (PVT) were independent factors associated with better overall survival. The median duration of sorafenib therapy was 93.0 days (range, 4-1504 days). After stopping sorafenib, the median survival was 93.0 days (range, 1-1254 days). The 1-year survival after stopping sorafenib was 21.2%. In chronic hepatitis B patients, total bilirubin level was the only factor associated with overall survival. Hepatitis C antibody RNA negativity, tumor size, PVT, and white blood cell count were the independent factors associated with survival among those chronic hepatitis C patients. There were different prognostic factors stratified by viral etiologies in aHCC patients receiving sorafenib. Viral eradication increased survival in chronic hepatitis C patients.

Integrated care for methadone maintenance patients with hepatitis C virus infection.

The majority of patients undergoing methadone maintenance treatment (MMT) are neither examined nor treated for hepatitis C virus (HCV) infection. We aimed to evaluate an integrated referral model in the management of HCV among MMT patients. This retrospective study included 390 HCV-infected MMT patients between April 2015 and May 2017. Patients who tested positive for HCV antibodies were referred to a liver clinic by MMT case managers or psychiatrists. Patients who agreed to receive anti-HCV treatment were treated with pegylated interferon and ribavirin. The rate of patient engagement at a liver clinic increased from 14.1% to 58.2% after integrated care. Multiple logistic regression analysis showed that higher education level (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.01-2.60) and elevated ALT level (OR, 4.30; 95% CI, 2.70-6.85) were independently associated with patients who accepted referral. Active drug use (OR, 0.52; 95% CI, 0.31-0.85) was inversely associated with referral acceptance. Of the 112 patients who met the criteria for anti-HCV therapy, 66 (58.9%) were treated with pegylated interferon and ribavirin. Finally, the rate of treatment completion and sustained virological response (SVR) was 65.2% and 54.5%, respectively, among the 66 patients. Treatment completion (OR, 39.67; 95% CI, 7.80-201.62) was found to be the only independent factor associated with SVR achievement. Although integrated care by psychiatrists and hepatologists significantly increased the rates of engagement and acceptance of antiviral treatment for HCV-infected MMT patients, only a minority of MMT patients achieved successful treatment.

Toxic Metals Increase Serum Tumor Necrosis Factor-α Levels, Modified by Essential Elements and Different Types of Tumor Necrosis Factor-α Promoter Single-nucleotide Polymorphisms.

BACKGROUND: Lead (Pb), cadmium (Cd), and arsenic (As) could cause health issues through oxidative stress that is indicated in the elevated tumor necrosis factor-alpha (TNF-α). However, some of the essential elements-selenium (Se), zinc (Zn), cobalt (Co), and copper (Cu)-are cofactors or structural components of antioxidant enzymes. It is suggested that single-nucleotide polymorphisms (SNPs) in the TNF-α gene have different TNF-α responses. This study aims to evaluate the effect of serum TNF-α levels through the interactions between toxic metals and essential elements and how the interactions between the toxic metals and TNF-α SNPs (-1031 T > C, -863 C > A, -857 C > T, -308 G > A, -238 G > A) influence serum TNF-α levels. METHODS: Blood samples were collected from 455 workers who carried out annual health examinations and multielements determined by inductively coupled plasma mass spectrometry (ICP-MS). TNF-α levels were detected by enzyme-linked immunosorbent assay (ELISA). TNF-α promoter SNPs were analyzed by specific primer probes using real-time polymerase chain reaction (PCR) methods. RESULTS: Increasing blood Pb, Cd, and As levels were associated with elevated TNF-α levels. The interaction between Pb and Cu decreased TNF-α levels and so did the interaction between Cd and Se. In the interaction between Pb and SNPs, individuals with AA/AG (-308 G > A) and AA/AG (-238 G > A) had higher serum TNF-α levels. However, lower TNF-α levels were noted in those individuals with AA/CA (-863 C > A). In the interaction between As and SNPs, workers with AA/AG (-238 G > A) had synergic effect with As and induced higher serum TNF-α levels. CONCLUSIONS: Blood Cu and Se were antagonists of toxic metals (Pb, As, and Cd) through lower serum TNF-α levels. Variant types of TNF-α SNPs (-308 G > A, -238 G > A) and wild type of -863 CC would be more susceptible to toxic metals.

Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naïve hepatitis C patients with a real-world cohort and database.

BACKGROUND: For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. METHODS: A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. RESULTS: The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naïve G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naïve G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. CONCLUSION: We investigated the real-world cost effectiveness data for different subgroups of treatment-naïve HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions regarding future therapeutic strategies comprising costly direct-acting antivirals.

n-Hexane intoxication in a Chinese medicine pharmaceutical plant: a case report.

BACKGROUND: n-Hexane is a well-known neurotoxicant. Polyneuropathy due to occupational n-hexane exposure has been reported worldwide, however, our case is the first report in the Chinese herb industry. CASE PRESENTATION: A 25-year-old Asian man experienced progressive weakness and numbness in his hands and feet after working as an operator in a Chinese medicine pharmaceutical plant for the manufacture of Chinese herbal pain relief patches for 10 months. Electrophysiological studies indicated a reduction in nerve conduction velocity, prolongation of distal latencies, mildly positive sharp waves, and reduced recruitment with polyphasic potentials, particularly at distal sites. Demyelination with axonal degeneration caused by occupational n-hexane exposure was strongly suspected. Through investigation of our patient's workplace, the ambient n-hexane concentration in air was found to considerably exceed the permissible exposure limit/time-weighted average for n-hexane in Taiwan. His symptoms were gradually relieved after 4 months of cessation of exposure to n-hexane. He was then confirmed as a case of occupational n-hexane intoxication. Further effective control measures should be implemented as soon as possible to prevent exposure of workers to n-hexane. CONCLUSIONS: Despite a typical clinical presentation, his exposure at workplace was appropriately investigated. Chemical exposure in Chinese medicine pharmaceutical plants could be an emerging issue that may affect workers' health. The lack of knowledge and management of solvents could endanger the health of workers. This case has profound educational implications for occupational health and is worthy of further follow-up for improving hazards control.

Perception of hearing impairment and the willingness to use hearing aids in an elderly population in southern Taiwan: A community-based study.

OBJECTIVES: To estimate the prevalence and severity of hearing impairment (HI), the self-perception of HI, and the willingness to use a hearing aid (HA) in the elderly population in southern Taiwan. DESIGN: This community-based study was performed in a metropolitan hospital. A questionnaire about the perception of HI and the willingness to use a HA was used. The severity of HI in speech-frequency pure-tone average (PTA) was evaluated. The associations between sex, age, severity of HI, self-perception of HI, and the willingness to use a HA were analysed. STUDY SAMPLE: A total of 599 volunteers were recruited from the health management center; 324 (54.1%) males and 275 (45.9%) females, who were 65 years of age or older. RESULTS: The prevalence of HI >25 dBHL in the elderly was 78%. The predicted levels for elderly persons to perceive HI and hearing difficulties were 34.38 dBHL and 54.38 dBHL, respectively. Males and younger participants were more willing to use HA. The primary reasons for refusing HA use were discomfort (25.1%) and a self-perception that the HA was unnecessary (19.7%). CONCLUSIONS: The prevalence of HI was high among the elderly population in southern Taiwan. Age and sex were the determinants of HA use.