Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors.

Our understanding of human hepatocellular carcinoma (HCC) development and progression has been hampered by the lack of in vivo models. We performed a genetic screen of 10 oncogenes and genetic mutations in Fah-ablated immunodeficient mice in which primary human hepatocytes (PHHs) are used to reconstitute a functional human liver. We identified that MYC, TP53R249S , and KRASG12D are highly expressed in induced HCC (iHCC) samples. The overexpression of MYC and TP53R249S transform PHHs into iHCC in situ, though the addition of KRASG12D significantly increases the tumorigenic efficiency. iHCC, which recapitulate the histological architecture and gene expression characteristics of clinical HCC samples, reconstituted HCC after serial transplantations. Transcriptomic analysis of iHCC and PHHs showed that MUC1 and FAP are expressed in iHCC but not in normal livers. Chimeric antigen receptor (CAR) T cells against these two surface markers efficiently lyse iHCC cells. The properties of iHCC model provide a biological basis for several clinical hallmarks of HCC, and iHCC may serve as a model to study HCC initiation and to identify diagnostic biomarkers and targets for cellular immunotherapy.

Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

OBJECTIVE: This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. METHODS: A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. RESULTS: The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. CONCLUSION: The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Exploring the effect of Wuzhi capsule on the pharmacokinetics of regorafenib and its main metabolites in rat plasma using liquid chromatography-tandem mass spectrometry.

Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (Cmax ), delayed the time to reach Cmax , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.

Evaluating linezolid dose regimens against methicillin-resistant Staphylococcus aureus based on renal function in populations with different body weight.

WHAT IS KNOWN AND OBJECTIVE: Linezolid is an alternative first-line agent for MRSA pneumonia. This study assessed whether dose adjustments of linezolid against methicillin-resistant Staphylococcus aureus (MRSA) infections were needed based on renal function in populations with different body weight. METHODS: Monte Carlo simulations were conducted to evaluate renal function in relation to the probability of target attainment (PTA) in three population groups with different body weight. Area under the concentration time curve (AUC)/ minimum inhibitory concentration (MIC) ratio and percentage of time above the MIC (%T > MIC) were regarded as pharmacokinetic/pharmacodynamic targets. The PTA and cumulative fractions of response (CFR) were calculated to assess the efficacy. Regarding safety, trough plasma concentration (Cmin ) > 8 mg/L was used as target for toxicity. RESULTS AND DISCUSSION: Using AUC/MIC >100 as the target pharmacodynamic (PD) index, the CFR of linezolid at the standard dose (600 mg every 12 h [q12h]) were 57.01%, 93.22%, and 99.93% in patients with normal renal function, patients with renal dysfunction and low body weight patients with renal dysfunction, respectively. Using 100%T > MIC as the target PD index, all the CFR of three population groups were more than 90% at the standard dose. The percentages of Cmin > 8 mg/L at the standard dose of linezolid were 24.16%, 53.24%, and 90.10% in three population groups on day 7. WHAT IS NEW AND CONCLUSION: The risk of thrombocytopenia of linezolid was extremely higher in low body weight patients with renal impairment when receiving standard linezolid dose compared with patients with normal renal function. 450 mg q12h and 300 mg q12h might be effective and safe against MRSA infection in patients with renal dysfunction and low body weight patients with renal dysfunction, respectively.

Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations.

OBJECTIVE: To assess the efficacy of loading dose on micafungin by simulating different dosage regimens. METHODS: A published study of micafungin in ICU patients was employed to simulate nine different dosage regimens which were sorted out three groups in terms of three maintenance doses. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations were conducted to simulate concentration-time profiles of micafungin, calculate probabilities of target attainment (PTAs), and cumulative fractions of response (CFRs) in terms of AUC/MIC targets. PTAs were calculated using AUC/MIC cut-offs: 285 (Candida parapsilosis), 3000 (all Candida spp.), and 5000 (non-parapsilosis Candida spp.). PTA or CFR > 90% was considered optimal for a dosage regimen. RESULTS: The concentration-time profiles of micafungin-simulated dosage regimens were obtained. PTA values were over 90% while applying the loading dose in each group of regimens: for Candida albicans and Candida glabrata (AUC/MIC = 5000), all regimens with loading dose provided PTAs of ≥ 90% for MIC ≤ 0.008 mg/L. The PTAs (AUC/MIC = 3000) were over 90% for MIC ≤ 0.008 mg/L in any regimen. However, for MIC inferior to 0.016 mg/L, only loading dosage regimens provided PTAs exceeding 90%. For C. parapsilosis (AUC/MIC = 285), the maximum MIC of achieving a PTA ≥ 90% was 0.25 mg/L both in the regimens of B (150 mg maintenance dose) and C (200 mg maintenance dose) with loading dose. In addition, CFR of any regimen with loading dose was ≥ 90% against C. albicans and C. glabrata. None of the dosage regimens achieved an expected CFR against C. parapsilosis. CONCLUSIONS: The dosage regimen of micafungin which had a loading dose of 1.5 times was more suitable for ICU patients infected by Candida spp.

Predictable Resistance and Overall Survival of Gemcitabine/Cisplatin by Platelet Activation Index in Non-Small Cell Lung Cancer.

BACKGROUND Gemcitabine/cisplatin (GP) resistance displays a negative role in treating advanced and metastatic non-small cell lung cancer (NSCLC). Several studies found that the association existed between platelets and cancer antigen 125 (CA125) with anticancer drugs. But the exact correlation between GP resistance and platelet activation index remains poorly understood. MATERIAL AND METHODS Pre-chemotherapy platelet activation index and CA125 were retrospectively evaluated in 169 advanced and metastatic NSCLC patients. All variables were screened by chi-square test and then evaluated by log-rank test. Survival curves were generated by Kaplan-Meier analysis. Univariate and multivariate survival analysis were performed by using Cox proportional hazards model. RESULTS The overall rate of GP resistance for NSCLC patients was 72.19%. Mean platelet volume (MPV) and plateletcrit (PCT) are negative predictors of GP resistance adenocarcinoma [Odds ratio (OR): 5.81, 95% confidence interval (CI): 1.082-31.195, P=0.004] and squamous cell carcinoma (PCT: R: 3.517, 95% CI: 1.087-11.387, P=0.036), respectively. But both were an independent factor associated with overall survival (OS). Moreover, only CA125 was a dependent factor associated with OS for squamous cell carcinoma [OS: hazard ratio (HR): 1.741, 95% CI: 1.002-3.024, P=0.049; GP resistance: OR: 4.862, 95% CI: 1.437-16.448, P=0.011]. CONCLUSIONS Platelet activation index will be a potential marker for predicting GP resistance. Besides, CA125 ≥16.9 could be used as a potential marker for predicting GP resistance and OS, which was more sensitive than CA125 ≥35 for squamous cell carcinoma.

Dose regimens for Chinese adult liver transplant recipients according to the genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A5 in recipients and donors.

OBJECTIVE: Genetic polymorphisms of the P450 2C9 enzyme (CYP2C9), CYP2C19 and CYP3A5 gene are known to affect the metabolism of many drugs applied in liver transplant recipients, such as warfarin, voriconazole, and tacrolimus. The aim of this study was to recommend dose regimens for the liver recipients based on CYP2C9, CYP2C19, and CYP3A5 genotypic combinations of liver transplant recipients and their donors. METHODS: 91 adult Han Chinese liver transplant recipients who underwent orthotopic liver transplantation at Tianjin First Central Hospital, China, between 2013 and 2014 were included in this study. CYP2C9*2, CYP2C9*3, CYP2C19* 2, CYP2C19*3 and CYP3A5*3, in both liver recipients and their grafted liver were tested by polymerase chain reaction-restriction fragment length polymorphism. The dose regimens for the liver recipients were recommended based on CYP genotypic combinations of the recipients and their donors. RESULTS: In the liver transplant recipients, the frequencies of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP3A5*3 were found to be 2.75%, 4.40%, 0%, 24.18%, and 75.27%, respectively. Allele frequencies were significantly different for CYP2C9*2, CYP2C19*2, and CYP2C19* 3 (p < 0.001) when comparing the recipients with Chinese, Eastern Asians and Caucasians populations. Most dose regimens of drugs, especially of immunosuppressive drugs, should be adjusted according to the variant metabolism activity affected by the genetic polymorphisms in both recipients and their grafted liver. CONCLUSION: The dose regimens would present considerable intraand inter-patient variability in liver transplant recipients since the genetic polymorphisms of P450 enzyme in their grafted liver might complicate the metabolism of drugs in liver transplant recipients. Giving careful consideration to the CYP genotypic combinations of transplant recipients and donors in clinical dose regimens could optimize outcomes.

A pharmacokinetic/pharmacodynamic analysis of a standard voriconazole regimen in different CYP2C19 genotypes by Monte Carlo simulation.

OBJECTIVES: The objective of this study was to evaluate the standard voriconazole dosage regimen (maintenance dose was 200 mg bid orally) against Aspergillus infections in different CYP2C19 genotypes from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. METHOD: Monte Carlo simulation (MCS) was applied to simulate 5,000 patients by integrating published pharmacokinetic (PK) parameters, variability of PK parameters on CYP2C19 genotypes and microbiological data. RESULTS: The standard dosage regimen for poor metabolizers (PM) with Aspergillus infections was effective except A. versicolor, for heterozygous extensive metabolizers (HEM), Aspergillus fumigatus, A. terreus and A. nidulans infections could be treated effectively with the standard dosage regimen; for extensive metabolizers (EM), the standard voriconazole dosage regimen failed to achieve the best outcome for the six Aspergillus spp. Increasing dose (e.g. 300 mg bid) or even changing the antifungal drug was needed for EM and most HEM patients with Aspergillus infection. CONCLUSION: Instead of using a standard dosage regimen for all patients, the voriconazole dosage regimen needs to be optimized for patients with different CYP2C19 genotypes.

Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Cost-effectiveness analysis of tislelizumab plus chemotherapy as the first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma in China.

OBJECTIVE: We aimed to investigate the cost-effectiveness of tislelizumab plus chemotherapy compared to chemotherapy alone as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (OSCC). METHODS: A partitioned survival model was developed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus chemotherapy alone in patients with advanced or metastatic OSCC over a 10-year lifetime horizon from the perspective of the Chinese healthcare system. Costs and utilities were derived from the drug procurement platform and published literature. The model outcomes comprised of costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were conducted to address uncertainty and ensure the robustness of the model. RESULTS: Tislelizumab plus chemotherapy yielded an additional 0.337 QALYs and incremental costs of $7,117.007 compared with placebo plus chemotherapy, generating an ICER of $21,116.75 per QALY, which was between 1 time ($12,674.89/QALY) and 3 times GDP ($38,024.67/QALY) per capita. In one-way sensitivity analysis, the ICER is most affected by the cost of oxaliplatin, paclitaxel and tislelizumab. In the probabilistic sensitivity analysis, when the willingness-to-pay threshold was set as 1 or 3 times GDP per capita, the probability of tislelizumab plus chemotherapy being cost-effective was 1% and 100%, respectively. CONCLUSION: Tislelizumab plus chemotherapy was probably cost-effective compared with chemotherapy alone as the first-line treatment for advanced or metastatic OSCC in China.

A Prognostic Cuproptosis-Related LncRNA Signature for Colon Adenocarcinoma.

Background: Cuproptosis, a recently discovered form of cell death, is caused by copper levels exceeding homeostasis thresholds. Although Cu has a potential role in colon adenocarcinoma (COAD), its role in the development of COAD remains unclear. Methods: In this study, 426 patients with COAD were extracted from the Cancer Genome Atlas (TCGA) database. The Pearson correlation algorithm was used to identify cuproptosis-related lncRNAs. Using the univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) was used to select cuproptosis-related lncRNAs associated with COAD overall survival (OS). A risk model was established based on the multivariate Cox regression analysis. A nomogram model was used to evaluate the prognostic signature based on the risk model. Finally, mutational burden and sensitivity analyses of chemotherapy drugs were performed for COAD patients in the low- and high-risk groups. Result: Ten cuproptosis-related lncRNAs were identified and a novel risk model was constructed. A signature based on ten cuproptosis-related lncRNAs was an independent prognostic predictor for COAD. Mutational burden analysis suggested that patients with high-risk scores had higher mutation frequency and shorter survival. Conclusion: Constructing a risk model based on the ten cuproptosis-related lncRNAs could accurately predict the prognosis of COAD patients, providing a fresh perspective for future research on COAD.

Population Pharmacokinetics of Tacrolimus in Pediatric Patients With Umbilical Cord Blood Transplant.

Tacrolimus was frequently used in pediatric patients with umbilical cord blood transplant for the prevention of graft-versus-host disease. The aim of the present study was to evaluate the population pharmacokinetics of tacrolimus among pediatric patients with umbilical cord blood transplant and find potential influenced factors. A total of 275 concentrations from 13 pediatric patients were used to build a polulation pharmacokinetic model using a nonlinear mixed-effects modeling approach. The impact of demographic features, biological characteristics, and concomitant medications, including sex, age, body weight, postoperative day, white blood cell count, red blood cell count, hemoglobin, platelets, hematocrit, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, total bilirubin, albumin, and total protein were investigated. The pharmacokinetics of tacrolimus were best described by a 1-compartment model with first- and zero-order mixed absorption and first-order elimination. The clearance and volume of distribution of tacrolimus were 1.93 L/h and 75.1 L, respectively. A covariate analysis identified that postoperative day and co-administration with trimethoprim-sulfamethoxazole were significant covariates influencing clearance of tacrolimus. Frequent blood monitoring and dose adjustment might be needed with the prolongation of postoperative day and coadministration with trimethoprim-sulfamethoxazole.

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study.

Background: Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods: First, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC-MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results: The LC-MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion: Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.

Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer.

PURPOSE: The objective of this study was to investigate the pharmacokinetic characteristics of pegylated liposomal doxorubicin (PLD) in Chinese female patients with advanced breast cancer by constructing population pharmacokinetic (popPK) models of liposome-encapsulated and free doxorubicin. Additionally, the relationship between pharmacokinetic parameters and drug-related adverse events (AEs) was explored through toxicity correlation analysis. METHODS: A total of 20 patients with advanced breast cancer were selected from a PLD bioequivalence study. All patients received a single intravenous dose of 50 mg/m2 PLD. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A popPK model was simultaneously built to characterize the pharmacokinetic profiles of liposome-encapsulated and free doxorubicin by non-linear mixed effects model (NONMEM). PLD-related toxicities were graded according to the common terminology criteria for adverse events (CTCAE) v5.0. The Spearman correlation analysis was conducted to explore the relationship between pharmacokinetic parameters and drug-related AEs of both liposome-encapsulated doxorubicin and free doxorubicin. RESULTS: The concentration-time profiles of both liposome-encapsulated doxorubicin and free doxorubicin were well described by a one-compartment model. The most common AEs to PLD were nausea, vomiting, neutropenia, leukopenia, and stomatitis, most of which were grade I-II. The toxicity correlation analysis results indicated that stomatitis was related to the Cmax of liposome-encapsulated doxorubicin (P < 0.05). No other AEs were found to be correlated with the pharmacokinetic parameters of either free or liposome-encapsulated doxorubicin. CONCLUSION: A one-compartment model adequately described the popPK characteristics of both liposome-encapsulated and free doxorubicin in Chinese female patients with advanced breast cancer. Most AEs to PLD were mild. Additionally, the occurrence of mucositis may be positively correlated with the Cmax of liposome-encapsulated doxorubicin.

Correlation of gene expression profiles to identify pancreatic cancer cell lines that best model primary human tumors.

Background: Cancer cell lines are important research models for studying tumor biology in vivo. The accuracy of such studies is highly dependent on the phenotypic and genetic similarity of cell lines to patient tumors, but this is not always the case, particularly for pancreatic cancer. Methods: We compared the gene expression profiles of various pancreatic cancer cell lines and primary human pancreatic tumor tissues to determine which pancreatic cancer cell line best models human primary tumor. Profiles of messenger RNA (mRNA) expression of 33 pancreatic cancer cell lines and 892 patient samples of pancreatic adenocarcinoma (PAAD) were obtained from the Gene Expression Omnibus (GEO) database. Microarray data were normalized using the robust multichip average (RMA) algorithm and batch effect removal was performed using ComBat. The pooled data of each PAAD cell line were compared to patient tumors based on the top 2,000 genes with largest interquartile range (IQR), 134 gene-collections of cancer-related pathways, and 504 gene-collections of cancer-related functions using pairwise Pearson's correlation analysis. Results: PAAD cell lines were poorly correlated with patient tumor tissues based on the top 2,000 genes. Up to 50% of cancer-related pathways were not strongly recommended in PAAD cell lines, and a small proportion of cancer-related functions (12-17%) were poorly correlated with PAAD cell lines. In pan-pathway analysis, the cell lines showing the highest genetic correlation to patient tumors were Panc 03.27 for PAAD cell lines from a primary lesion site and CFPAC-1 for PAAD cell lines from a metastatic lesion site. In pan-function analysis, the cell lines showing the highest genetic correlation to patient tumors were Panc 03.27 for PAAD cell lines from a primary lesion site and Capan-1 for PAAD cell lines from a metastatic lesion site. Conclusions: The gene expression profiles of PAAD cell lines correlate weakly with those of primary pancreatic tumors. Through comparison of the genetic similarity between PAAD cell lines and human tumor tissue, we have provided a strategy for choosing the appropriate PAAD cell line.

Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors.

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. 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. A population pharmacokinetic model was established using nonlinear mixed-effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1-compartment model with first-order absorption and first-order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. 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 based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.

Cost-effectiveness analysis of durvalumab plus etoposide: platinum in the first-line therapy of extensive stage small-cell lung cancer from the Chinese payers' perspective.

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.

Modified microvessel density based on perfusion distance: a preferable NSCLC prognostic factor.

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 (Dmvcc), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-Dmvcc were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. Results: The Dmvcc 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-Dmvcc (~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.

Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes.

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.

Cost effectiveness of immune checkpoint inhibitors for treatment of non-small cell lung cancer: A systematic review.

BACKGROUND: Immune 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. OBJECTIVES: The aim of this study was to evaluate the cost effectiveness of immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC). METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Immunotherapy 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.