Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. RESEARCH DESIGN AND METHODS: Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. RESULTS: We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809-0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). CONCLUSIONS: We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.

Use of Minimal Residual Disease Status to Reduce Uncertainty in Estimating Long-term Survival Outcomes for Newly Diagnosed Multiple Myeloma Patients.

Background: Demonstrating the cost-effectiveness of new treatments for multiple myeloma (MM) often relies on the extrapolation of overall survival (OS) trial data. This method can introduce uncertainty in long-term survival estimates if OS data are immature, as is often the case in newly diagnosed MM (NDMM). We explore the use of the relationship between minimal residual disease (MRD) status and OS to reduce uncertainty of long-term survival outcomes. Objectives: To evaluate if uncertainty in long-term modeled outcomes in NDMM is reduced using a response-based partitioned survival model (PSM), whereby patients were categorized as MRD-positive or -negative, relative to a standard PSM, when OS data are immature. Methods: Standard and response-based PSMs, estimating patient life-years (LYs) over a lifetime horizon, were developed for NDMM patients treated with bortezomib, thalidomide, and dexamethasone (BTd) with or without daratumumab as induction and consolidation therapy. In the standard PSM, LYs were determined by extrapolations from individual patient data from CASSIOPEIA. In the response-based PSM, survival was dependent on MRD status at the time of the response assessment via a landmark analysis. Cox-proportional hazard ratios from external sources and CASSIOPEIA informed the relationship for OS between MRD-positive and MRD-negative, and between patients receiving BTd and daratumumab plus BTd, respectively. Uncertainty was assessed by comparing LYs and OS extrapolations from deterministic and probabilistic analyses. Results: This response-based PSM demonstrated reduced uncertainty in long-term survival outcomes compared with the standard PSM (range across extrapolations of 3.4 and 7.7 LYs for daratumumab plus BTd and BTd, respectively, vs 14.8 and 11.8 LYs for the standard PSM). It also estimated a narrower interquartile range of LYs in the probabilistic analyses for the majority of parametric extrapolations. Discussion: Alternative methods to estimate long-term survival outcomes, such as a response-based PSM, can reduce uncertainty in modeling predictions around cost-effectiveness estimates for health technology assessment bodies and payers, thereby supporting faster market access for novel therapies with immature survival data. Conclusions: Use of MRD status in a response-based PSM reduces uncertainty in modeling long-term survival in patients with NDMM and provides a greater number of clinically plausible extrapolations compared with a standard PSM.

Anosognosia in Amnestic Mild Cognitive Impairment Is Related to Diminished Hippocampal Volume Comparable to Alzheimer's Disease Dementia: Preliminary MRI Findings.

Although the presence of anosognosia in amnestic mild cognitive impairment (aMCI) may be predictive of conversion to Alzheimer's disease (AD), little is known about its neural correlates in AD and aMCI. Four different groups were compared using volumetric and diffusion magnetic resonance imaging metrics in regions of interest (hippocampus and cingulum cortex gray matter, cingulum bundle white matter): aMCI subjects with anosognosia (n = 6), aMCI subjects without anosognosia (n = 12), AD subjects with anosognosia (n = 6), and AD subjects without anosognosia (n = 9). aMCI subjects with anosognosia displayed a significantly lower gray matter density (GMD) in the bilateral hippocampus than aMCI subjects without anosognosia, which was accounted for by bilateral hippocampal differences. Furthermore, we identified that the mean hippocampal gray matter density of aMCI subjects with anosognosia was not statistically different than that of AD subjects. The groups of aMCI and AD subjects with anosognosia also displayed a lower GMD in the bilateral cingulum cortex compared to subjects without anosognosia, but these differences were not statistically significant. No statistically significant differences were found in the fractional anisotropy or mean diffusivity of the hippocampus or cingulum between subjects with and without anosognosia in aMCI or AD groups. While these findings are derived from a small population of subjects and are in need of replication, they suggest that anosognosia in aMCI might be a useful clinical marker to suspect brain changes associated with AD neuropathology.

The Impact of Price Reductions After Loss of Exclusivity in a Cost-Effectiveness Analysis: Fingolimod Versus Interferon Beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Cost-effectiveness analyses tend not to take into account the availability of lower-priced generics following loss of exclusivity (LOE) of branded products. By not considering these generics, which are typically adopted quickly, total costs are likely to be overestimated and may be unreflective of real-world payer conditions in the United States. OBJECTIVE: To assess the impact of including future price reductions following LOE on the cost-effectiveness of fingolimod versus intramuscularly administered interferon beta-1a (IM IFNß-1a) as treatments for multiple sclerosis. METHODS: This model was adopted from a previously published Markov model and was conducted from a U.S. payer perspective over a 10-year time horizon. Patients with relapsing-remitting multiple sclerosis entered the model and received either fingolimod (an oral therapy) or IM IFNß-1a (an injectable). These treatments reflect the interventions studied in the TRANSFORMS randomized clinical trial. Clinical, cost, and utility inputs were based on a recent cost-effectiveness review of therapies for multiple sclerosis. To model LOE, price reductions and the proportion of patients switching to generic versions following LOE were based on published estimates. Price reductions varied to reflect the difference in product types (oral vs. large molecule injectable). Assumptions were also made around the proportion of patients switching to generic versions over time following LOE and the projected date of LOE. Outcomes included per-patient total direct costs (medication, administration and monitoring, and disease-related costs including relapses), quality-adjusted life-years, and the incremental cost per quality-adjusted life-year. RESULTS: Assuming no price reductions following LOE, fingolimod was considered cost-effective versus IM IFNß-1a ($118,434 per quality-adjusted life-year), despite having higher total direct costs over 10 years ($475,740 vs. $446,792). When including future price reductions following LOE, total direct costs were reduced with fingolimod and were lower than those accrued with IM IFNß-1a over the model time horizon ($308,570 vs. $442,653). Cost-effectiveness results were sensitive to changes in both clinical parameters and medication costs. Scenario analyses demonstrated that an earlier date of LOE was associated with lower total costs. CONCLUSIONS: Health economic models may predict higher total costs when the price reductions following LOE are not considered. Here, oral fingolimod was seen to be cost-saving versus IM IFNß-1a over the model time horizon when such price reductions were included. The cost implications of not accounting for future price changes may determine whether an intervention is considered cost-effective and as such may influence reimbursement decisions based on cost-effectiveness thresholds. Multiple product types (e.g., oral, injectable, and infused agents) have been approved for use as treatments for multiple sclerosis in the United States, and LOE is likely to have a different effect on each of these therapies. DISCLOSURES: This study was funded by Novartis Pharmaceuticals Corporation. Hua and Hersh report consulting fees from Novartis for work on this study. Hua also reports speaking, advisory board, and consulting fees from Biogen, Genzyme, Teva, EMD Serono, Genentech, TG Therapeutics, and Novartis for activities outside of this study. Hersh also reports speaking and consulting fees from Novartis, Biogen, Genzyme, Genentech, and EMD Serono for activities outside of this study, and research grants from PCORI and Biogen. At the time of this research, Morten and Kusel were paid employees of Costello Medical, which was contracted by Novartis to undertake some of this study's work. Lin, Cave, Herrera, and Ko were paid employees of Novartis at the time of this research. Cave, Herrera, and Ko also report owning stock in Novartis Pharmaceuticals. Varga provided services to Novartis at the time of this research and has nothing further to disclose. This research was presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2017; March 27-30, 2017; Denver, CO.

DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.

BACKGROUND: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. RESULTS: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. CONCLUSIONS: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation.