The Health Economics of Metastatic Hormone-Sensitive and Non-Metastatic Castration-Resistant Prostate Cancer-A Systematic Literature Review with Application to the Canadian Context.

Background: Health economic evaluations are needed to assess the impact on the healthcare system of emerging treatment patterns for advanced prostate cancer. The objective of this study is to review the scientific literature identifying cost-effectiveness and cost analyses that are assessing treatments for metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC). Methods: On 29 June 2021, we searched the scientific (MEDLINE, Embase, and EBSCO) and grey literature for health economic studies targeting mHSPC and nmCRPC. We used the CHEC-extended checklist and the Welte checklist for risk-of-bias assessment and transferability analysis, respectively. Results: We retained 20 cost-effectiveness and 4 cost analyses in the mHSPC setting, and 14 cost-effectiveness and 6 cost analyses in the nmCRPC setting. Docetaxel in combination with androgen deprivation therapy (ADT) was the most cost-effective treatment in the mHSPC setting. Apalutamide, darolutamide, and enzalutamide presented similar results vs. ADT alone and were identified as cost-effective treatments for nmCRPC. An increase in costs as patients transitioned from nmCRPC to mCRPC was noted. Conclusions: We concluded that there is an important unmet need for health economic evaluations in the mHSPC and nmCRPC setting incorporating real-world data to support healthcare decision making.

Trimodal therapy vs. radical cystectomy for muscle-invasive bladder cancer: A Canadian cost-effectiveness analysis.

INTRODUCTION: Trimodal therapy (TMT) is a suitable alternative to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC). In this study, we conducted a cost-effectiveness evaluation of RC±NAC vs. TMT for MIBC in the universal and publicly funded Canadian healthcare system. METHODS: We developed a Markov model with Monte-Carlo microsimulations. Rates and probabilities of transitioning within different health states (e.g., cure, locoregional recurrence, distant metastasis, death) were input in the model after a scoped literature review. Two main scenarios were considered: 1) academic center; and 2) populational-level. Results were reported in life-years gained (LYG), quality-adjusted life years (QALY), and incremental cost-effectiveness ratio (ICER). A sensitivity analysis was performed. RESULTS: A total of 20 000 patients were simulated. For the academic center model, TMT was associated with increased effectiveness (both in LYG and QALY) at a higher cost compared to RC±NAC at five and 10 years. This resulted in an ICER of $19 746/QALY per patient undergoing the TMT strategy at 10 years of followup. For the populational-level model, RC±NAC was associated with higher effectiveness at 10 years, with an ICER of $3319/QALY per patient. This study was limited by heterogeneity within the studies used to build the model. CONCLUSIONS: In this study, TMT performed in academic centers was cost-effective compared to RC±NAC, with higher effectiveness at a higher cost. On the other hand, RC±NAC was considered cost-effective compared to TMT at the populational-level. Further studies are needed to confirm these results.

Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic impacted transplant programs across Canada. OBJECTIVE: We evaluated the implications of delays in transplantation among Canadian end-stage kidney disease (ESKD) patients to allow pretransplant vaccination. DESIGN: We used a Markov microsimulation model and ESKD patient perspective to study the effectiveness (quality-adjusted life years [QALY]) of living (LD) or deceased donor (DD) kidney transplantation followed by 2-dose SARS-CoV-2 vaccine versus delay in LD ("Delay LD") or refusal of DD offer ("Delay DD") to receive 2-dose SARS-CoV-2 vaccine pretransplant. SETTING: Canadian dialysis and transplant centers. PATIENTS: We simulated a 10 000-waitlisted ESKD patient cohort, which was predictively modeled for a lifetime horizon in monthly cycles. MEASUREMENTS: Inputs on patient and graft survival estimates by patient, LD or DD characteristics, were extracted from the Treatment of End-Stage Organ Failure in Canada, Canadian Organ Replacement Register, 2009 to 2018. In addition, a literature review provided inputs on quality of life, SARS-CoV-2 transmissibility, new variants of concern, mortality risk, and antibody responses to 2-dose SARS-CoV-2 mRNA vaccines. METHODS: We conducted base case, scenario, and sensitivity analyses to illustrate the impact of patient, donor, vaccine, and pandemic characteristics on the preferred strategy. RESULTS: In the average waitlisted Canadian patient, receiving 2-dose SARS-CoV-2 vaccine post-transplant provided an effectiveness of 22.32 (95% confidence interval: 22.00-22.7) for LD and 19.34 (19.02-19.67) QALYs for DD. Delaying transplants for 6 months to allow 2-dose SARS-CoV-2 vaccine before LD and DD transplant yielded effectiveness of 22.83 (21.51-23.14) and 20.65 (20.33-20.96) QALYs, respectively. Scenario analysis suggested a benefit to short delays in DD transplants to receive 2-dose SARS-CoV-2 vaccine in waitlisted patients ≥55 years. Two-way sensitivity analysis suggested decreased effectiveness of the strategy prioritizing 2-dose SARS-CoV-2 vaccine prior to DD transplant the longer the delay and the higher the Kidney Donor Risk Index of the eventual DD transplant. When assessing the impact of SARS-CoV-2 variants of concern (infection rates ≥10-fold and associated mortality ≥3-fold vs base case), we found short delays to allow 2-dose SARS-CoV-2 vaccine administration pretransplant to be preferable. LIMITATIONS: Risks associated with nosocomial exposure of LDs were not considered. There was uncertainty regarding input parameters related to SARS-CoV-2 infection, new variants, and COVID-19 severity in ESKD patients. Given rollout of population-level SARS-CoV-2 vaccination, we assumed a linear decrease in infection rates over 1 year. Proportions of patients mounting an antibody response to 2-dose SARS-CoV-2 mRNA vaccines were considered in lieu of data on vaccine efficacy in dialysis and following transplantation. Non-age-stratified annual mortality rates were used for waitlisted candidates. CONCLUSIONS: Our analyses suggest that short delays allowing pretransplant vaccination offered comparable to greater effectiveness than pursuing transplantation without delay, proposing transplant candidates should be prioritized to receive at least 2 doses of SARS-CoV-2 vaccine. Our scenario and sensitivity analyses suggest that caution must be exercised when declining DD offers in patients offered low risk DD and who are likely to incur significant delays in access to transplantation. While population-level herd immunity may decrease infection risk in transplant patients, more data are required on vaccine efficacy against SARS-CoV-2 and variants of concern in ESKD, and how efficacy may be modified by a third vaccine dose, maintenance immunosuppression and timing of induction and rejection therapies.

Time course and progression of pressure overload-induced cardiac hypertrophy in rats.

AIM: To study the time course and progression of pressure overload-induced left ventricular hypertrophy METHODS: Left ventricular hypertrophy was induced in rats by abdominal aorta constriction and assessed at different time points (10, 15, 20, 25, 35, and 45 days) after operation. RESULTS: The cardiac index (the ratio of heart weight to body weight) in aortic-banded animals was characterised by phasic changes when compared with the sham operated and the control animals. In aortic-banded rats the cardiac index rose sharply at days 10 and 15 after operation. This sharp increase was followed by a phase of slight increase (day 20), and then it again sharply increased (day 25). At the remaining time points (days 35 and 45) the cardiac index was significantly increased in comparison with that of the sham operated and the control animals but the increase diminished gradually. CONCLUSION: Our results suggest that left ventricular hypertrophy develops not in a linear but in a phasic way. Yet, the experimental model we used produced a relatively stable left ventricular hypertrophy.

Interleukin-6, interleukin-8, interleukin-10, and C-reactive protein in febrile neutropenia in children with malignant diseases.

AIM: To compare serum levels of interleukin-6, interleukin-8 and interleukin-10 in bacteremic and non-bacteremic episodes of febrile neutropenia in children with malignant diseases, and determine their changes and correlation with C-reactive protein (CRP). MATERIAL AND METHODS: Between January 2003 and June 2004, we examined 41 episodes of febrile neutropenia in 24 children with malignant diseases who were receiving polychemotherapy. C-reactive protein was measured at the onset of febrile episodes and on days 3 and 5 from beginning of therapy. The soluble interleukins-6, -8, and -10 were determined in the serum using enzyme bound immunosorbent analysis at the onset of fever and at 24 and 72 hours after initiation of an empiric antibiotic therapy. RESULTS: The CRP baseline levels differentiated the patients with unexplained fever from those with local infection but did not differentiate them from those with bacteremia. Interleukin-8 at 24 hours differentiated bacteremic from non-bacteremic episodes (P < 0.05) and at a cut-off value of 130 pg/ml it had a sensitivity of 72% and a specificity of 84% to differentiate bacteremia. Interleukin-10 at 24 hours yielded higher values in Gram (-) bacteremia in comparison with the non-bacteremic episodes (P < 0.001) and Gram (+) bacteremia (P < 0.05). Interleukin-6 at 24 hours had significantly higher values in febrile episodes of more than 3 days duration (P < 0.05). CONCLUSIONS: Interleukin-8 could differentiate in the first 24 hours bacteremic from non-bacteremic episodes in febrile neutropenia, while interleukin-10 is perhaps a more accurate marker for Gram (-) bacteremia.

Long-term changes in dyspnea, lung function, and exercise capacity in COPD patients.

OBJECTIVE: To examine longitudinal changes in dyspnea, lung function, and exercise capacity in COPD patients and to compare baseline data of frequent and infrequent exacerbators at trial entry. METHODS: Nineteen stable COPD patients without significant co-morbidity (age, 58.4 +/- 8.4 years; FEV1% = 33 +/- 12%; mean +/- SD) participated in the study. After a mean period of 36 months (range = 24 - 49) the patients were retested using an identical protocol. RESULTS: Repeated measures analysis showed that there was significant deterioration of FEV1 L (from 1.028 +/- 0.349 to 0.928 +/- 0.307; p = 0.007), PImax cm H2O (from 61.9 +/- 24.2 to 42.0 +/- 22.1; p = 0.007), PaO2 mm Hg (from 69.0 +/- 8.6 to 60.1 +/- 6.8; p = 0.003), PaCO2 mm Hg (from 43.1 +/- 4.9 to 47.3 +/- 4.5; p = 0.001), ATS (from 2.4 +/- 1.0 to 2.8 +/- 0.8; p = 0.031), and 6MWD m (from 389 +/- 130 to 341 +/- 135; p = 0.014). There were also changes in IC, T(L,CO)/V(A), PAP and Borg, but they were not statistically significant. Differentiation of patients by frequency of exacerbations per year of observation (> 2 < or =) discriminated them with respect to functional parameters (FEV1, FVC, IC), dyspneic indices (ATS, VAS and Borg) and exercise capacity (6MWD) at the time of enrollment. CONCLUSIONS: 1) Lung function parameters, blood-gas and dyspneic indices, and exercise capacity decline over a mean period of 36 month in patients with COPD; 2) Patients with frequent exacerbations experience more dyspnea and have lower levels of lung function and exercise capacity at trial entry.

Tidal breathing analysis in school-age children. Comparison with the parameters of forced expiration.

UNLABELLED: Tidal breathing analysis is a method which has the potential to be used for distinguishing and follow-up of airflow obstruction (AFO) in infants, children and critically ill patients. The aim of the present study was to analyse the tidal breathing parameters (TBP) in healthy and in asthmatic school-age children and to compare them with the parameters of forced expiration. SUBJECTS: Two hundred and twenty five healthy children and 100 asthmatics (7 to 14 years- old) took part in the present study. RESULTS: The results show that TBPs exhibit great inter- and intraindividual variability, even if the mean value of 10 consecutive breathing cycles is used. Parameters that reflect the tidal expiratory flow pattern--V(PTEF)/V(E) and T(PTEF)/T(E) demonstrate high variability and no correlation with age, sex and anthropometric parameters in healthy children. These indices are useful for detection of acute changes in bronchomotor tonus in asthmatics - V(PTEF)/V(E) = 36.1 +/- 6.6% vs. 32.6 +/- 6.2% (methacholine) vs. 37.4 +/- 7.5% (salbutamol) and T(PTEF)/T(E) = 34.2 +/- 6.2% vs. 28.6 +/- 7.8% vs. 35.3 +/- 7.5%, resp. (P < 0.05 everywhere; n = 34) as well as for discriminating a group of subjects with AFO vs. controls (V(PTEF)/V(E) = 30.9 +/- 6.5% vs. 35.3 +/- 8.0%; P = 0.005, and T(PTEF)/T(E) = 29.0 +/- 6.7% vs. 32.8 +/- 7.6%; P = 0.016). The evaluation of the area under the ROC curves (AUC) in the asthmatic group showed weak discriminative capacity of T(PTEF)/T(E) and V(PTEF)/V(E) in comparison to FEV1 (AUC of T(PTEF)/T(E) = 0.62; 95%CI 0.51-0.74). CONCLUSIONS: Tidal breathing parameters could add insight t.o the functional profile but are not capable of substituting forced expiration regarding detection of overt airflow obstruction in school-age children.

A reproducible model of cardiac hypertrophy in rats. Problems and obstacles we faced.

AIM: To develop a reproducible model of significant left ventricular hypertrophy in order to study the role played by the tumor suppressor protein 53 (P53) in the mechanisms of cardiac hypertrophy, the cross-talk with the other factors and the connection between expression and activity of P53, cardiac myocyte apoptosis and heart hypertrophy; to discuss the problems and obstacles we faced. METHODS: Male Wistar rats were used in the experiments. Left ventricular hypertrophy was induced by banding the abdominal aorta. Three series of the experiment were performed differing in the place of banding and the size of constriction in order to find the most suitable model for our further research. RESULTS: Forty five days after banding the abdominal aorta just below the diaphragm the cardiac index increased by 30% in comparison with that in the controls. CONCLUSION: We have developed a reproducible model of significant left ventricular hypertrophy in rats. The main advantages of the model are: a) it is technically simple; b) it may be realised in any laboratory all over the world; c) it allows the most common lab animals (male Wistar rats) to be used for studies without having to be subjected to thoracotomy and hence requiring a long recovery period.