Economic evaluation of isavuconazole for suspected invasive pulmonary aspergillosis in Canada.

BACKGROUND: Invasive mold infections (IMI) directly impact life expectancy, especially with delayed therapy. Among IMI, aspergillosis (IA) is more common than mucormycosis (IM), resulting in IA-targeted empirical treatment with voriconazole for suspected invasive pulmonary aspergillosis (IPA), despite IM ineffectiveness. Recently, isavuconazole was approved in Canada for IA and IM. The primary objective was to assess the cost-effectiveness of isavuconazole compared to voriconazole for suspected IPA in Canada. A secondary objective was to assess the impact of varying time horizons to address the wide spectrum of life expectancies, according to patients underlying diseases. RESEARCH DESIGN AND METHODS: A 5-year decision-tree was developed from the Canadian Ministry of Health (MoH) and societal perspectives. Efficacy parameters were extracted from SECURE/VITAL trials. Costs included treatment acquisition, hospitalization, adverse events and productivity loss. 3- and 10-year time horizon alternative scenarios and extensive sensitivity analyses were also conducted. RESULTS: From a MoH perspective, isavuconazole compared to voriconazole resulted in an incremental cost-utility ratio (ICUR) of $C30,160/QALY. 3- and10-year ICURs were also cost-effective, relative to a willingness-to-pay threshold of $C50,000/QALY. CONCLUSIONS: This study demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.

Economic Evaluation of Budesonide Orodispersible Tablets for the Treatment of Eosinophilic Esophagitis: A Cost-Utility Analysis.

INTRODUCTION: Budesonide orodispersible tablets (BOT) have been approved in Europe and Canada for the treatment of eosinophilic esophagitis (EoE), a rare and chronic disease. The objective of this study was to assess the economic impact of BOT on both the induction and maintenance of clinico-pathological remission of EoE by performing a cost-utility analysis (CUA). METHODS: For both the induction and maintenance settings, BOT was compared to no treatment in a target population of adult patients with EoE non-responsive to proton pump inhibitor (PPI) treatment. Markov models were developed for the induction and maintenance settings over 52-week and life-time horizons, respectively. Analyses were performed from both a Canadian Ministry of Health (MoH) and societal perspective. The resulting incremental cost-utility ratios (ICURs) were compared to a willingness-to-pay (WTP) threshold of $50,000 Canadian dollars/quality-adjusted life-year (QALY). Sensitivity and scenario analyses were conducted to assess the robustness of the base-case results. RESULTS: In the base-case probabilistic analysis, BOT compared to no treatment resulted in an ICUR of $1073/QALY and $30,555/QALY from a MoH perspective in the induction and maintenance settings, respectively. BOT was a cost-effective option for both induction and maintenance in > 99% of Monte Carlo simulations. In the scenario analyses, the deterministic ICUR of BOT compared to no treatment varied from $682/QALY to $8510/QALY in the induction setting and $21,005/QALY to $55,157/QALY in the maintenance setting. CONCLUSION: BOT was cost-effective compared to no treatment for both the induction and maintenance of clinico-pathological remission of EoE in patients non-responsive to PPIs.

A global economic model to assess the cost-effectiveness of new treatments for advanced breast cancer in Canada.

Objective Considering the increasing number of treatment options for metastatic breast cancer (MBC), it is important to develop high-quality methods to assess the cost-effectiveness of new anti-cancer drugs. This study aims to develop a global economic model that could be used as a benchmark for the economic evaluation of new therapies for MBC. Methods The Global Pharmacoeconomics of Metastatic Breast Cancer (GPMBC) model is a Markov model that was constructed to estimate the incremental cost per quality-adjusted life years (QALY) of new treatments for MBC from a Canadian healthcare system perspective over a lifetime horizon. Specific parameters included in the model are cost of drug treatment, survival outcomes, and incidence of treatment-related adverse events (AEs). Global parameters are patient characteristics, health states utilities, disutilities, and costs associated with treatment-related AEs, as well as costs associated with drug administration, medical follow-up, and end-of-life care. The GPMBC model was tested and validated in a specific context, by assessing the cost-effectiveness of lapatinib plus letrozole compared with other widely used first-line therapies for post-menopausal women with hormone receptor-positive (HR+) and epidermal growth factor receptor 2-positive (HER2+) MBC. Results When tested, the GPMBC model led to incremental cost-utility ratios of CA$131 811 per QALY, CA$56 211 per QALY, and CA$102 477 per QALY for the comparison of lapatinib plus letrozole vs letrozole alone, trastuzumab plus anastrozole, and anastrozole alone, respectively. Results of the model testing were quite similar to those obtained by Delea et al., who also assessed the cost-effectiveness of lapatinib in combination with letrozole in HR+/HER2 + MBC in Canada, thus suggesting that the GPMBC model can replicate results of well-conducted economic evaluations. Conclusions The GPMBC model can be very valuable as it allows a quick and valid assessment of the cost-effectiveness of any new treatments for MBC in a Canadian context.

Relationship between progression-free survival and overall survival in chronic lymphocytic leukemia: a literature-based analysis.

BACKGROUND: The endpoints of progression-free survival (pfs) and time-to-progression (ttp) are frequently used to evaluate the clinical benefit of anticancer drugs. However, the surrogacy of those endpoints for overall survival (os) is not validated in all cancer settings. In the present study, we used a trial-based approach to assess the relationship between median pfs or ttp and median os in chronic lymphocytic leukemia (cll). METHODS: The pico (population, interventions, comparators, outcomes) method was used to conduct a systematic review of the literature. The population consisted of patients with cll; the interventions and comparators were standard therapies for cll; and the outcomes were median pfs, ttp, and os. Two independent reviewers screened titles, abstracts, and full papers for eligibility and then extracted data from selected studies. Correlation coefficients were calculated to assess the relationship between median pfs or ttp and median os. Subgroup correlation analyses were also conducted according to the characteristics of the selected studies (such as line of treatment and type of treatment under investigation). RESULTS: Of the 1263 potentially relevant articles identified during the literature search, twenty-three were included. On average, median pfs or ttp was 16.0 months (standard deviation: 12.4 months) and median os was 43.5 months (standard deviation: 31.2 months). Results of the correlation analysis indicated that median pfs or ttp is highly correlated with median os (Spearman correlation coefficient: 0.813; p ≤ 0.001). A significant correlation between median pfs or ttp and median os was observed in second- and subsequent-line therapies, but not in the first-line setting. CONCLUSIONS: Our study demonstrates a strong correlation between median pfs or ttp and median os in previously treated cll, which reinforce the hypothesis that pfs and ttp could be adequate surrogate endpoints for os in this cancer setting.

Information processing mechanisms in microtubules at physiological temperature: Model predictions for experimental tests.

Both direct and indirect experimental evidence has shown signaling, communication and conductivity in microtubules (MTs). Theoretical models have predicted that MTs can be potentially used for both classical and quantum information processing although controversies arose in regard to physiological temperature effects on these capabilities. In this paper, MTs have been studied using well-established principles of classical statistical physics as applied to information processing, information storage and signal propagation. To investigate the existence of information processing in MTs we used cellular automata (CA) models with neighbor rules based on the electrostatic properties of the molecular structure of tubulin, and both synchronous and asynchronous updating methods. We obtained a phase diagram of possible dynamic behaviors in MTs that depend on the values of characteristic physical parameters that can be experimentally verified.

TL antigen is not linked to radioinduced thymic lymphoma.

X irradiation of C57BL/Ka mice induces thymic lymphoma after a period of 8 to 36 weeks. This latency period represents an ideal time window in which to follow the development of prelymphoma cells that give rise to overt thymic lymphoma. Several attempts have been made to identify an unequivocal prelymphoma cell marker but these efforts have so far been unsuccessful. We monitored the evolution of thymocyte populations containing prelymphoma cells during the latency period, using CD3 and TL as markers, in a transfer assay. We demonstrated that: (1) particular cell populations could appear or disappear; (2) there were at least two prelymphoma phenotypes: CD3loTL+ and CD3hiTL-; (3) TL could be present transiently; and (4) TL could be absent throughout the latency period. We conclude that split-dose irradiation may induce both TL gene expression and a prelymphoma state but that the two are not necessarily related.

The fate of thymocytes labeled in vivo with CFSE.

The fate of thymic emigrants had so far been studied using a variety of markers, each of which had inherent limitations as to stability, toxicity, or selectivity. We describe a new technique which relies on the in vivo injection of CFSE, an esterified vital dye hitherto used at 80 times lower concentrations for in vitro cell labeling. We show that CFSE labels a representative sample of all thymocyte subsets and that these migrate at a rate of approximately 2-3 x 10(6) cells/day to peripheral lymphoid organs. We show that they enter lymph nodes at day 1 postinjection and stay for at least 21 days, whereas the turnover in the spleen is more rapid. We also show by immunohistochemistry, using peroxidase-labeled anti-FITC antibodies, that CFSE-labeled thymic emigrants are confined to T-dependent areas of peripheral lymphoid organs.

Dendritic cells prevent radiation-induced thymic lymphoma.

Thymic lymphomas develop in C57BL/Ka mice within 36 weeks after split-dose X-irradiation. Lymphoma development can be abrogated in such mice by the injection of syngeneic bone marrow from healthy donors. The abrogation mechanism is unknown, but since bone marrow supplies the thymus with precursors of thymocytes and of dendritic cells, we tested the ability of early thymocytes and of immortalized thymic dendritic cells to abrogate lymphomagenesis. Fifteen weeks after irradiation, mice which had received bone marrow or dendritic cells had an equally low incidence of lymphoma, whereas mice which had received thymocytes or which had been only irradiated developed equally high levels of lymphomas, indicating that thymic dendritic cells played a key role in the prevention of lymphoma development. When thymuses from 15-week survivors were tested for pre-lymphoma cells, those from dendritic cell-treated mice proved to be endowed with a level of lymphomagenic potential intermediate between that from bone marrow-treated mice (nonlymphomagenic) and that from untreated or thymocyte-treated mice (highly lymphomagenic). These data indicate that lymphoma abrogation by bone marrow cells involves the participation of marrow-derived thymic dendritic cells.

Expression of protein tyrosine kinases in the murine thymus stroma.

Thymocytes not only receive signals from thymic epithelial cells but can also activate the latter, at least in the medulla. We have previously reported tyrosine phosphorylation of medullary epithelial cell substrates, after co-culture with thymocytes, and identified a number of protein tyrosine kinases in a line of thymic epithelial cells. We report here the in situ localisation by immunohistochemistry of JAK2 in medullary epithelial cells, of PDGF-R in medullary vascular endothelium, of FGF-R in Hassall's corpuscles, and the weak expression of JAK1 and RYK throughout the thymus.

Up-regulation of a thymic epithelial ligand after contact with thymocytes.

Thymic medullary epithelial cells of the E-5 line were shown to form in vitro complexes with thymocytes resulting in no apparent modification to the thymocytes participating in the complex, but in tyrosine phosphorylation on a glycoprotein associated with the epithelial adhesion molecule. Because signal transduction from lymphocytes to stromal cells is poorly documented, we examine in this work events which follow epithelial cell activation. Our findings indicate that one chain of the epithelial adhesion molecule (gp23), after complex formation with thymocytes, undergoes a rapid and transient tyrosine kinase-dependent up-regulation.

Continuous measurement of dissolved H2 in an anaerobic reactor using a new hydrogen/air fuel cell detector.

A miniature fuel cell, using a hydrophobic Teflon(R) membrane, designed to continuously measure dissolved H(2) in nonbiological media, was tested for use in anaerobic digestion conditions. In water, this detector responds quickly and efficiently to variation of hydrogen concentration in the range from 80 to 770 nM The media used, and the metabolites or products found in anaerobic digestion media, i. e. inorganic carbon and phosphate buffers, formate, acetate, and dissolved methane, did not interfere with the signal of the detector cell. Dissolved hydrogen sulfide did not poison the cell but was detected. In spite of the detector's high sensitivity to hydrogen (about 21,000 times higher for hydrogen than for hydrogen sulfide), interferences can occur in media containing high sulfide levels.In a methanogenic reactor, the detector cell response to dissolved hydrogen was fast and reliable with time. The observed values ranged values ranged from 2 to 3.5 microM. Dissolved hydrogen concentrations were 40 to 70 times higher than values calculated from measured hydrogen partial pressures and Henry's coefficient, suggesting a limitation of the process in the hydrogen transfer from the liquid to the gaseous phase.

Establishment and characterization of a thymic medullary epithelial cell clone.

Thymic stromal cells were cultured in conditions which select for epithelial cells. These were then transformed in vitro by contact with N-methyl-N'-nitro-N-nitrosoguanidine and cloned at limit dilution. One of the clones was characterized as being of medullary origin on the basis of its reactivity with a battery of antibodies previously shown to distinguish cortical from medullary thymic epithelial cells. The importance of this clone lies in the potential it offers to delineate how various T cell subpopulations acquire their distinct markers and function within the thymus.