The cost-effectiveness of including liquid biopsy into molecular profiling strategies for newly diagnosed advanced non-squamous non-small cell lung cancer in an Asian population.

OBJECTIVES: Liquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. MATERIALS AND METHODS: A decision tree and partitioned-survival model was developed from the Singapore healthcare system's perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. RESULTS: The sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. CONCLUSION: The sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

OBJECTIVES: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. MATERIALS AND METHODS: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. RESULTS: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. CONCLUSIONS: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

Next generation covered stents made from nanocomposite materials: A complete assessment of uniformity, integrity and biomechanical properties.

Covered stents are stents wrapped with a thin polymeric membrane, and are typically used to treat vessel aneurysms and seal perforated arteries. Current covered stents suffer from restenosis due to limitations in material and fabrication methods which leaves metallic struts directly exposed to blood. We have developed a biocompatible and haemocompatible nanocomposite polymer, polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU). We devised a novel combination of ultrasonic spray atomisation system and dip-coating process to produce small calibre covered stents with metal struts fully embedded within the membrane, which also yields greater coating uniformity. Stent-polymer bonding was enhanced via silanisation and coating of reactive pre-polymer. Platelet studies supported the non-thrombogenicity of POSS-PCU. Biomechanical performances including diametrical compliance, bending strength, radial strength and recoil were evaluated and optimised. This proof-of-principle manufacturing technique could lead to the development of next-generation small calibre adult and paediatric covered stents. These stents are currently undergoing preclinical trial. From the Clinical Editor: The use of stents to treat vascular diseases is now the standard of care in the clinical setting. Nonetheless, a major problem of the current stents is the risk of restenosis and thrombosis. The authors developed a nanocomposite material using polyhedral oligomeric silsesquioxane and poly(carbonate-urea) urethane (POSS-PCU) and incorporated into metallic stents. Preliminary data have already shown promising results. It is envisaged that this would further lead to better stent technology in the future.

A polyhedral oligomeric silsesquioxane-based bilayered dermal scaffold seeded with adipose tissue-derived stem cells: in vitro assessment of biomechanical properties.

BACKGROUND: Although commercial skin substitutes are widely available, its use remains challenging at surgery and postoperatively. The high cost is also prohibitive. We designed and characterized a scaffold for dermal replacement, using advanced nanocomposite materials, which are known to have unique nanoscale features that enhance cellular behavior. METHODS: A bilayered scaffold was developed using the nanocomposite, polyhedral oligomeric silsesquioxane, incorporated into poly(caprolactone-urea)urethane, resulting in a mechanically robust bioabsorbable polymer; forming the inner layer, which was designed with a range of porosities. The removable outer layer contained nanosilver. Tensile testing, surface tension, permeability, and scanning electron microscopy were performed. Optimal pore morphology for cellular proliferation was elucidated through adipose tissue-derived stem cell culture and a cell viability assay. All tests were repeated on Integra Dermal Regeneration Template. RESULTS: The physical construct was easy to handle and clinically applicable. Macroporosity and permeability of scaffolds was demonstrated, confirmed by scanning electron microscopy. Both tensile strength and surface tension were comparable with skin; outer layer demonstrated hydrophobicity and inner layer showed hydrophilicity. Cell assay confirmed cellular proliferation onto the scaffold, comparable with Integra. CONCLUSIONS: We demonstrate that a porous bilayered dermal scaffold could form the basis of a new generation of skin substitute that is both mechanically robust and harbors the ability for enhancing cell regeneration.

An anti-CD34 antibody-functionalized clinical-grade POSS-PCU nanocomposite polymer for cardiovascular stent coating applications: a preliminary assessment of endothelial progenitor cell capture and hemocompatibility.

In situ endothelialization of cardiovascular implants has emerged in recent years as an attractive means of targeting the persistent problems of thrombosis and intimal hyperplasia. This study aimed to investigate the efficacy of immobilizing anti-CD34 antibodies onto a POSS-PCU nanocomposite polymer surface to sequester endothelial progenitor cells (EPCs) from human blood, and to characterize the surface properties and hemocompatibility of this surface. Amine-functionalized fumed silica was used to covalently conjugate anti-CD34 to the polymer surface. Water contact angle, fluorescence microscopy, and scanning electron microscopy were used for surface characterization. Peripheral blood mononuclear cells (PBMCs) were seeded on modified and pristine POSS-PCU polymer films. After 7 days, adhered cells were immunostained for the expression of EPC and endothelial cell markers, and assessed for the formation of EPC colonies. Hemocompatibility was assessed by thromboelastography, and platelet activation and adhesion assays. The number of EPC colonies formed on anti-CD34-coated POSS-PCU surfaces was not significantly higher than that of POSS-PCU (5.0±1.0 vs. 1.7±0.6, p>0.05). However, antibody conjugation significantly improved hemocompatibility, as seen from the prolonged reaction and clotting times, decreased angle and maximum amplitude (p<0.05), as well as decreased platelet adhesion (76.8±7.8 vs. 8.4±0.7, p<0.05) and activation. Here, we demonstrate that POSS-PCU surface immobilized anti-CD34 antibodies selectively captured CD34+ cells from peripheral blood, although only a minority of these were EPCs. Nevertheless, antibody conjugation significantly improves the hemocompatibility of POSS-PCU, and should therefore continue to be explored in combination with other strategies to improve the specificity of EPC capture to promote in situ endothelialization.