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Li-Wei Zhang,1– 3,&ast; Man-Qing Luo,4,&ast; Ji-Lang Zeng,1– 3,&ast; Zhe-Bin You,2,3,5 Li-Chuan Chen,1– 3 Jun-Han Chen,1– 3 Kai-Yang Lin,1– 3 Yan-Song Guo1– 3 1Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 2Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases, Fuzhou, People’s Republic of China; 3Fujian Heart Failure Center Alliance, Fuzhou, People’s Republic of China; 4Department of Cardiology, Fuwai Hospital, National Clinical Research Center for Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Geriatric Medicine, Fujian Key Laboratory of Geriatrics, Fujian Provincial Hospital, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai-Yang Lin; Yan-Song Guo, Tel +86-13559355708 ; +86-059188217410, Email lky7411@sina.com; ysguo1234@126.comPurpose: The estimated glomerular filtration rate (eGFR) based on creatinine is crucial for the risk assessment of contrast-associated acute kidney injury (CA-AKI). In recent, the difference between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr) has been widely documented. We aimed to explore whether intraindividual differences between eGFRcys and eGFRcr had potential value for CA-AKI risk assessment in patients undergoing elective percutaneous coronary intervention (PCI).Patients and Methods: From January 2012 to December 2018, we retrospectively observed 5049 patients receiving elective PCI. To determine eGFR, serum creatinine and cystatin C levels were measured. CA-AKI was defined as serum creatinine being increased ≥ 50% or 0.3 mg/dL within 48 h after contrast agents exposure. Chronic kidney disease (CKD) was defined as the eGFR < 60 mL/min/1.73 m2.Results: Approximately half of the participants (2479, 49.1%) had a baseline eGFRdiff (eGFRcys-eGFRcr) between − 15 and 15 mL/min/1.73 m2. Restricted cubic splines analysis revealed a nonlinear relationship between eGFRdiff and CA-AKI. Multivariable logistic regression analysis indicated that compared with the reference group (− 15 to 15 mL/min/1.73 m2), the negative-eGFRdiff group (less than − 15 mL/min/1.73 m2) had a higher risk of CA-AKI (OR, 3.44; 95% CI, 2.57– 4.64). Furthermore, patients were divided into four groups based on CKD identified by eGFRcys or eGFRcr. Multivariable logistic analysis revealed that patients with either CKDcys (OR, 2.94; 95% CI, 2.19– 3.95, P < 0.001) or CKDcr (OR, 2.44; 95% CI, 1.19– 4.63, P < 0.001) had an elevated risk of CA-AKI compared to those without CKDcys and CKDcr.Conclusion: There are frequent intraindividual differences between eGFRcys and eGFRcr, and these differences can be used to forecast the risk of CA-AKI.Keywords: estimated glomerular filtration rate, contrast-associated acute kidney injury, cystatin C, percutaneous coronary intervention

Ji-Lang Zeng,1– 3,&ast; Yi-Fei Xiang,1– 3,&ast; Li-Wei Zhang,1– 3,&ast; Li-Chuan Chen,1– 3 Jun-Han Chen,1– 3 Wen-Jia Liang,1– 3 Zhebin You,2– 4 Chang-Xi Wang,1– 3 Zhi-Jie Lin,1– 3 Kai-Yang Lin,1– 3 Yansong Guo1– 3 1Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 2Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases, Fuzhou, People’s Republic of China; 3Fujian Heart Failure Center Alliance, Fuzhou, People’s Republic of China; 4Fujian Key Laboratory of Geriatrics, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yansong Guo; Kai-Yang Lin, Fujian Provincial Hospital, Dongjie Street 134, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-13559355708, Fax +86-591-87557768, Email ysguo1234@126.com; lky7411@sina.comPurpose: Prior research has demonstrated a key role of systemic inflammatory state in the pathogenesis and progression of contrast-associated acute kidney injury (CA-AKI). Recently, the systemic inflammation score (SIS) has been introduced to evaluate the inflammatory status, utilizing the lymphocyte-to-monocyte ratio (LMR) and albumin. The primary objective of this study was to determine whether the SIS can predict CA-AKI and long-term prognosis in patients undergoing elective percutaneous coronary intervention (PCI).Patients and Methods: A total of 5726 patients who underwent elective PCI were included from January 2012 to December 2018. The primary outcome was CA-AKI, defined as an increase in serum creatinine (SCr) ≥ 0.3 mg/dl or ≥ 50% than baseline SCr within 48 h after the PCI procedure. The secondary outcome was long-term mortality. All patients were classified into low- and high-SIS groups.Results: During hospitalization, 349 (6.1%) patients developed CA-AKI. Multivariate logistic regression analysis showed that patients in the high SIS group had a 1.47-fold higher risk of developing CA-AKI than those in the low SIS group [odds ratio (OR): 1.50, 95% confidence interval (CI): 1.12– 2.01, P =0.006]. Furthermore, the SIS showed the greatest prediction performance for CA-AKI compared with other inflammatory hematological ratios. In the multivariate Cox regression analysis, the high SIS group was found to be closely associated with long-term mortality [hazard ratio (HR): 1.58, 95% CI: 1.26– 1.97, P < 0.001, vs low SIS group]. The Kaplan-Meier curve analysis also demonstrated a difference in long-term mortality between the two groups (Log rank test, P < 0.001).Conclusion: The SIS was closely associated with CA-AKI and long-term mortality in patients after elective PCI. Thus, more attention should be paid to exploring the potential benefits of anti-inflammatory strategies in preventing CA-AKI and improving the prognosis of patients undergoing PCI.Keywords: contrast-associated acute kidney injury, mortality, percutaneous coronary intervention, systemic inflammation score

Aleksi Hamina,1,&ast; Ingvild Odsbu,2,&ast; Petter Christian Borchgrevink,3,4 Li-Chia Chen,5 Thomas Clausen,1 Ketil Arne Espnes,6,7 Kine Gjesdal,8,9 Marte Handal,1,10 Sirpa Hartikainen,11 Vidar Hjellvik,10 Marianne Therese Smogeli Holter,12 Trond Høibø,13 Geana Paula Kurita,14– 16 Harald Christian Langaas,7 Torgeir Gilje Lid,8,9 Torunn Hatlen Nøst,3,17 Per Sjøgren,15 Svetlana Skurtveit1,2 On behalf of the POINT study group1Norwegian Centre for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 2Department of Mental Disorders, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 3Department of Pain and Complex Disorders, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 4Institute of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 5Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; 6Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 7Regional Medicines Information and Pharmacovigilance Centre (RELIS), Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 8Faculty of Health Sciences, University of Stavanger, Stavanger, Norway; 9Center for Alcohol and Drug Research (KORFOR), Stavanger University Hospital, Stavanger, Norway; 10Department of Chronic Diseases, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 11School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 12Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway; 13Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway; 14Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 15Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 16Department of Anaesthesiology, Pain and Respiratory Support, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 17Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway&ast;These authors contributed equally to this workCorrespondence: Ingvild Odsbu, Department of Mental Disorders, Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, Oslo, 0213, Norway, Tel +47 41454379, Email ingvild.odsbu@fhi.noAim: The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients’ pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage.Data Sources: The project utilises data from nationwide healthcare and population registers in Norway. Using the Norwegian Prescription Database, we identified a cohort of persons who have been dispensed drugs reimbursed for chronic pain and a cohort of persons who used opioids long term from 2010 to 2019. Data from the Norwegian Registry for Primary Health Care and the Norwegian Patient Registry (2008– 2019), Cancer Registry (1990– 2018) Cause of Death Registry (2010– 2019) and demographic and socioeconomic registers from Statistics Norway (2010– 2019) were linked to the cohorts.Study Population: There were 568,869 participants with chronic pain. Sixty-three percent of the cohort was women, and the mean age was 57.1 years. There were 336,712 long-term opioid users (58.6% women; 60.9 years). In chronic pain and long-term opioid user cohorts, the most frequent musculoskeletal diagnosis was back pain diagnosed in primary care (27.6% and 30.7%). Psychiatric diagnoses were also common.Main Variables: Upcoming studies will utilise psychiatric and somatic diagnoses from the patient registers, drug use from the prescription register, causes of death, demographics, and socioeconomic status (eg, education, income, workability, immigrant status) as exposures or outcomes.Conclusion and Future Plans: The two cohorts have numerous pain-related diagnoses, especially in the musculoskeletal system, and noticeably frequent somatic and psychiatric morbidity. The POINT project also includes later work packages that explore prescriber and patient perspectives around safe and effective treatment of chronic pain.Keywords: opioids, chronic pain, healthcare registers

Wei-Jie Cheng,1,&ast; Shyr-Yi Lin,2,3,&ast; Kuo-Hsiang Chuang,4,5,&ast; Michael Chen,4 Hsiu-O Ho,1 Ling-Chun Chen,6 Chien-Ming Hsieh,1 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; 5PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 6Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chien-Ming Hsieh; Ming-Thau Sheu, Email cmhsieh@tmu.edu.tw; mingsheu@tmu.edu.twIntroduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis.Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations.Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs.Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.Graphical Abstract: Keywords: docetaxel, pictilisib, nanocarriers, bispecific antibodies, dual epitopes, HER2-positive breast cancer

Shang-Yu Chou,1 Hung-I Lu,2 Yen-Hao Chen,3 Chien-Ming Lo,2 Yun-Hsuan Lin,1 Tzu-Ting Huang,1 Fu-Min Fang,1 Li-Chun Chen,2 Yu Chen,2 Yi-Chun Chiu,4 Yeh-Pin Chou,4 Shau-Hsuan Li,3,&ast; Yu-Ming Wang1,5,&ast; 1Department of Radiation Oncology & Proton and Radiation Therapy Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yu-Ming Wang, Department of Radiation Oncology & Proton and Radiation Therapy Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 129, Ta-Pei Road, Niaosong Dist., Kaohsiung, 833, Taiwan, Tel +886-7-7317123 ext. 7000, Fax +886-7-7322813, Email scorpion@cgmh.org.tw Shau-Hsuan Li, Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niaosong Dist., Kaohsiung, 833, Taiwan, Tel +886-7-7317123 ext. 8303, Fax +886-7-7322813, Email lee0624@cgmh.org.twPurpose: For locally advanced esophageal cancer, definitive concurrent chemoradiotherapy (CCRT) with a radiation dose of 50– 50.4 Gy/25-28 Fx is prescribed, followed by adjuvant esophagectomy for better local control or salvage treatment if locoregional recurrence occurs. However, radiation injury before surgery may delay wound healing. We performed cervical anastomosis directly inside the left supraclavicular fossa (SCF), the irradiation target for esophageal cancer. The significance of radiation injury in patients with cervical anastomotic leak (AL) remains unclear. Thus, we assessed the influence of radiation on cervical AL in patients undergoing preoperative CCRT followed by esophagectomy.Patients and Methods: We defined the SYC zone, a portion of the region overlapping the left SCF. The radiation dose to the SYC zone was analyzed and correlated with AL in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were administered preoperative CCRT (radiation dose with 50– 50.4 Gy/25-28 Fx to the primary esophageal tumor) followed by esophagectomy between October 2009 and January 2018. Receiver operating characteristic curve analysis and logistic regression were used to identify the optimal radiation factor to predict AL and the cutoff value.Results: The optimal radiation factor to predict AL was the mean dose to the SYC zone (area under the curve (AUC)=0.642), and the cutoff point of the mean dose was 48.55 Gray (Gy). For a mean SYC zone dose ≥ 48.55 Gy, the AL risk was sevenfold greater than that for < 48.55 Gy (OR = 7.805; 95% CI: 1.184 to 51.446; P value = 0.033).Conclusion: Recognizing the SYC zone as an organ at risk and performing radiation evaluation are meaningful. A reduced mean dose of the SYC zone below 48.55 Gy results in a lower cervical AL rate following esophagectomy.Keywords: esophageal squamous cell carcinoma, preoperative concurrent chemoradiotherapy, radiation therapy

Bee Kim Tan,1 Ping Chong Bee,2 Siew Siang Chua,1 Li-Chia Chen3 1School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, 47500, Malaysia; 2Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 3Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UKCorrespondence: Bee Kim TanSchool of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, 47500, MalaysiaTel +6 03 5629 5000Email beekim.tan@taylors.edu.myPurpose: Suboptimal adherence to tyrosine kinase inhibitors (TKIs) is a widely recognized issue compromising the disease control and survival of patients with chronic myeloid leukemia (CML). A recently published review by Heiney et al reported inconclusive findings on the effects of a broad range of adherence enhancing interventions. The current systematic review aimed to identify studies that evaluated adherence-enhancing interventions implemented by healthcare professionals and determine their effect on CML patients’ medication adherence and clinical outcomes.Methods: A systematic literature search was performed in 5 databases for articles published between 2002 and 2021. Studies that compared adherence enhancing interventions implemented by healthcare professionals with a comparison group were included. Relevant data on study characteristics were extracted. Medication adherence and clinical outcomes between intervention and control arms were compared.Results: Nine studies were included in two randomised controlled trials, four cohort studies, and three before-and-after comparison studies. All the included studies incorporated complex interventions, including intensive education or consultation with pharmacists, nurses or multidisciplinary team, in combination with one or more other strategies such as structured follow-up, written materials or video, psychotherapy, medication reminder or treatment diary, with the overall goal of monitoring and improving TKI adherence. Most (7 out of 9) studies demonstrated significantly better adherence to TKIs in the intervention group than the comparison group. The relative proportion of participants who adhered to TKIs ranged from 1.22 to 2.42. The improvement in the rate of TKI doses taken/received ranged from 1.5% to 7.1%. Only one study showed a significant association between intervention and clinical outcomes, with a 22.6% higher major molecular response rate and improvement in 6 out of 20 subscales of health-related quality-of-life.Conclusion: Complex interventions delivered by healthcare professionals showed improvement in adherence to TKIs in CML patients. Further studies are required to clarify the cost-effectiveness of adherence-enhancing interventions.Keywords: medication adherence, tyrosine kinase inhibitors, chronic myeloid leukemia, systematic review, complex interventions

Wen-Ting Cheng,1,&ast; Hsiu-O Ho,1,&ast; Shyr-Yi Lin,2,3 Der-Zen Liu,4 Ling-Chun Chen,5 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China; 4Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan, Republic of China; 5Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan, Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming-Thau SheuSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan, Republic of ChinaTel/Fax +886 2 2377 1942Email mingsheu@tmu.edu.twLing-Chun ChenDepartment of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, No. 306, Yuanpei Street, Hsinchu, 30015, Taiwan, Republic of ChinaTel/Fax +886 2 2377 1942Email d8801004@mail.ypu.edu.twPurpose: Therapeutic efficacy of pancreatic adenocarcinomas (PACs) with combined therapy of carfilzomib (CFZ) and paclitaxel (PTX) co-loaded in human serum albumin (HSA) nanoparticles (NPs) was examined.Methods: CFZ and PTX were encapsulated individually or combined into HSA NPs by a simple reverse self-assembly method developed to achieve an optimal combination ratio for synergistic therapy. CFZ or/and PTX loaded HSA nanoparticles were physically characterized and the evaluation of combination index, drug release, pharmacokinetic, anti-tumor, and biodistribution studies were conducted.Results: All resultant drug-loaded HSA NPs were spherical with a particle size of < 150 nm and a zeta potential of − 21.1∼− 23.0 mV. Drug loading rates and entrapment efficiencies were 9.1%∼ 10.1% and 90.7%∼ 97.1%, respectively. CFZ and PTX demonstrated synergistic effects in an MIA PaCa-2 cytotoxicity at a 1:2 ratio (CI50 were 0.01∼ 0.25). In vitro dissolution revealed that the CFZ/PTX ratio released from the co-loaded HSA NPs (CFZ/PTX/HSA NPs) was about 1.77∼ 2.08, which conformed to the designated loaded ratio. In vivo evaluation showed that the combined therapy of CFZ and PTX at a 1:2 ratio co-loaded in HSA NPs (CFZ/PTX/HSA NPs) demonstrated optimal synergistic improvement of the growth inhibition of MIA PaCa-2 cells with less systematic toxicity, even though the pharmacokinetic profiles observed did not show obvious beneficial and their biodistributions in tumors were found to be smaller.Conclusion: The one-pot reverse assembly method developed was environmentally friendly and capable of co-loading an optimal combination ratio of two chemodrugs into HSA NPs for synergistic therapy.Keywords: human serum albumin, nanoparticles, carfilzomib, paclitaxel, co-loading, synergism

Wei-Jie Cheng,1,* Shyr-Yi Lin,2,3,* Michael Chen,4 Ling-Chun Chen,5 Hsiu-O Ho,1 Kuo-Hsiang Chuang,4,6 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 5Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan; 6Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Kuo-Hsiang Chuang; Ming-Thau Sheu Email khchuang@tmu.edu.tw; mingsheu@tmu.edu.twPurpose: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy.Methods: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy.Results: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects.Conclusion: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.Keywords: lecithin-stabilized mPEGylated mixed polymeric micelle, bispecific antibody, trispecific antibody, active targeting, tumor-associated fibroblast, tumor antigen

Meng-Tsang Hsieh,1– 3,* Kuo-Chang Huang,4,* Cheng-Yang Hsieh,5,6 Tzu-Tung Tsai,1 Li-Ching Chen,1 Sheng-Feng Sung7– 9 1Stroke Center and Department of Neurology, E-Da Hospital, Kaohsiung, Taiwan; 2School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Division of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan; 5Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan; 6School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Division of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan; 8Department of Information Management and Institute of Healthcare Information Management, National Chung Cheng University, Chiayi County, Taiwan; 9Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan, Taiwan*These authors contributed equally to this workCorrespondence: Sheng-Feng SungDivision of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, TaiwanTel +886 5 276 5041 Ext 7283Fax +886 5 278 4257Email richard.sfsung@gmail.comPurpose: The performance of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for identifying acute hemorrhagic stroke in Taiwan’s National Health Insurance claims database has not been assessed. This study aimed to construct and validate the case definitions for acute hemorrhagic stroke based on ICD-10-CM diagnostic codes.Patients and Methods: From January 2018 to December 2019, all inpatient records with ICD-10-CM code of I60 or I61 in any field of the discharge diagnoses were retrieved from the hospitalization claims data and all hospitalizations with a final diagnosis of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) were identified from the stroke registry databases. The clinical diagnosis in the stroke registry was treated as the reference standard. For hospitalizations not recorded in the stroke registry, manual review of the medical records and images was done to ascertain the diagnosis. The positive predictive value (PPV) and sensitivity of various case definitions for acute hemorrhagic stroke were estimated.Results: Among the 983 hospitalizations, 860, 111, and 12 were determined to be true-positive, false-positive, and false-negative episodes of acute hemorrhagic stroke, respectively. The PPV and sensitivity of the ICD-10-CM codes of I60 or I61 for identifying acute hemorrhagic stroke were 88.6% and 98.6%, respectively. The PPV increased to 98.2%, whereas the sensitivity decreased to 93.1% when acute hemorrhagic stroke was defined as hospitalizations in which the primary diagnosis field contained I60 or I61. Hemorrhagic transformation of ischemic stroke and concomitant cerebrovascular diseases other than SAH or ICH were the main reasons for a false-positive and false-negative diagnosis of acute hemorrhagic stroke, respectively.Conclusion: This study demonstrated the performance of ICD-10-CM codes for identifying acute hemorrhagic stroke and may offer a reference for future claims-based stroke studies.Keywords: administrative claims data, diagnosis, ICD-10-CM, hemorrhagic stroke

Hong-Liang Lin,1 Wen-Ting Cheng,2 Ling-Chun Chen,3 Hsiu-O Ho,2 Shyr-Yi Lin,4,5 Chien-Ming Hsieh2 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China; 2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan, Republic of China; 3Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 30015, Taiwan, Republic of China; 4Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, Republic of China; 5Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, Republic of ChinaCorrespondence: Shyr-Yi Lin; Chien-Ming Hsieh 250 Wu-Hsing Street, Taipei 11031, Taiwan, Republic of ChinaTel +886-2-27361661 ext 6112Fax +886-2-23771942Email sylin@tmu.edu.tw; cmhsieh@tmu.edu.twObjective: This study was intended to utilize lecithin-based mixed polymeric micelles (lbMPMs) for enhancing the solubility and bioavailability of honokiol and magnolol to resolve the hindrance of their extreme hydrophobicity on the clinical applications.Methods: Lecithin was selected to increase the volume of the core of lbMPMs, thereby providing a greater solubilization capacity. A series of amphiphilic polymers (sodium deoxycholate [NaDOC], Cremophor®, and Pluronic® series) were included with lecithin for screening and optimization.Results: After preliminary evaluation and subsequentially optimization, two lbMPMs formulations composed of honokiol/magnolol:lecithin:NaDOC (lbMPMs[NaDOC]) and honokiol/magnolol:lecithin:PP123 (lbMPMs[PP123]) in respective ratios of 6:2:5 and 1:1:10 were optimally obtained with the mean particle sizes of 80– 150 nm, encapsulation efficacy (EEs) of > 90%, and drug loading (DL) of > 9.0%. These lbMPMs efficiently stabilized honokiol/magnolol in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C. PK study demonstrated that lbMPMs[NaDOC] showed much improvement in enhancing bioavailability than that by lbMPMs[PP123] for both honokiol and magnolol. The absolute bioavailability for honokiol and magnolol after intravenous administration of lbMPMs[NaDOC] exhibited 0.93- and 3.4-fold increases, respectively, compared to that of free honokiol and magnolol. For oral administration with lbMPMs[NaDOC], the absolute bioavailability of honokiol was 4.8%, and the absolute and relative bioavailability of magnolol were 20.1% and 2.9-fold increase, respectively.Conclusion: Overall, honokiol/magnolol loaded in lbMPMs[NaDOC] showed an improvement of solubility with suitable physical characteristics leading to enhance honokiol and magnolol bioavailability and facilitating their wider application as therapeutic agents for treating human disorders.Keywords: lecithin, mixed polymeric micelles, honokiol, magnolol, sodium deoxycholate, pluronic

Hong-Liang Lin,1 Ting-Huan Wu,2 Hsiu-O Ho,2 Fang-Ching Chao,2 Meng-Huang Wu,3,4 Der-Zen Liu,5 Ling-Chun Chen,6 Ming-Thau Sheu2 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China; 2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China; 3Department of Orthopedics, Taipei Medical University Hospital, Taipei, Taiwan, Republic of China; 4Department of Orthopedics, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China; 5Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, Republic of China; 6Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan, Republic of ChinaCorrespondence: Ling-Chun Chen; Ming-Thau SheuTaipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan, Republic of ChinaTel +886-2-27361661 ext. 6112Fax +886-2-23771942Email d8801004@tmu.edu.tw; mingsheu@tmu.edu.twIntroduction: In this study, the combination of TEMPO-oxidized sacchachitin nanofibers (TOSCNFs) with chitosan-activated platelet-rich plasma (cPRP) was evaluated for remedying dry eye syndrome (DES).Methods: TOSCNFs, designated T050SC, were generated. T050SC combined with chitosan-activated (cPRP) was formulated as eye drops for application for severe DES. To evaluate the effects of cPRP and TOSCNFs on the repair of corneal injury, in vitro studies were conducted using Statens Seruminstitut rabbit corneal (SIRC) epithelial cells for cell proliferation and cell migration assays, and a severe DES animal model using rabbits was established with benzalkonium chloride (BAC) treatment for the evaluation.Results: Results showed that the optimal eye formulation contained PRP activated by 350 μg/mL of the low-molecular-weight chitosan group (L3) combined with 300 μg/mL TO50SC (L3+T050SC). In the WST-1 cell-proliferation assay, L3 and L3+TO50SC significantly increased Statens SIRC cell proliferation after 24 hrs of incubation. In the SIRC cell migration assay, the L3+TO50SC group showed a wound-healing efficiency of 89% after 24-hr treatment. After 5 days of treatment, Schirmer’s test results did not simulate the dry eye animal model. Typical cornea appearance and eye fluorescein staining results showed that the L3 group had the best effect on improving cornea haze and epithelial damage.Conclusion: This study has determined that TOSCNFs effectively promoted the healing effect on severe cases of corneal damage, and also might enhance the clinical application and medical potential of PRP in ophthalmology.Keywords: TEMPO-oxidation, sacchachitin, PRP, dry eye syndrome, nanofibers

Guan-Sheng Zeng,* Li-Chang Chen,* Hui-Zhen Fan, Ling-Ling Wu, Xi-Ping Wu, Ze-Kui Fang, Xi He, Hua-Peng Yu Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China *These authors contributed equally to this work Background and objective: The distance of 6-minute walk test (D6MWT) has been widely used in the assessment of functional status in patients with COPD, while very little attention has been paid to the role of steps of 6-minute walk test (S6MWT). The purpose of this study was to investigate the relationship between S6MWT and other physiologic parameters of COPD. Patients and methods: Seventy patients with stable COPD were enrolled consecutively in this cross-sectional study. Pulmonary function tests, including spirometry, impulse oscillometry (IOS) and the single-breath diffusing capacity of the lungs for carbon monoxide (DLCO), were carried out at rest. Quality of life was assessed by health-related quality of life (HRQoL) questionnaires, including modified Medical Research Council dyspnea scale (mMRC), St George’s Respiratory Questionnaire, Chronic Obstructive Pulmonary Disease Assessment Test (CAT) and Clinical Chronic Obstructive Pulmonary Questionnaire. Both steps and distance were measured in the following 6-minute walk test (6MWT). Results: Both S6MWT and D6MWT showed significant correlation with spirometry, IOS, DLCO parameters and HRQoL questionnaires score. Both pre- and post-6MWT inspiratory capacity showed significant correlation with S6MWT (ρ=0.338, P=0.004; ρ=0.359, P=0.002, respectively), whereas did not correlate with D6MWT (ρ=0.145, P=0.230; ρ=0.160, P=0.189, respectively). In stepwise multiple regression analysis, mMRC grade, age and CAT score remained as significant predictors in the final model for D6MWT (adjusted R2=0.445, P

Wei-Jie Cheng,1,* Ling-Chun Chen,2,* Hsiu-O Ho,1 Hong-Liang Lin,3 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan; 3School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan *These authors contributed equally to this work Purpose: In this study, a double emulsion method for complexing plasmids with stearyl polyethylenimine (stPEI) as the core to form human serum albumin (HSA) (plasmid/stPEI/HSA) nanoparticles (NPs) was developed for gene delivery by non-covalently binding onto plasmid/stPEI/HSA nanoparticles with CRISPR/Cas9 or siRNA, which disrupts or silences the expression of programmed cell death ligand-1 (PD-L1) for immunotherapy. Materials and methods: Chemically synthesized stearyl-polyethyenimine (stPEI)/ plasmids /HSA nanoparticles were maded by double emulsion method. They were characterized by dynamic light scattering (DLS), transmission electron microscope and also evaluated by in vitro study on CT 26 cells. Results: stPEI was synthesized by an N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC)–N-hydroxysuccinimide (NHS) reaction, and we found that the degree of substitution was ~1.0 when the ratio of PEI to stearic acid was 1:7 in the reaction. Then, two sgRNA sequences were selected and evaluated for their ability to knock out PD-L1 by decreasing its expression by about 20%. Based on the trend of particle size/zeta potential values as a function of ratio, F25P1 containing 25 µg of plasmid/stPEI/HSA NPs noncovalently bound to 1 µg plasmids via charge–charge interactions was found to be optimal. Its particle size was about 202.7±4.5 nm, and zeta potential was 12.60±0.15 mV. In an in vitro study, these NPs showed little cytotoxicity but high cellular uptake. Moreover, they revealed the potential for transfection and PD-L1 knockout in an in vitro cell model. Furthermore, F25P1S0.5 containing 25 µg of plasmid/stPEI/HSA NPs noncovalently bound to 1 µg of plasmids and 0.5 µg siRNA was prepared to simultaneously deliver plasmids and siRNA. An in vitro study demonstrated that the siRNA did not interfere with the transfection of plasmids and showed a high-transfection efficiency with a synergistic effect on inhibition of PD-L1 expression by 21.95%. Conclusion: The plasmids/stPEI/HSA NPs could be a promising tool for gene delivery and improved immunotherapy. Keywords: stearyl polyethylenimine, human serum albumin nanoparticles, PD-L1, CRISPR, Cas9, siRNA, gene delivery

Bee Kim Tan,1,2 Seng Beng Tan,3 Li-Chia Chen,4 Kian Meng Chang,5 Siew Siang Chua,1,6 Sharmini Balashanker,7 Habiba Nazeera Begum Kamarul Jaman,5 Syed Carlo Edmund,8 Ping Chong Bee3 1Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia; 3Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 4Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; 5Department of Hematology, Ampang Hospital, Ampang, Selangor, Malaysia; 6School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Lakeside Campus, Subang, Selangor, Malaysia; 7School of Pharmacy, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia; 8Clinical Research Center, Ampang Hospital, Ampang, Selangor, Malaysia Purpose: Poor adherence to tyrosine kinase inhibitors (TKIs) could compromise the control of chronic myeloid leukemia (CML) and contributes to poorer survival. Little is known about how medication-related issues affect CML patients’ adherence to TKI therapy in Malaysia. This qualitative study aimed to explore these issues.Patients and methods: Individual face-to-face, semistructured interviews were conducted at the hematology outpatient clinics of two medical centers in Malaysia from August 2015 to January 2016. CML patients aged ≥18 years who were prescribed a TKI were invited to participate in the study. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed.Results: Four themes were identified from 18 interviews: 1) concerns about adverse reactions to TKIs, 2) personal beliefs regarding the use of TKIs, 3) mismanagement of TKIs in daily lives, and 4) financial burden in accessing treatment. Participants skipped their TKIs due to ineffective emesis control measures and perceived wastage of medication from vomiting. Participants also modified their TKI therapy due to fear of potential harm from long-term use, and stopped taking their TKIs based on belief in curative claims of traditional medicines and misconception about therapeutic effects of TKIs. Difficulty in integrating the dosing requirements of TKIs into daily lives led to unintentional skipping of doses, as well as the risk of toxicities from inappropriate dosing intervals or food interactions. Furthermore, financial constraints also resulted in delayed initiation of TKIs, missed clinic appointments, and treatment interruptions.Conclusion: Malaysian CML patients encountered a range of medication-related issues leading to a complex pattern of nonadherence to TKI therapy. Further studies should investigate whether regular contact with patients to improve understanding of treatment rationale, to elicit and address patients’ concerns about adverse reactions, and to empower patients with skills to self-manage their medications might promote better adherence to TKIs and improve CML patients’ outcome. Keywords: medication-related issues, adherence, tyrosine kinase inhibitors, chronic myeloid leukemia, qualitative study, thematic analysis

Ling-Chun Chen,1,* Ying-Chen Chen,1,* Chia-Yu Su,1 Chung-Shu Hong,1 Hsiu-O Ho,1 Ming-Thau Sheu1,2 1School of Pharmacy, College of Pharmacy, 2Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Abstract: Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic® P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60±5.02 nm, 0.589±0.198, 96.87%±9.04%, and 12.18%±1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17–7.7 µg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 µM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration–time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core–shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability. Keywords: quercetin, micelle, lecithin, Pluronic®, DSPE-PEG, mixed micelles, bioavailability

Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome) was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc) showed a high relationship between cell number and its bioluminescent intensity (R2=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P

GA Walker,1 M Xenophontos,2 LC Chen,3 KL Cheung2 1Clinical Oncology, East Midlands Deanery, 2Breast Surgery, School of Graduate Entry Medicine and Health; 3Medicine Use, School of Pharmacy, University of Nottingham, Nottingham, UK Abstract: Exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948–2012), Embase (1980–2012), and Web of Science (1899–2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease, exemestane is superior to megestrol acetate after progression on tamoxifen. There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2–3 years of tamoxifen is superior to 5 years of tamoxifen. Exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in “at-risk” postmenopausal women. Exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence shows nonadherence in 23%–32% of patients. Evidence is growing in support of exemestane in all clinical settings. It is generally more efficacious and has a better safety profile than tamoxifen. How it compares with the nonsteroidal aromatase inhibitors remains to be established. Further studies are required on adherence to ensure that maximum benefit is obtained. Keywords: breast cancer, exemestane, review, adherence, metastatic, adjuvant

Ray-Neng Chen,1,* Lin-Wen Lee,2,5,* Ling-Chun Chen,3 Hsiu-O Ho,3 Shiao-Chuan Lui,2 Ming-Thau Sheu,3,4 Ching-Hua Su2 1Department of Cosmetic Science and Management, Mackay Medicine, Nursing and Management College, Taipei, 2Department of Microbiology and Immunology, School of Medicine, College of Medicine, 3School of Pharmacy, College of Pharmacy, 4Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei Medical University, 5Research Center for Biomedical Devices and Prototyping Production, Taipei Medical University, Taipei, Taiwan, Republic of China*These authors contributed equally to this workAbstract: The extraction residue of the Ganoderma fruiting body, named sacchachitin, has been demonstrated to have the potential to enhance cutaneous wound healing by inducing cell proliferation. In this study, a nanogel formed from micronized sacchachitin (mSC) was investigated for the potential treatment of superficial chemical corneal burns. Reportedly, mSC has been produced successfully and its chemical properties confirmed, and physical and rheological properties characterized. An in vitro cell proliferation study has revealed that at the concentrations of 200, 300, and 400 µg/mL, mSC nanogel significantly increased Statens Seruminstitut rabbit corneal (SIRC) cell proliferation after 24 hours of incubation. In cell migration assay, migration of SIRC cell to wound closure was observed after 24 hours of incubation with the addition of 200 µg/mL mSC of nanogel. In an animal study, acceleration of corneal wound healing was probably due to the inhibition of proteolysis. In conclusion, the findings of this study substantiate the potential application of sacchachitin in the form of mSC nanogel for the treatment of superficial corneal injuries.Keywords: corneal wound healing, sacchachitin, matrix metalloproteinase

Wen-Chuan Lee1,*, Chih-Hsien Chang2,3,*, Chih-Min Huang1, Yu-Tse Wu1, Liang-Cheng Chen2, Chung-Li Ho2, Tsui-Jung Chang2, Te-Wei Lee2, Tung-Hu Tsai1,41Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, 2Division of Isotope Application, Institute of Nuclear Energy Research, Taoyuan, 3Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 4Department of Education and Research, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workBackground: The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [111In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111In-VNB-liposome.Methods: The VNB-liposome and 111In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111.Results: High uptake of the 111In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation (r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111In-VNB-liposome.Conclusion: A significant positive correlation between the pharmacokinetics and biodistribution of 111Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the 111In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation.Keywords: Indium-111, vinorelbine, liposome, pharmacokinetics, radiochemotherapy

Chia-Che Tsai1, Chih-Hsien Chang1, Liang-Cheng Chen1, Ya-Jen Chang1, Keng-Li Lan2, Yu-Hsien Wu1, Chin-Wei Hsu1, I-Hsiang Liu1, Chung-Li Ho1, Wan-Chi Lee1, Hsiao-Chiang Ni1, Tsui-Jung Chang1, Gann Ting3, Te-Wei Lee11Institute of Nuclear Energy Research, Taoyuan, 2Cancer Center, Taipei Veterans General Hospital, Taipei, 3National Health Research Institutes, Taipei, Taiwan, ROCBackground: Nanoliposomes are designed as carriers capable of packaging drugs through passive targeting tumor sites by enhanced permeability and retention (EPR) effects. In the present study the biodistribution, pharmacokinetics, micro single-photon emission computed tomography (micro-SPECT/CT) image, dosimetry, and therapeutic efficacy of 188Re-labeled nanoliposomes (188Re-liposomes) in a C26 colonic peritoneal carcinomatosis mouse model were evaluated.Methods: Colon carcinoma peritoneal metastatic BALB/c mice were intravenously administered 188Re-liposomes. Biodistribution and micro-SPECT/CT imaging were performed to determine the drug profile and targeting efficiency of 188Re-liposomes. Pharmacokinetics study was described by a noncompartmental model. The OLINDA|EXM® computer program was used for the dosimetry evaluation. For therapeutic efficacy, the survival, tumor, and ascites inhibition of mice after treatment with 188Re-liposomes and 5-fluorouracil (5-FU), respectively, were evaluated and compared.Results: In biodistribution, the highest uptake of 188Re-liposomes in tumor tissues (7.91% ± 2.02% of the injected dose per gram of tissue [%ID/g]) and a high tumor to muscle ratio (25.8 ± 6.1) were observed at 24 hours after intravenous administration. The pharmacokinetics of 188Re-liposomes showed high circulation time and high bioavailability (mean residence time [MRT] = 19.2 hours, area under the curve [AUC] = 820.4%ID/g*h). Micro-SPECT/CT imaging of 188Re-liposomes showed a high uptake and targeting in ascites, liver, spleen, and tumor. The results were correlated with images from autoradiography and biodistribution data. Dosimetry study revealed that the 188Re-liposomes did not cause high absorbed doses in normal tissue but did in small tumors. Radiotherapeutics with 188Re-liposomes provided better survival time (increased by 34.6% of life span; P < 0.05), tumor and ascites inhibition (decreased by 63.4% and 83.3% at 7 days after treatment; P < 0.05) in mice compared with chemotherapeutics of 5-fluorouracil (5-FU).Conclusion: The use of 188Re-liposomes for passively targeted tumor therapy had greater therapeutic effect than the currently clinically applied chemotherapeutics drug 5-FU in a colonic peritoneal carcinomatosis mouse model. This result suggests that 188Re-liposomes have potential benefit and are safe in treating peritoneal carcinomatasis of colon cancer.Keywords: biodistribution, dosimetry, 5-fluorouracil, micro-SPECT/CT, 188Re-liposomes

Abstract The energy relaxation of electrons in γ-In2Se3nanorods was investigated by the excitation-dependent photoluminescence (PL). From the high-energy tail of PL, we determine the electron temperature (T e) of the hot electrons. TheT evariation can be explained by a model in which the longitudinal optical (LO)-phonon emission is the dominant energy relaxation process. The high-quality γ-In2Se3nanorods may be a promising material for the photovoltaic devices.