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Purpose To determine the intensity of corneal pigmented arc in orthokeratology (ortho-k)-treated children and its correlation with wide epithelial thickness map (ETM) obtained through anterior segment optical coherent tomography (AS-OCT). Methods This retrospective case series reviews medical records of children who received ortho-k treatment for myopia control. Intensity of ortho-k-associated pigmented arc after wearing ortho-k lens more than 12 months and its correlation with each sector/zone of wide ETM obtained by AS-OCT was explored. Pigmented arcs were further divided into apparent and unapparent groups, and the clinical differences between groups were determined. Results This study included 57 eyes of 29 children (mean age, 11.4 years, range 9–15); after initiating ortho-k treatment, the incidence of the corneal pigmented arc was 91.2% with mean lens wear duration of 26.1 months. Intensity of pigmented arc was significantly correlated with lens wear duration, target power, baseline degree of myopia, C zone and sectors I2, I3 and IT3 on wide ETM. Comparison between apparent and unapparent groups showed the same significant results except for C zone. After adjusting for lens wear duration and target power, sector I2 has the highest association with pigmented arc severity. Conclusion Children treated with ortho-k are likely to develop ortho-k-associated pigmented arcs. The new wide ETM of AS-OCT can provide important information regarding the intensity of pigmented arc in these children. This can support customized pigmented arc-free ortho-k treatment for children in the future.

Background Pseudoprogression is difficult to diagnose in patients undergoing immunotherapy. Subjective response assessment is still common in clinical practice. Purpose To evaluate the differences between response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), immune-related response criteria (irRC), and modified RECIST 1.1 for immunotherapy (iRECIST) through semi-automatic software, and to compare iRECIST-based response evaluation with subjective assessment. Material and Methods The best overall response of each patient based on RECIST 1.1, irRC, and iRECIST was determined on CT scans through semi-automatic software and the differences between the criteria were evaluated. Criteria-based response evaluation through semi-automatic software was compared with subjective assessment on radiology report by correlating the best overall response to overall survival. Results A total of 21 patients were included (five patients with melanoma, 12 patients with non-small-cell lung cancer, and four patients with hepatocellular carcinoma). Two patients with progressive disease by RECIST 1.1 but non-progressive disease by irRC and iRECIST eventually experienced tumor response and had favorable outcomes, indicating pseudoprogression. The survival difference between patients with non-progressive disease and progressive disease was better stratified through iRECIST-based response evaluation ( P = 0.078) than that through subjective assessment ( P = 0.501). Conclusion Pseudoprogression in immunotherapy may be captured through semi-automatic software utilizing irRC or iRECIST criteria. iRECIST-based response evaluation may provide a better survival stratification compared with subjective assessment.

Background We previously developed a robust prognostic model (GS model) to predict the survival outcome of patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy with gemcitabine plus S‐1 (GS). This study aimed to validate the application of the GS model in APC patients receiving chemotherapy other than the GS regimen. Patients and methods We retrospectively analyzed 727 APC patients who received first‐line palliative chemotherapy other than the GS regimen between 2010 and 2016 at four institutions in Taiwan. The patients were categorized into three prognostic groups based on the GS model for comparisons of survival outcome, best tumor response, and in‐group survival differences with monotherapy or combination therapy. Results The median survival times for the good, intermediate, and poor prognostic groups were 13.4, 8.4, and 4.6 months, respectively. The hazard ratios for the comparisons of intermediate and poor to good prognostic groups were 1.51 (95% confidence interval [CI]), 1.22‐1.88, P, This study provided validation of the previously developed gemcitabine + S‐1 model in predicting the survival outcome of advanced pancreatic cancer patients receiving first‐line palliative chemotherapy.

BackgroundsBranch retinal vein occlusion (BRVO) is one of the most important causes of visual loss in retinal vascular diseases. The aim of this study is to predict the treatment response of anti-vascular endothelial growth factor (anti-VEGF) therapy in BRVO using semi-automated quantified fluorescein angiography (FA) features.MethodsThis retrospective case-control study enrolled patients with BRVO who are receiving anti-VEGF therapy and have been followed up for > 1 year. Those receiving ResultsEighty-nine patients (56 males, 33 females, mean age 62.5 ± 10.9 years) with BRVO were enrolled. Of the 89 eyes, 47 (53%) were in the responsive group and 42 (47%) were in the refractory group. The refractory group had a significantly higher number of anti-VEGF injections in the first year (5.9 ± 1.6 versus 2.4 ± 1.2,p p = 0.011), post-treatment best CRT (p p p p p = 0.005 andp = 0.016, respectively) when predicting treatment response.ConclusionThe refractory group had a more severe fluorescein leakage over the parafoveal and the perifoveal regions than the responsive group had. Semi-automated quantified FA leakage can be used as a biomarker for the prediction of anti-VEGF treatment response in macular edema due to BRVO.

Background The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. Methods We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Results: Overall, the patients who experienced grade 1–2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27–0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24–1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21–0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17–0.69, p = 0.003) than patients without any of these irAEs. Conclusions Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1–2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Background Femtosecond laser-assisted cataract surgery (FLACS) has been reported to reduce phacoemulsification time and energy compared to the manual phacoemulsification technique. This technique has been used in several complex cases such as zonular weakness, subluxated lens and traumatic cataracts because it causes less damage to weakened zonules. However, corneal opacity is considered a relative contraindication to FLACS, as it may interfere with laser beam delivery, thus causing unpredictable capsulorhexis and lens fragmentation/liquefaction. Case presentation We present here a case with traumatic cataract and corneal opacity after laser-assisted in situ keratomileusis (LASIK). The patient was successfully treated using FLACS, capsular tension ring and intraocular lens (IOL) implantation. Posterior capsule rupture and vitreous loss were noted during the operation. However, the intraocular lens was successfully captured because of a complete capsulorhexis performed by FLACS. Conclusion This case report demonstrates that FLACS is a useful tool in selected patients with concurrent corneal opacity and traumatic cataract.

No gold standard of nutritional assessment is established among patients with head and neck cancer (HNC) receiving concurrent chemoradiotherapy (CCRT). This study aimed to evaluate the clinical significance of pre-treatment nutritional status using the Mini Nutritional Assessment-short form (MNA-SF) among HNC patients receiving CCRT. A total of 461 consecutive patients with newly diagnosed HNC treated with definitive CCRT at three medical institutes were prospectively enrolled. Nutritional status was assessed using MNA-SF within 7 days before CCRT initiation. Patients were classified as having normal nutrition, at risk of malnutrition, and malnourished groups according to MNA-SF for comparison. The 1-year overall survival rates were 89.8%, 76.8%, and 67.7% in the normal nutrition, at risk of malnutrition, and malnourished groups, respectively. Patients with normal nutrition had significantly lower rates of uncompleted radiotherapy and chemotherapy (4.5% and 4.1%, respectively) compared with patients at risk for malnutrition (14.1% and 11.5%, respectively) and those malnourished (11.1% and 11.1%, respectively). Patients with normal nutrition had significantly lower treatment-related complication rates regarding emergency room visits, hospital admission, and need for tubal feeding than those with at risk of malnutrition and malnourished. Patients with normal nutrition had significantly fewer severe hematologic toxicities (p = 0.044) and severe non-hematologic toxicities (p = 0.012) of CCRT than those malnourished. Pre-CCRT nutritional status identifies HNC patients vulnerable to treatment interruption and treatment complications. We suggest that nutritional assessment with MNA-SF should be incorporated in pre-CCRT evaluation for all HNC patients.

Aim Pazopanib is a multitargeted tyrosine kinase inhibitor used as a standard treatment for chemotherapy-refractory recurrent or metastatic soft tissue sarcoma. This study aimed to evaluate the efficacy and safety of pazopanib for treatment of metastatic soft tissue sarcoma in the Asian population. Methods Fifty patients with chemotherapy-refractory recurrent or metastatic soft tissue sarcoma, who had received pazopanib treatment between 2015 and 2016 were enrolled. We reviewed patients' clinical characteristics and studied survival outcomes following pazopanib treatment. Results Median follow-up was 5.7 months. Seven patients were still on pazopanib by the end of this study and the disease had progressed in the other 43 patients, leading to 23 deaths. We found that despite treatment more than half the patients experienced disease progression (56% vs 14% partial response and 30% stable disease). The median progression-free survival and overall survival was 3.1 and 11.0 months, respectively. Multivariate analysis identified good Eastern Cooperative Oncology Group performance status (0 or 1) and occurrence of hand-foot skin reaction as independent factors associated with better outcome. Hand-foot skin reaction was 32% in our cohort and the median onset time was 4 (1.00-8.29) weeks. It had dose-dependent effect by clinical observation. Conclusions Our study showed that the incidence rate of hand-foot skin reaction in Taiwan is higher than western population, and it is an independent predictive factor for better treatment outcomes.

Background: To clarify the effect of induction chemotherapy (ICT) in patients with advanced pharyngeal and laryngeal squamous cell carcinoma (PLSCC) treated with concurrent chemoradiotherapy (CCRT). Methods: Patients with treatment-naïve nonmetastatic advanced PLSCC were stratified according to disease stage (III or IV) and resectability before being randomized to either a ICT/CCRT or CCRT arm. A cisplatin/tegafur-uracil/leucovorin regimen was administered during ICT and CCRT. The primary end point was overall survival (OS). Results: We enrolled 151 patients during December 2006 to February 2011. The median follow-up of surviving patients was 54.5 months. The ICT/CCRT arm included more patients with hypopharynx cancer (57.1% vs 40.5%, p = 0.09) and N2 or N3 diseases (85.7% vs 74.4%, p = 0.02). In the ICT/CCRT and CCRT arms, the 5-year OS was 48.1% and 53.2% (p = 0.45); progression-free survival (PFS) was 31.8% and 55.6% (p = 0.015); and locoregional control (LRC) was 37.7% and 56.2% (p = 0.026), respectively. The adverse events and compliance to radiotherapy were similar. However, the proportion of patients receiving a total dose of cisplatin during CCRT

Purpose Data on end-of-life care practices in Asia are scarce. This study aimed to analyze the clinical factors associated with the recommended premedication protocol for mechanical ventilation withdrawal, in Taiwan. Methods A total of 135 terminally ill patients who had mechanical ventilation withdrawn between 2013 and 2016 from a single medical center in Taiwan were enrolled. A premedication protocol of morphine and midazolam intravenous bolus was routinely recommended for the patients before mechanical ventilation withdrawal. Receipt of opioids and/or benzodiazepines during the withdrawal process was defined as full (both), partial (1 drug), and no (none) adherence. The clinical factors relevant to the adherence of recommended premedication protocol for mechanical ventilation withdrawal were analyzed. Results Overall, 126 (93.3%) patients died, 8 (5.9%) patients were transferred to other institutions for further care, and 1 (0.7%) patient was discharged to home after mechanical ventilation withdrawal. The median survival time was 45 minutes, and 102 (75.6%) patients died within 1 day after the withdrawal process. The full, partial, and no adherence rates for premedication guideline were 17.8%, 40.0%, and 42.2%, respectively. The main diagnosis of cancer, receipt of hospice care, and preservation of spontaneous respiration were independent variables associated with the partial or full adherence to the premedication protocol. Conclusion Our data show that adherence to the premedication protocol for mechanical ventilation withdrawal in terminally ill patients was inadequate in Taiwan. Promoting hospice care and educating medical personnel in the compassionate withdrawal of mechanical ventilation, especially in patients with noncancer disease, are warranted.

Various blood collection methods were developed and used in the pharmacokinetic evaluation of drugs. However, the influence of different blood sampling methods on plasma drug concentrations has not been clarified. In the present study, we aimed to determine whether the plasma concentration of a target drug changes based on the collection site and elucidate the mechanism responsible for this change. We compared three blood sampling methods commonly used in small animals. Eight clinical drugs were selected and administered to rats simultaneously via intracardiac injection or oral gavage. Blood samples were collected from different sites at the same individual, and pharmacokinetic properties of the drugs were then evaluated. Study results showed that the maximum plasma concentration or area under the curve of three study drugs was significantly higher in rats when blood was sampled from the carotid artery than when it was sampled from the caudal vein or by tail snip. Pharmacokinetics of certain drugs may differ based on the blood sampling site. The acid-base properties of drugs may influence pharmacokinetic evaluation. The rate and extent of drug distribution may also cause such differences and have significant effects on plasma drug levels.

A simplified, rapid, and selective liquid chromatography-tandem mass spectrometry method for the determination of the activities of cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in two separate settings was developed and successfully applied to 8 CYP isoenzymes and UGT2B7 enzyme activities in rat liver microsomes. The triple-quadrupole mass spectrometric detection was operated in positive mode for the probe metabolites: CYP1A2 (resorufin), CYP2B6 (hydroxybupropion), CYP2C19 (5-hydroxyomeprazole), CYP2D6 (dextrophan), CYP3A4 (6β-hydroxytestosterone), and UGT2B7 (morphine-3-glucuronide); also in negative mode for CYP2C9 (4-hydroxytolbutamide), CYP2E1 (6-hydroxychloroxazone), and CYP4A (hydroxylauric acid). The metabolic reactions were terminated with acetonitrile, containing metoprolol and acetaminophen as the internal standard for positive and negative ion electrospray ionization, respectively. The method was validated over the concentration range of 25-2500 ng/mL for 5-hydroxyomeprazole, dextrophan, hydroxylauric acid, and morphine-3-glucuronide; 5-500 ng/mL for resorufin; 3-300 ng/mL for hydroxybupropion; 10-1000 ng/mL for 4-hydroxytolbutamide; 40-4000 ng/mL for 6-hydroxychloroxazone; and 63-6300 ng/mL for 6β-hydroxytestosterone. All of the extraction recoveries of these analytes were greater than 85%, except for hydroxylauric acid at mid-concentration with a recovery of 83.2% ± 3.2%. The matrix effects were between 85.8% and 119.9%; the respective within- and between-run precisions were 0.9-12.0% and 2.0-13.9%; and the within- and between-run accuracy levels were 0.6-17.2% and 0.1-15.1%, respectively, for all these analytes. All of the analytes were stable during the assay and storage in the liver microsomes of Sprague-Dawley rats. The measurement activity of multiple enzymes was feasible using a cocktail approach. This method proved to be a robust, fast, accurate, specific and sensitive assay, and was successfully used to investigate in vivo enzyme activities of 8 major CYP isoenzymes and UGT2B7 in Sprague-Dawley rats with fatty livers. By the end of the eighth week, the CD-fed induced fatty liver rats showed a significant decrease in the activities of CYP1A2 and UGT2B7 as compared to the standard diet group.

Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.

The purpose of this study is to evaluate the effects of Chinese herbal medicines on the enzymatic activity of CYP3A4 and the possible metabolism-based herb-drug interactions in human liver microsomes and in rats. Fifty single-herbal preparations were screened for the activity of CYP3A4 using human liver microsomes for an in vitro probe reaction study. The enzymatic activity of CYP3A4 was estimated by determing the 6β-hydroxytestosterone metabolized from testosterone performed on a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Huang Qin (Scutellaria baicalensis Geprgi), Mu Dan Pi (Paeonia suffruticosa Andr.), Ji Shiee Terng (Spatholobus suberectus Dunn.) and Huang Qi (Astragalus membranaceus [Fisch] Bge) have been demonstrated to have remarkable inhibiting effects on the metabolism of CYP3A4, whereas Xi Yi Hua (Magnolia biondii Pamp.) exhibited a moderate inhibition. These five single herbs were further investigated in an animal study using midazolam. Mu Dan Pi, Ji Shiee Terng and Huang Qi were observed to have greatly increased in the Cmaxand AUC of midazolam. This study provides evidence of possible herb-drug interactions involved with certain single herbs.

Nalbuphine (NAL) is a potent opioid analgesic, but can only be administered by injection. The major aim of this study was to develop an oral NAL formulation employing known excipients as UDP-glucuronosyltransferase 2B7 (UGT2B7) inhibitors to improve its oral bioavailability.Twenty commonly used pharmaceutical excipients were screened in vitro by using liver microsomes to identify inhibitors of UGT2B7, the major NAL metabolic enzyme. Tween 20 and PEG 400 were potent UGT2B7 inhibitors and both were co-administered (Tween-PEG) with NAL to rats and humans for pharmacokinetic and/or pharmacodynamic analyses.In animal studies, oral Tween-PEG (4 mg/kg of each) significantly increased the area under the plasma NAL concentration-time curve (AUC) and the maximal plasma concentration (Cmax) by 4- and 5-fold, respectively. The results of the pharmacodynamic analysis were in agreement with those of the pharmacokinetic analysis, and showed that Tween-PEG significantly enhanced the analgesic effects of orally administered NAL. In humans, oral Tween-PEG (240 mg of each) also increased NAL Cmax 2.5-fold, and AUC by 1.6-fold.Tween-PEG successfully improved oral NAL bioavailability and could formulate a useful oral dosage form for patient's convenience.

A rapid, simple, sensitive and selective ultraperformance liquid chromatography-tandem spectrometry (UPLC-MS/MS) method for the determination of nalbuphine and its prodrug sebacoly dinalbuphine ester (SDE) was developed and validated in human plasma. The sample pretreatment involves basification and iterative liquid-liquid extraction with ethyl-ether-dichloromethane (7:3, v/v) solution, followed by LC separation and positive electrospray ionization (ESI) API-3000 mass spectrometry detection. The chromatography was on a Waters Acquity UPLC BEH HILIC column (2.1 × 100 mm, 1.7 µm). The mobile phase was composed of acetonitrile and water (83:17, v/v) that contained 0.2% formic acid and 4 mm ammonium formate at a flow rate of 0.25 mL/min. Ethylmorphine and naloxine were selected as the SDE and nalbuphine internal standard (IS), respectively. The calibration curve for both was linear over the range from 0.05 to 20 ng/mL, with correlation coefficients ≥0.995. The lower limit of quantification was set at 0.05 ng/mL. The intra- and inter-day precision values for nalbuphine and SDE were acceptable as per FDA guidelines. The method was applied successfully to determine nalbuphine concentration in human plasma samples obtained from four Taiwanese volunteers receiving intramuscularly administration of sebacoyl dinalbuphine ester. The method is sensitive, selective and directly applicable to human pharmacokinetic studies involving nalbuphine.

A simple, simultaneous, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of triazolam and its metabolites, α-hydroxytriazolam (α-OHTRZ) and 4-hydroxytriazolam (4-OHTRZ), in human urine was developed and validated. Triazolam-d4 was used as the internal standard (IS). This analysis was carried out on a Thermo(®) C(18) column, and the mobile phase was composed of acetonitrile/H(2)O/formic acid (35:65:0.2, v/v/v). Detection was performed on a triple-quadrupole tandem MS using positive ion mode electrospray ionization, and quantification was performed by multiple reaction monitoring mode. The MS-MS ion transitions monitored were m/z 343.1 → 308.3, 359.0 → 331.0, 359.0 → 111.2, and 347.0 → 312.0 for triazolam, α-OHTRZ, 4-OHTRZ, and triazolam-d(4), respectively. The lower limits of quantification of the analytical method were 0.5 ng/mL for triazolam, 5 ng/mL for α-OHTRZ, and 0.5 ng/mL for 4-OHTRZ. The within- and between-run precisions were less than 15%, and accuracy was -12.33% to 9.76%. The method was proved to be accurate and specific, and it was applied to a urinary excretion study of triazolam in healthy Chinese volunteers.