The epidemiology, treatment patterns, healthcare utilizations and costs of Acute Myeloid Leukaemia (AML) in Taiwan.

BACKGROUNDS: An increasing incidence of Acute Myeloid Leukaemia (AML) has been reported in several Western countries. However, the epidemiology of AML in Asia is very limited. According to the National Comprehensive Cancer Network (NCCN) guideline of AML, a range of conventional therapy options is available to AML patients. Nevertheless, different treatment strategies may result in diverse healthcare utilization and costs. Understanding the treatment patterns, healthcare utilization and costs of AML would thus be essential for clinicians and policymakers to optimize the treatment strategies of AML. OBJECTIVES: The objective of this study was to investigate the incidence, treatment patterns, healthcare utilization and costs of AML in Taiwan using a nationwide population database. METHODS: We retrospectively identified AML patients diagnosed from 2006 to 2015 from the Taiwan Cancer Registry Database (TCRD) and estimated the epidemiology of AML in Taiwan. The TCRD was linked to National Health Insurance Research Database (NHIRD) to collect the treatment patterns and health care utilization. Patients diagnosed with AML from 2011 to 2015 were further identified to analyze treatment patterns, healthcare utilization and costs. RESULTS: The crude annual incidence of AML increased from 2.78 to 3.21 cases per 100,000 individuals from 2006 to 2015. However, the age-standardized rate (ASRs) of AML slightly declined from 2.47 to 2.41 cases per 100,000 individuals in the same period. Among 2,179 AML patients who received induction therapy (median age: 56 years), most of them (n = 1744; 80.04%) received standard-dose cytarabine (SDAC) regimen. The remaining 162 patients received high dose cytarabine (HDAC) and 273 patients received non-standard dose cytarabine (N-SDAC) regimen as the induction therapy. The median medical costs in our study for patients treated with chemotherapy alone was $42,271 for HDAC, $36,199 for SDAC and $36,250 for N-SDAC. For those who received hematopoietic stem cell transplantation (HSCT) after induction therapy, their median medical costs were $78,876 for HDAC, $78,593 for SDAC and $79,776 for N-SDAC. CONCLUSIONS: This study is the first population-based study conducted in Asia to provide updated and comprehensive information on epidemiology, treatment patterns and healthcare resource utilization and costs of AML.

Energy Achievement Rate Is an Independent Factor Associated with Intensive Care Unit Mortality in High-Nutritional-Risk Patients with Acute Respiratory Distress Syndrome Requiring Prolonged Prone Positioning Therapy.

Early enteral nutrition (EN) and a nutrition target >60% are recommended for patients in the intensive care unit (ICU), even for those with acute respiratory distress syndrome (ARDS). Prolonged prone positioning (PP) therapy (>48 h) is the rescue therapy of ARDS, but it may worsen the feeding status because it requires the heavy sedation and total paralysis of patients. Our previous studies demonstrated that energy achievement rate (EAR) >65% was a good prognostic factor in ICU. However, its impact on the mortality of patients with ARDS requiring prolonged PP therapy remains unclear. We retrospectively analyzed 79 patients with high nutritional risk (modified nutrition risk in the critically ill; mNUTRIC score ≥5); and identified factors associated with ICU mortality by using a Cox regression model. Through univariate analysis, mNUTRIC score, comorbid with malignancy, actual energy intake, and EAR (%) were associated with ICU mortality. By multivariate analysis, EAR (%) was a strong predictive factor of ICU mortality (HR: 0.19, 95% CI: 0.07-0.56). EAR >65% was associated with lower 14-day, 28-day, and ICU mortality after adjustment for confounding factors. We suggest early EN and increase EAR >65% may benefit patients with ARDS who required prolonged PP therapy.

Caloric Intake with High Ratio of Enteral Nutrition Associated with Lower Hospital Mortality for Patients with Acute Respiratory Distress Syndrome Using Prone Position Therapy.

Positioning patients in the prone position leads to reduced hospital mortality rates for those with severe acute respiratory distress syndrome (ARDS). What constitutes the optimal feeding strategy for prone patients with ARDS is controversial. We conducted a retrospective study that enrolled 110 prone patients with ARDS in two medical intensive care units (ICUs) from September 2015 to November 2018. Inclusion criteria were as follows: age ≥20 years, diagnosis of respiratory failure requiring mechanical ventilation, diagnosis of ARDS within 72 h of ICU admission, placement in a prone position within the first 7 days of ICU admission, and ICU stay of more than 7 days. Exclusion criteria were as follows: nil per os orders because of gastrointestinal bleeding or hemodynamic instability, and ventilator dependency because of chronic respiratory failure. The consecutive daily enteral nutrition(EN)/EN + parenteral nutrition(PN) ratio could predict hospital mortality rates within the first 7 days of admission when using generalized estimating equations (p = 0.013). A higher average EN/EN + PN ratio within the first 7 days predicted (hazard ratio: 0.97, confidence interval: 0.96-0.99) lower hospital mortality rates. To reduce hospital mortality rates, caloric intake with a higher EN ratio may be considered for patients in prone positions with ARDS.

Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease.

Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.

Effect of Chinese Herbal Medicine Therapy on Overall and Cancer Related Mortality in Patients With Advanced Nasopharyngeal Carcinoma in Taiwan.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007-2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676-0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53-0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Inflammatory bowel disease and its treatment in 2018: Global and Taiwanese status updates.

The global incidence and prevalence of inflammatory bowel disease (IBD) has increased over the last 2-4 decades, likely because of the adoption of a more "western" lifestyle as well as improved detection and awareness, and Taiwan is no exception. To characterize the increasing burden of IBD, we conducted a comprehensive review of IBD in the existing literature. The following parameters were reviewed: background knowledge and current standard care for IBD, including natural history, epidemiology, pathogenesis, diagnosis, monitoring, and treatment. In addition, new imaging modalities and treatment options such as combined positron emission tomography and magnetic resonance enterography, new biologic agents, small-molecule therapy, biosimilar therapeutics, mesenchymal stem cell transplantation, and fecal microbiota transplantation, all of which have been introduced for IBD management, were reviewed. We also used the hospital-based as well as population-based Taiwan National Health Insurance Research Database to assess Taiwan-specific trends for comparison with global trends.

Conventional treatment integrated with Chinese herbal medicine improves the survival rate of patients with advanced non-small cell lung cancer.

OBJECTIVES: The main objective of this study was to assess whether treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with Chinese herbal medicine (CHM), can improve the five-year survival rate in patients suffering from advanced non-small cell lung cancer (NSCLC), compared to patients treated by EGFR-TKIs alone. INTERVENTIONS AND MAIN OUTCOME MEASURES: The study is based on information in the sub-dataset of the National Health Insurance Research Database (NHIRD) from years 2000 to 2010, during which time a total of 14,244 patients were diagnosed with NSCLC in Taiwan. After selection by exclusion criteria and matching process, 2,616 NSCLC patients were included in the study. Statistical analysis was utilized to evaluate the differences in characteristic distribution, and to compare the survival rates between the CHM cohort and non-CHM cohort. RESULTS: Patients with advanced NSCLC using CHM as an adjunct therapy exhibited a significantly improved survival rate [hazard ration (HR) = 0.8; 95% confidence interval (CI): 0.73-0.87, p value<0.001], compared with non-CHM users. Based on a survival analysis by Kaplan-Meier method, the 5-year survival rate of CHM users was 4.9% higher, with the most notable difference being an elevated 2-year survival rate of up to 12.75%. In addition to the survival rate analysis, we provide the ten most used single herbs and herbal formulas prescribed for patients with advanced NSCLC. CONCLUSIONS: This nationwide retrospective cohort study provides evidence supporting CHM as an effective adjunctive therapy to ameliorate the side effects of target therapy and prolong the five-year survival rate of patients with advanced NSCLC.

Visualisation of the unmet treatment need of osteoporotic fracture in Taiwan: A nationwide cohort study.

AIMS: Recent clinical guidelines have suggested that patients experience an osteoporotic fracture should initiate anti-osteoporosis medications (AOMs). However, whether clinical guidelines translate well in "real-world" practices remain questioned. This study aimed to evaluate the "real-world" prescription pattern of AOMs and visualise the unmet treatment needs in different geographical areas in Taiwan. METHODS: Using Taiwan's National Health Insurance Research Database, we identified patients diagnosed with a hip or vertebral fracture between 2009 and 2012. The treatment rate was defined as the proportion of patients receiving AOMs within 1 year after their index fracture. The qualitative geographical information systems approach was adopted to visualise the treatment needs of postfracture patients in different geographical areas. RESULTS: Our study included 276,492 patients diagnosed with a hip or vertebral fracture between 2009 and 2012. The proportion of patients who received AOMs within 1 year after their index fracture increased with age and differed with fracture types and sex. For patients with hip fractures, the treatment rate ranged from 3.43% to 20.88% for female patients and from 0.69% to 10.04% for male patients in different age groups. For patients with vertebral fractures, the treatment rate ranged from 3.23% to 37.08% for female patients and from 1.85% to 23.05% for male patients. Cities in the mid-northern and southern areas of Taiwan had the highest unmet treatment need, with a treatment rate of less than 15%. CONCLUSION: The treatment rate of osteoporotic fractures with AOMs was diverse and suboptimal in Taiwan, especially among male patients. This study used a visualisation technique to display information about the treatment status in different geographical areas and help policymakers allocate resource appropriately.

Epidemiology and long-term disease burden of herpes zoster and postherpetic neuralgia in Taiwan: a population-based, propensity score-matched cohort study.

BACKGROUND: The objectives of this study were to characterize the burden of herpes zoster, as well as the longitudinal and incremental changes of healthcare service utilization among individuals with herpes zoster and postherpetic neuralgia (PHN) compared to those without. METHODS: Using the National Health Insurance Research Database (NHIRD), we established a herpes zoster cohort of people diagnosed with herpes zoster between 2004 and 2008 as study cases. Another subset of the NHIRD, which was randomly selected from all elderly beneficiaries between 2004 and 2008 served as a non-herpes-zoster elderly control pool. Each case was then assigned one matched control according to age, gender, index date and propensity score. PHN cases were defined as those with persisting pain for more than 90 days after the onset of herpes zoster. RESULTS: Between 2004 and 2008, about 0.6 million patients were newly diagnosed with herpes zoster. The incidence increased with age, and most cases were identified during the summer period. Herpes zoster cases were found to have higher consumption of all types of healthcare services in the first year after the index date. Such increases were particularly obvious for patients with PHN, who showed incremental increases on average of 16.3 outpatient visits, 0.4 emergency room visits and 0.24 inpatient admissions per year. CONCLUSIONS: The incidence of herpes zoster increased with age and changed according to the seasons. Patients with herpes zoster were associated with higher healthcare utilization and this increase in healthcare utilization was most obvious for herpes zoster patients with PHN.

[Effect of litchi seed aqueous extracts on learning and memory obstacles induced by D-galactose in mice and its mechanism].

OBJECTIVE: To investigate the improving effect of Litchi Seed Aqueous Extracts on learning and memory obstacles model and its mechanism. METHODS: The learning and memory obstacles model was incluced by subcutoneous injection of D-galactose (500 mg/kg) for 8 weeks. The model group and treatment groups were given huperzine A (0.4 mg/kg) and Litchi Seed Aqueous Extracts (15,60 g/kg) respectively for 4 weeks by ig at the 5th week. After huperzine A and Litchi Seed Aqueous Extracts treatment for 4 weeks, water maze test was used to determine the ability of mice's spatial learning and memory. The contents of advanced glycation end products (AGEs) in serum, the content of nitric oxide (NO) and acetylcholine (Ach), the activity of nitric oxide synthase (NOS) and acetylcholinesterase (AchE) in the brain tissue were detected. RESULTS: Litchi Seed Aqueous Extracts significantly ameliorated the learning and memory ability in mice, decreased the level of AGEs in serum, and reduced the content of NO and activity of NOS in brain tissues. No significantly influence was observed for the Ach and Ach-E in brain tissues. CONCLUSION: Litchi Seed Aqueous Extracts possesses improving the learning and memory effects on the model mice induced by D-galactose, which may be related to inhibiting too much AGEs and NO formation and reducing damage in the brain cells.

Rapid screening of lignans from Phyllanthus myrtifolius and stilbenoids from Syagrus romanzoffiana by HPLC-SPE-NMR.

INTRODUCTION: Application of on-line solid-phase extraction (SPE) as an interface between HPLC and NMR has gained great improvement in solving sensitivity problems and signal interferences by the eluents. OBJECTIVE: Rapid analysis and characterisation by HPLC-SPE-NMR and LC/MS of the arylnaphthalene-type lignans present in Phyllanthus myrtifolius and the minor stilbenoids present in the polyphenol-rich fraction from the ethanol extract of the seeds of Syagrus romanzoffiana. METHODOLOGY: Pretreatment of fractions by liquid-liquid partitioning, followed by Sephadex LH-20 fractionation, was found very useful to facilitate the focusing and analysis of the polyphenolic fraction. HPLC-DAD-SPE-NMR (400 MHz and 600 MHz) analysis was carried out using an Agilent 1100 liquid chromatography, followed by a Prospekt 2 automated solid-phase extraction unit, containing 96 HySphere-Resin GP cartridges (10 × 2 mm, 10-12 µm), which was connected to a 120 or 60 µL LC probe. RESULTS: Seven arylnaphthalene-type lignans from the chloroform-soluble fraction of P. myrtifolius and nine stilbenoids from a polyphenol-rich butanol-soluble fraction of the seeds of S. romanzoffiana were characterised. CONCLUSIONS: HPLC-SPE-NMR associated with HR-ESI/MS, which consumed only analytical amounts of partially purified mixtures, was demonstrated to be a good tool for rapid screening of both known and new natural products.

Ellagic Acid, the Active Compound of Phyllanthus urinaria, Exerts In Vivo Anti-Angiogenic Effect and Inhibits MMP-2 Activity.

This study aimed to assess the potential anti-angiogenic mechanism of Phyllanthus urinaria (P. urinaria) and characterize the major compound in P. urinaria that exerts anti-angiogenic effect. The water extract of P. urinaria and Ellagic Acid were used to evaluate the anti-angiogenic effect in chorioallantoic membrane (CAM) in chicken embryo and human vascular endothelial cells (HUVECs). The matrix metalloproteinase-2 (MMP-2) activity was determined by gelatin zymography. The mRNA expressions of MMP-2, MMP-14 and tissue inhibitor of metalloproteinase-2 (TIMP-2) were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Level of MMP-2 proteins in conditioned medium or cytosol was determined by western blot analysis. We confirmed that P. urinaria's in vivo anti-angiogenic effect was associated with a reduction in MMP-2 activity. Ellagic acid, one of the major polyphenolic components as identified in P. urinaria by high performance liquid chromatography mass spectrometry (HPLC/MS), exhibited the same anti-angiogenic effect in vivo. Both P. urinaria and Ellagic Acid inhibited MMP-2 activity in HUVECs with unchanged mRNA level. The mRNA expression levels of MMP-14 and TIMP-2 were not altered either. Results from comparing the change of MMP-2 protein levels in conditioned medium and cytosol of HUVECs after the P. urinaria or Ellagic Acid treatment revealed an inhibitory effect on the secretion of MMP-2 protein. This study concluded that Ellagic Acid is the active compound in P. urinaria to exhibit anti-angiogenic activity and to inhibit the secretion of MMP-2 protein from HUVECs.

[Effect of phosphorus on the production of microcystin].

Effect of phosphorus on the production of microcystin was researched. The effects of soluble reactive phosphorus (SRP) on the growth of cells and on the production of Microcystin were studied. In addition, the efficiency of four different phosphorus compounds was researched. The results showed that microcystin increased with the increase of SRP, and c(TP) = 0.55 mg x L(-1) was the best growth concentration. When c(TP) < or = 0.55 mg x L(-1), the microcystin production increased with the increase of phosphorus concentration and was the lowest without phosphorus. Moreover, when c(TP) > 0.55 mg x L(-1), the microcystin was restrained by the content of phosphorus. At the same time, the effects of three inorganic substance of different phosphorus forms (K3PO4, K2HPO4, and KH2PO4) were no significant difference, but their effects on the production of microcystis were larger than organic phosphorus of sodium beta-glycerophosphate (GP).

Wogonin, an active compound in Scutellaria baicalensis, induces apoptosis and reduces telomerase activity in the HL-60 leukemia cells.

Crude extract of Scutellaria baicalensis (S. baicalensis) has cytotoxic effect on human myelogenous leukemia cells (HL-60). We invesigated which compound from the crude extract is responsible for the cytotoxic effect on HL-60 cells. We identified 29 compounds from the crude extract using high performance liquid chromatography mass spectrometry (HPLC/MS). Two of the compounds, baicalin and wogonoside, are converted to baicalein and wogonin, respectively, after treatment with beta-glucuronidase. We observed a dose-dependent reduction in cell viability when cells with either wogonin or aqueous extract of S. baicalensis. Several of the apoptotic features including deoxyribonucleic acid (DNA) fragmentation and increased caspase-3 activity were found in cells treated with wogonin and aqueous extract. The changes were associated with down-regulation of Bcl-2, and not Bax. Furthermore, treatment of HL-60 cells with wogonin or S. baicalensis led to the inhibition of human telomerase reverse transcriptase (hTERT), human telomerase-associated protein 1 (hTP1) and c-myc messenger ribonucleic acid (m-RNA) expression. Wogonin and S. baicaleisis down-regulated the telomerase activity. Our findings suggest that wogonin may be the major compound in S. baicalensis responsible for HL-60 growth inhibition in vitro. The inhibition of HL-60 cell growth is mediated partly through the induction of Bax/Bcl-2 apoptosis and by telomerase inhibition through suppression of c-myc, which is a promoter of hTERT.

Phyllanthus urinaria increases apoptosis and reduces telomerase activity in human nasopharyngeal carcinoma cells.

BACKGROUND: This study was designed to obtain the chemical fingerprint and to investigate the effect of Phyllanthus urinaria on telomerase activity and apoptotic pathways in the human nasopharyngeal carcinoma cell line (NPC-BM1). MATERIALS AND METHODS: The polyphenol compounds in P. urinaria were investigated by HPLC/MS. Cell viability with the treatment of P. urinaria, gallic acid, ellagic acid, quercetin and cisplatin was detected by MTT assay. TUNEL assay, DNA fragmentation analysis and caspase3 activity were used to confirm apoptotic changes. Telomerase activity was determined using the TRAP assay. RNA isolation and RT-PCR were used to analyze the related genes expression. All experiments on treatments with P. urinaria from 0-3 mg/ml were carried out for 24 h. RESULTS: 5 major compounds including gallic acid, brevifolin carboxylic acid, corilagin, phyllanthusiin C and ellagic acid were identified as a plant fingerprint by HPLC/MS. With the MTT assay, we demonstrated that P. urinaria, gallic acid and ellagic acid reduce cell viability. The apoptosis features showed DNA fragmentation and increased caspase-3 activity associated with the down-regulation of Bcl-2, but not of Bax, p53, and PCNA (proliferating cell nuclear antigen) in P. urinaria-treated NPC-BM1 cells. Furthermore, treatment of NPC-BM1 cells led to an inhibition of hTERT (human telomerase reverse transcriptase), hTP1 (human telomerase-associated protein 1) and c-myc mRNA expression and to decreased telomerase activity. CONCLUSION: This study suggests that P. urinaria induces the death of NPC-BM1 cells in vitro through the induction of apoptosis and inhibited telomerase activity.

YY1AP, a novel co-activator of YY1.

With the aim of identifying potential cellular proteins that mediate the transcriptional regulation of YY1, a HeLa cDNA library was screened using the yeast two-hybrid system. A previously unknown protein interacting with YY1 was identified and named YY1AP. By using the 5'-rapid amplification of cDNA ends technique, the full-length cDNA of YY1AP was cloned and sequenced. The cDNA was 2253 bp in length and encoded an open reading frame of 750 amino acids. The chromosomal gene was made up of 10 exons separated by nine introns and is localized on chromosome 1 (1q21.3). Northern blot analysis revealed that YY1AP is ubiquitously expressed in various human tissues and cancer cell lines. Co-immunoprecipitation and immunostaining of cells further indicated that YY1AP co-localizes with YY1 in the nucleus. Furthermore, YY1AP was shown to be capable of enhancing the transcriptional activation of an YY1 responsive promoter. Subsequent analysis by glutathione S-transferase pull-down assay showed that YY1AP contained two YY1 binding regions. The transactivation region of YY1AP would seem to be localized within the section of amino acids 260-345. It is proposed that YY1AP is a novel co-activator of YY1.

Pharmacokinetic and metabolic studies of retrojusticidin B, a potential anti-viral lignan, in rats.

The pharmacokinetics and metabolism of retrojusticidin B, an anti-HIV reverse transcriptase agent isolated from Phyllanthus myritifolius, were studied in rats. The phase II conjugated metabolites were characterized after solvolysis and enzymatic hydrolysis. The oral bioavailabilities of retrojusticidin B, suspended in Tween 80 and in corn oil, were found to be 22.1% and 33.1%, respectively. The elimination half-lives (T1/2) were 22.9 and 36.2 minutes, respectively. The T1/2, clearance, and the volume of distribution (Vz) of retrojusticidin B estimated from i.v. measurements were 24.5 min, 2.6 +/- 0.4 L/min, and 90.6 +/- 6.4 L, respectively. 9,9'-Secoretrojusticidin B was shown to be phase I metabolite.