Search

Purpose The objective of this study was to develop a population pharmacokinetic (popPK) model of anlotinib and to investigate the impact of various covariates in patients with malignant tumors. Methods A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. PopPK model was established using nonlinear mixed-effects model (NONMEM) method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetic was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. Results The pharmacokinetic profile of anlotinib was best described by a one-compartment model with first-order absorption and linear elimination. The population estimates of the apparent total clearance (CL/F), apparent volume of distribution (V/F) and absorption rate constant (Ka) were 8.91 L/h, 1950 L and 0.745 h-1, respectively. Body weight was identified as a significant covariate on V/F. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant in the simulations of the individual body weight effects. No obvious bias was found in the final model by bootstrap and VPC methods. Conclusion This popPK model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors. Anlotinib does not need any dose modifications since the effect size for the individual covariate is not considered clinically relevant with anlotinib exposure.

Background Sorafenib, the first approved targeted therapy for advanced hepatocellular carcinoma (HCC), is often reported to comprised survival-benefit due to resistance. An underlying mechanism of resistance was proposed using bioinformatics analysis based on differentially expressed genes (DEGs) from microarrays. However, most DEGs were invalidated at both the expression level, and the role in causing resistance. Therefore, we conducted a bioinformatics analysis based on experimentally determined sorafenib-resistance-related genes (SRRGs) to elucidate the mechanism of sorafenib resistance. Methods The SRRGs, which have been experimentally determined to promote or inhibit resistance, were collected from published studies. The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform Gene Ontology (GO) and pathway enrichment analysis, respectively. A corresponding protein-protein interaction network (PPI) was created using the Cytoscape software program, and network hub genes were proposed. Results A total of 145 SRRGs, with 117 promoting and 28 inhibiting resistance, were identified. Cell proliferation, migration, development, response to oxygen levels, epithelial-to-mesenchymal transition (EMT), cell skeleton, protein function, and autophagy were all proposed as crucial gene functions related to resistance. The pathways related to cell proliferation or apoptosis, immune function, endocrine metabolism, stem cell function, and differentiation were identified as key resistance-related pathways. A total of 81 hub genes were proposed, including the following top 10 genes: TP53, AKT1, EGFR, STAT3, VEGFA, JUN, MAPK1, IL6, PTEN, and CTNNB1. Conclusions In conclusion, this study gathered experimentally validated genes that determine sorafenib resistance in HCC, provided an overview of the underlying mechanisms of resistance, and further validated sorafenib resistance in HCC.

Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain.A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population.A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events.Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain.ClinicalTrials.gov identifier: NCT03439904.

Model structural inference on semiparametric measurement error models have not been well developed in the existing literature, partially due to the difficulties in dealing with unobservable covariates. In this study, a framework for adaptive structure selection is developed in partially linear error-in-function models with error-prone covariates. Firstly, based on the profile-least-square estimators of the current models, we define two test statistics via generalized likelihood ratio (GLR) test method (Fan et al. in Ann Stat 29(1):153–193, 2001). The proposed test statistics are shown to possess the Wilks-type properties, and a class of new Wilks phenomenon is unveiled in the family of semiparametric measurement error models. Then, we demonstrate that the GLR statistics asymptotically follow chi-squared distributions under null hypotheses. Further, we propose efficient algorithms to implement our methodology and assess the finite sample performance by simulated examples. A real example is given to illustrate the performance of the present methodology.

BACKGROUND: Total parenteral nutrition (TPN) is an essential treatment for patients who undergo abdominal surgery. Due to the gap of knowledge background between clinicians and pharmacists, the participation of the latter may improve TPN standardization. However, the impact on clinical outcome is unknown. In this study, we evaluated the impact of appropriacy and efficacy of TPN prescription, after a pharmacist-led TPN standardization program introduced. METHODS: A pharmacist-led TPN standardization program was introduced in the Zhejiang Cancer Hospital and the clinical outcomes were assessed. The TPN standardization program includes a pre-established standard multidisciplinary evaluation standard, a computerized TPN management system and regular evaluations of TPN prescription performed by pharmacists. Any concerns were identified and improved via discussed with doctors. To evaluate the effect of pharmacists’ intervention in nutritional status and postoperative complications, an observational before-and-after cohort study was performed. All patients admitted in hospital with colorectal cancer (CRC) and receiving abdominal surgery in June 2019 (pre-intervention cohort) and June 2020 (post-intervention cohort) were retrospectively analyzed. Nutritional status of patients was evaluated using the levels of postoperative serum albumin, prealbumin, total protein, and their decrease extent. Surgical or TPN-related complications and recovery time were collated as the clinical outcomes. RESULTS: There were no significant differences in the basic clinical information of the two cohorts, suggesting that the two groups are comparable. The average postoperative prealbumin levels were elevated in 2020 compared to 2019 (192.3±5.5 mg/L for 2019 and 229.5±4.8 mg/L for 2020, P

BACKGROUND: Despite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC. METHODS: A total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (D(mvcc)), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-D(mvcc) were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. RESULTS: The D(mvcc) ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2–70; median 23) was counted from tMVD according to the cutoff-D(mvcc) (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff. CONCLUSIONS: Perfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life.Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035).In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522).Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain.ClinicalTrials.gov, NCT03455023.

Background The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). Methods Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. Results MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. Conclusions Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.

Background: Sustained tumor growth and metastasis require sufficient blood supply, and microvessel area (MVA) has been reported that is related to prognosis of cancer patients. However, tumor cells may not be nourished enough by blood vessels when the cells are separated from vessels by thick stroma. Therefore we investigated whether stroma-area normalized MVA (SnMVA) is a more important prognostic factor than MVA. Materials and Methods: 100 NSCLC patients who underwent resection between July 2011 and October 2012 were randomly selected. We determined the MVA of the tumor tissues by anti-CD31 immunostaining of microvessels. Stroma-area normalized MVA (SnMVA) was a ratio of MVA to stromal area. Correlation of MVA and SnMVA with overall survival (OS) or progression-free survival (PFS) was assessed using multivariate analysis. Results: Median MVA was 0.0228 (range, 0.00393 to 0.172), and median SnMVA was 0.0441 × 10-6 (range, 0.00393 × 10-6 to 0.259 × 10-6). There was no significant difference in OS between groups of different MVA (HR 0.58, 95%CI 0.28 to 1.19, p = 0.148). In contrast, the risk of death was significantly decreased in high SnMVA group (at or below the median) than in group with low SnMVA (HR 0.47, 95%CI 0.23 to 0.97, p = 0.046). Furthermore, in multivariate analysis, high SnMVA, but not MVA, was an independent prognostic factor after adjusting for age, sex, tumor stage and other factors. OS was significantly associated with SnMVA in six of seven subgroup analysis, but with MVA in only three. Conclusions: Our study showed that the NSCLC patients with high SnMVA had higher OS. And SnMVA is a prognostic factor with greater accuracy than MVA. Since stroma exists widely in a variety of cancer tissues, we infer that SnMVA may also predict the prognostic of other types of cancers.

Introduction: Results from the CASPIAN trial (Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer) trial demonstrated the clinical benefit of durvalumab plus etoposide–platinum (EP) chemotherapy as first-line treatment for patients with extensive stage small-cell lung cancer (ES-SCLC). However, considering the high price of durvalumab, it is unclear whether addition of durvalumab to EP chemotherapy has economic value compared with EP alone. In this study, we aimed to evaluate the cost-effectiveness of durvalumab plus EP chemotherapy as a first-line treatment for patients with ES-SCLC. Methods: A Markov model comprising three health states (stable, progressive, and dead) was developed to simulate the process of small-cell lung cancer. Utility and costs were obtained from published resources. Health outcomes were derived from the CASPIAN trial. Costs were calculated based on the standard medical fees in Zhejiang Province from Chinese patients’ perspective. Utility values were obtained from published data. One-way and probabilistic sensitivity analyses were applied to verify model robustness. Results The addition of durvalumab to EP chemotherapy costs more than $32,220, with a gain of 0.14 quality-adjusted life years (QALYs) compared with EP alone. The incremental cost-effective ratio was $230,142.9 per QALY, which exceeds the willingness to pay threshold of $28,527 per QALY. In the sensitivity analysis, the utility values for the progressive state, costs of durvalumab and EP chemotherapy, and costs for the progressive state were considered to be the three most sensitive factors in the model. Conclusion: The addition of durvalumab to EP chemotherapy is not a cost-effective strategy in the first-line therapy of ES-SCLC from the Chinese payers’ perspective.

Background: Doxorubicin-Induced Cardiotoxicity (DIC) has greatly limited the clinical benefits of this frontline drug in oncotherapy. Drug combination with Natural Compounds (NCs) that possess potency against DIC is considered as a promising intervention strategy. However, the Mechanisms of Action (MoAs) underlying such drug interactions remain poorly understood. The aim of this study was to systematically pursuit of the molecular mechanisms of NCs against DIC. Methods: First, the gene expression signatures of DIC were characterized from transcriptomics datasets with doxorubicin-treated and untreated cardiomyocytes using differentially expressed gene identification, functional enrichment analysis, and protein-protein interaction network analysis. Secondly, reverse pharmacophore mapping-based network pharmacology was employed to illustrate the MoAs of 82 publicly reported NCs with anti-DIC potency. Cluster analysis based on their enriched pathways was performed to gain systematic insights into the anti-DIC mechanisms of the NCs. Finally, the typical compounds were validated using Gene Set Enrichment Analysis (GSEA) of the relevant gene expression profiles from a public gene expression database. Results: Based on their anti-DIC MoAs, the 82 NCs could be divided into four groups, which corresponded to ten MoA clusters. GSEA and literature evidence on these compounds were provided to validate the MoAs identified through this bioinformatics analysis. The results suggested that NCs exerted potency against DIC through both common and different MoAs. Conclusion: This strategy integrating different types of bioinformatics approaches is expected to create new insights for elucidating the MoAs of NCs against DIC.

BackgroundPembrolizumab was recently demonstrated to have survival benefit in patients with recurrent or metastatic head and neck squamous cell carcinoma (r/mHNSCC). However, the cost-effectiveness of pembrolizumab versus chemotherapy in China remains uncertain.ObjectiveThis analysis aimed to describe the cost-effectiveness of pembrolizumab versus standard-of-care (SOC) therapy in r/mHNSCC in China.DesignA Markov model consisting of three health states (stable, progressive and dead) was developed to compare the cost and effectiveness of pembrolizumab with SOC in platinum-resistant r/mHNSCC. Model inputs for transition probabilities and toxicity were collected from the KEYNOTE-040 trial, while health utilities were estimated from a literature review. Cost data were acquired for the payer’s perspective in China. Costs and outcomes were discounted at an annual rate of 3.0%. Sensitivity analyses were conducted to test the uncertainties surrounding model parameters.Outcome measuresThe primary outcome was incremental cost-effectiveness ratios (ICERs), which were calculated as the cost per quality-adjusted life years (QALYs).ResultsThe total mean cost of pembrolizumab and SOC was US$45 861 and US$41 950, respectively. As for effectiveness, pembrolizumab yielded 0.31 QALYs compared with 0.25 QALYs for SOC therapy. The ICER for pembrolizumab versus SOC was US$65 186/QALY, which was higher than the willingness-to-pay threshold (WTP) of US$28 130/QALY in China. The univariate sensitivity analysis indicated that utility values for progressive state, probability from stable to progressive in the SOC group, as well as cost of pembrolizumab were the three most influential variables on ICER. The probabilistic sensitivity analysis demonstrated that standard therapy was more likely to be cost-effective compared with pembrolizumab at a WTP value of US$28 130/QALY. Results were robust across both univariate analysis and probabilistic sensitivity analysis.ConclusionsPembrolizumab is not likely to be a cost-effective strategy compared with SOC therapy in patients with platinum-resistant r/mHNSCC in China.Trial registration numberNCT02252042; Post-results.

BackgroundImmune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC) have been rapidly evolving. ICIs are likely to be more effective but also lead to escalating healthcare costs.ObjectivesThe aim of this study was to evaluate the cost effectiveness of immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC).MethodsWe searched the PubMed, Web of Science, and Cochrane Library for studies comparing the cost effectiveness of ICIs for NSCLC. Potential studies identified were independently checked for eligibility by two authors, with disagreement resolved by a third reviewer. Quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards checklists.ResultsA total of 22 economic studies were included. Overall reporting of the identified studies largely met CHEERS recommendations. In the first-line setting, for advanced or metastatic NSCLC patients with PD-L1 ≥ 50%, pembrolizumab appeared cost-effective compared with platinum-based chemotherapy in the US and Hong Kong (China), but not in the UK and China. The cost-effectiveness of pembrolizumab versus chemotherapy for first-line treatment of NSCLC in PD-L1 ≥ 1% patients remained obscure. Regardless of PD-L1 expression status, pembrolizumab in combination with chemotherapy could be a cost-effective first-line therapy in the US. On the contrary, addition of atezolizumab to the combination of bevacizumab and chemotherapy was not cost-effective for patients with metastatic non-squamous NSCLC from the US payer perspective. In the second-line setting compared with docetaxel, pembrolizumab was cost-effective; though nivolumab was not cost-effective in the base case, it could be by increased PD-L1 threshold. Results of the cost-effectiveness of atezolizumab second-line treatment remained inconsistent. In addition, the adoption of durvalumab consolidation therapy after chemoradiotherapy could be cost-effective versus no consolidation therapy for patients with stage III NSCLC.ConclusionsImmunotherapy can be a cost-effective option for treatment of NSCLC in several scenarios. A discount of the agents or the use of PD-L1 expression as a biomarker improves the cost-effectiveness of immunotherapy.

BACKGROUND: Botrychium schaffneri Underw. has been popularly consumed since ancient times as a traditional medicine in China to treat whooping cough, bronchial asthma, and febrile convulsive twitch disease. This led us to investigate whether Botrychium schaffneri Underw. extract (BSE) may be effective against lung cancer, especially non-small cell lung carcinoma (NSCLC). METHODS: In this study, we extracted the ethanolic root extract of the grass, Botrychium schaffneri Underw. In vitro study, the change of NCI-H1299 cell proliferation was observed with CCK8 and MTT assays. Cell apoptosis was assessed using a kit based on staining with FITC-conjugated annexin V. In vivo study, we establish a stable animal model of NSCLC in nude mice, tumor volume and weight was measured twice a week. We conduct gene microarray screened for differentially expressed genes (DEGs), between NCI-H1299 cells treated by BSE or not. Then the DEGs were functionally annotated and path enriched. RESULTS: It was revealed that BSE significantly suppressed NSCLC cell proliferation (IC(50) 134 μg/mL) and induced apoptosis. It also slowed tumor growth without affecting body weight, and a dose of 25 g/kg led to significantly smaller tumors than in control animals (13.85±3.36 vs. 23.40±6.05, P=0.044). Apoptosis-related protein direct IAP Binding protein with low PI (DIABLO) expression was up-regulated by BSE, and DIABLO knockdown significantly attenuated the anti-tumor effects of the extract. CONCLUSIONS: In conclusion, BSE reduces the viability of NSCLC cells and promotes apoptosis, and these effects may be mediated by DIABLO.

Node importance is a key factor affecting the overall operation efficiency of a railway freight transportation network (RFTN) that can be measured with the indicators of Hub and PageRank. Based on complex network theory and the national railway cargo exchange data of China’s provinces, this study constructs an RFTN model with the 31 provinces as the nodes and measures the values of Hub and PageRank for the 31 provinces. Then, the time evolution law of the importance of the provincial nodes is analyzed comprehensively, and, using a regression model, the influencing factors of the importance of the provincial nodes are identified. The results show the following. (1) The uneven distribution of natural resources will affect the spatial changes in the importance of RFTN nodes. The Hub values tended to cluster around the average, and the economic structure of the output-oriented provinces improved as a whole. At the same time, the PageRank values of many provinces in the central and western regions significantly increased, and those provinces exhibited more frequent exchanges of goods with other provinces and closer economic ties with other regions. (2) The traffic fixed asset investments and the population density have the most obvious influences on the importance of the provincial nodes with a positive effect. In contrast, the railway freight concentration (RFC) coefficient, geographical location (longitude and latitude), and coastal region all have negative effects on the importance of provincial nodes. The results of this study provide scientific decision-making support for the reasonable establishment and distribution of RFTN hubs in China.

Motivated by a heart disease data, we propose a new partially linear error-in-variable models with error-prone covariates, in which mismeasured covariate appears in the noparametric part and the covariates in the parametric part are not observed, but ancillary variables are available. In this case, we first calibrate the linear covariates, and then use the least-square method and the local linear method to estimate parametric and nonparametric components. Also, under certain conditions the asymptotic distributions of proposed estimates are obtained. Simulated and real examples are conducted to illustrate our proposed methodology.

The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD-based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp.

Tumor-targeted drug delivery systems (Tt-DDSs) are proposed as a promising strategy for cancer care. However, the dense collagen network in tumors stroma significantly reduces the penetration and efficacy of Tt-DDS. In order to investigate the effect of asiatic acid (AA) on antitumor effect of pegylated liposomal doxorubicin (PLD) by attenuating stroma-collagen, colon cancer xenograft mice (SW620 cell line) were treated by PLD, AA, or combined regimes, respectively; the collagen levels were estimated by Sirius red/fast green dual staining and immunohistochemistry (IHC) staining; the intratumor exposure of doxorubicin was visualized by ex vivo fluorescence imaging and quantified by HPLC/MS analysis. In addition, the impact of AA on collagen synthesis of fibroblast cell (HFL-1) and cytotoxic effect of PLD and doxorubicin to cancer cell (SW620) were studied in vitro. In the presence of AA (4 mg/kg), the intratumor collagen level was restricted in vivo (reduced by 22%, from 4.14% ± 0.30% to 3.24% ± 0.25%, P = 0.051) and in vitro. Subsequently, doxorubicin level was increased by ~30%. The antitumor activity of PLD was significantly improved (57.3% inhibition of tumor growth and 44% reduction in tumor weight) by AA combination. Additionally, no significant improvement in cytotoxic effect of PLD or doxorubicin induced by AA was observed. In conclusion, AA is a promising sensitizer for tumor treatment by enhancing intratumor drug exposure via stromal remodeling.

A simple, reliable method for simultaneous determination of the ten components in Danhong injection (DHI) in combination of chromatographic fingerprint analysis was developed by high performance liquid chromatography coupled with diode-array-detector (HPLC-DAD). The separation was performed on an Agilent Zorbax SB-C 18 column with a linear gradient elution of acetonitrile and 0.5% formic acid. The method was validated by linearity, precision, stability and recovery. The developed method was subsequently applied to evaluate 15 batches of DHI and testified to be suitable for its quality control.

Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluorouracil (5-FU) dosing on patients with solid tumors. A comprehensive retrieval was performed to identify all of the prospective controlled studies that compared the body surface area (BSA)-based algorithm with the PKG algorithm of 5-FU in patients with solid tumors. Overall, four studies with 504 patients were included. The PKG algorithm significantly improved the objective response rate of 5-FU-based chemotherapy compared with the BSA-based algorithm. Furthermore, PKG dosing markedly decreased the risk of total grade 3/4 adverse drug reactions, especially those related to hematological toxicity. Overall, the PKG algorithm may serve as a reliable strategy for individualized dosing of 5-FU.

The application of near-infrared (NIR) spectroscopy for in-line monitoring of extraction process of scutellarein from Erigeron breviscapus (vant.) Hand-Mazz was investigated. For NIR measurements, two fiber optic probes designed to transmit NIR radiation through a 2 mm pathlength flow cell were utilized to collect spectra in real-time. High performance liquid chromatography (HPLC) was used as a reference method to determine scutellarein in extract solution. Partial least squares regression (PLSR) calibration model of Savitzky-Golay smoothing NIR spectra in the 5450-10,000 cm(-1) region gave satisfactory predictive results for scutellarein. The results showed that the correlation coefficients of calibration and cross validation were 0.9967 and 0.9811, respectively, and the root mean square error of calibration and cross validation were 0.044 and 0.105, respectively. Furthermore, both the moving block standard deviation (MBSD) method and conformity test were used to identify the end point of extraction process, providing real-time data and instant feedback about the extraction course. The results obtained in this study indicated that the NIR spectroscopy technique provides an efficient and environmentally friendly approach for fast determination of scutellarein and end point control of extraction process.

Background To assess the association between hypoglycemic agents and prognosis of lung cancer patients with diabetes. Methods A comprehensive literature search was performed in PubMed, Web of Science, Embase, and Cochrane Library until May 2017. The search yielded 2593 unique citations, of which 18 articles met inclusion criteria. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated by a fixed-effects or random-effects model. Results The pooled HRs favoring metformin users were 0.77 for overall survival (OS) (n = 15, 95% CI: 0.68-0.86) and 0.50 for disease-free survival (n = 5, 95% CI: 0.39-0.64). One study assessed the relationship between metformin and cancer-specific survival (CSS), reporting no significant results. No significant association between insulin and OS (n = 2, HR: 0.95, 95% CI: 0.79-1.13) or CSS (n = 2, HR: 1.03, 95% CI: 0.76-1.41) was noted. One study evaluated association of sulfonylureas with lung cancer survival and reported no clinical benefit (HR: 1.10, 95% CI: 0.87-1.40). One study reported no association of thiazolidinediones with lung cancer survival (HR: 1.04, 95% CI: 0.65-1.66). Conclusions This meta-analysis demonstrated that metformin exposure might improve survival outcomes in lung cancer patients with diabetes.

Preforms were made from 1K PAN plain carbon cloth and densified using the rapid directional diffusion chemical vapor infiltration (RDD CVI) processes. Four carbon/carbon (C/C) composite specimens treated at 1800 (specimen A), 1800+2000 (B), 2000 (C), and 2300 °C (D), respectively, were prepared, then machined into ring-on-ring specimen configurations. The influence of high-temperature heat treatment and the test temperatures on the static friction properties of the C/C composites has been researched. The results show that the high-temperature heat treatment processes has an important impact on the static friction behaviors of RDD CVI C/C composites. With raising the treatment temperature, the interlayer spacing of the matrix carbon in them becomes small, and the crystallite width as well as height increase. Under the test at room temperature, the static friction coefficients (FC) of the specimen treated at 1800 °C (A) are the lowest, but become very big and the highest under the test temperature of 260 °C due to desorption of the water absorbed on the friction surface. The composites treated at 2000 °C (C) exhibit enough high static friction coefficients under room temperature owing to their absorption of less water and the difficult delamination of the matrix carbon. However, in the test temperature of 260 °C or after the dynamic friction tests, their static FC is low. The specimen treated at 2300 °C (D) has a low FC at 260 °C heat condition, but its FC is higher than that of A and C under room temperature and largest after dynamic friction tests. No matter how high the heated temperatures are, the static FC of C/C composites decreases with an increase of the brake-specific pressure. When the specific pressure is very high and exceeds a certain value, the static FC is almost the same for specimens B, C, and D.

The effect of high temperature heat treatment on the tribological behavior of carbon/carbon (C/C) composites has been investigated. C/C composite preforms were made from 1K PAN plain carbon cloth, and densified using rapid directional diffusion (RDD) CVI processes. Four specimens treated at 1800, 1800+2000, 2000, and 2300 degreesC, respectively, were prepared. A ring-on-ring specimen configuration was used to simulate aircraft brakes. The brake initial angular velocity ranged from 1800 to 7500 rpm (6.2-26.0 m s(-1) average linear sliding velocity). The specific pressure and moment of inertia were 392-784 kPa and 0.25-0.31 kg m(2), respectively (1.9-42.3 MJ m(-2) kinetic energy loading per unit friction surface area). The results showed that the stability of the brake moment-time curves increased with increasing heat treatment temperature (HTT) for the four composites, and those treated at 2300 degreesC possessed the lowest initial brake moment peak ratio values (from 1.1 to 1.3). The high degree of graphitization and low shear forces of the matrix carbon resulting from the high HTT could allow friction films to develop and reduce those values under the present brake conditions. The friction coefficients of four RDD CVI C/C composites decreased with an increase in specific pressure. The resulting changes in the friction coefficient of the four composites due to the specific pressure changes have basically nothing to do with the interface temperature under those conditions. According to the practical brake conditions, the friction properties of RDD CVD C/C composites could be improved by regulating the structure of the brake discs, changing the specific pressure exerted on the discs and the heat treatment. The linear wear rates of the four materials increased with increasing HTT. The composites treated at 2000 degreesC had both high enough friction coefficients and the lower linear wear rates. The different heat treatment methods at 2000 degreesC had no obvious effect on the friction and wear properties of RDD CVI C/C composites. (C) 2003 Elsevier Ltd. All rights reserved.

e21617 Background: Although hypoglycemic agents (metformin, insulin, sulfonylureas [SUs] and thiazolidinediones [TZDs]) may influent prognosis of cancer at several sites, very little is known about their effects on clinical outcomes of lung cancer patients with diabetes mellitus (DM) and results from clinical trials are often inconsistent. Methods: To assess the association between hypoglycemic agents and clinical outcomes of lung cancer, we performed a systematic review of published studies from PubMed, EMBASE, Web of Science and The Cochrane Library up to January, 2016. Meta-analysis was performed to calculate the pooled hazard ratio (HR) and 95% confidence interval (95% CI). Results: The pooled HRs favoring metformin users was 0.77 for overall survival (OS) (n = 12, 95% CI: 0.66-0.89) and 0.59 for disease-free survival (DFS) (n = 6, 95% CI: 0.47-0.72). Only one study assessed the relation between metformin and cancer-specific survival (CSS) in lung cancer patients, reporting no statistically significant results. No significant association between insulin use and OS (n = 2, HR: 0.95, 95% CI: 0.79-1.13) or CSS (n = 2, HR: 1.03, 95% CI: 0.76-1.41) was noted. Only one study evaluated the effect of SUs in patients with lung cancer and reported no statistically clinical benefit (HR: 1.10; 95% CI: 0.87-1.40). Likewise, one study evaluated the effect of TZDs on OS in patients of lung cancer and reported no significant difference between TZDs and non-TZDs groups (HR: 1.04, 95% CI: 0.65-1.66). Conclusions: This meta-analysis demonstrated that metformin could improve survival outcomes of patients with lung cancer and DM. No association between insulin, TZDs or SUs and lung cancer outcomes was found.

An on-line detection method combining near infrared (NIR) spectroscopy with local partial least squares regression (PLSR) was investigated for the elution process of sodium aescinate. A 2 mm pathlength flow cell which transmitted NIR radiation through two fiber optic probes was placed in bypass of the macroporous resin column to collect real-time spectra of the sodium aescinate eluate. To compare the predictive accuracy, both local and global PLSR were employed to build mathematical models between NIR spectra and reference values. Meanwhile, Mahalanobis distance was introduced to select the appropriate local model for the prediction of unknown samples. Experimental results demonstrated that local PLSR was superior to global PLSR in both calibration performance and predictive accuracy. Moreover, the on-line detection method was proven to be feasible in real application and thereby would be of great value for monitoring the elution process of sodium aescinate in real time as well as determining the start and end points of eluate collection.