Cost-effectiveness analysis of nivolumab plus ipilimumab versus platinum-doublet chemotherapy for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: We evaluated the cost-effectiveness of nivolumab in combination with ipilimumab (NIVO + IPI) versus platinum-doublet chemotherapy (PDC) for the first-line treatment of stage IV or recurrent non-small cell lung cancer (NSCLC) from a third-party payer perspective in the United States (US). METHODS: A partitioned survival model was developed using efficacy, safety, and utility inputs derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826) with 37.7-month minimum follow-up for overall survival (OS). OS and progression-free (PF) survival were extrapolated over a 20-year time-horizon using parametric spline-based models selected based on goodness of fit and validated with data from external sources. Duration of treatment Kaplan-Meier curves were used for treatment cost calculations. US-specific costs (2021 dollars) for drug acquisition, administration, and monitoring; disease management (PF and progressed disease health states); end-of-life care; adverse events; and subsequent treatments were derived from publicly available sources. Time-to-death utilities were applied in the base case, whereas treatment-specific progression-based utilities were tested in a scenario analysis. Main outcomes included incremental cost per life-year gained (LYG) and quality-adjusted life-year (QALY). Model uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: NIVO + IPI resulted in 1.53 additional life-years, 1.33 additional QALYs, and $142 088 in additional costs compared with PDC. The incremental cost per LYG was $92 651, whereas incremental cost per QALY gained was $106 553. The application of treatment-specific progression-based utilities yielded an incremental cost per QALY gained of $117 076. Probabilistic sensitivity analysis revealed a 98% probability that NIVO + IPI was cost-effective versus PDC at a willingness-to-pay threshold of $150 000 per QALY. CONCLUSIONS: NIVO + IPI was estimated to be cost-effective as a first-line treatment for stage IV or recurrent NSCLC in the US, with increased survival and higher cost compared with PDC.

Modeling the public health impact of different meningococcal vaccination strategies with 4CMenB and MenACWY versus the current toddler MenACWY National Immunization Program in Chile.

Invasive meningococcal disease (IMD) is an uncommon yet unpredictable, severe, and life-threatening disease with the highest burden in young children. In Chile, most IMD is caused by meningococcal serogroup B (MenB) and W (MenW) infection. In response to a MenW outbreak in 2012, a toddler vaccination program was implemented using quadrivalent meningococcal conjugate vaccine against serogroups A, C, W and Y (MenACWY). The vaccine program, however, does not protect infants or other unvaccinated age groups and does not protect against MenB IMD. Since 2017, MenB IMD cases are becoming increasingly prevalent. Using a dynamic transmission model adapted for Chile, this analysis assessed the public health impact (reduction in IMD cases, long-term sequelae, deaths, and quality-adjusted life-years) of six alternative vaccination strategies using MenACWY and/or the four-component MenB (4CMenB) vaccine in infants, toddlers, and/or adolescents compared to the National Immunization Program (NIP) implemented in 2014. Strategies that added infant 4CMenB to MenACWY in toddlers or adolescents would prevent more IMD than the current NIP, observed within the first 5 years of the program. Replacing the NIP by an adolescent MenACWY strategy would prevent more IMD in the longer term, once herd immunity is established to protect unvaccinated infants or older age groups. The strategy that maximized reduction of IMD cases and associated sequelae in all age groups with immediate plus long-term benefits included infant 4CMenB and MenACWY in both toddlers and adolescents. This analysis can help policymakers determine the best strategy to control IMD in Chile and improve public health. A set of audio slides linked to this manuscript can be found at https://doi.org/10.6084/m9.figshare.16837543.

Plain Language Summary (PLS)What is the context?Invasive meningococcal disease (IMD) is a severe, sometimes fatal, unpredictable disease with highest rates in infants, young children, and adolescents. It is caused by different serogroups of Neisseria meningitidis bacteria. Most cases in Chile are due to meningococcal serogroups B (MenB) and W (MenW). Following a MenW IMD outbreak in 2012, vaccination was introduced, leading to the current National Immunization Program (NIP) in toddlers with quadrivalent meningococcal conjugate vaccine (MenACWY) (protecting against IMD caused by MenA, C, W, and Y).What is new?A disease model to predict the impact of vaccination strategies in the Chilean population compared six alternative strategies, using the multi-component MenB (4CMenB) vaccine for infants (protecting against MenB, with potential cross-protection against MenW and Y IMD) and/or the MenACWY vaccine for toddlers and/or adolescents.What is the impact?Results, compared to the NIP, show that: Strategy 1 (a program targeting only infants with 4CMenB) would reduce more MenB cases but fewer MenA, C, W and Y cases resulting in a lower reduction of total IMD cases in the long term; Strategy 3 (a program targeting only adolescents with MenACWY) would have a similar effect to the NIP in the short term but a far greater IMD reduction in the long term (as vaccinating this age group eventually reduces transmission to other age groups, reducing their risk of disease); all the other strategies targeted more than one age group, further reducing numbers of IMD cases compared with the NIP. The greatest benefits were seen with infant 4CMenB vaccination combined with toddler and adolescent MenACWY vaccination. Results can help policymakers determine the best IMD strategy to maximize the benefits of available meningococcal vaccines.

Cost-Effectiveness of 4CMenB Infant Vaccination in England: A Comprehensive Valuation Considering the Broad Impact of Serogroup B Invasive Meningococcal Disease.

OBJECTIVES: This cost-effectiveness analysis (CEA) of 4CMenB infant vaccination in England comprehensively considers the broad burden of serogroup B invasive meningococcal disease (MenB IMD), which has not been considered, or was only partially considered in previous CEAs. METHODS: A review of previous MenB vaccination CEAs was conducted to identify aspects considered in the evaluation of costs and health outcomes of the disease burden of MenB IMD. To inform the model structure and comprehensive analysis, the aspects were grouped into 5 categories. A stepwise analysis was conducted to analyze the impact of each category, and the more comprehensive consideration of disease burden, on the incremental cost-effectiveness ratio (ICER). RESULTS: MenB IMD incidence decreased by 46.0% in infants and children 0-4 years old within 5 years after introduction of the program. Stepwise inclusion of the 5 disease burden categories to a conventional narrow CEA setting reduced the ICER from £360 595 to £18 645-that is, considering the impact of all 5 categories, 4CMenB infant vaccination is cost-effective at a threshold of £20 000 per QALY gained. CONCLUSIONS: When considering comprehensively the MenB IMD burden, 4CMenB infant vaccination can be cost-effective, a finding contrary to previous CEAs. This analysis allows policy decision-makers globally to infer the impact of current disease burden considerations on the cost-effectiveness and the comprehensive assessment necessary for MenB IMD. Although this comprehensive CEA can help inform decision making today, it may be limited in capturing the full disease burden and complex interactions of health and economics of MenB IMD.

Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: An application to England.

Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups. A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and 'Other' mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact. Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent. This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases.

Comparative proteomics of cell division mutants and wild-type of Synechococcus sp. strain PCC 7942.

Bacterial cell division is a highly co-ordinated and fine-tuned process. In the unicellular cyanobacterium Synechococcus sp. strain PCC 7942, inactivating mutations in the ftn2 and ftn6 genes block cell division and result in a phenotype with extensively elongated cells. In order to establish the pleiotropic responses induced and cellular processes affected by blocked cell division, the proteomes of wild-type and the cell division mutants Ftn2 and Ftn6 of Synechococcus sp. strain PCC 7942 were characterized and compared. By separating soluble extracted proteins on 2D gels, more than 800 protein spots were visualized on each SYPRO Ruby-stained gel. Quantitative differences in protein composition were detected by using the PDQuest software, and comparative analysis revealed that 76 protein spots changed significantly in the cell division mutants. These protein spots were selected for identification using peptide mass fingerprints generated by MALDI-TOF MS. Fifty-three protein spots were successfully identified, representing 44 different proteins. The upregulated proteins include proteins involved in cell division/cell morphogenesis, protein synthesis and processing, oxidative stress response, amino acid metabolism, nucleotide biosynthesis, and glycolysis, as well as unknown proteins. Among the downregulated proteins are those involved in chromosome segregation, protein processing, photosynthesis, redox regulation, carbon dioxide fixation, nucleotide biosynthesis, the biosynthetic pathway to fatty acids, and energy production. Besides eliciting common responses, inactivation of Ftn2 and Ftn6 in the mutants may result in different responses in protein levels between the mutants. Among 18 identified differentially affected protein spots, 75 % (9/12) of the protein spots affected in the Ftn2 mutant were upshifted, whereas in the Ftn6 mutant 70 % (7/10) of the affected protein spots were downshifted. Identification of such differentially expressed proteins provides new targets for future studies that will allow assessment of their physiological roles and significance in cyanobacterial cell division.

Proteomic analyses of the photoauto- and diazotrophically grown cyanobacterium Nostoc sp. PCC 73102.

The filamentous cyanobacteria of the genus Nostoc are globally distributed, phenotypically complex organisms, capable of cellular differentiation and of forming symbiotic associations with a wide range of plants. To further our understanding of these processes and functions, the proteome of photoautotrophically and diazotrophically grown Nostoc sp. PCC 73102 (N. punctiforme) cells was examined. Extracted proteins were separated into membrane and soluble protein fractions and analysed using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). The analysis led to the identification of 82 proteins that could be divided into 12 functional categories. Significantly, 65 of these proteins have not been previously documented in the Nostoc proteome. Many of the proteins identified were readily recognized as housekeeping proteins involved in carbon, nitrogen and energy metabolism, but a number of proteins related to stress, motility, secretion and post-translational modifications were also identified. Ten unclassified proteins were also detected, representing potential novel functions. These proteins were highly expressed, suggesting that they play key roles during photoautotrophic and diazotrophic growth. Nineteen of the proteins expressed under the growth conditions examined contained putative thioredoxin (Trx) targets, a motif that functions in redox regulation via redox equivalent mediators and is known to be significant in a wide range of biological processes. These observations contribute to our understanding of the complex Nostoc life cycle.

FtsZ may have dual roles in the filamentous cyanobacterium Nostoc/Anabaena sp. strain PCC 7120.

The cellular and subcellular localization of FtsZ, a bacterial cell division protein, were investigated in vegetative cells of the filamentous cyanobacterium Nostoc/Anabaena sp. strain PCC 7120. We show by using immunogold-transmission electron microscopy that FtsZ forms a ring structure in a filamentous cyanobacterium, similar to observations in unicellular bacteria and chloroplasts. This finding, that the FtsZ in a filamentous cyanobacterium accumulates at the growing edge of the division septa leading to the formation of the typical prokaryotic Z-ring arrangement, is novel. Moreover, an apparent cytoplasmic distribution of FtsZ occurred in vegetative cells. During the transition of vegetative cells into terminally differentiated heterocysts the cytoplasmic FtsZ levels decreased substantially. These findings suggest a conserved function of FtsZ among prokaryotes, including filamentous cyanobacteria with cell differentiation capacity, and possibly a role of FtsZ as a cytoskeletal component in the cytoplasm.

Protein expression profiles in an endosymbiotic cyanobacterium revealed by a proteomic approach.

Molecular mechanisms behind adaptations in the cyanobacterium (Nostoc sp.) to a life in endosymbiosis with plants are still not clarified, nor are the interactions between the partners. To get further insights, the proteome of a Nostoc strain, freshly isolated from the symbiotic gland tissue of the angiosperm Gunnera manicata Linden, was analyzed and compared with the proteome of the same strain when free-living. Extracted proteins were separated by two-dimensional gel electrophoresis and were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry combined with tandem mass spectrometry. Even when the higher percentage of differentiated cells (heterocysts) in symbiosis was compensated for, the majority of the proteins detected in the symbiotic cyanobacteria were present in the free-living counterpart, indicating that most cellular processes were common for both stages. However, differential expression profiling revealed a significant number of proteins to be down-regulated or missing in the symbiotic stage, while others were more abundant or only expressed in symbiosis. The differential protein expression was primarily connected to i) cell envelope-associated processes, including proteins involved in exopolysaccharide synthesis and surface and membrane associated proteins, ii) to changes in growth and metabolic activities (C and N), including upregulation of nitrogenase and proteins involved in the oxidative pentose phosphate pathway and downregulation of Calvin cycle enzymes, and iii) to the dark, microaerobic conditions offered inside the Gunnera gland cells, including changes in relative phycobiliprotein concentrations. This is the first comprehensive analysis of proteins in the symbiotic state.