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To identify factors associated with posttraumatic growth (PTG) of head-and-neck cancer squamous cancer (HNC) patients with oncologic emergencies (OE) within the first six months post-treatment.We conducted a cross-sectional study of HNC patients in Taiwan from May 2019 to April 2021 using patient-reported outcomes. Patients were assessed for symptom distress, anxiety, fear of recurrence (FCR), and PTG. Multiple regression analysis was conducted to identify factors associated with PTG. The independent-samples t-test was used to compare PTG and its five specific domains in patients with low FCR, high FCR, low anxiety, and high anxiety.Of the 114 patients surveyed, 46.5% reported little-to-no PTG, and 53.5% had moderate-to-high PTG. Greater PTG was associated with greater FCR, longer time since OE, less anxiety, having a cancer recurrence, and greater educational attainment. These factors explained 38.6% of the variance in PTG.A notable proportion of HNC patients with OE-reported PTG but almost half-reported little-to-no PTG. PTG occurred most in the domain of appreciation of life. The study results also suggest that training patients in coping skills and inviting them to group growth experiences can help them increase PTG and cope with cancer-related psychological threats related to OE.

STUDY OBJECTIVES: This study aimed to identify prospectively the correlation between obstructive sleep apnea (OSA) severity, ocular microcirculation changes, and visual function changes in patients with glaucoma. METHODS: We prospectively enrolled patients with glaucoma who were willing to undergo overnight polysomnography. The enrolled patients were further divided into normal tension glaucoma, high-tension glaucoma, and control. Visual field progression was analyzed using sequential standard automated perimetry. Peripapillary and macular vessel density were assessed through optical coherence tomography angiography (OCT-angiography). The associations between polysomnography parameters, OCT-angiography parameters, and visual field progression were analyzed. RESULTS: A total of 22 patients with normal tension glaucoma, 30 patients with high-tension glaucoma, and 24 control patients were enrolled. Through regression analysis, glaucoma was found to be an independent predictor of moderate-to-severe OSA (P = .035); furthermore, moderate-to-severe OSA was significantly associated with visual field progression (P = .008 in the high-tension glaucoma subgroup and P = .008 in the overall glaucoma). Additionally, OSA severity was negatively correlated with the ganglion cell complex thinning rate in the normal tension glaucoma subgroup. CONCLUSIONS: Presence of glaucoma increased the risk of moderate-to-severe OSA compared with the control group. OSA severity was related to visual field deterioration in patients with glaucoma and further associated with structural progression in the normal tension glaucoma subgroup. Careful monitoring of the comorbid OSA status of patients with glaucoma is essential to prevent disease progression. CITATION: Chan Y-H, Chuang L-H, Yu C-C, et al. Prospective evaluation of the comorbidity of obstructive sleep apnea in patients with glaucoma. J Clin Sleep Med. 2022;18(1):47–56.

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.

Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.

Background: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. Methods: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. Results: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (&gt, 0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031–2.927), 5.497 (95% CI: 1.818–16.615), and 0.176 (95% CI: 0.056–0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102–0.852). Conclusions: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies.

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.

The 2018 Nobel Prize in Physiology or Medicine was awarded to Tasuku Honjo and James Allison for their discoveries in cancer immunology. Professor Honjo was awarded due to his discovery of the programmed death molecule-1 (PD-1) on T cells. Professor Allison discovered another important immunosuppressive molecule: cytotoxic T-lymphocyte antigen-4 (CTLA-4). Suppression of T cell activation by PD-1 and/or CTLA-4 is considered one of the major escape mechanisms of cancer cells. Inhibition of these molecules by immune checkpoint inhibitors can successfully activate the immune system to fight cancer. Checkpoint inhibitors have brought about a major breakthrough in cancer immunotherapy, reviving the hope of curing patients with end-stage cancer, including a wide variety of cancer types. In metastatic malignant melanoma, the previous long-term survival of only 5% can now be extended to 50% with anti-PD-1 plus anti-CTLA-4 combined treatment in the latest report. More checkpoint molecules such as lymphocyte-activation gene 3 and T cell immunoglobulin and mucin domain 3 are under investigation. The achievement of Drs. Honjo and Allison in cancer immunotherapy has encouraged research into other immune-pathological diseases. Keywords: Cancer immunotherapy, Immune checkpoint inhibitors, Nobel Prize

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.

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.

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.

Additional file 2: Supplementary Table 1. Adverse events.

Additional file 1: Supplementary Figure S1. Progression-free survival (PFS) and overall survival (OS) in melanoma patients receiving anti-PD-1 antibodies. The numbers below the charts correspond to patients at risk at each time point. Supplementary Figure S2. Progression-free survival (PFS) (A, C, E) and overall survival (OS) (B, D, F) in melanoma patients receiving anti-PD-1 antibodies, who had skin (A, B), vitiligo (C, D), and endocrine (E, F) irAEs. The patients experiencing skin/vitiligo (C, p = 0.092) and endocrine (E, p = 0.094) irAEs showed a trend of favorable PFS. The patients experiencing skin (p = 0.054), vitiligo (p = 0.047), and endocrine (p = 0.062) irAEs had a trend of favorable OS. The numbers below the charts correspond to patients at risk at each time point. irAEs, immune-related adverse events.

e16113 Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.

A simple and sensitive method for the determination of hesperidin and hesperetin was necessary for a pharmacokinetic (PK) study in Wistar rats. Polarity-switching mode was utilized to acquire positive ion electrospray data for hesperidin and neohesperidin dihydrochalcone-d3, and negative ionization data for hesperetin and rac-hesperetin-d3. The analytes were investigated in the multiple reaction monitoring mode as the precursor/product ion pair of m/z 611.2 → 303.1 for hesperidin, m/z 616.3 → 308.3 for neohesperidin dihydrochalcone-d3, m/z 301.3 → 164.1 for hesperetin, and m/z 304.3 → 164.1 for rac-hesperetin-d3. Hesperidin and hesperetin in rat plasma were separated with solid-phase extraction using a HyperSep Retain PEP column and separated on a Hypersil GOLD Phenyl reversed-phase column using a gradient elution of 0.1% formic acid in water and acetonitrile. Hesperidin was validated over the concentration range of 1–1000 ng mL−1, and hesperetin was validated over the range of 0.2–100 ng mL−1, both with r > 0.999. The respective within- and between-run precisions were 2.06–9.54% and 2.11–7.76%, and the within- and between-run accuracies were −6.52% to 3.82% and −1.62% to 2.33%, respectively, for both analytes. Extraction recoveries of these analytes were >87%. The matrix effects were between 94.7% and 113.6%. All of the analytes were stable during the assay and storage in Wistar rat plasma. The lower limit of quantification of the active metabolite hesperetin is up to 200 pg mL−1, so complete plasma concentration–time profiles can be obtained by the LC-MS/MS method without the need for enzymatic hydrolysis of the serum sample.

Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival prediction in patients with APC, treated with GS. Records of 111 patients with newly diagnosed APC who received first-line palliative GS chemotherapy during 2010&ndash, 2016 in Taiwan were analyzed retrospectively. Univariate and multivariate analyses were performed for the identification of prognostic factors. A prognostic model using prognosticators from the multivariate analysis was developed for survival prediction. The median overall survival (OS) for the cohort was 9.3 months (95% confidence interval [CI], 8.0&ndash, 10.6). The prognostic model was constructed based on four independent prognosticators: performance status, tumor stage, pre-treatment albumin level, and neutrophil-to-lymphocyte ratio. Patients were categorized by tertiles into good, intermediate, and poor prognostic groups. The median OS values for each of these groups were 21.1 (95% CI, 8.2&ndash, 33.9), 9.2 (95% CI, 8.3&ndash, 10.1), and 5.8 months (95% CI, 4.4&ndash, 7.1, log-rank p &lt, 0.001), respectively. The bootstrapped corrected C-index of this model was 0.80 (95% CI, 0.71&ndash, 0.89). The developed model was robust and could accurately predict survival in this population, and can assist clinicians and patients in survival discrimination and the determination of appropriate medical care goals. Additional research is needed to externally validate the model&rsquo, s performance.

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.

This paper proposes a new structure to reduce the commonmode noise (CMN) of weakly coupled differential serpentine delay lines (DSDLs) in microstrip line structure. In the proposed CMN reductions structure, different-layer-routing-turned traces are used as substitutes for same-layer-routing-coupled turned traces (i.e., as in the conventional scheme). The proposed reduction schemes, which are based on different-layer-routing-turned traces, include the original reduction scheme, in which all traces are impedance matched, and the improved reduction scheme, in which all traces have a narrow width. In the time domain, the peak-to-peak amplitude of the CMN obtained by the proposed solution is more than 90% higher than that obtained by the conventional scheme. Implementing the reduction scheme in DSDLs reduces differential-to-common mode conversion (|S cd21 |) by at least 20 dB (range 0.8-16 GHz). The causes of the improved signal integrity are also investigated. Therefore, an improved CMN reduction scheme for DSDLs is proposed. Regarding the frequency domain, the asymmetry can limit the CMN reduction at low frequencies. Symmetry is an important requirement for DSDLs in the proposed CMN reduction scheme. Finally, a favorable comparison between the simulated and measured results confirms the substantial CMN reduction achieved by the proposed schemes.

This paper investigates how ground bounce noise (GBN) is generated by crosstalk noises for two parallel ground planes with a narrow open-stub line (NOSL) and adjacent signal traces in a multilayer package structure. A noise reduction scheme and design guidelines for preventing intense noises (GBN and coupled noise) are also proposed. A graphical method that is based on wave tracing is also developed to elucidate the generation of crosstalk noise by adjacent signal traces on an NOSL. The mechanism of generation of the GBN by crosstalk noise can be elucidated based on reflection theory, open-stub quarter-wavelength resonance, and parallel-plane resonance. The time-domain simulation results are analyzed using a 3-D full-wave simulator, Computer Simulation Technology. Using an additional shorting via at the connection between the NOSL and parallel ground planes, the proposed noise reduction scheme can significantly reduce the GBN and coupled noise. Moreover, guidelines for designing the test structure to minimize noise (GBN and coupled noise) are presented. Finally, the simulation and measurement results in the time domain are compared to validate the proposed analysis and noise reduction scheme.

A safe and efficient semi-synthetic narcotic nalbuphine (NAL) which was broadly applied in analgesic therapy has long been considered to eliminate from human body via phase II conjugation. However, up to the present, neither the complete metabolic pathways nor the identified metabolites of NAL have been clarified in documented reports. In this study, four novel metabolites were discovered by incubating NAL with human liver microsomes. These metabolites were later quantified in blood samples from human volunteers treated with NAL. An accurate and precise new method for simultaneously determining NAL and its metabolites was also established. Their chemical structures were elucidated on the basis of one- and two-dimensional NMR spectroscopic analyses including 1H–1H correlation spectroscopy, nuclear overhauser enhancement spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple bond correlation, and further confirmed by mass spectrometry. The analytical method was validated and applied successfully to a pilot human study with ultra-high performance liquid chromatography–tandem mass spectrometry employed with positive ion electrospray ionization via multiple reaction monitoring mode. This is the first report on the qualitative and quantitative analysis of NAL coupled with its two hydroxylated (3′-hydroxynalbuphine and 4′-hydroxynalbuphine) and two conjugated metabolites (nalbuphine-3-β-d-glucuronide and nalbuphine-6-β-d-glucuronide). The present method offers a rapid and simple way of performing pharmacokinetic studies of NAL, and assists in elucidating its metabolic pathway in humans.

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. Copyright © 2013 John Wiley & Sons, Ltd.

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.

In this paper, a framework for integrating a real-time digital simulator and EMS-OPF program is proposed and addressed, through two different communication architectures: asynchronous and synchronous. Validation of these communication architectures is carried out by Ethernet UDP/IP (asynchronous) and analog channels of IO card (synchronous). With this framework, both dynamic and steady-state performance of a power system can be studied easily in real-time mode.

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.

A novel sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method simultaneously determined buprenorphine (BUP) and its active metabolite, norbuprenorphine (NBUP), and a coformulant, naloxone was developed, validated and applied successfully in humans. Buprenorphine-d 4 and norbuprenorphine-d 3 were used as the internal standard. The analysis was performed on a silica column, and the mobile phase was isocratic and composed of acetonitrile:2 mM ammonium formate in H2O (82:18, v/v). Mass spectrometry employed multiple reaction monitoring modes with transitions of m/z 468.1–55.2 for BUP, 414.2–101.2 for NBUP, 328.3–310.3 for naloxone, 472.1–59.2 for buprenorphine-d 4 and 417.2–101.2 for norbuprenorphine-d 3. Lower limit of quantification (LLOQ) of the analytical method was 0.05 ng mL−1 for BUP, 0.1 ng mL−1 for NBUP and 0.025 ng mL−1 for naloxone, respectively. The standard calibration curves of BUP, NBUP and naloxone were linear over the concentration range of 0.05–20 ng mL−1, 0.1–20 ng mL−1 and 0.025–20 ng mL−1, respectively. The precisions (RSD) and accuracies (RE) of LLOQ and other QC samples were in acceptable range, with RSD

Juxtaglomerular cell tumor (JGCT) is a rare pathologically benign renal neoplasm mostly reported as localized disease, which can secrete renin and induce hypertension, hypokalemia, and hyperaldosteronism. In this report, a young male was diagnosed with JGCT with lung metastases. In general, the diagnosis of JGCT is made by a pathological examination, and the standard treatment of localized disease is to resect the tumor completely. However, there is currently no standard treatment for metastatic or unresectable JGCT, and chemotherapy plays a debatable role.

Many sensor network applications require location awareness, but it is often too expensive to equip a global positioning system (GPS) receiver for each network node. Hence, localization schemes for sensor networks typically use a small number of seed nodes that know their locations and protocols whereby other nodes estimate their locations from the messages they receive. For the inherent shortcomings of general particle filter (the sequential Monte Carlo method) this paper introduces particle swarm optimization and weighted centroid algorithm to optimize it. Based on improvement a distributed localization algorithm named WC-IPF (weighted centroid algorithm improved particle filter) has been proposed for localization. In this localization scheme the initial estimate position can be acquired by weighted centroid algorithm. Then the accurate position can be gotten via improved particle filter recursively. The extend simulation results show that the proposed algorithm is efficient for most condition.

Most existing media access control (MAC) protocols in power line communication (PLC) networks just discard the colliding data packets when collision occurs. The collision deteriorates throughput and delay performance of system under high traffic conditions. This article presents a novel media access scheme with fast collision resolution for in-home power line networks. It works by first recognizing the colliding stations through detecting the inserted unique ID sequence ahead of data packets, then the source nodes retransmitting their packets immediately after the collision slot. The proposed protocol maintains the benefits of ALOHA systems. It needs no scheduling overhead and is suitable for bursty sources, such as multimedia data packets. Computer simulations have demonstrated that this approach can achieve high throughput due to its ability of resolving collisions.

In personal communication services (PCS), the complete location information and subscribers' profiles are kept in a database called the home location register (HLR). Another database, the visitor location register (VLR), is used to store partial location information. When a mobile user is called, the system queries the HLR to determine the location of the called party. Distributed databases have been introduced to improve the efficiency of querying the HLR. This paper presents an alternative means of constructing a distributed database. The proposed database design employs fixed pointers to link distributed data. Each database contains a portion of the system's information as well as several pointers. The pointers identify the location of real data, enabling the system to obtain the required information efficiently. The database of the proposed design is markedly smaller than the fully distributed databases since each database of the proposed design stores only partial information. Subscriber information is stored only in one database, thus allowing a single database, rather than multiple databases, to be updated. The single update presented herein notably reduces the signal traffic load. If the caller is in the registration area of some HLR, which holds the called party's information, the response time is significantly decreased since the transactions are served only by the local database. This phenomenon is referred to as the calling locality. The proposed method effectively shares the database and the network loading that originates from several databases' tracking mobile users in a PCS system. According to the results presented, this method is highly effective for systems with a heavy load and high calling locality. The single update feature of the proposed design reduces the traffic in the signaling link and the processing load of a database. However, the proposed method includes no fault tolerance and therein differs from the fully distributed design.

This work proposes a new common-mode noise (CMN) reduction scheme that involves different-layers-routing turned traces to reduce the CMN in weakly coupled differential serpentine delay microstrip lines (DSDMLs). The purpose of using different-layers-routing turned traces instead of same-layer-routing coupled turned traces (CTTs) (conventional scheme) is to cause the difference between the delay times of the two traces of the turn-traces section to approach zero to minimize the CMN. Moreover, the CMNs in weakly coupled DSDMLs achieved using various reduction schemes are compared. The proposed solution obtains a peak-to-peak amplitude of CMN in the time domain simulation that is more than 90 % with respect to the corresponding value obtained using the conventional scheme. The proposed reduction scheme in DSDMLs reduces the differential-to-common mode conversion (|S cd21 |) by more than 20dB in the range 4.5GHz~16GHz. The range of frequencies over which CMN is reduced is very wide, being almost the full band (DC~16GHz). The reduction using the proposed reduction scheme exceeds those achieved using previous reduction schemes, strongly coupled turned-traces and guard traces.

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.