Preferences and Willingness to Pay for Medication in Patients with Renal Cell Carcinoma in China: A Discrete-Choice Experiment.

OBJECTIVE: We aimed to assess the relative importance of attributes and the willingness to pay for pharmacological therapies among patients with renal cell carcinoma in China. METHODS: Patients with renal cell carcinoma completed a D-efficient-designed, discrete-choice experiment online survey that presented a series of ten trade-off questions and one examining scenario. Based on the literature review and consultations with patients with renal cell carcinoma and clinicians, each question included a pair of hypothetical renal cell carcinoma medication profiles characterized by seven attributes including progression-free survival, objective response rate, medication regimen, fatigue, gastrointestinal reaction, hand-foot syndrome, and monthly out-of-pocket costs. Relative importance and willingness to pay were calculated using coefficients estimated by mixed logit regression in the main analysis. Subgroup analyses were conducted considering the heterogeneity of the participants, based on sex, education level, and income level, using conditional logit regression. RESULTS: The analysis incorporated responses from 182 Chinese respondents. Except for the medication regimen, all attributes were statistically significant. Progression-free survival was the most important attribute, followed by objective response rate, monthly out-of-pocket costs, fatigue, gastrointestinal reaction, and hand-foot syndrome. Patients were willing to pay ï¿¥2010.51 ($298.30), ï¿¥494.93 ($73.43) for 1 unit improvement of progression-free survival, and objective response rate, andï¿¥7558.93 ($1121.50), ï¿¥6927.24 ($1027.78) to avoid experiencing fatigue and gastrointestinal reaction, respectively. Differences in preferences and willingness to pay were found according to patients' gender, income, and education level. CONCLUSIONS: In China, patients with renal cell carcinoma preferred medications with better efficacy (objective response rate and progression-free survival) and lower out-of-pocket costs. Heterogeneity can be found in preferences and willingness to pay based on patients' gender, income, and education levels.

Prognostic models for predicting overall and cancer-specific survival of patients with initially diagnosed metastatic cervical squamous cell carcinoma: A study based on SEER database.

Cervical squamous cell carcinoma (CSCC) is the most common histological type of cervical cancer (CC). And mCSCC is the end stage of CSCC. The aim of this study was to develop prognostic nomograms that provide better predictions for overall survival (OS) and cancer-specific survival (CSS) in mCSCC patients. Data from patients with initially diagnosed mCSCC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The nomograms for OS and CSS were constructed based on Cox regression analysis. The validation of the newly established nomograms was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). A total of 2198 patients with mCSCC were included and randomly split into training (n = 1539) and validation (n = 659) cohorts in a 7:3 ratio. Multivariate analyses revealed that the prognostic variables significantly related to the OS and CSS were marital status, T stage, brain metastasis, lung metastasis, tumor size, number of positive lymph nodes, chemotherapy, and radiotherapy. The nomograms were constructed based on these factors. The C-index value of the nomograms for predicting OS and CSS was 0.714 and 0.683, respectively. The calibration curves of the nomograms showed good consistency between nomogram prediction and actual survival for both OS and CSS, and the DCAs showed great clinical usefulness of the nomograms. The mCSCC patients were classified into low- and high-risk groups based on the scores from the nomograms. In the validation cohort, mCSCC patients with low-risk had much higher OS and CSS than those with high-risk. We constructed nomograms for predicting the OS and CSS of patients with initially diagnosed mCSCC. Our models had satisfactory predictive performance and could be useful in survival prediction for mCSCC.

A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor that is being developed for the treatment of hyperuricemia and gout. The primary aim of the present study was to study the pharmacokinetic drug‒drug interactions (DDIs) of HP501, febuxostat, and colchicine in hyperuricemic patients. METHODS: Hyperuricemic patients were randomly divided into group A, receiving HP501 40 mg once daily on days 1 and 4-10, and group B, receiving febuxostat 40 mg once daily on day 1 and HP501 40 mg plus febuxostat 40 mg on days 4-10. All patients received 0.5 mg colchicine once daily from day 4 to 12. Blood samples were collected for measurement of drug concentrations and serum uric acid (sUA) levels. RESULTS: Coadministration of colchicine with HP501 or HP501 plus febuxostat did not affect steady-state exposure to colchicine. Coadministration of HP501 and febuxostat did not significantly change the pharmacokinetic profiles of either drug. Following multiple administrations of HP501 40 mg once daily for 7 days, the maximal percent sUA change from baseline in group A was - 24.77%. The coadministration of HP501 40 mg and febuxostat 40 mg in group B for 7 days resulted in a - 55.82% maximal sUA reduction from baseline, and all patients achieved the goal of sUA < 360 µmol/L. All adverse events (AEs) were either mild or moderate, and the most frequently reported AEs were diarrhea and elevated alanine aminotransferase (ALT) levels. CONCLUSIONS: The concomitant use of HP501, febuxostat, and colchicine did not produce clinically meaningful DDIs in terms of their pharmacokinetic properties. CLINICAL TRIAL REGISTRATION: No. CTR20212261 ( http://www.chinadrugtrials.org.cn/ ) registered September 2021.

A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia.

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Therapeutic targeting of VEGF and/or TGF-ß to enhance anti-PD-(L)1 therapy: The evidence from clinical trials.

Normalizing the tumor microenvironment (TME) is a potential strategy to improve the effectiveness of immunotherapy. Vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß pathways play an important role in the development and function of the TME, contributing to the immunosuppressive status of TME. To inhibit VEGF and/or TGF-ß pathways can restore TME from immunosuppressive to immune-supportive status and enhance sensitivity to immunotherapy such as programmed death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. In this review, we described the existing preclinical and clinical evidence supporting the use of anti-VEGF and/or anti-TGF-ß therapies to enhance cancer immunotherapy. Encouragingly, adopting anti-VEGF and/or anti-TGF-ß therapies as a combination treatment with anti-PD-(L)1 therapy have been demonstrated as effective and tolerable in several solid tumors in clinical trials. Although several questions need to be solved, the clinical value of this combination strategy is worthy to be studied further.

New insights of necroptosis and immune infiltration in sepsis-induced myocardial dysfunction from bioinformatics analysis through RNA-seq in mice.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host immune response to infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in patients with severe sepsis and is associated with increased mortality. The molecular mechanisms underlying SIMD are complex and not well characterized. Excessive inflammation due to impaired regulation of immune response is one of the major causes of SIMD. Necroptosis is a novel type of cell death that is closely related to tissue injury and inflammation. However, the role of necroptosis in SIMD is not known. Therefore, in this study, we performed an in-depth bioinformatics analysis to investigate the relationship between necroptosis and SIMD using a mouse model generated by intraperitoneal injection of lipopolysaccharide (LPS) and the underlying mechanisms. Myocardial function was assessed by echocardiography. Histopathological changes in SIMD were analyzed by hematoxylin and eosin (H&E) staining. Gene expression profiles of the heart tissues from the SIMD and control mice were analyzed by bioinformatics analysis. Transcriptome sequencing demonstrated significant differences in the expression levels of 3654 genes in the heart tissues of SIMD mice including 1810 up-regulated and 1844 down-regulated genes. The necroptosis pathway genes were significantly enriched in the heart tissues from the SIMD group mice. We identified 35 necroptosis-related differentially expressed genes (NRDEGs) including MLKL and RIPK3. Cardiomyocyte necroptosis was confirmed by qRT-PCR and western blot analysis. The expression levels of most NRDEGs showed positive correlation with the infiltration levels of mast cells, macrophages, and neutrophils, and negative correlation with the infiltration levels of B cells and plasma cells in the heart tissues of the SIMD group mice. In conclusion, this study demonstrated that necroptosis was associated with changes in the infiltration levels of several immune cell types in the heart tissues of the SIMD model mice. This suggested that necroptosis influenced SIMD development by modulating the immune microenvironment. This suggested that NRDEGs are potential diagnostic biomarkers and therapeutic targets for patients with SIMD.

Degarelix vs. leuprorelin for the treatment of prostate cancer in China: A cost-utility analysis.

Objective: To explore the cost-effectiveness of degarelix acetate for injection (degarelix) compared to leuprorelin in prostate cancer (Pca) castration treatment from Chinese healthcare system perspective. Methods: A Markov model, adapted from the one established in Finland was conducted for the cost-effectiveness analysis of degarelix and leuprorelin for Pca treatment. The main data were derived from global phase III clinical trials of degarelix (CS21), published study and expert surveys. Outcomes, utility and costs of prostate cancer patients were calculated on a 30-year time horizon. The CS21 study based population of intention-to-treat (ITT) population and three scenarios were modeled. Taking three times of the Gross domestic product (GDP) per capita (242,928 yuan, 2021) as the acceptable threshold for cost-effectiveness. One-way and probabilistic sensitivity analyses were performed on key parameters, including transition probabilities, costs, utility, and discount rate to test the robustness of the model. Results: Base case analysis for ITT population revealed that total costs of degarelix and leuprorelin were 566,226 yuan and 489,693 yuan, while the total quality-adjusted life years (QALYs) were 5.19 and 4.51 during the 30-year time horizon, resulting an incremental cost effectiveness ratio (ICER) of 112,674 yuan/QALY which was 1.39 times the GDP per capita, lower than willingness-to-pay level of three times the GDP per capita. The results for scenario analyses revealed that compared to leuprorelin, degarelix for Pca treatment in China was cost-effective. One-way sensitivity analysis showed that the model was most sensitive to price of 80 mg degarelix, utility of 1st-line therapy, hazard ratio of PSA recurrence, price of 3.75 mg leuprorelin, response rate of docetaxel per cycle, and discount rate of cost. In probabilistic sensitivity analysis, compared to leuprorelin, the probability of degarelix to be cost-effective was 53 and 81% for willingness-to-pay threshold of one and three times the GDP per capita. Conclusion: Compared to leuprorelin, degarelix for prostate cancer treatment is cost-effective. Moreover, scenario, one-way, and probabilistic sensitivity analyses revealed that the model was robust.

PROTACs in gastrointestinal cancers.

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Novel therapies for malignant pleural effusion: Anti­angiogenic therapy and immunotherapy (Review).

Patients with a variety of malignancies can develop malignant pleural effusion (MPE). MPE can cause significant symptoms and result in a marked decrease in quality of life and a poor prognosis. MPE is primarily considered as an immune and vascular manifestation of pleural metastases. In the present review, the existing evidence supporting the applicability of anti­angiogenic therapy and immunotherapy for the treatment of MPE was summarized. Patients with MPE have benefited from anti­angiogenic agents, including bevacizumab and endostar; however, no relevant prospective phase III trial has, thus far, specifically analyzed the benefit of anti­angiogenic therapy in MPE. Immunotherapy for MPE may be sufficient to turn a dire clinical situation into a therapeutic advantage. Similar to anti­angiogenic therapy, more clinical data on the efficiency and safety of immunotherapy for controlling MPE are urgently required. The combined use of anti­angiogenic therapy and immunotherapy may be a promising strategy for MPE, which requires to be further understood.

Effect of Irisin on Pressure Overload-Induced Cardiac Remodeling.

BACKGROUND: Irisin has been considered a prognostic factor in several cardiovascular diseases. Nevertheless, no data are available on the role of irisin in cardiac remodeling. AIM OF THE STUDY: This study aimed to determine the potential role of irisin in cardiac remodeling and explore potential mechanisms. METHODS: A total of 40 rats that underwent transverse abdominal aortic constriction (TAC) surgery or sham operation were divided into four groups: sham + saline (NS), sham + irisin, TAC + NS, and TAC + irisin. After 6 weeks of treatment, echocardiography was performed to assess in vivo cardiac morphology. The left ventricular myocardium was prepared and observed by pathological examination. The effect of irisin on cardiomyocyte apoptosis and the expression of oxidative stress and cardiac hypertrophy markers were observed. Then, the effect of irisin on the Akt signaling system was also detected. RESULTS: The rats in the TAC group displayed obvious signs of cardiac dysfunction and cardiac hypertrophy, and irisin treatment could reverse these changes. Irisin could inhibit the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 and xanthine oxidase in TAC rats and increase the expression of antioxidant enzymes. Furthermore, the expression of phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and phosphorylated glycogen synthase kinase 3ß (p-GSK3ß) was much higher in the cardiac remodeling groups (p <0.05 vs. sham rats). Irisin could relieve the inhibition effect and reduce the expression level of these three proteins. CONCLUSIONS: Irisin treatment could significantly improve cardiac remodeling by inhibiting oxidative stress via attenuating the Akt signaling activation.