Hepatic Arterial Infusion Chemotherapy Followed by Lipiodol Infusion for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Single-Center Experience.

Background and Objectives: To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) followed by lipiodol infusion in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Materials and Methods: Thirty-two patients with advanced HCC and PVTT who received HAIC with regimens of cisplatin, mitomycin-C, and 5-fluorouracil followed by lipiodol infusion were enrolled. The primary efficacy endpoint was tumor response rate. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used for assessment of treatment response. The secondary endpoints were overall survival (OS) and progression free survival (PFS). Prognostic factors for survival also were evaluated. Results: The median OS and PFS were 11.9 and 9.5 months, respectively. Seventeen patients (53.1%) achieved objective response, and 23 patients (71.9%) achieved disease control. The length of survival in the responder and disease control groups was longer than in the non-responder and progressive disease groups after two cycles of HAIC (responder vs. non-responder: 16.5 vs. 7.9 months, p = 0.001; disease control vs. progressive disease: 12.3 vs. 5.6 months, p < 0.001) and after completing HAIC (responder vs. non-responder: 15.7 vs. 6.9 months, p = 0.001; disease control vs. progressive disease: 13.6 vs. 6.9 months, p < 0.001). Better survival was associated with Child-Pugh A liver function (p = 0.013), with early response to two HAIC cycles (p = 0.009), and with response (p = 0.02) and disease control (p = 0.001) after completing HAIC treatment. Conclusion: HAIC followed by lipiodol infusion is a safe and feasible treatment for advanced HCC with PVTT. Patients with early response could continue HAIC treatment with expected prolonged survival.

Glutamine in Alleviation of Radiation-Induced Severe Oral Mucositis: A Meta-Analysis.

The aim of this meta-analysis was to assess the effectiveness of glutamine to treat severe mucositis induced by radiation therapy in patients with head and neck cancer. We undertook electronic searches of PubMed (1990 to January 2015), Embase (1990 to January 2015), and the Cochrane Library (2013, Issue 2) to identify relevant studies. We included randomized controlled trials of glutamine to alleviate oral mucositis (OM) in patients with head and neck cancer who received radiotherapy. Information regarding methods, patients, results, and risk of bias was independently extracted by two authors. Statistical analyses were conducted to calculate the odds ratio and 95% confidence intervals (95%CIs) using fixed-effect models. We identified five clinical studies that included 234 patients with head and neck cancer. All studies were assessed as being at low risk of bias in most items of six domains. In this meta-analysis, glutamine treatment showed a statistically significant benefit with respect to reducing the risk and severity of OM induced by radiotherapy compared to either placebo or no treatment (risk ratio 0.17, 95%CI 0.06-0.47). Overall, glutamine significantly reduces the risk and severity of OM during radiotherapy or chemotherapy. Further prospective and large trials are required to support the findings.

Hypothyroidism and hyperthyroidism related to gynecologic cancers: a nationwide population-based cohort study.

The purpose of this study was to assess the risks of hyperthyroidism and hypothyroidism related to gynecological cancers. Population-based retrospective cohort study. We conducted a cohort study using the Taiwan National Health Insurance Research Database to explore hyperthyroidism and hypothyroidism associated with site-specific gynecologic cancers in women from January 1, 2000 to December 31, 2018. The examined gynecologic cancers included endometrial (EC), uterine corpus cancer (UC), and ovarian cancer (OC). The incidence and hazard ratios were quantified using Cox proportional hazards models. The incidence of developing gynecological (Gyn) cancers in the hyperthyroid and hypothyroid women was 0.29 and 0.44 per 1000 person-years, which was 0.86 fold lower and 1.13 fold higher than that in the comparison cohort (p < 0.001). Compared with patients aged 20-40 years, patients in older age groups had a lower and higher risk of developing Gyn cancers (for hyperthyroid, 40-65 years: adjusted hazard ratio (aHR) = 0.82; > 65 years: aHR = 0.94; for hypothyroid, adjusted hazard ratio (aHR) = 1.26; > 65 years: aHR = 1.38). Compared with the non-hypothyroid women and non-hyperthyroid women beyond 6 years of follow-up, hypothyroid and hyperthyroid women showed decreased risk of Gyn cancers. Medication treatment for hyperthyroid and hypothyroid disease did not showed significant association in subgroup analyses (aHR = 0.99 and 0.80, respectively). Our results show that women with hyperthyroidism have a significantly reduced risk of gynecological cancers, whereas women with hypothyroidism have a slightly increased risk of gynecological cancers suggesting an association between thyroid function level and risk of gynecological cancers.

Comparative efficacy and safety of multimodality treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: patient-level network meta-analysis.

Background: Portal vein tumor thrombus (PVTT) is a common complication and an obstacle to treatment, with a high recurrence rate and poor prognosis. There is still no global consensus or standard guidelines on the management of hepatocellular carcinoma (HCC) with PVTT. Increasing evidence suggests that more aggressive treatment modalities, including transarterial chemoembolization, radiotherapy, targeted therapy, and various combination therapies, may improve the prognosis and prolong the survival of advanced hepatocellular carcinoma (aHCC) patients with PVTT. We aim to comprehensively review and compare the efficacy and safety of these advanced options for aHCC with PVTT. Methods: A comprehensive literature search was conducted on PubMed and EMBASE for phase II or III randomized controlled trials (RCTs) investigating multimodality treatments for aHCC with PVTT. Kaplan-Meier curves for overall survival (OS) and progression-free survival were constructed to retrieve individual patient-level data to strengthen the comparison of the benefits of all multimodality treatments of interest. Each study was pooled in a fixed-effects network meta-analysis (NMA). We also conducted subgroup analyses using risk ratios extracted from each study, including viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion or portal vein tumor thrombosis, and extrahepatic spread. Multimodality treatments were ranked using SUCRA scores. Results: We identified 15 randomized controlled trials with 16 multimodality regimens that met the inclusion criteria. Among them, 5,236 patients with OS results and 5,160 patients with PFS results were included in the analysis. The hepatic arterial infusion chemotherapy of fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) showed OS and PFS benefits over all the other therapies. In terms of OS, HAIC-FO, nivolumab, and TACE+Len were superior to sorafenib, lenvatinib, and donatinib monotherapies, as well as HAIC-FO+Sor. In terms of PFS, TACE+Len showed better benefits than lenvatinib, donatinib, and tremelimumab+durvalumab. A low heterogeneity (I 2 < 50%) and consistency were observed. The SUCRA score for OS ranked HAIC-FO+sorafenib as the best treatment option among all multimodality treatments in hepatitis B, MVI, or PVTT with EHS and AFP 400 µg/L subgroups. Conclusion: HAIC-FO and HAIC-FO+sorafenib are statistically better options for unresectable hepatocellular carcinoma with PVTT among the multimodality treatments, and their effective and safe implementation may provide the best outcomes for HCC-PVTT patients.

Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis.

BACKGROUND: We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. METHODS: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. RESULTS: This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. CONCLUSIONS: Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.

Systematic review and quality assessment of cost-effectiveness analysis of pharmaceutical therapies for advanced colorectal cancer.

OBJECTIVE: To systematically review and assess the quality of cost-effectiveness analyses (CEAs) of pharmaceutical therapies for metastatic colorectal cancer (mCRC). DATA SOURCES: The MEDLINE, EMBASE, Cochrane, and EconLit databases were searched for the Medical Subject Headings or text key words quality-adjusted, QALY, life-year gained (LYG), and cost-effectiveness (January 1, 1999-December 31, 2009). STUDY SELECTION: Original CEAs of mCRC pharmacotherapy published in English were included. CEAs that measured health effects in units other than quality-adjusted life years or LYG and letters to the editor, case reports, posters, and editorials were excluded. DATA EXTRACTION: Each article was independently assessed by 2 trained reviewers according to a quality checklist created by the Panel on Cost-Effectiveness in Health and Medicine. RESULTS: Twenty-four CEA studies pertaining to pharmaceutical therapies for mCRC were identified. All studies showed a wide variation in methodologic approaches, which resulted in a different range of incremental cost-effectiveness ratios reported for each regimen. We found common methodologic flaws in a significant number of CEA studies, including lack of clear description for critique of data quality; lack of method for adjusting costs for inflation and methods for obtaining expert judgment; no results of model validation; wide differences in the types of perspective, time horizon, study design, cost categories, and effect outcomes; and no quality assessment of data (cost and effectiveness) for the interventions evaluation. CONCLUSIONS: This study has shown a wide variation in the methodology and quality of cost-effectiveness analysis for mCRC. Improving quality and harmonization of CEA for cancer treatment is needed. Further study is suggested to assess the quality of CEA methodology outside the mCRC disease state.

Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.

Empirical data regarding the choice of antipsychotics for the management of psychosis in patients with Parkinson's disease are limited. This study aimed to evaluate the incidence and prescribing patterns of antipsychotics and to determine the predictors associated with the prescribing of typical antipsychotics in patients with Parkinson's disease. This was a retrospective cohort study analyzing data from the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2006, in which patients with Parkinson's disease (ICD-9-CM codes 332) initially receiving any antiparkinsonian drug (n = 2095) were followed up to evaluate the subsequent use of antipsychotics. Kaplan-Meier statistics and multiple logistic regression were employed to evaluate the cumulative probability of antipsychotic use and determinants of prescribing of typical antipsychotics, respectively. The cumulative probability of initiation of an antipsychotic within 6 years was found to be 51%, and the proportion of patients who began taking an atypical antipsychotic increased from 11.1% in 2001 to 36.1% in 2005. Physician specialty was found to be the most influential predictor of the prescribing of typical antipsychotics: physicians with an internal medicine specialty were 10.62 times more likely (95% confidence interval, 4.64-24.32) to prescribe typical antipsychotics than were neurologists. The use of antipsychotics in Parkinson's disease is common, and the use of typical antipsychotics dominates antipsychotic treatment. Particular attention needs to be paid to improving practice, including efforts that encourage primary care providers to have the appropriate choice of antipsychotics in patients with Parkinson's disease.

Multivitamin supplement use and risk of breast cancer: a meta-analysis.

BACKGROUND: The association between consumption of multivitamins and breast cancer is inconsistent in epidemiologic studies. OBJECTIVE: To perform a meta-analysis of cohort and case-control studies to evaluate multivitamin intake and its relationship with breast cancer risk. METHODS: The published literature was systematically searched and reviewed using MEDLINE (1950 through July 2010), EMBASE (1980 through July 2010), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010 issue 1). Studies that included specific risk estimates were pooled using a random-effects model. The bias and quality of these studies were assessed with REVMAN statistical software (version 5.0) and the GRADE method of the Cochrane Collaboration. RESULTS: Eight of 27 studies that included 355,080 subjects were available for analysis. The total duration of multivitamin use in these trials ranged from 3 to 10 years. The frequency of current use in these studies ranged from 2 to 6 times/week. In analyses by duration of use 10 years or longer or 3 years or longer and by frequency 7 or more times/week that were reported in these studies, multivitamin use was not significantly associated with the risk of breast cancer. Only 1 recent Swedish cohort study concluded that multivitamin use is associated with an increased risk of breast cancer. The results of a meta-analysis that pooled data from 5 cohort studies and 3 case-control studies indicated that the overall multivariable relative risk and odds ratio were 0.10 (95% CI 0.60 to 1.63; p = 0.98) and 1.00 (95% CI 0.51 to 1.00; p = 1.00), respectively. The association was not statistically significant. CONCLUSIONS: Multivitamin use is likely not associated with a significant increased or decreased risk of breast cancer, but these results highlight the need for more case-control studies or randomized controlled clinical trials to further examine this relationship.

Efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors as second-line treatment in postmenopausal patients with hormone receptor-positive, HER-2-negative metastatic breast cancer: a network meta-analysis.

BACKGROUND: We compared the efficacy and safety of combinations of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and PI3K/AKT/mTOR inhibitors as second-line treatment in postmenopausal women with HR+, HER2- metastatic breast cancer. METHODS: We searched the Medline, Embase, and Cochrane Library electronic databases for phase II/III randomized trials evaluating CDK4/6 and PI3K/AKT/mTOR inhibitors plus fulvestrant. We compared the results with a network meta-analysis. Study quality was assessed following the GRADE approach. Outcomes of interest were progression-free survival, overall response rate, overall survival and G3-4 adverse drug events (ADEs). RESULTS: Eight RCTs were identified in the network meta-analysis. PFS was significantly improved by treatment with abemaciclib plus fulvestrant and ribociclib plus fulvestrant compared to pictilisib plus fulvestrant. The ORR following treatment with abemaciclib plus fulvestrant, ribociclib plus fulvestrant, palbociclib plus fulvestrant, buparlisib plus fulvestrant, and alpelisib plus fulvestrant significantly differed from that observed following treatment with placebo plus fulvestrant. In terms of OS, compared with placebo plus fulvestrant, abemaciclib plus fulvestrant, ribociclib plus fulvestrant, and buparlisib plus fulvestrant had a significant difference. The risks of ADEs were similar among three CDK4/6 inhibitors. CONCLUSION: As second-line treatment, three CDK4/6 inhibitors showed superior clinical efficacy compared to other PI3K/AKT/mTOR inhibitors with comparable safety profiles.

Risk of digoxin intoxication in heart failure patients exposed to digoxin-diuretic interactions: a population-based study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Increased frequency of electrolyte abnormalities and cardiac arrhythmias among patients exposed to digoxin-diuretic interactions has been well-documented in numerous descriptive studies. * Nonetheless, a clear causal relationship has not been established in these studies. WHAT THIS STUDY ADDS * The risks of digoxin intoxication associated with use of digoxin in combination with any diuretic use, types of diuretics, combinations of diuretics, and individual diuretics were quantified using a population-based nested case-control study design. * The combined therapy of digoxin with any diuretic is associated with a 3.08-fold increase in the risk of digoxin intoxication. * Regarding diuretic class, the risk carried by loop diuretics is greater than that of thiazides or potassium-sparing diuretics, and the risk varies with different combinations of diuretic classes and individual diuretics. AIMS To quantify the digoxin intoxication risk associated with exposure to digoxin-diuretic interactions, and evaluate whether the risk varies by diuretic type, individually or in combination. METHODS This was a population-based nested case-control study in which data from the National Health Insurance Research Database (NHIRD) in Taiwan were analysed. RESULTS The study cohort comprised 154 058 heart failure (HF) patients taking digoxin between 2001 and 2004, in whom digoxin intoxication requiring a hospitalization (ICD-9 code 972.1) occurred in 595 cases. A total of 28 243 matched controls were also selected for analysis. Cases were 3.08 times (adjusted OR 3.08, 95% CI 2.50, 3.79) more likely to have been prescribed diuretic medication in the previous month than controls. Regarding the class of diuretics, loop diuretics carried the greatest risk (adjusted OR 2.97, 95% CI 2.35, 3.75), followed by thiazides (OR 2.36, 95% CI 1.70, 3.29) and potassium-sparing diuretics (OR 1.72, 95% CI 0.83, 3.56). The risk was also observed to vary with different combinations of diuretics, and the loops/thiazides/potassium-sparing diuretics combination carried the greatest risk (adjusted OR 6.85, 95% CI 4.93, 9.53). Among the individual diuretics examined, hydrochlorothiazide carried the greatest risk (adjusted OR 4.63, 95% CI 2.50, 8.57). CONCLUSIONS This study provided empirical evidence that digoxin-diuretic interactions increased the risk of hospitalization for digoxin intoxication in HF patients. The risk was particularly high for concomitant use of digoxin with a combination of loop diuretics, thiazide and potassium-sparing diuretics. The combined use of digoxin and diuretics should be avoided if possible.

Reliability of 95% confidence interval revealed by expected quality-of-life scores: an example of nasopharyngeal carcinoma patients after radiotherapy using EORTC QLQ-C 30.

BACKGROUND: Many researchers use observed questionnaire scores to evaluate score reliability and to make conclusions and inferences regarding quality-of-life outcomes. The amount of false alarms from medical diagnoses that would be avoided if observed scores were substituted with expected scores is interesting, and understanding these differences is important for the care of cancer patients. Using expected scores to estimate the reliability of 95% confidence intervals (CIs) is rarely reported in published papers. We investigated the reliability of patient responses to a quality-of-life questionnaire and made recommendations for future studies of the quality of life of patients. METHODS: A total of 115 patients completed the EORTC core questionnaire QLQ-C30 (version 3) after radiotherapy. The observed response scores, assumed to be one-dimensional, were summed and transformed into expected scores using the Rasch rating scale model with WINSTEPS software. A series of simulations was performed using a unified bootstrap procedure after manipulating scenarios with different questionnaire lengths and patient numbers to estimate the reliability at 95% confidence intervals. Skewness analyses of the 95% CIs were compared to detect different effects between groups according to the two data sets of observed and expected response scores. RESULTS: We found that (1) it is necessary to report CIs for reliability and skewness coefficients in papers; (2) data derived from expected response scores are preferable to making inferences; and (3) visual representations displaying the 95% CIs of skewness values applied to item-by-item analyses can provide a useful interpretation of quality-of-life outcomes. CONCLUSION: Reliability coefficients can be reported with 95% CIs by statistical software to evaluate the internal consistency of respondent scores on questionnaire items. The SPSS syntax procedures for estimating the reliability of the 95% CI, expected score generation and visual skewness analyses are demonstrated in this study. We recommend that effect sizes such as a 95% CI be reported along with p values reporting significant differences in quality-of-life studies.

Cost-effectiveness of trastuzumab as adjuvant therapy for early breast cancer: a systematic review.

OBJECTIVE: To identify published, original, cost-effectiveness analyses presenting cost/quality-adjusted life year (QALY) ratios for trastuzumab used as an adjuvant treatment for HER2-positive early breast cancer and to evaluate the quality of reporting the favorable cost-effectiveness ratios. DATA SOURCES: The terms trastuzumab adjuvant therapy, cost-effectiveness, quality-adjusted, QALY, and early breast cancer were searched in MEDLINE, PubMed, Embase, and CancerLit, as well as in Cochrane economic evaluation and reference lists from 1998 to June 2008. Only English-language publications were eligible. STUDY SELECTION AND DATA EXTRACTION: All published studies examining cost-effectiveness outcomes on the basis of modeling or clinical trials were included. Cost-effectiveness analysis that measured health effects in units other than QALY, life year gained, neoadjuvant data, reviews, and comments were excluded. Each study was assessed independently by 2 trained reviewers. DATA SYNTHESIS: Thirteen of the 239 articles identified met the inclusion criteria, with 23 cost-effectiveness ratios pertaining to treatment of early breast cancer. These ratios ranged from $5020/QALY to $134,610/QALY. Most studies reported favorable cost-effectiveness values (ie, below $50,000/QALY). About 84.6% were conducted using a Markov model based on data from clinical trials and 15.3% were analyzed by other economic or cost models; 84.6% reported sensitivity analysis, 11 studies (84.6%) clearly described a justification of selecting study design, and only 15.3% noted study limitations. All studies mentioned their perspective; 92.3% did not show the funding source. Methods of reporting costs, effectiveness, and time-horizons for disease states varied significantly. Nine (69.2%) studies used a discount rate of 3%, 3 studies used a discount rate of 5%, and 1 study used 3.5%. The mean quality of the studies was 4.43. CONCLUSIONS: Most studies presenting the frequently proposed threshold of QALY suggest that trastuzumab may be cost-effective for treatment of early breast cancer in a 1-year treatment regimen.

Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study.

OBJECTIVE: To quantify the effect of exposures to digoxin­clarithromycin interactions on the risk of digoxin toxicity requiring hospitalizations in a population-based manner in a Taiwanese population. METHODS: This is a retrospective population-based nested case­control study. Data were retrieved from the National Health Insurance Research Database. Heart failure (HF) patients newly treated with digoxin between 1 January 2001 and 31 December 2004 were retrieved from the database as the study cohort. Case patients, admitted to the hospitals with the diagnosis of digoxin intoxication (ICD-9 code 972.1) were identified from the study cohort and compared with the matched controls for the receipt of clarithromycin. RESULTS: A total of 154,058 patients were identified as the study cohort; from these, 595 cases and 27,020 matched controls were selected for study. The prescription of clarithromycin at 7, 14, and 30 days prior to the index date was associated with a 4.36- (95% CI 1.28­14.79), 5.07- (95% CI 2.36­10.89), and 2.98-fold (95% CI 1.59­5.63) increase in hospitalization for digoxin intoxication, respectively. The results of the dose­response relationship also indicated that clarithromycin prescribed with a prescribed daily dose (PDD)/defined daily dose (DDD) ratio >2 led to a 55.41-fold (95% CI 9.31­329.9) increase of the risk, which is significantly greater than that prescribed with a 1­2 PDD/DDD ratio (adjusted OR 4.81; 95% CI 1.88­12.30) or with a <1 PDD/DDD ratio (adjusted OR 0.78; 95% CI 0.19­3.20). CONCLUSION: This study provides empirical evidence that digoxin­clarithromycin interactions do increase the risk of hospitalization for digoxin intoxication in HF patients and that this risk could reach as high as 55.4-fold. We strongly recommend that the combined use of digoxin with clarithromycin should be avoided and that digoxin concentrations should be monitored closely in situations where the combination can not be avoided.

Stevens-Johnson syndrome induced by combination of imatinib and allopurinol.

We report a case of Stevens-Johnson syndrome (SJS) caused by imatinib combined with allopurinol. An 82-year-old female patient who had a diagnosis of chronic myeloid leukemia was initially treated with imatinib 200 mg/day and allopurinol 100 mg for 42 days, and had a satisfactory hematological response. The dose of imatinib was adjusted to 400 mg/day for 14 days. After two weeks, she developed SJS and was transferred to the intensive care unit for further treatment because her general condition had deteriorated. The aggravated cutaneous adverse reaction improved approximately 7 days after withdrawal of imatinib. Oral steroids with antihistamines were prescribed for the treatment of severe cutaneous reaction. The symptoms of SJS completely improved 1 month after discontinuation of imatinib and allopurinol. We concluded that imatinib alone may cause serious cutaneous reaction, but the combination of 2 high-risk drugs may increase the likelihood of exposed patients developing SJS. Physicians should be aware of the possibility of SJS caused by imatinib and allopurinol prescribed simultaneously.

Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity.

Evodiamine (EVO), an alkaloidal compound isolated from Evodia rutaecarpa (Juss.), has been reported to affect many physiological functions. Topoisomerase inhibitors have been developed in a variety of clinical applications. In the present study, we report the topoisomerase I (TopI) inhibitory activity of EVO, which may have properties that lead to improved therapeutic benefits. EVO is able to inhibit supercoiled plasmid DNA relaxation catalyzed by TopI. Upon treatment 0-10 microM EVO TopI was depleted in MCF-7 breast cancer cells in a concentration-dependent and time-dependent manner in 0-120 min. A K-SDS precipitation assay was performed to measure the extent of Top I-trapped chromosomal DNA. The ability of EVO to cause the formation of a TopI-DNA complex increased in a concentration-dependent manner, in that the DNA trapped increased by 24.2% in cells treated with 30 microM. The results suggest that EVO inhibits TopI by stabilizing the enzyme and DNA covalent complex.

Direct medical costs in patients with Alzheimer's disease in Taiwan: A population-based study.

BACKGROUND: Alzheimer's disease (AD) has the potential to become a major health concern and associated health care costs may become a significant economic burden on society. OBJECTIVE: The aim of this study was to estimate the direct medical costs attributable to AD in patients aged ≥60 years in Taiwan from 2000 through 2002 and to explore the correlation of these costs with patients' age and sex. METHODS: This study was based on the National Health Insurance Research Database of Taiwan's National Health Insurance (NHI) program. The NHI program insures >98% of the 23 million inhabitants of Taiwan. Detailed data were extracted from a random sample of 0.2% of inpatient and 5% of outpatient recipients with AD (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 331.0) who were aged ≥60 years and who received inpatient or outpatient services with claims from January 1, 2000, to December 31, 2002. Duplicate charges for a specific patient and diagnoses of other types of dementia were excluded from this study. RESULTS: A total of 69,780 patients were found to have a diagnosis of AD. The direct medical costs for outpatients were estimated at US $1.2 million in 2000, US $1.9 million in 2001, and US $2.3 million in 2002; the costs for inpatient care were estimated at US $670,000 in 2000, US $2.4 million in 2001, and US $3.2 million in 2002. The total direct medical costs were estimated at US $1.86 million in 2000, US $4.24 million in 2001, and US $5.48 million in 2002. The increase of total direct medical costs was not significantly correlated with patients' age or sex. CONCLUSIONS: From 2000 through 2002, the direct medical costs of AD increased annually in Taiwan among patients with AD aged ≥60 years. No significant correlation was found between increased total direct medical costs and sex or age. The cost estimate presented here has implications for future decision making about reallocating medical resources for treating AD in Taiwan.

Transdermal delivery of treatment for Alzheimer's disease: development, clinical performance and future prospects.

There is increasing interest in the potential of transdermal drug delivery systems for the treatment of neurological disorders, especially in the elderly. In this population, the higher incidence of chronic diseases, such as diabetes mellitus, cardiovascular disease, neurological disease and chronic pain, has dramatically increased the need for long-term medications. Additionally, elderly patients often have a combination of several chronic diseases, meaning drug delivery, drug-drug interactions, absorption/blood concentrations, toxicity and compliance are of concern for patients as well as for their caregivers and physicians. Recent efforts have focused on developing pharmaceutical preparations that overcome these issues. For example, rate-controlled drug delivery systems have been under active development. Transdermal drug delivery systems have been developed to deliver phenserine, rivastigmine, nicotine and estradiol for the management of cognitive and behavioural dysfunctions in patients with Alzheimer's disease because this form of administration has several advantages, including maintenance of sustained therapeutic plasma concentrations of drugs, easy application and reduced systemic adverse effects. Thus, transdermal drug delivery for elderly patients offers promise as the ideal therapeutic approach to treating Alzheimer's disease.This article reviews the technical principles underlying the development of transdermal drug delivery systems, focusing on cholinesterase inhibitors, and the prospects for future development. The clinical performance of transdermal patches, again with emphasis on cholinesterase inhibitors, is also reviewed.

Cost evaluation of adverse drug reactions in hospitalized patients in Taiwan: A prospective, descriptive, observational study.

BACKGROUND: Adverse drug reactions (AADRs) are a leading cause of morbidity and mortality. In the United States, ADR-related morbidity and mortality costs have been estimated at US $330 billion to US $1130 billion annually. OBJECTIVES: The aim of this study was to evaluate the incidence of ADRs in Taiwan, to identify the drug classes that are most commonly related to ADRs, and to determine the direct medical costs to hospitals associated with prolonged hospitalizations due to ADRs. METHODS: In this prospective, descriptive, observational study, patients who experienced ADRs during their hospitalization at a Taiwan teaching hospital or who were admitted due to an ADR from January 1, 2002, through December 31, 2004, were included in the study. The patients were identified actively by clinical pharmacists and passively by physicians and nurses who reported ADRs. The World Health Organization (WWHO) definition of ADR severity was adopted, and degrees of probability for each ADR were determined using the Naranjo algorithm. The direct medical costs incurred to the hospital in the treatment of ADRs that prolonged hospitalization were calculated (ie, costs of emergency department [ED] visits, intensive care unit visits, extra days of hospitalization, monitoring and laboratory studies, pharmacist dispensing fees, physician fees, room charges, ED charges). RESULTS: During the study period, 43 of the 142,295 hospitalized patients (00.03%)) were admitted because of an ADR. A total of 564 (00.40%)) of the hospitalized patients were verified to have ADRs. Three hundred eighteen of the patients (56.44%) with ADRs were male and the overall mean (SD) age was 66(2) years. The most common drug classes associated with the ADRs were antibiotics (219 patients [38.8% ]), analgesics (62 [11.0%]), and cardiovascular agents (56 [9.9%]). The systems most commonly involved in ADRs were cutaneous (296 patients [52.5%]), hematologic (61 [10.8%]), and cardiovascular (54 [9.66%]). The causes of the ADRs were anaphylactic (464 patients [82.3%]), drug overdose (78 [13.8%]), and drug-drug interactions (22 [3.9%]). Of the ADRs, 474 (884.0%) were idiosyncratic type B reactions (predictable). ADR-related costs, estimated at US $3489/ADR, were mostly due to prolonged length of stay. Based on the WHO definition, of the 564 ADRs, 330 (58.5%) and 40 (7.1%) were classified as moderate and severe, respectively. Two patients died of ADRs associated with allopurinol. CONCLUSION: In this hospital, 0.40% of patients were identified as having ADRs that were associated with high direct costs, mostly due to extended hospitalizations.

Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis.

BACKGROUND: Using network meta-analysis, we assessed the efficacy and safety of a combination regimen of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer. METHODS: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2-targeted agents combined with trastuzumab or chemotherapy. A network meta-analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival. RESULTS: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3-4 adverse events compared to other regimens. CONCLUSIONS: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens.

Cost-effectiveness of pertuzumab combined with trastuzumab and docetaxel as a first-line treatment for HER-2 positive metastatic breast cancer.

OBJECTIVE: To provide perspective for the National Health Insurance Bureau (NHIB), we determined the cost-effectiveness of pertuzumab combined with trastuzumab and docetaxel (TDP) versus trastuzumab and docetaxel (TD) as a first-line treatment for HER-2 positive metastatic breast cancer. METHODS: We used a Markov model to simulate cost-effectiveness, disease progression, and survival, based on clinical data and transition probabilities extracted from the CLEOPATRA study. Direct medical costs were acquired from the NHIB claims database.The utilities in health state were based on a recent cost-effectiveness study on trastuzumab and pertuzumab. Outcomes included quality-adjusted life-years (QALYs), costs in New Taiwan dollars (NT$), and the incremental cost-effectiveness ratio (ICER). We performed one-way deterministic and probabilistic sensitivity analyses to assess the impact of specific parameters on the model. RESULTS: Modeled median survival was 39.1 months for TD and 50.1 months for TDP. The ICER was NT$18,999,687 (US$593,741) per QALY gained. The sensitivity analyses indicated that TDP could be cost-effective under favorable assumptions; TDP had a 68% chance of being cost-effective, if TDP costs could be reduced with 10% in the stable disease state. CONCLUSION: Our model predicted that TDP would be cost-effective as a first-line treatment for HER-2 positive metastatic breast cancer, but only under favorable drug cost assumptions.