Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

The impact of patients' hostile attribution bias on aggression in doctor-patient interactions.

Background: Doctor-patient conflict is trending in social attention research. However, the existing literature rarely explores whether a patient's hostile attribution bias (HAB) in the doctor-patient interaction affects the aggression level against doctors. Objective: This study aimed to explore the relationship and mechanism between different types of HAB and aggression in patients. Method: In Study 1, 80 patients completed the word sentence association paradigm for hostility (WSAP-Hostility), and their explicit and implicit aggression levels were measured using the hot sauce paradigm and the single-category implicit association test (SC-IAT), respectively. In Study 2, 63 patients were randomly divided into an experimental (rejection) and a control group. Their state hostile attribution bias (SHAB) was activated through social rejection materials. They completed the SHAB questionnaire and anger expression inventory, and their explicit and implicit aggression levels were measured as in Study 1. Results: In both studies, results indicated that patients' trait and state HAB were significantly related to explicit aggression but not implicit aggression. Hostile interpretation positively predicted explicit aggression, whereas benign interpretation had a negative predictive effect on explicit aggression. Patients' anger played a mediating role between SHAB and explicit aggression. Conclusions: These findings suggest that patients' HAB affects explicit aggression toward doctors and anger plays a mediating role.

How does emotional abuse affect adolescents' non-suicidal self-injury urges? A moderated chain mediation model.

BACKGROUND: Studying non-suicidal self-injury (NSSI) among adolescents has high clinical significance. Its urges have been identified as a potential predictor of NSSI behavior and may serve as a crucial intervention target. OBJECTIVE: This study uses a moderated chain mediation model to explore the relationship between emotional abuse and adolescent NSSI urges. Additionally, we examine the mediating roles of ego depletion and self-esteem and the moderating effect of resilience. PARTICIPANTS AND SETTING: We recruited 1129 Chinese adolescents (age M = 16.68; SD = 0.78; 49.4 % men) from secondary vocational schools in China. METHODS: We assessed emotional abuse, ego depletion, self-esteem, and NSSI urges in a longitudinal investigation across two time points (T1: March 2023, T2: June 2023). RESULTS: After controlling for age, sex, NSSI urges and self-esteem at T1, our study validates a moderated chain mediation model and finds that the mediating effect via self-esteem is 0.026 (95%CI = [0.011,0.046]), and the chain mediating effect via ego depletion and self-esteem is 0.031 (95%CI = [0.022,0.045]), whereas the direct effect of emotional abuse T1 on NSSI urges T2 is not significant (DE = 0.082, 95%CI = [-0.002, 0.167]) and the mediating effect via ego depletion is also not significant (IE = -0.003, 95%CI = [-0.022, 0.015]). Resilience moderates the impact of emotional abuse on ego depletion (ß = 0.09, p < 0.01). CONCLUSIONS: These findings suggest that ego depletion and self-esteem are potential mechanisms related to emotional abuse and adolescents' NSSI urges, whereas resilience can play a moderating role in reducing ego depletion.

Dietary consumption trend and its correlation with global cancer burden: A quantitative and comprehensive analysis from 1990 to 2019.

OBJECTIVE: The aim of this study was to estimate the effect of dietary consumption on cancer burden and formulate an effective solution. METHODS: Dietary consumption, number of cancer deaths, disability-adjusted life years, and corresponding age-standardized rates were extracted from the Global Burden of Disease Study 2019. The annual percentage change was used to quantify the temporal trends in cancer burden and dietary consumption. Age, sex, location, and sociodemographic index were stratified to further analyze the discrepancy in cancer burden attributable to dietary intake. RESULTS: Five cancers (breast, colon and rectal, tracheal, bronchus and lung, esophageal, and stomach) were documented to be associated with dietary consumption in the Global Burden of Disease database. The age-standardized death rate and age-standardized disability-adjusted life years rate in 2019 were 7.56 and 1168.77 per 100 000 population, respectively. For most cancers, the age-standardized death rate and age-standardized disability-adjusted life years rate displayed a decreasing tendency, with annual percentage change varying from -3.60 to -0.29 and from -3.64 to -0.03 from 1990 to 2019, respectively. The age-standardized death rate and age-standardized standardized disability-adjusted life years rate were higher in men than in women (9.68 vs 5.79 and 213.16 vs 129.18, respectively). In addition, the diet-related cancer burden in higher sociodemographic index regions exceeded that in lower sociodemographic index regions. CONCLUSION: Dietary consumption has a considerable influence on cancer burden, among which colon and rectal cancer burden account for the largest proportion. Increasing the intake of whole grains, milk, fiber, calcium, vegetables, and fruits and reducing the consumption of processed meat and sodium are instrumental in lowering the disease burden of cancer. The quantitative analysis of dietary consumption would provide a more detailed reference for diet-related decision makers and raise awareness of healthy dietary habits in diet management departments, food production enterprises, and the general public.

Long-term trend of future Cancer onset: A model-based prediction of Cancer incidence and onset age by region and gender.

OBJECTIVES: This study provided estimates of cancer incidence rate and onset age by Socio-demographic Index (SDI) regions and gender from 2020 to 2040, aiming to clarify the long-term patterns of future cancer onset. METHOD: Based on the incidence data from the Global Burden of Diseases (GBD) 2019 study, we constructed the Bayesian age-period-cohort model to calculate the age-standardized incidence rates (ASIR) of cancers from 2020 to 2040. Using the average annual percentage change (AAPC) to quantify the trends of ASIR and the onset age. In addition, the incidences in 2019 were fixed to distinguish the age onset changes caused by demographic and incidence from 2020 to 2040. RESULTS: Globally, two-thirds of cancers have escalating trends of incidence rate, and the proportion of cancer weighted average onset age above 60 years old will grow from 62% to 76% between 2020 and 2040. In five SDI regions, the proportion of weighted average onset age above 60 years old will rise above 10% in the next 20 years and increase sequentially with the rise of the SDI level. Preclude sex-specific cancers, the onset age is younger in men than in women in 2040. Rule out the influence of changing demographics, half of cancer's morbidity has a youth-oriented tendency globally, which is concentrated in hormone-related and digestive tract cancer. CONCLUSION: From 2020 to 2040, the incidence and onset age changes demonstrate marked geographic and gender variations in the cancer spectrum. Cancer incidence and onset age are predicted to continuously increase worldwide in the future.

Precise Differentiation of Wobble-Type Allele via Ratiometric Design of a Ligase Chain Reaction-Based Electrochemical Biosensor for CYP2C19*2 Genotyping of Clinical Samples.

Due to the comparable stability between the perfect-base pair and the wobble-base pair, a precise differentiation of the wobble-type allele has remained a challenge, often leading to false results. Herein, we proposed a ligase chain reaction (LCR)-based ratiometric electrochemical DNA sensor, namely, R-eLCR, for a precise typing of the wobble-type allele, in which the traditionally recognized "negative" signal of wobble-base pair-mediated amplification was fully utilized as a "positive" one and a ratiometric readout mode was employed to ameliorated the underlying potential external influence and improved its detection accuracy in the typing of the wobble-type allele. The results showed that the ratio between current of methylene blue (IMB) and current of ferrocene (IFc) was partitioned in three regions and three types of wobble-type allele were thus precisely differentiated (AA homozygote: IMB/IFc > 2; GG homozygote: IMB/IFc < 1; GA heterozygote: 1 < IMB/IFc < 2); the proposed R-eLCR successfully discriminated the three types of CYP2C19*2 allele in nine cases of human whole blood samples, which was consistent with those of the sequencing method. These results evidence that the proposed R-eLCR can serve as an accurate and robust alternative for the identification of wobble-type allele, which lays a solid foundation and holds great potential for precision medicine.

Cost-effectiveness analysis of an orphan drug tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing.

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator's choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.

Cost-effectiveness analysis of ovarian function preservation with GnRH agonist during chemotherapy in premenopausal women with early breast cancer.

STUDY QUESTION: Is it economically worthwhile to use GnRH agonist (GnRHa) to prevent menopausal symptoms (MS) and protect fertility in premenopausal women with breast cancer (BC) during chemotherapy from the US perspective? SUMMARY ANSWER: It is cost-effective to administer GnRHa during chemotherapy in order to forefend MS in premenopausal patients with BC when the willingness-to-pay (WTP) threshold is $50 000.00 per quality-adjusted life-year (QALY), and to preserve fertility in young patients with BC who undergo oocyte cryopreservation (OC), or no OC, when the WTP thresholds per live birth are $71 333.33 and $61 920.00, respectively. WHAT IS KNOWN ALREADY: Chemotherapy often results in premature ovarian insufficiency (POI) in premenopausal survivors of BC, causing MS and infertility. Administering GnRHa during chemotherapy has been recommended for ovarian function preservation by international guidelines. STUDY DESIGN, SIZE, DURATION: Two decision-analytic models were developed, respectively, for preventing MS and protecting fertility over a 5-year period, which compared the cost-effectiveness of two strategies: adding GnRHa during chemotherapy (GnRHa plus Chemo) or chemotherapy alone (Chemo). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were early premenopausal women with BC aged 18-49 years who were undergoing chemotherapy. Two decision tree models were constructed: one for MS prevention and one for fertility protection from the US perspective. All data were obtained from published literature and official websites. The models' primary outcomes included QALYs and incremental cost-effectiveness ratios (ICERs). The robustness of the models was tested by sensitivity analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the MS model, GnRHa plus Chemo resulted in an ICER of $17 900.85 per QALY compared with Chemo, which was greater than the WTP threshold of $50 000.00 per QALY; therefore, GnRHa plus Chemo was a cost-effective strategy for premenopausal women with BC in the USA. Probabilistic sensitivity analysis (PSA) results showed an 81.76% probability of cost-effectiveness in the strategy. In the fertility model, adding GnRHa for patients undergoing OC and those who were unable to undergo OC resulted in ICERs of $67 933.50 and $60 209.00 per live birth in the USA, respectively. PSA indicated that GnRHa plus Chemo was more likely to be cost-effective over Chemo when the WTP for an additional live birth exceed $71 333.33 in Context I (adding GnRHa to preserve fertility in young patients with BC after OC) and $61 920.00 in Context II (adding GnRHa to preserve fertility in young patients with BC who cannot accept OC). LIMITATIONS, REASONS FOR CAUTION: The indirect costs, such as disease-related mental impairment and non-medical costs (e.g. transportation cost) were not included. All data were derived from previously published literature and databases, which might yield some differences from the real world. In addition, the POI-induced MS with a lower prevalence and the specific strategy of chemotherapy were not considered in the MS model, and the 5-year time horizon for having a child might not be suitable for all patients in the fertility model. WIDER IMPLICATIONS OF THE FINDINGS: When considering the economic burden of cancer survivors, the results of this study provide an evidence-based reference for clinical decision-making, showing that it is worthwhile to employ GnRHa during chemotherapy to prevent MS and preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Natural Science Foundation of Fujian Province [2021J02038]; and the Startup Fund for Scientific Research, Fujian Medical University [2021QH1059]. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Nucleic Acid Amplification by Template-Dominated Click Chemistry for Ultrasensitive DNA/RNA Detection on an Electrochemical Readout Platform.

As an enzyme-free exponential nucleic acid amplification method, the click chemistry-mediated ligation chain reaction (ccLCR) has shown great prospects in the molecular diagnosis. However, the current optics-based ccLCR is challenged by remarkable nonspecific amplification, severely hindering its future application. This study demonstrated that the severe nonspecific amplification was generated probably due to high random collision in the high DNA probe concentration (µM level). To solve this hurdle, a nucleic acid template-dominated ccLCR was constructed using nM-level DNA probes and read on an electrochemical platform (cc-eLCR). Under the optimal conditions, the proposed cc-eLCR detected a low-level nucleic acid target (1 fM) with a single-base resolution. Furthermore, this assay was applied to detect the target of interest in cell extracts with a satisfactory result. The proposed cc-eLCR offers huge possibility for click chemistry-mediated enzyme-free exponential nucleic acid amplification in the application of medical diagnosis and biomedical research.

The correlation between the costs and clinical benefits of PD-1/PD-L1 inhibitors in malignant tumors: An evaluation based on ASCO and ESMO frameworks.

Background: Life expectancy for patients with malignant tumors has been significantly improved since the presence of the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors in 2014, but they impose heavy financial burdens for patients, the healthcare system and the nations. The objective of this study was to determine the survival benefits, toxicities, and monetary of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors and quantify their values. Methods: Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors for malignant tumors were identified and clinical benefits were quantified by American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The drug price in Micromedex REDBOOK was used to estimate monthly incremental drug costs (IDCs) and the correlation between clinical benefits and incremental drug costs of experimental and control groups in each randomized controlled trial, and the agreement between two frameworks were calculated. Results: Up to December 2022, 52 randomized controlled trials were included in the quantitative synthesis. All the randomized controlled trials were evaluated by American society of clinical oncology value framework, and 26 (50%) met the American society of clinical oncology value framework "clinical meaningful value." 49 of 52 randomized controlled trials were graded by European society for medical oncology magnitude of clinical benefit scale, and 30 (61.2%) randomized controlled trials achieved European Society for Medical Oncology criteria of meaningful value. p-values of Spearman correlation analyses between monthly incremental drug costs and American society of clinical oncology value framework/European society for medical oncology magnitude of clinical benefit scale scores were 0.9695 and 0.3013, respectively. In addition, agreement between two framework thresholds was fair (κ = 0.417, p = 0.00354). Conclusion: This study suggests that there might be no correlation between the cost and clinical benefit of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors in malignancy, and the same results were observed in subgroups stratified by drug or indication. The results should be a wake-up call for oncologists, pharmaceutical enterprises and policymakers, and meanwhile advocate the refining of American Society of Clinical Oncology and European Society for Medical Oncology frameworks.

Disease burden of prostate cancer from 2014 to 2019 in the United States: estimation from the Global Burden of Disease Study 2019 and Medical Expenditure Panel Survey.

OBJECTIVES: The aim of this study was to evaluate the disease burden of prostate cancer (PC) and assess key influencing factors associated with the disease expenditures of PC in the United States. METHODS: The total deaths, incidence, prevalence, and disability-adjusted life-years of PC were obtained from the Global Burden of Disease Study 2019. The Medical Expenditure Panel Survey was used to estimate healthcare expenditures and productivity loss and to investigate patterns of payment and use of healthcare resources in the United States. A multivariable logistic regression model was conducted to identify key factors influencing expenditures. RESULTS: For patients aged 50 and older, the burden for all age groups showed a modest increase over the 6-year period. Annual medical expenditures were estimated to range from US$24.8 billion to US$39.2 billion from 2014 to 2019. The annual loss in productivity for patients was approximately US$1,200. The top 3 major components of medical costs were hospital inpatient stays, prescription medicines, and office-based visits. Medicare was the largest source of payments for survivors. In terms of drug consumption, genitourinary tract agents (57.0%) and antineoplastics (18.6%) were the main therapeutic drugs. High medical expenditures were positively associated with age (p=0.005), having private health insurance (p=0.016), more comorbidities, not currently smoking (p=0.001), and patient self-perception of fair/poor health status (p<0.001). CONCLUSIONS: From 2014 to 2019, the national real-world data of PC revealed that the disease burden in the United States continued to increase, which was partly related to patient characteristics.

Prophylaxis for Pneumocystis carinii pneumonia in non-Hodgkin's lymphoma undergoing R-CHOP21 in China: a meta-analysis and cost-effectiveness analysis.

OBJECTIVE: Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, once every 3 weeks (R-CHOP21) is commonly used in non-Hodgkin's lymphoma (NHL), but accompanied by Pneumocystis carinii pneumonia (PCP) as a fatal treatment complication. This study aims to estimate the specific effectiveness and cost-effectiveness of PCP prophylaxis in NHL undergoing R-CHOP21. DESIGN: A two-part decision analytical model was developed. Prevention effects were determined by systemic review of PubMed, Embase, Cochrane Library and Web of Science from inception to December 2022. Studies reporting results of PCP prophylaxis were included. Enrolled studies were quality assessed with Newcastle-Ottawa Scale. Costs were derived from the Chinese official websites, and clinical outcomes and utilities were obtained from published literature. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses (DSA and PSA). Willingness-to-pay (WTP) threshold was set as US$31 315.23/quality-adjusted life year (QALY) (threefold the 2021 per capita Chinese gross domestic product). SETTING: Chinese healthcare system perspective. PARTICIPANTS: NHL receiving R-CHOP21. INTERVENTIONS: PCP prophylaxis versus no prophylaxis. MAIN OUTCOME MEASURES: Prevention effects were pooled as relative risk (RR) with 95% CI. QALYs and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: A total of four retrospective cohort studies with 1796 participants were included. PCP risk was inversely associated with prophylaxis in NHL receiving R-CHOP21 (RR 0.17; 95% CI 0.04 to 0.67; p=0.01). Compared with no prophylaxis, PCP prophylaxis would incur an additional cost of US$527.61, and 0.57 QALYs gained, which yielded an ICER of US$929.25/QALY. DSA indicated that model results were most sensitive to the risk of PCP and preventive effectiveness. In PSA, the probability that prophylaxis was cost-effective at the WTP threshold was 100%. CONCLUSION: Prophylaxis for PCP in NHL receiving R-CHOP21 is highly effective from retrospective studies, and routine chemoprophylaxis against PCP is overwhelmingly cost-effective from Chinese healthcare system perspective. Large sample size and prospective controlled studies are warranted.

Avelumab Maintenance Treatment After First-line Chemotherapy in Advanced Urothelial Carcinoma-A Cost-Effectiveness Analysis.

BACKGROUND: Recently, a clinical trial (NCT02603432) showed that avelumab maintenance treatment, post first-line chemotherapy, can significantly prolong the overall survival of patients with advanced urothelial carcinoma (UC), however, the treatment was very expensive. This study aimed to determine the cost-effectiveness of avelumab maintenance therapy in advanced or metastatic UC from the US taxpayer perspective. METHODS: Based on the data of the JAVELIN Bladder 100 clinical trial (NCT02603432), a Markov multi-state model was constructed to investigate the costs and clinical outcomes of avelumab maintenance after platinum-based chemotherapy versus best supportive care (BSC) for advanced or metastatic UC. Parameters of the model came from the 2020 Average Sales Price Drug Pricing Files and published literature. The main outputs were costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Robustness was tested by deterministic and probabilistic sensitivity analyses. The analysis was stratified to include both the overall population and a subset of programmed death-ligand 1 (PD-L1)-positive patients. RESULTS: Avelumab maintenance therapy was estimated to generate an additional 0.26 QALYs (1.46 vs. 1.20 QALYs) and costs $183,271 ($278,323 vs. $95,052) more compared to BSC alone in the overall population, yielding an ICER of $699,065/QALY. For the PD-L1-positive population, avelumab produced a 0.42 increase in QALYs (1.74 vs. 1.32 QALYs) and raised costs to $223,238 ($320,355 vs. $97,117), resulting in an ICER of $521,850/QALY for this population. Both ICERs were above the willingness-to-pay (WTP) threshold of $200,000/QALY. Sensitivity analyses manifested that the model was robust. CONCLUSION: From the perspective of the US taxpayer, avelumab maintenance therapy is considered cost-ineffective for patients with advanced or metastatic UC at a WTP threshold of $200,000/QALY in the overall population as well as in PD-L1-positive population.

A simple system for measuring the transmittance curve of x-ray filters at low x-ray energies.

To prevent the x-ray detectors from the interference of optical photons, x-ray filters are widely used in x-ray space missions. As the flux of low energy x-rays would be significantly attenuated by the filters, it is important to derive the transmittance of the filters below 10 keV. In this paper, we present a simple experimental apparatus and data processing method to measure the transmittance curve of x-ray filters in the energy range from 1.6 to 10 keV. The measured spectra were further processed with Geant4 Monte Carlo simulation results and a direct demodulation algorithm. The obtained transmittance is in good accordance with the theoretical calculation and the synchrotron radiation test result, which proves that the proposed system with the algorithm is a reasonable way to characterize the x-ray transmittance performance of filters above 1.6 keV.

Multimodal Ochratoxin A-Aptasensor Using 3'-FAM-Enhanced Exonuclease I Tool and Magnetic Microbead Carrier.

Thanks to its preparatory ease, close affinity, and low cost, the aptasensor can serve as a promising substitute for antibody-dependent biosensors. However, the available aptasensors are mostly subject to a single-mode readout and the interference of unbound aptamers in solution and non-target-induced transition events. Herein, we proposed a multimodal aptasensor for multimode detection of ochratoxin A (OTA) with cross-validation using the 3'-6-carboxyfluorescein (FAM)-enhanced exonuclease I (Exo I) tool and magnetic microbead carrier. Specifically, the 3'-FAM-labeled aptamer/biotinylated-cDNA hybrids were immobilized onto streptavidin-magnetic microbeads via streptavidin-biotin interaction. With the presence of OTA, an antiparallel G-quadruplex conformation was formed, protecting the 3'-FAM labels from Exo I digestion, and then anti-FAM-horseradish peroxidase (HRP) was bound via specific antigen-antibody affinity; for the aptamers without the protection of OTA, the distal ssDNA was hydrolyzed from 3' → 5', releasing 3'-FAM labels to the solution. Therefore, the OTA was detected by analyzing the "signal-off" fluorescence of the supernatant and two "signal-on" signals in electrochemistry and colorimetry through the detection of the coating magnetic microbeads in HRP's substrate. The results showed that the 3'-FAM labels increased the activity of Exo I, producing a low background due to a more thorough digestion of unbound aptamers. The proposed multimodal aptasensor successfully detected the OTA in actual samples. This work first provides a novel strategy for the development of aptasensors with Exo I and 3'-FAM labels, broadening the application of aptamer in the multimode detection of small molecules.

The Predictive Value of PD-L1 Expression Level in Evaluating the Cost-Effectiveness of Atezolizumab/Pembrolizumab.

Objective: Recently, the significant improvement of atezolizumab and pembrolizumab over chemotherapy for treatment-naïve stage IV non-small cell lung cancer (NSCLC) has been demonstrated, but the cost-effectiveness of these regimens remains unknown. Methods: A Markov model was adapted from the US healthcare perspective to assess the cost-effectiveness of atezolizumab, pembrolizumab, and chemotherapy in treatment-naïve NSCLC. Pseudo-individual patient data were generated from digitized Kaplan-Meier curves. Direct medical costs and utility values were sourced from the database and literature. Quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs) were computed. Sensitivity analyses and budgetary impact analyses were calculated. Results: In any and high programmed cell death 1-ligand 1 (PD-L1) expression populations, with chemotherapy, atezolizumab provided ICERs of $234,990 and $130,804 per QALY, while pembrolizumab yielded ICERs of $424,797 and $140,873 per QALY. The ICER of atezolizumab vs. pembrolizumab was $56,635 and $115,511.82 in any and high PD-L1 expression population, respectively. The critical drivers of ICERs included the cost of atezolizumab and pembrolizumab. The accumulated incremental budgetary impact of atezolizumab vs. chemotherapy increased to approximately $39.1 million in high PD-L1 expression patients over 5 years. Conclusions: In the high PD-L1 expression population, both atezolizumab and pembrolizumab were cost-effective for stage IV NSCLC compared to chemotherapy, which is contrary to that in any PD-L1 expression population. Atezolizumab shows a higher acceptability in both populations. Treating with immune checkpoint inhibitors (ICIs) has a substantial budgetary impact on the medical burden. The PD-L1 expression level has the potential to be a predictor for the economics of ICIs.

Evaluation of osimertinib for advanced non-small cell lung cancer with leptomeningeal metastases: a cost-effectiveness and budget impact analysis.

Background Few regimens for non-small cell lung cancer (NSCLC) with leptomeningeal metastases (LM) patients exist up to date, most with low efficacy. A retrospective analysis showed that osimertinib significantly improved the overall survival of LM patients by 11.5 months (17.0 vs. 5.5) as compared to no osimertinib treatment. Until now, no pharmacoeconomic evaluation of osimertinib has been performed to determine its feasibility for widespread use in LM patients. Aim This study analyzed the cost-effectiveness of osimertinib in LM of NSCLC from the perspective of the Chinese health care system. Methods Based on a retrospective analysis from the Samsung Medical Center, a Markov model was constructed to estimate the lifetime benefits and costs for LM patients who were treated with osimertinib. The main outcomes were cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to verify the robustness of model. A budget impact analysis was conducted to estimate the annual incremental cost of osimertinib treatment. Results Compared with patients who were not treated with osimertinib, the survival time of patients treated with osimertinib was higher by 0.69 (1.24 vs. 0.55) QALYs. The incremental cost was $11,877 ($29,232 vs. $17,355) and the ICER was $17,214/QALY, which was below the willingness-to-pay threshold of $30,867/QALY. Osimertinib treatment will increase national cancer spending by $220 million in the first year and increase to $474 million in the fifth year. Conclusions Osimertinib treatment is deemed to be cost-effective for NSCLC with LM patients, however, its use would significantly increase annual cancer spending.

Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis.

PURPOSE: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective. MATERIALS AND METHODS: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed. RESULTS: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs. CONCLUSION: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib.

Is olaparib cost effective in metastatic castration-resistant prostate cancer patients with at least one favorable gene mutation in BRCA1, BRCA2 or ATM?

Aim: To compare the cost-effectiveness of olaparib versus control treatment in metastatic castration-resistant prostate cancer patients with at least one gene mutation in BRCA1, BRCA2 or ATM from the US payer perspective. Methods: A Markov model was constructed to assess the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties. Results: The base-case result indicated that, for patients with specific gene mutations, olaparib gained 1.26 QALYs and USD$157,732 total cost. Compared with control treatment, the incremental cost-effectiveness ratio of olaparib was USD$248,248/QALY. The price of olaparib was the most influential parameter. Conclusion: Olaparib is not cost effective in comparison with control treatment in metastatic castration-resistant prostate cancer patients with specific gene mutations.

First-Line Durvalumab in Addition to Etoposide and Platinum for Extensive-Stage Small Cell Lung Cancer: A U.S.-Based Cost-Effectiveness Analysis.

BACKGROUND: The latest published CASPIAN trial demonstrated that adding durvalumab to etoposide and platinum (EP) improved survival dramatically for patients with extensive-stage small cell lung cancer (ES-SCLC). Considering the high cost of durvalumab, this study evaluated the cost-effectiveness of durvalumab plus EP (DEP) in the first-line setting for treatment-naïve patients with ES-SCLC from the U.S. payer perspective. MATERIALS AND METHODS: We developed a three-state Markov model to simulate the disease course and source consumption of ES-SCLC over a lifetime horizon. Pseudo-individual patient-level data were generated from digitized Kaplan-Meier curves. Direct medical costs, including drug and administration costs, disease management and adverse events treatment fees, best supportive care and terminal care costs were obtained from sources including the Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, and relevant literature. Health state utility values were derived from published literature. Main outcomes considered were total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). All costs were adjusted for inflation to reflect 2019 U.S. dollars. The willingness-to-pay threshold was set as $150,000/QALY. One-way and probabilistic sensitivity analyses were used to explore the uncertainty of model assumptions. RESULTS: Compared with EP, DEP was projected to increase life expectancy by 0.86 LYs (1.73 vs. 0.87) and 0.44 QALYs (0.93 vs. 0.49). The incremental treatment cost was $95,907, and the corresponding ICER was $216,953/QALY. The result was most sensitive to the variation of durvalumab acquisition cost. Probabilistic sensitivity analysis revealed that the probability of DEP over EP regimen to be cost-effective was 9.4% at a willingness-to-pay threshold of $150,000/QALY. In the case of reducing the price of durvalumab by 30.7%, DEP was more cost-effective than EP. CONCLUSION: From the perspective of the U.S. payer, adding durvalumab to EP is estimated to be not cost-effective compared with EP alone for patients with untreated ES-SCLC. IMPLICATIONS FOR PRACTICE: The information provided by this analysis serves as a reference for decision makers. Lowering the price of durvalumab would be a potential measure to improve the economics of durvalumab plus etoposide and platinum (DEP), and the inclusion of durvalumab in the Medicare pharmacopeia could make DEP more economically available. These results may also guide physicians and patients to choose the most economically feasible treatment.