Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Quantitative trait loci analysis of Verticillium wilt resistance in interspecific backcross populations of Gossypium hirsutum × Gossypium barbadense.

BACKGROUND: Verticillium wilt (VW) caused by Verticillium dahliae (Kleb) is one of the most destructive diseases of cotton. The identification of highly resistant QTLs or genes in the whole cotton genome is quite important for developing a VW-resistant variety and for further molecular design breeding. RESULTS: In the present study, BC1F1, BC1S1, and BC2F1 populations derived from an interspecific backcross between the highly resistant line Hai1 (Gossypium barbadense L.) and the susceptible variety CCRI36 (G. hirsutum L.) as the recurrent parent were constructed. Quantitative trait loci (QTL) related to VW resistance were detected in the whole cotton genome using a high-density simple sequence repeat (SSR) genetic linkage map from the BC1F1 population, with 2292 loci covering 5115.16 centiMorgan (cM) of the cotton (AD) genome, and the data concerning VW resistance that were obtained from four dates of BC2F1 in the artificial disease nursery and one date of BC1S1 and BC2F1 in the field. A total of 48 QTLs for VW resistance were identified, and 37 of these QTLs had positive additive effects, which indicated that the G. barbadense alleles increased resistance to VW and decreased the disease index (DI) by about 2.2-10.7. These QTLs were located on 19 chromosomes, in which 33 in the A subgenome and 15 QTLs in the D subgenome. The 6 QTLs were found to be stable. The 6 QTLs were consistent with those identified previously, and another 42 were new, unreported QTLs, of which 31 QTLs were from G. barbadense. By meta-analysis, 17 QTL hotspot regions were identified and 10 of them were new, unreported hotspot regions. 29 QTLs in this paper were in 12 hotspot regions and were all from G. barbadense. CONCLUSIONS: These stable or consensus QTL regions warrant further investigation to better understand the genetics and molecular mechanisms underlying VW resistance. This study provides useful information for further comparative analysis and marker-assisted selection in the breeding of disease-resistant cotton. It may also lay an important foundation for gene cloning and further molecular design breeding for the entire cotton genome.

Constructing a high-density linkage map for Gossypium hirsutum × Gossypium barbadense and identifying QTLs for lint percentage.

To introgress the good fiber quality and yield from Gossypium barbadense into a commercial Upland cotton variety, a high-density simple sequence repeat (SSR) genetic linkage map was developed from a BC1 F1 population of Gossypium hirsutum × Gossypium barbadense. The map comprised 2,292 loci and covered 5115.16 centiMorgan (cM) of the cotton AD genome, with an average marker interval of 2.23 cM. Of the marker order for 1,577 common loci on this new map, 90.36% agrees well with the marker order on the D genome sequence genetic map. Compared with five published high-density SSR genetic maps, 53.14% of marker loci were newly discovered in this map. Twenty-six quantitative trait loci (QTLs) for lint percentage (LP) were identified on nine chromosomes. Nine stable or common QTLs could be used for marker-assisted selection. Fifty percent of the QTLs were from G. barbadense and increased LP by 1.07%-2.41%. These results indicated that the map could be used for screening chromosome substitution segments from G. barbadense in the Upland cotton background, identifying QTLs or genes from G. barbadense, and further developing the gene pyramiding effect for improving fiber yield and quality.

Cost-effectiveness of first-line immunotherapy for advanced non-small cell lung cancer with different PD-L1 expression levels: A comprehensive overview.

BACKGROUND: Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. FINDINGS: Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53-95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. CONCLUSIONS: None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings.

Poor sample size reporting quality and insufficient sample size in economic evaluations conducted alongside pragmatic trials: a cross-sectional survey.

OBJECTIVES: Economic evaluations based on well-designed and -conducted pragmatic randomized controlled trials (pRCTs) can provide valuable evidence on the cost-effectiveness of interventions, enhancing the relevance and applicability of findings to healthcare decision-making. However, economic evaluation outcomes are seldom taken into consideration during the process of sample size calculation in pragmatic trials. The reporting quality of sample size and information on its calculation in economic evaluations that are well-suited to pRCTs remain unknown. This study aims to assess the reporting quality of sample size and estimate the power values of economic evaluations in pRCTs. STUDY DESIGN AND SETTING: We conducted a cross-sectional survey using data of pRCTs available from PubMed and OVID from 1 January 2010 to 24 April 2022. Two groups of independent reviewers identified articles; three groups of reviewers each extracted the data. Descriptive statistics presented the general characteristics of included studies. Statistical power analyses were performed on clinical and economic outcomes with sufficient data. RESULTS: The electronic search identified 715 studies and 152 met the inclusion criteria. Of these, 26 were available for power analysis. Only 9 out of 152 trials (5.9%) considered economic outcomes when estimating sample size, and only one adjusted the sample size accordingly. Power values for trial-based economic evaluations and clinical trials ranged from 2.56% to 100% and 3.21%-100%, respectively. Regardless of the perspectives, in 14 out of the 26 studies (53.8%), the power values of economic evaluations for quality-adjusted life years (QALYs) were lower than those of clinical trials for primary endpoints (PEs). In 11 out of the 24 (45.8%) and in 8 out of the 13 (61.5%) studies, power values of economic evaluations for QALYs were lower than those of clinical trials for PEs from the healthcare and societal perspectives, respectively. Power values of economic evaluations for non-QALYs from the healthcare and societal perspectives were potentially higher than those of clinical trials in 3 out of the 4 studies (75%). The power values for economic outcomes in Q1 were not higher than those for other journal impact factor quartile categories. CONCLUSION: Theoretically, pragmatic trials with concurrent economic evaluations can provide real-world evidence for healthcare decision makers. However, in pRCT-based economic evaluations, limited consideration, and inadequate reporting of sample-size calculations for economic outcomes could negatively affect the results' reliability and generalisability. We thus recommend that future pragmatic trials with economic evaluations should report how sample sizes are determined or adjusted based on the economic outcomes in their protocols to enhance their transparency and evidence quality.