Cost-effectiveness of Pembrolizumab in Combination with Chemotherapy as Neoadjuvant Treatment and Continued as a Single Agent Adjuvant Treatment for High-Risk Early-Stage Triple-Negative Breast Cancer in Hong Kong.

INTRODUCTION: The phase III randomized KEYNOTE-522 trial demonstrated that pembrolizumab in combination with chemotherapy as neoadjuvant treatment followed by adjuvant pembrolizumab (pembrolizumab + chemotherapy) provided significant improvements in event-free survival (EFS) and overall survival (OS) for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The objective was to assess the cost-effectiveness of pembrolizumab + chemotherapy compared to neoadjuvant chemotherapy alone (chemotherapy) in patients with high-risk eTNBC from a Hong Kong third-party payer perspective. METHODS: A multistate transition model with four health states (event-free), locoregional recurrence, distant metastases, and death) was developed to assess the lifetime medical costs and health outcomes (3% annual discount), along with incremental cost-effectiveness ratios (ICERs) using efficacy and safety data from the KEYNOTE-522 trial. The health state utilities were derived from KEYNOTE-522 Euro-QoL-five-dimension five-level questionnaire (EQ-5D-5L) data. Costs were expressed in 2022 Hong Kong dollars (HKD). Scenario and sensitivity analyses were performed to assess the robustness of results. RESULTS: Over a 32-year time horizon, base case results showed that pembrolizumab + chemotherapy was associated with a 3.42 year longer EFS and expected gains of 3.05 life years (LYs) and 2.45 quality-adjusted life years (QALYs) compared to chemotherapy. The resultant ICERs were HKD 135,200 per QALY gained and HKD 108,463 per LY gained, which were lower than the World Health Organization (WHO) cost-effectiveness threshold of three times gross domestic product (GDP) per capita for Hong Kong of HKD 1,171,308 per QALY. The one-way sensitivity analyses (OWSA) and probabilistic sensitivity analysis (PSA) showed the results were robust across various inputs and alternative scenarios. CONCLUSION: On the basis of the analysis conducted for a 56-year-old cohort with high-risk eTNBC and assumptions in the model, pembrolizumab + chemotherapy represents a cost-effective proposition (as the ICER is approximately 35% of the GDP per capita in Hong Kong) for patients with high-risk eTNBC in Hong Kong.

The manuscript outlines the methods and results of a health economic model to estimate the cost-effectiveness of pembrolizumab + chemotherapy compared to neoadjuvant chemotherapy alone (chemotherapy) in patients with high-risk early-stage triple-negative breast cancer in the Hong Kong setting. The results of the manuscript show that the combination of pembrolizumab and chemotherapy provides an additional 3.05 life years and 2.45 quality-adjusted life years. Despite the potential drawbacks of employing gross domestic product (GDP) as a proxy for cost-effectiveness thresholds, the incremental cost-effectiveness ratio was less than three times GDP per capita in Hong Kong. Therefore, the new intervention was cost-effective. However, like any similar study, the results rely substantially on extrapolation of trial outcomes and thus sensitivity analysis has also been performed to handle the uncertainty associated with results. The one-way sensitivity analyses and probabilistic sensitivity analysis showed the results were robust. The manuscript provides economic evidence of the new intervention and provides new clinical insights.

Clinical Evaluation of Xpert Xpress CoV-2/Flu/RSV plus and Alinity m Resp-4-Plex Assay.

The performance of the Xpert Xpress CoV-2/Flu/RSV plus and Alinity m Resp-4-Plex Assays were evaluated using 167 specimens, including 158 human respiratory specimens and 9 external quality assessment program (EQAP) samples. For respiratory specimens, CoV-2/Flu/RSV plus exhibited perfect agreement with the standard-of-care (SOC) methods (Cohen's κ: 1, 100% agreement). The overall positive and negative percent agreement (PPA and NPA) were 100%, with 95% confidence intervals of 96.50 to 100% and 85.70 to 100%, respectively. On the other hand, Resp-4-Plex revealed an almost perfect agreement with the SOC methods (Cohen's κ: 0.92, 97.71% agreement). The overall PPA and NPA were 100% (95.76 to 100%) and 88.46% (70.20 to 96.82%), respectively. For EQAP samples, the results of CoV-2/Flu/RSV plus (9/9) and Resp-4-Plex (4/4) were concordant with the expected results. The experimental limit of detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the lowest (25 copies/mL for both methods), and that of the respiratory syncytial virus was the highest (400 copies/mL for CoV-2/Flu/RSV plus and 100 copies/mL for Resp-4-Plex). Threshold cycle (Ct) value correlation showed a large positive linear association between CoV-2/Flu/RSV plus and Resp-4-Plex, with R-squared values of 0.92-0.97, and on average, the Ct values of CoV-2/Flu/RSV plus were higher than that of Resp-4-Plex by 1.86-2.78, except for Flu A1 target (-0.66). To conclude, the performance of both assay was comparable to the SOC methods for both upper and lower respiratory specimens. Implementation of these rapid assay may reinforce the diagnostic capacity for the post-pandemic co-circulation of SARS-CoV-2 and other respiratory viruses.

Clinical Evaluation of the BIOFIRE SPOTFIRE Respiratory Panel.

The BIOFIRE SPOTFIRE Respiratory (R) Panel is a novel, in vitro diagnostic PCR assay with 15 pathogen targets. The runtime is about 15 min which is the shortest among similar panels in the market. We evaluated the performance of the SPOTFIRE R Panel with 151 specimens, including 133 collected from the upper respiratory tract (URT), 13 from the lower respiratory tract (LRT) and 5 external quality assessment program (EQAP) samples. The respiratory specimens were enrolled throughout the first two post-COVID-19 influenza seasons in Hong Kong (March to December 2023). For URT specimens, full concordance was observed between the SPOTFIRE R Panel and the standard-of-care FilmArray Respiratory 2.1 plus Panel (RP2.1plus) for 109 specimens (109/133, 81.95%). After discrepant analysis, the SPOTFIRE R Panel identified more pathogens than the RP2.1plus in 15 specimens and vice versa in 3 specimens. The per-target negative and positive percentage agreement (NPA and PPA) were 92.86-100% except the PPA of adenovirus (88.24%). For LRT and EQAP samples, all results were fully concordant. To conclude, the performance of the SPOTFIRE R Panel was comparable to the RP2.1plus.

The effectiveness of physiotherapy interventions on fecal incontinence and quality of life following colorectal surgery: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: To investigate the effectiveness of physiotherapy interventions compared to control conditions on fecal incontinence (FI) and quality of life (QoL) following colorectal surgery. METHODS: Electronic searches in English-language (Scopus, Web of Science, Embase, AMED, CENTRAL, CINAHL, MEDLINE, Ovid, and PEDro) and Chinese-language (CNKI, Wanfang Data) databases were conducted. Trials comparing physiotherapy interventions against control conditions and assessing FI and QoL outcomes were included in the review. RESULTS: Ten trials were included. Meta-analysis revealed statistically significant improvements in lifestyle (0.54; 95% CI 0.03, 1.05; p = 0.04), coping behavior (MD 1.136; 95% CI 0.24, 2.04; p = 0.01), and embarrassment (0.417; 95% CI 0.14, 0.70; p = 0.00) components of QoL among individuals receiving pelvic floor muscle training (PFMT) compared with those receiving usual care (UC). Meta-analysis showed biofeedback to be significantly more effective than UC in enhancing anal resting pressure (ARP; 9.551; 95% CI 2.60, 16.51; p = 0.007), maximum squeeze pressure (MSP; 25.29; 95% CI 4.08, 48.50; p = 0.02), and rectal resting pressure (RRP; 0.51; 95% CI 0.10, 0.9; p = 0.02). Meta-analysis also found PFMT combined with biofeedback to be significantly more effective than PFMT alone for ARP (3.00; 95% CI 0.40, 5.60; p = 0.02), MSP (9.35, 95% CI 0.17, 18.53; p = 0.05), and RRP (1.54; 95% CI 0.60, 2.47; p = 0.00). CONCLUSIONS: PFMT combined with biofeedback was more effective than PFMT alone, but both interventions delivered alone were superior to UC. Future studies remain necessary to optimize and standardize the PFMT parameters for improving QoL among individuals who experience FI following CRC surgery. REVIEW REGISTRATION: This systematic review is registered in the PROSPERO registry (Ref: CRD42022337084).

Restoration of CPEB4 prevents muscle stem cell senescence during aging.

Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence.