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Introduction: Chronic insomnia in adults affects the health and quality of life of patients. Chinese patent medicines (CPMs) combined with benzodiazepines/non-benzodiazepines (BZDs/N-BZDs) are used frequently in routine clinical practice. However, evidence on the efficacy and safety of these combined interventions is lacking. A multiple treatment meta-analysis (MTMA) was conducted to evaluate the comparative efficacy and safety of 16 CPMs combined with BZDs/N-BZDs for the treatment of chronic insomnia in adults. Methodology: We systematically reviewed 171 randomized controlled trials (RCTs) involving 16,874 participants (8506 in intervention groups and 8368 in control groups) from the inception of several databases to 2023. This review encompassed electronic databases, regulatory-agency websites, and international registers of published trials involving adult patients with chronic insomnia who received CPM + BZDs/N-BZDs therapies. A random-effects MTMA was undertaken using Stata/MP17, RevMan (5.3), and R. Outcome measures were the Pittsburgh Sleep Quality Index (PSQI), overall efficacy rate, as well as the incidence of dry mouth, dizziness, and somnolence. Results: Our MTMA showed that BZD/N-BZD therapy as a co-intervention for Tianmengjiaonang (TMJN) was likely to be the optimal option for improving the PSQI (surface under the cumulative sorting curve (SUCRA) = 95.00 %), whereas shensongyangxinjiaonang (SSYXJN) had the highest probability of improving overall effectiveness (SUCRA = 88.20 %). Jiaotaiwan (JTW), Bailemian (BLMJN), and Wulinjiaonang (WLJN) had the highest probability of reducing the incidence of somnolence (SUCRA = 90.00 %), dry mouth (SUCRA = 72.90 %), and dizziness (SUCRA = 84.40 %). Conclusions: All CPMs in combination with BZDs/N-BZDs were more efficacious and safer than using BZDs/N-BZDs alone in adults with chronic insomnia. SSYXJN + BZDs/N-BZDs and TMJN + BZDs/N-BZDs are likely to be optimal CPMs because they improve overall efficacy and sleep quality and reduce the risk of adverse effects. However, the effects of these interventions may vary from person to person. Hence, patients, carers, and clinicians should carefully consider the efficacy, safety, and risk–benefit profile of all active interventions for patients with insomnia based on real-world data.

Abstract Background Metastases within liver or the brain are the most common causes of mortality from lung cancer (LC). Predicting liver or brain metastases before having evidence from imaging of the tumors is challenging but important for early patient intervention. According to mounting evidence, exosomes circulating within blood may facilitate cancer spread by transporting certain proteins for target cells. Methods Using liquid chromatography–MS/MS, we investigated the plasma exosomes’ proteomic profiles derived from 42 metastatic LC patients [16 solitary liver metastasis (LM), together with 26 solitary brain metastasis (BM)] and 25 local advanced (LA) lung cancer cases without metastasis, together with five healthy controls (HC), assessing the LM and BM pathogenesis and find potential novel organ-designated proteomic biomarkers. Using ELISA assay, we verified the expression levels of three plasma exosomal protein biomarkers in 110 LC patients, including 40 solitary LM, 32 solitary BM and 38 LA, and 25 HC. Results In total, 143 and 120 differentially expressed exosome-based proteins (DEEPs) were found to be dysregulated in LM and BM of lung cancer (LM-DEEPs, BM-DEEPs), compared for LA lung cancer samples, respectively. The bioinformatics analyses indicated the heterogeneity and homogeneity in LM-DEEPs and BM-DEEPs. They were primarily engaged within proteomic triggering cascade, ECM-receptor interaction, and the collagen-containing extracellular matrix. Regarding heterogeneity, LM-DEEPs primarily consisted of proteoglycans, lipoprotein, integrin, and heat shock protein, whereas the BM-DEEPs consisted of calcium-dependent/S100 proteins. Furthermore, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)-plasma-stemming exosome proteomics showed heterogeneity, which helped to explain some of the differences between SCLC and NSCLC's metastatic features. We also found that SELL and MUC5B could be used as diagnostic markers of BM, while APOH, CD81, and CCT5 could help diagnose LM in LC patients. Additionally, we demonstrated in a validation cohort that MUC5B and SELL could serve as biomarkers for diagnosing BM, and APOH could be a novel potential diagnostic biomarker of LM. Conclusion We presented the comprehensive and comparative plasma-stemming exosomes’ proteomic profiles from cases of LC who had isolated liver and brain metastases for the first time. We also suggested several possible biomarkers and pathogenic pathways that might be a great starting point for future research on LC metastasis.

Objective: Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1/ligand-1 (PD-1/PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and lymphocyte-activation gene-3 (LAG-3) have been widely studied and applied throughout the course of cancer treatment. This study aimed to provide a comprehensive profile of ICI-associated toxicity and elucidate the toxicity patterns of ICIs across different treatment lines. Methods: In total, 155 cohorts comprising 24 539 eligible patients were included in the safety analysis. Trial name, registration number, cancer type, trial phase, clinical setting, trial design, regimen, dosing schedule, age, sex and ethnicity distributions, number of patients, number of treatment-related adverse events (trAEs), and number of treatment-related death were extracted. We defined a timeline from the neoadjuvant setting to the third-line setting. We also introduced a synthesizing principle for adverse event rates (SPAER) of immunotherapy to ensure the comparability and reliability across different treatment lines. The study protocol was registered and approved by the PROSPERO protocol review committee (CRD42021242368). Results: After excluding the neoadjuvant setting group, we observed a distinct reduction in the incidence of treatment-related adverse events (trAEs) with an advancement of the line of ICI treatment. The incidence of trAEs was negatively correlated with the line of treatment, irrespective of whether monotherapy or dual-ICI combination therapy was administered. Sensitivity analyses also confirmed the coincident negative correlations. Conclusion: In summary, using a timeline-based concept centered around treatment lines, we revealed the dynamic landscape of ICI-associated toxicity and found that patients treated with ICIs during later lines of therapy may have a lower risk of trAEs.

Abstract Background China has one of the highest numbers of liver disease cases in the world, including 6.4 million cirrhosis associated with alcohol-related liver disease (ALD) cases. However, there is still a lack of urgent awareness about the growth of alcohol consumption and the increased burden of ALD in China. Therefore, we aimed to project the potential impact of changes in alcohol consumption on the burden of ALD in China up to 2040 under different scenarios. Methods We developed a Markov model to simulate the natural history of ALD until 2040 in China. We estimated the incidence and mortality of alcohol-related cirrhosis and hepatocellular carcinoma between 2022 and 2040 under four projected scenarios: status quo scenario and scenarios with a 2%, 4%, and 8% annual decrease in excessive alcohol consumption, respectively. Results Under the status quo scenario, the cumulative new cases of cirrhosis from 2022 to 2040 was projected to be 3.61 million (95% UI 3.03–4.44 million), resulting in a cumulative 1.96 million (1.66–2.32 million) deaths from alcohol-related cirrhosis and hepatocellular carcinoma. However, a 2% annual reduction in excessive alcohol consumption was expected to avert 0.3 million deaths associated with ALD, and a 4% annual reduction was projected to prevent about 1.36 million new cases of cirrhosis and prevent 0.5 million ALD-related deaths. Moreover, an 8% annual reduction would prevent about 2 million new cases of cirrhosis and 0.82 million deaths. Conclusions Without any substantial change in alcohol attitudes and policies to regulate excessive drinking, the disease burden of ALD in China will increase enormously. Strengthening the implementation of alcohol restriction interventions is critical and urgent to reduce the impact of ALD on the Chinese population.

Abstract Background Osimertinib is the first‐line treatment for patients with epidermal growth factor receptor (EGFR) mutations, but the treatment options after drug resistance are limited. Previous studies have suggested that EGFR is in an immunosuppressive tumor immune microenvironment (TIME). However, the evolution of TIME after osimertinib resistance and whether this resistance can be overcome by targeting TIME needs to be further investigated. Methods The remodeling process and mechanism of TIME during the treatment with osimertinib were studied. Results The proportion of EGFRL858R+T790M mutant tumor immune infiltrating cells was extremely low. Osimertinib treatment transiently triggered inflammatory cells, but several immunosuppressive cells infiltrated after drug resistance and formed a myeloid‐derived suppressor cell (MDSC)‐enriched TIME. The programmed cell death protein‐1 monoclonal antibody was not able to reverse the MDSC‐enriched TIME. Further analysis revealed that the activation of nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) pathways recruited a large number of MDSCs via cytokines. Finally, MDSC secreted high levels of interleukin‐10 and arginase‐1 and created an immunosuppressive TIME. Conclusions Thus, our findings lay the foundation for the evolution of TIME in osimertinib treatment, establish the mechanism of immunosuppressive TIME after osimertinib resistance, and propose potential solutions.

Abstract Background The effectiveness of sacituzumab govitecan for metastatic triple-negative breast cancer (TNBC) has been reported in recent research, however, the value of the effectiveness and cost of sacituzumab govitecan is still unclear. Methods A microsimulation model was developed using data from the ASCENT trial to assess the cost-effectiveness of sacituzumab govitecan for patients with relapsed or refractory metastatic TNBC over a lifetime. Model inputs, including clinical data, patient characteristics, and direct medical costs, were based on the ASCENT trial, public databases, and published literature. The primary outcomes of the model were the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). Univariate and probabilistic sensitivity analysis (PSA) and multiple scenario analyses were performed to address the uncertainty of the model. Results Our results revealed that sacituzumab govitecan versus chemotherapy costs $293,037 and yielded an additional 0.2340 of QALYs in the whole population with metastatic TNBC, leading to an ICER of $1,252,295 gained. And in the population with metastatic TNBC without brain metastasis, the sacituzumab govitecan versus chemotherapy costs $309,949 and obtained an extra 0.2633 of QALYs, which resulted in an ICER of $1,177,171/QALYs. Univariate analyses indicated that the model outcomes were most sensitive to the drug cost of sacituzumab govitecan, the utility of progression-free disease, and the utility of progressed disease. Conclusion From the US payer perspective, sacituzumab govitecan is unlikely to be a cost-effective option for patients with relapsed or refractory metastatic TNBC compared with chemotherapy. Based on the value standpoint, a price decrease of sacituzumab govitecan is expected to increase the cost-effectiveness of sacituzumab govitecan in patients with metastatic TNBC.

Purpose: To evaluate the effectiveness of ACT-based interventions on improving the mental health of parents of children with SHCN compared to active/inactive controls and to investigate the characteristics/components of the effective interventions in the included studies. Methods: Eight databases were searched from inception to 14 February 2023. We included all randomized controlled trials (RCTs) of ACT-based interventions for parents of children with SHCN published in English or Chinese journals and dissertations reporting at least one parental mental health outcome postintervention. Results: Fourteen RCTs were included. The results indicated significant improvements of ACT-based interventions in the stress (Hedges' g = −0.36), depressive symptoms (g = −0.32), anxiety (g = −0.29), distress (g = −0.29), psychological flexibility (g = 0.51), mindful awareness/mindfulness abilities (g = 0.41), and confidence/self-efficacy (g = 0.30) of parents, as well as in the emotional and behavioural problems (EBP; g = −0.39) of their children with SHCN postintervention, with moderate to high certainty of evidence. Furthermore, the optimal components of ACT-based interventions, including the intervention approaches (ACT combined with another parenting technique/program), active participants (only involving parents), delivery mode (in-person) and format (group-based format), and desirable number of sessions (4–8 sessions), were identified to inform the design of future interventions/studies. Conclusion: This review highlights the positive effects of ACT-based interventions on mental health, psychological flexibility, mindful awareness/mindfulness abilities, and confidence/self-efficacy in parents and EBP in children with SHCN. Since group-based ACT combined with a parenting technique/program was identified as the optimal effective strategy, its effects could be further examined in larger-scale RCTs with parents and children with SHCN with diverse ethnic and sociodemographic characteristics.

Background: Considering the limitations of Western medicine (WM) in treating Insomnia among adults, and the extensive use of Chinese patent medicines (CPMs), a comprehensive evaluation of the efficacy and safety of Different CPMs used in combination with WM for Insomnia in adults is necessary. To this end, a systematic investigation was conducted to scrutinize the effectiveness and safety of using 16 different CPMs in conjunction with WM in treating Insomnia in adults. The present study employed a network meta-analysis technique to compare and evaluate the combined therapeutic potential of these 16 CPMs and WM in treating adults with Insomnia. Methods: Literary databases were scrupulously combed through from their commencement until November 2022 to collect all randomized controlled trials (RCTs) that centered on adult patients afflicted with insomnia and treated with a blend of Chinese patent medicines (CPMs) and Western medicine (WM). The investigation analyzed diverse outcomes, comprising total effective rate, Pittsburgh sleep quality index (PSQI), occurrence of somnolence, occurrence of dry mouth, and occurrence of dizziness. The examination utilized advanced statistical tools such as RevMan (5.3), Stata/MP17, and R software, and also calculated the surface under the cumulative ranking curve (SUCRA) probability values, which were employed to rank the examined treatments. In addition, the inquiry executed clustering analysis to contrast the effects and safety of CPMs on distinct outcomes. Results: A total of 283studies involving 27,151patients and 16 CMPs were included. The 16 CMPs were: Wulingjiaonang (WLJN), Anshenbunaoye (ASBNY), Baileminjiaonang (BLWJN), Shenqiwuweizi (SQWWZ), Shensongyangxinjiaonang (SSYXJN), Jiaotaiwan (JTW), Yangxinanshengwan (YXASW), Tianwangbuxindan (TWBXD), Zhushaanshenwan (ZSASW), Yangdanxinnaotong (YDXNT), Yangxueqingnaokeli (YXQNKL), Tianmengjiaonang (TMJN), Zaorenanshenjiaonang (ZRASJN), Shuganjieyujiaonang (SGJYJN), Xiaoyaosan (XYS), Shumianjiaonang (SMJN). The results of the network meta-analysis showed that, with WM treatment as a co-intervention, SSYXJN was most likely to improve the total efficiency rate (SUCRA= 84.70%), ASBNY had the highest probability of being the best option for improving the Sleep quality (SUCRA= 99.20%), JTW had the highest probability of reducing the incidence of somnolence (SUCRA= 94.10%), ZSASW had the highest probability of reducing the incidence of dry mouth (SUCRA= 74.70%), while WLJN had the highest probability of reducing the incidence of dizziness (SUCRA= 73.10%). Conclusions: CPMs combined with WM is proved to be more effective and safer than WM alone, which may be beneficial to adults with Insomnia patients. SQWWZ+WM(Level of evidence, moderate) and ZSASW+WM(Level of evidence, moderate) are most likely the optimal CPM to improve total efficiency rates, Sleep quality, and reduce adverse effects. This study, however, has some limitations as discussed in this article; therefore, higher quality RCTs and real-world evidence are required to support our conclusions.

BackgroundOral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC.MethodsA three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER).ResultsThe total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs.ConclusionFor oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.

Abstract Background With the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in non-small cell lung cancers (NSCLC), identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatase receptor-type (PTPRs) and ICIs responses are unknown. Methods Whole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1 therapy was carried out with corresponding clinical data collected as a discovery cohort to find the associations of PTPR mutations and ICI responses. Three validation cohorts consolidated by 7 public cohorts of 1920 NSCLC patients with WES or target sequencing data of tumor tissue-derived DNA or circulating tumor DNA (ctDNA) and relevant clinical data were applied as validation cohorts. The lung adenocarcinoma (LUAD) cohort (n=586) in The Cancer Genome Atlas (TCGA) database was used for analyzing the potential anti-tumor immunologic mechanisms. Results With the highest mutation frequency among all PTPRs, PTPRD mutations in non-squamous NSCLC (ns-NSCLC) were linked to longer progression-free survivals (PFS, 324 vs 63 days, hazard ratio (HR)=0.36, p= 0.0152) and higher objective response rate (ORR, p=0.0099). In validation cohort 1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.0184) and ORR (p=0.013). In validation cohort 2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable overall survivals (OS, over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort 3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD’s prediction efficiency. In addition, in validation cohort 3, ctDNA phosphatase-mut also functioned as a predictive biomarker helping identify patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed that phosphatase-mut was independent on PD-L1 expression and tumor mutation burden (TMB) to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients. Conclusions Tissue or ctDNA PTPRD phosphatase domain deleterious mutations might function as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients, independent on TMB or PD-L1 expression.

Background: Given the limitations of Western medicine (WM) for the treatment of non-small cell lung cancer (NSCLC) and the wide exploration of Chinese herbal injections (CHIs), systematically evaluate the efficacy of Various CHIs Combined with WM for Non-small Cell Lung Cancer. In this study, we performed a network meta-analysis to evaluate the comparative efficacy of 16 CHIs combined with WM regimens for the treatment of NSCLC.Methods: Literature databases were searched from their inception to November 2021, and all randomized control trials (RCTs) involving NSCLC patients treated with a combination of Chinese and WM were retrieved. Outcomes, including disease control rate, survival quality score, incidence of gastrointestinal adverse reactions, incidence of leukopenia, and incidence of thrombocytopenia, were analyzed using RevMan (5.3), Stata17, and R software. Surface under the cumulative ranking curve (SUCRA) probability values were calculated to rank the treatments examined, and clustering analysis was used to compare the effects of CHIs on different outcomes.Results: A total of 389 studies involving 31,263 patients and 16 CHIs were included. The 16 CHIs were: Aidi injection (ADI), Huachansu injection (HCSI), oil of Ophiopogon injection (OOMI), disodium cantharidinate and vitamin B6 injection (DCI), Shenfu injection (SFI), Shenmai injection (SMI), Shenqi Fuzheng injection (SQFZI), Chansu injection (CSI), Delisheng injection (DLSI), Fufang Kushen injection (FFKSI), Huangqi injection (HQI), Kangai injection (KAI), Kanglaite injection (KLTI), Shengmai injection (SI), Xiangguduotang injection (XGDTI), and Xiaoaiping injection (XAPI). The results of the network meta-analysis showed that, with WM treatment as a co-intervention, CSI was most likely to improve the disease control rate (SUCRA = 80.90%), HQI had the highest probability of being the best option for improving the survival quality score (SUCRA = 82.60%), DCI had the highest probability of reducing the incidence of gastrointestinal adverse reactions (SUCRA = 85.50%), HCSI + WM had the highest probability of reducing the incidence of thrombocytopenia (SUCRA = 91.30%), while SMI had the highest probability of reducing the incidence of leukopenia (SUCRA = 79.10%).Conclusion: CHIs combined with WM is proved to be more effective than WM alone, which may be beneficial to NSCLC patients. SMI + WM and DCI + WM are most likely the optimal CHI to improve disease control rates, survival quality score, and reduce adverse effects. This study has limitations; therefore, higher quality RCTs and real-world evidence are required to support our conclusions.

ObjectiveCurrent guidelines recommend the gastric cancer risk score scale (GCRSS) for screening in gastric cancer (GC) high-risk populations in China. This study aimed to estimate the clinical benefits, harms, cost, and cost-effectiveness of the GCRSS screening strategy from a Chinese healthcare system perspective.Materials and methodsUsing a microsimulation model, we evaluated 7 screening scenarios of the GCRSS with varying starting ages. We simulated 100,000 individuals from the age of 20 for each screening scenario. The main outcomes included GC incidence reduction, number of cause-specific deaths, costs, quality-adjusted life year (QALY), incremental cost-effectiveness ratio (ICER), and benefit-to-harm ratio. Deterministic and probabilistic sensitivity analyses were done to explore the robustness of model findings.ResultsScreening with the GCRSS strategy at the age of 40 years (40-GCRSS) provided the greatest reduction of GC incidence by 70.6%, with 7,374 GC deaths averted per 100,000 individuals and the lowest benefit-to-harm ratio of 0.392. Compared with no screening or previous less costly strategy, at a willingness-to-pay (WTP) threshold of $37,655 per QALY, the 40-GCRSS strategy was cost-effective, with ICERs of $12,586 and $29,115 per QALY, respectively. Results were robust across univariate and probabilistic sensitivity analyses. The 40-GCRSS strategy showed a 0.856 probability of being cost-effective at a $37,655 per QALY WTP threshold.ConclusionsThe findings suggest that the GCRSS strategy is effective and cost-effective in reducing the GC disease burden in China from a Chinese healthcare system perspective. Screening from the age of 40 would be the optimal strategy.

This review aims to systematically summarize existing evidence to determine the effectiveness of cognitive-based interventions (CBIs) on psychological health and well-being among parents of children with developmental disabilities (DD). Six databases were searched to identify eligible randomized controlled trials (RCTs) from their inception to April 2023. The revised Cochrane Risk of Bias tool for RCTs was applied to assess the risk of bias and the certainty of evidence was evaluated using the Grading of Recommendation, Assessment, Development and Evaluation. Meta-analyses were conducted using a random-effects model. Twenty-five RCTs involving 1915 participants were identified. The results indicated that CBIs reduced parental stress levels (Hedges' g = - 0.69), depressive symptoms (g = - 0.95), anxiety levels (g = - 0.78), and parental distress (g = - 0.29), and improved parental well-being (g = 0.62) and parent-child relationships (g = 0.43) postintervention compared with the active/inactive control groups. Subgroup analysis of the effectiveness of interventions using mindfulness-based interventions and cognitive behavioural therapy showed positive effects. The favourable intervention duration and participant targets were also identified in this review. Furthermore, the effects of CBIs were impacted by the different types of DD among the children. This review highlighted the positive effects of CBIs on parental stress levels, depressive symptoms, anxiety levels, parental distress levels, parental well-being levels, and parent-child relationships. Future well-designed RCTs are needed to further investigate the effects of MBIs and CBT interventions on children with DD and their parents, as well as the factors and mechanisms of action affecting the efficacy of these interventions.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system.Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively.Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results.Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

Objective: The ORIENT-32 clinical trial revealed that sintilimab plus bevacizumab biosimilar significantly improved the median progression-free survival and median overall survival (OS) compared with sorafenib. This analysis evaluated the cost-effectiveness of sintilimab plus bevacizumab biosimilar as a first-line treatment for unresectable hepatocellular carcinoma from the Chinese perspective of healthcare system.Materials and methods: A Markov model with three mutual health states was constructed to evaluate the economic outcome of sintilimab plus bevacizumab biosimilar. The model cycle was 21 days, and the simulation time horizon was a lifetime. The output parameters of the model were the total cost, life-year (LY), quality-adjusted LY (QALY), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were conducted to assess the robustness of the results.Results: The base-case results found that sintilimab plus bevacizumab biosimilar provided an improvement of 1.27 QALYs and 1.84 LYs compared with sorafenib, and the ICER was $23,352/QALY. The hazard ratio for OS had the greatest influence on the ICER. The probability of sintilimab plus bevacizumab biosimilar was 85% at willingness-to-pay thresholds of $30,552/QALY.Conclusion: The findings of this analysis suggested that sintilimab plus bevacizumab biosimilar was a cost-effective first-line therapy for patients with unresectable hepatocellular carcinoma.

The LIM domain family genes play a crucial role in various tumors, including non-small-cell lung cancer (NSCLC). Immunotherapy is one of the most significant treatments for NSCLC, and its effectiveness largely depends on the tumor microenvironment (TME). Currently, the potential roles of LIM domain family genes in the TME of NSCLC remain elusive. We comprehensively evaluated the expression and mutation patterns of 47 LIM domain family genes in 1089 NSCLC samples. Using unsupervised clustering analysis, we classified patients with NSCLC into two distinct gene clusters, i.e., the LIM-high group and the LIM-low group. We further investigated the prognosis, TME cell infiltration characteristics, and immunotherapy in the two groups. The LIM-high and LIM-low groups had different biological processes and prognoses. Moreover, there were significant differences in TME characteristics between the LIM-high and LIM-low groups. Specifically, enhanced survival, immune cell activation, and high tumor purity were demonstrated in patients of the LIM-low group, implying an immune-inflamed phenotype. Moreover, the LIM-low group had higher immune cell proportion scores than the LIM-high group and was more responsive to immunotherapy than the LIM-low group. Additionally, we screened out LIM and senescent cell antigen-like domain 1 (LIMS1) as a hub gene of the LIM domain family via five different algorithms of plug-in cytoHubba and the weighted gene co-expression network analysis. Subsequently, proliferation, migration, and invasion assays demonstrated that LIMS1 acts as a pro-tumor gene that promotes the invasion and progression of NSCLC cell lines. This is the first study to reveal a novel LIM domain family gene-related molecular pattern associated with the TME phenotype, which would increase our understanding of the heterogeneity and plasticity of the TME in NSCLC. LIMS1 may serve as a potential therapeutic target for NSCLC.

Background: In a recent randomized, phase 3 trial (CheckMate 9ER), nivolumab combined with cabozantinib significantly improved patient outcomes compared with sunitinib. However, the cost-effectiveness of these novel agents for untreated advanced renal cell carcinoma (aRCC) remains unknown.Materials and Methods: We constructed a microsimulation decision-analytic model to measure the healthcare costs and outcomes of nivolumab plus cabozantinib compared with those of sunitinib for patients with aRCC. The transition probability of patients was calculated from CheckMate 9ER using parametric survival modeling. Lifetime direct medical costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated for nivolumab-plus-cabozantinib treatment compared with sunitinib from a US payer perspective. We conducted one-way and probabilistic sensitivity analyses and a series of scenario analyses to evaluate model uncertainty.Results: Nivolumab plus cabozantinib was associated with an improvement of 0.59 LYs and 0.56 QALYs compared with sunitinib. However, incorporating nivolumab plus cabozantinib into first-line treatment was associated with significantly higher lifetime costs ($483,352.70 vs. $198,320.10), causing the incremental cost-effectiveness ratio for nivolumab plus cabozantinib to be $508,987/QALY. The patients’ age of treatment, first-line utility, and cost of nivolumab had the greatest influence on the model. The outcomes were robust when tested in sensitivity and scenario analyses.Conclusion: For aRCC, substituting nivolumab plus cabozantinib in the first-line setting is unlikely to be cost-effective under the current willingness-to-pay threshold ($150,000/QALY). Significant price decreases for nivolumab used in first-line therapy would be needed to drop ICERs to a more diffusely acceptable value.

ObjectiveThe use of ipilimumab plus anti-PD-1 has recently been shown to significantly improve the survival of patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy. The study assessed the cost-effectiveness of ipilimumab plus anti-PD-1 therapy in this population from the US payer perspective.Materials and MethodsA Markov model was created based on a retrospective analysis of patients with metastatic melanoma who were resistant to anti-PD-(L)1. Cost information was obtained from the Centers for Medicare and Medicaid Services and literature-based costs. The utility value was derived from the published literature. The results of the model was the total cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was addressed through sensitivity analysis. In addition, we also conducted subgroup analysis.ResultsIpilimumab plus anti-PD-1 provided an improvement of 1.39 QALYs and 2.48 LYs, at a ICER of $73,163 per QALY. The HR of OS was the variable that had the greatest impact on ICER. Compared to ipilimumab, the probability of ipilimumab plus anti-PD-1 being cost-effective was 94% at the WTP of $150,000/QALY. The results of the subgroup analysis showed that the ICER in the majority of the subgroups was less than $150,000/QALY.ConclusionsIpilimumab plus anti-PD-1 was likely to be cost-effective compared to ipilimumab for patients with metastatic melanoma who are resistant to anti-PD-(L)1 at a WTP threshold of 150,000/QALY.

Treatment with immune checkpoint inhibitors (ICIs) has considerably improved prognosis in multiple cancers. However, regardless of PD-L1 expression and TMB, better predictive biomarkers are required to identify ICI-responsive patients. We analyzed a pan-cancer cohort as the discovery cohort to identify the role of Max’s giant associated protein (MGA) mutation in the outcome of ICI treatment in different types of cancers. A pooled lung adenocarcinoma (LUAD) cohort was considered as the validation cohort. Another two LUAD cohorts who received conventional treatment were included for prognostic analysis and mechanism exploration. In the discovery cohort, MGA mutation was a favorable survival biomarker for patients with LUAD than in those with other types of cancers. MGA mutation was positively correlated with the TMB score. The results of the validation cohort were consistent with those of the discovery cohort. Patients with MGA mutation in the TMB-low subgroup had longer survival. Two LUAD cohorts who received standard treatment showed that the MGA mutation was not a prognostic biomarker for standard treatment. Mechanically, we found that the co-mutant genes did not affect the prognostic role of MGA mutation. Gene-set enrichment analysis revealed that genes belonging to the immunodeficiency pathway were enriched in the MGA wild-type group in LUAD. Moreover, activated NK cells were more enriched in the MGA mutant LUAD group. In conclusion, our results demonstrated that MGA mutation was an independent predictive biomarker for ICI therapy. These results may provide a novel insight into identifying potential patients with LUAD for ICI therapy.

Background: Recent randomized controlled trials have demonstrated that immune checkpoint inhibitors (ICIs) improve patient outcomes, but whether these novel agents are cost-effective for untreated advanced renal cell carcinoma (aRCC) remains unclear.Materials and Methods: A microsimulation model was created to project the healthcare costs and outcomes of six strategies (lenvatinib-plus-pembrolizumab, nivolumab-plus-cabozantinib, nivolumab-plus-ipilimumab, pembrolizumab-plus-axitinib, avelumab-plus-axitinib, and sunitinib monotherapy) for patients with aRCC. Transition probability of patients was estimated from CLEAR, CheckMate 9ER, CheckMate 214, KEYNOTE-426, JAVELIN Renal 101, and other data sets by using parametric survival modeling. Lifetime direct medical costs, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated from a United States payer perspective. One-way and probabilistic sensitivity analyses were performed, along with multiple scenario analyses, to evaluate model uncertainty.Results: Of the six competing strategies, nivolumab-plus-cabozantinib yielded the most significant health outcomes, and the sunitinib strategy was the least expensive option. The cost-effective frontier consisted of the nivolumab-plus-cabozantinib, pembrolizumab-plus-axitinib, and sunitinib strategies, which displayed the ordered ICERs of $81282/QALY for pembrolizumab-plus-axitinib vs sunitinib and $453391/QALY for nivolumab-plus-cabozantinib vs pembrolizumab-plus-axitinib. The rest of the strategies, such as lenvatinib-plus-pembrolizumab, nivolumab-plus-ipilimumab, and avelumab-plus-axitinib, were dominated. The cost of sunitinib drove the model most influentially.Conclusions: For aRCC, the pembrolizumab-plus-axitinib strategy is likely to be the most cost-effective alternative at the willingness-to-pay threshold of $100,000.

BackgroundThe endoplasmic reticulum oxidoreductin-1-like (ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia, however, the role of ERO1L in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in lung adenocarcinoma (LUAD).MethodsIn this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy.ResultsThis study found that ERO1L was significantly overexpressed in LUAD in comparison to normal tissue. This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Tregs), cancer associated fibroblasts, M2-type macrophages, and myeloid-derived suppressor cells. Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate to immunotherapy in comparison to the ERO1Llow group. Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT and NF-κB signaling pathways, thus affecting chemokine and cytokine patterns in the TIME.ConclusionsThis study found that overexpression of ERO1L was associated with poor prognoses in patients with LUAD. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. Further studies are required to assess the potential role of ERO1L as a biomarker for immunotherapy efficacy in LUAD.

IntroductionRecently, a phase III CROWN trial compared the efficacy of two anaplastic lymphoma kinase (ALK) inhibitors and demonstrated that lorlatinib displayed clinical improvement over crizotinib for advanced non-small cell lung cancer (NSCLC) patients. Therefore, the aim of this study was to estimate the cost-effectiveness of lorlatinib as a first-line therapy for patients with advanced ALK-positive (+) NSCLC.Materials and MethodsA cost-effectiveness analysis was performed using a microsimulation model from the US payer perspective and a lifetime horizon (30 years) in patients with previous untreated advanced ALK+ NSCLC. Based on the CROWN trial, patient characteristics were obtained, and the transition probabilities were estimated. All direct costs were derived from official sources and published literature. The main outcomes of the model were total costs, incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and life years (LYs). One-way and probabilistic sensitivity analyses and multiple scenario analyses were conducted to test the robustness of the model outcomes.ResultsIn the base case analysis, in which 1 million patients were simulated, treatment with lorlatinib or crizotinib as the first-line treatment was related to a mean cost of $909,758 and $616,230 (incremental cost: $293,528) and a mean survival of 4.81 QALYs and 4.09 QALYs (incremental QALY: 0.72) per patient, respectively. The main drivers of cost effectiveness were drug price and subsequent cost. PAS indicated that lorlatinib has 90% cost-effectiveness when compared to crizotinib when the willingness-to-pay (WTP) threshold in increased to $448,000/QALY. Scenario analysis demonstrated that lorlatinib has 100% cost-effectiveness at a WTP threshold of 200,000/QALY compared to crizotinib treatment when the price of lorlatinib is decreased to 75% ($424.5) of its original price.ConclusionsIn this study, lorlatinib was unlikely to be cost effective compared with crizotinib for patients with previously untreated advanced ALK+ NSCLC at a WTP threshold of 200,000/QALY.

Primary pulmonary adenoid cystic carcinomas are salivary tumors that are low-grade malignant and prone to recurrence and metastasis. Surgery is currently the main treatment, but there is no standard with regard to postoperative adjuvant therapy. Adenoid cystic carcinoma is more sensitive to radiotherapy and patients benefit less from chemotherapy, but few studies have focused on targeted therapy, and their conclusions are inconsistent. With respect to primary pulmonary adenoid cystic carcinoma, large-scale studies cannot be conducted due to its low incidence, and studies on the targeted therapy of it are very scarce. A few case reports indicate that targeted therapy can be effective however, suggesting that it may be a good option. The current report is the first on the occurrence of human epidermal growth factor receptor 2 amplification in pulmonary adenoid cystic carcinoma. The patient was treated with pyrotinib for 6 months and achieved stable disease.

The drug resistance of first-line crizotinib therapy for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion non-small cell lung cancer (NSCLC) is inevitable. Whether the administration of immune checkpoint inhibitor (ICI) therapy is suitable for ROS 1 fusion NSCLCs or after the development of crizotinib resistance is still unknown. In this study, five different crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 cells were cultured. Ba/F3 cells expressing crizotinib sensitive ROS1 fusion and crizotinib resistant ROS1-G2032R mutation were used to explore the relationship between ROS1 fusion, ROS1-G2032R mutation and programmed death-ligand 1 (PD-L1) expression and the clinical potential of anti-PD-L1 ICI therapy. The signaling pathway net was compared between HCC78 and HCC78CR1-5 cells using RNA sequencing. Anti- PD-L1 ICI therapy was performed on mouse xenograft models with Ba/F3 ROS1 fusion or ROS1-G2032R mutation. HCC78CR1-5 showed more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was remarkably higher in HCC78CR1-5 with ROS1 fusion upregulation than HCC78 primary cell. Furthermore, the expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated lower in Ba/F3 ROS1-G2032R resistant mutation than ROS1 fusion. Western blotting analysis showed the ROS1–SHP2 signaling pathway activation in HCC78CR1-5 cells, Ba/F3 ROS1 fusion and ROS1-G2032R resistant mutation. Mouse xenograft models with Ba/F3 ROS1 fusion showed more CD3+PD-1+ T cells both in blood and tissue, and more sensitivity than the cells with Ba/F3 ROS1-G2032R resistant mutation after anti-PD-L1 therapy. Our findings indicate that PD-L1 upregulation depends on ROS1 fusion more than ROS1-G2032R mutation. We share our insights of NSCLCs treatment management into the use of anti-PD-L1 ICI therapy in ROS1 fusion and not in ROS1-G2032R resistant mutation.

AimThat clinical trial (RAINBOW) showed that a 7.4 months overall survival benefit with the combination therapy with ramucirumab (RAM) and paclitaxel (PAC) as second-line therapy for patients with recurrent or metastatic gastric or gastro-oesophageal junction adenocarcinoma, compared with placebo (PLA) plus paclitaxel. We performed an analysis to assess the cost-effectiveness of RAM from a Chinese perspective and recognized the range of drug costs.MethodsBy building a Markov model to estimate quality-adjusted life-years (QALYs), life-years (LYs) and lifetime costs. Transition probabilities, costs and utilities were estimated for the published literature, Chinese health care system and local price setting. We performed threshold analyses and probabilistic sensitivity analyses to evaluate the uncertainty of the model.ResultsCompared with PLA strategy, RAM strategy provided an incremental survival benefit of 1.22 LYs and 0.64 QALYs. The probabilistic sensitivity analysis showed that when RAM costs less than $151 or $753 per 4 weeks, the incremental cost-effectiveness ratio (ICER) approximated the willingness-to-pay threshold (WTP), suggesting that there was 50% likelihood that the ICER for RAM + PAC would be less than $44528.4 per QALY or $48121 per QALY, respectively.ConclusionsFor patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who fail first-line chemotherapy, our results are conducive to the multilateral drug price guidance negotiations of RAM in China.

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