Tsung-Cheng Hsieh

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Standard treatment for severe granulomatosis with polyangiitis (Wegeners) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).

A comparison of moment-based and probability-based criteria for assessment of follow-on biologics.

For approval of generic drugs, the U.S. Food and Drug Administration (FDA) requires the evidence of bioequivalence in average bioavailability from the bioavailability/bioequivalence studies. The criterion for assessment of bioequivalence adopted by the FDA is a moment-based criterion evaluating log-transformed pharmacokinetic responses such as area under the blood or plasma concentration–time curve (AUC) or maximum concentration (Cmax). Unlike traditional small molecule drug products, the characteristics and development of biologic products are more complicated and sensitive to many factors. Thus, it is of concern to know whether the current bioequivalence criterion is applicable to the assessment of biosimilarity between biologic products. In this article, we compare the moment-based criterion with a probability-based criterion proposed by Tse et al. (2006) for assessment of bioequivalence or biosimilarity between two drug products in terms of consistency/inconsistency for correctly concluding bioequivalence or biosimilarity. A simulation study was conducted to study relative performance of the two criteria. The feasibility and applicability of the proposed criteria for assessment of biosimilarity of follow-on biologics are discussed.

Male sex, hiatus hernia, and Helicobacter pylori infection associated with asymptomatic erosive esophagitis

Background and Aims:  Asymptomatic erosive esophagitis (AEE) is an easily forgotten subgroup of gastroesophageal reflux disease due to its lack of warning symptoms, despite having the risk of developing complications, such as bleeding, stricture, or even esophageal adenocarcinoma.

Statistical Test for Evaluation of Biosimilarity in Variability of Follow-On Biologics

As more biologic products are going off patent protection, the development of follow-on biologics products has received much attention from both biotechnology industry and the regulatory agencies. Unlike small-molecule drug products, the development of biologic products is very different and variable via the manufacture process and environment. Thus, Chow et al. (2010) suggested that the assessment of biosimilarity between biologic products focus on variability rather than average biosimilarity. In addition, it is also suggested that a probability-based criterion, which is more sensitive to variability, should be employed. In this article, we propose a probability-based asymptotic statistical testing procedure to evaluate biosimilarity in variability of two biologic products. A numerical study is conducted to investigate the relationship between the probability-based criterion in variability and various study parameters. Simulation studies were also conducted to empirically investigate the performance of the proposed probability-based asymptotic statistical testing procedure in term of empirical sizes and powers. A numerical example is provided to illustrate the proposed methods.

The evaluation of biosimilarity index based on reproducibility probability for assessing follow‐on biologics

Unlike small molecule drug products, biological products are therapeutic agents producted using of a living system or organism. Thus, the development of biologic products is a very different and complicated process that is sensitive to environmental factors such as light and temperature. Therefore, the therapeutic effect of follow-on biologic products may not be equivalent to the innovative products even though the average biosimilarity has been established. Thus, Chow et al. suggested that the assessment of biosimilarity between biologic products should be conducted on the basis of variability in 2010. In this article, we propose a biosimilar index that is derived on the basis of estimated reproducibility probability approach and Bayesian approach, respectively. We conducted simulation studies to empirically investigate the relationship of reproducibility probability under various parameter combinations. The simulation results demonstrate that the proposed method based on biosimilar index can reflect the characteristics and impact of variability on the therapeutic effect of biologic products.

Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers: A Nationwide Population-based Study

AbstractSome statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug–drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwans National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription.In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non-CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35–3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36–6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16–2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08–1.68) than those who received non-CYP3A4-metabolized statins.This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. Therefore, it is important to take into account the potential adverse events while coprescribing CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.

Diagnostic value of tumor markers in lung adenocarcinoma-associated cytologically negative pleural effusions.

Cytology fails to detect neoplastic cells in approximately 40% to 50% of malignant pleural effusions (PEs), which commonly accompany lung adenocarcinomas. The diagnostic accuracy of various tumor markers in lung adenocarcinoma‐associated cytologically negative pleural effusions (LAC‐CNPEs) has been poor. The current study attempted to maximize diagnostic efforts in distinguishing LAC‐CNPEs from benign PEs.

Severity of fatty liver on ultrasound correlates with metabolic and cardiovascular risk

Non‐alcoholic fatty liver disease is associated with an increased risk of metabolic and cardiovascular diseases. Whether the severity of fatty liver on ultrasound correlates with metabolic or cardiovascular risk remains unclear. A total of 1000 people receiving health examinations were enrolled, and 126 were excluded due to the presence of HBsAg, anti‐HCV, known hepatic disorders or alcohol use (>140 g/wk). Significant fatty liver consisted of moderate and severe fatty liver on ultrasound. The definition of central obesity was modified to a waist circumference of >90 cm in men and >80 cm in women. Framingham risk score was used to estimate the risk of cardiovascular disease. A total of 874 subjects (485 women and 388 men with a mean age of 52.07 ± 11.68 years) were included in the final analysis. By using logistic regression analyses stratified by gender, the odds ratio for the prevalence of diabetes mellitus, metabolic syndrome and risk of cardiovascular disease increased with increasing fatty liver status in both genders (p ≤ 0.001). The difference was not only present between individuals with fatty liver vs. non‐fatty liver but also between the mild fatty liver and significant fatty liver groups (p < 0.05). In conclusion, the severity of fatty liver on ultrasound could be useful for the risk stratification of metabolic syndrome, diabetes mellitus and cardiovascular disease in clinical practice.

Increased risks of mortality and atherosclerotic complications in incident hemodialysis patients subsequently with bone fractures: A nationwide case-matched cohort study

Background Hemodialysis (HD) patients with bone fractures have an increased risk for death. However, the risks for mortality and atherosclerotic complications in incident HD patients subsequently with bone fractures are unknown. Methods Data derived from the Taiwan National Health Institute Research Database between January 1997 and December 2008 was analyzed. The enrolled patients included 3,008 incident HD patients subsequently with a single long bone fracture (LB Fx) and 2,070 incident HD patients subsequently with a single non-long bone fracture (NLB Fx). These patients were matched (1:5 ratio) for age, sex, and same duration of HD with incident HD patients who had no fractures and outcomes were measured over a 3-year follow-up. Results After demographic and co-morbidity adjustment, LB Fx increased the risk for overall mortality (HR = 1.59, p < 0.001) and stroke (HR = 1.09, p = 0.028) in incident HD patients. NLB Fx increased the risk for overall mortality (HR = 1.52, p < 0.001), stroke (HR = 1.19, p < 0.001), coronary artery disease (CAD), (HR = 1.13, p = 0.003), and peripheral arterial occlusive disease (PAOD), (HR = 1.41, p < 0.001) in incident HD patients. Moreover, incident patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx. Conclusions The rates of mortality and stroke were significantly higher in incident HD patients subsequently with bone fractures than in matched patients without bone fractures. Incident HD patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx and without bone fractures. Thus, incident HD patients subsequently with bone fractures should be closely followed for a higher mortality and possible development of atherosclerotic complications.

Effectiveness of Thermal Stimulation for the Moderately to Severely Paretic Leg After Stroke: Serial Changes at One-Year Follow-Up

UNLABELLED Liang C-C, Hsieh T-C, Lin C-H, Wei Y-C, Hsiao J, Chen J-C. Effectiveness of thermal stimulation for the moderately to severely paretic leg after stroke: serial changes at one-year follow-up. OBJECTIVE To evaluate the serial changes of long-term effects of thermal stimulation (TS) on acute stroke patients. DESIGN A prospective study with follow-up at 3, 6, and 12 months after TS to assess motor and balance function of the paretic leg of acute stroke patients. SETTING A general hospital rehabilitation department. PARTICIPANTS Poststroke patients (N=30) with moderate to severe impairment of leg function. INTERVENTIONS In addition to receiving standard rehabilitation, eligible patients were randomly assigned to a TS group (5 thermal stimulations per week for 6wk) or a control group (3 consultations per week for 6wk). MAIN OUTCOME MEASURES Fugl-Meyer lower extremity score, Medical Research Council Scale for the Lower Extremity, Berg Balance Scale, Modified Motor Assessment Scale, Functional Ambulation Classification, and Barthel Index were administered at baseline, after 4 and 6 weeks of treatment, and at the 3-, 6-, and 12-month follow-up. RESULTS No significant differences were found between the 2 groups at baseline. After TS, the Fugl-Meyer lower extremity score, Medical Research Council Scale for the Lower Extremity, Modified Motor Assessment Scale, and Functional Ambulation Classification were significantly better in the TS group, and the effects persisted for 3 months (P<.05). Significant differences were found between the 2 groups for the Berg Balance Scale and Barthel Index only at the 3-month follow-up (P<.05). However, all the effects except for the Fugl-Meyer lower extremity score had disappeared at the 6-month follow-up (P>.05). CONCLUSIONS The long-term benefits of TS for patients with acute stroke may be sustained for 3 months but disappear by the 6-month and 1-year follow-up.