Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Azatriseptanes: Strained Framework Analogs of [7,7,7]Circulenes.

Invited for the cover of this issue is the group of Michel Rickhaus at the University of Zurich. The image depicts the "unearthing" of the highly contorted azatriseptane, a carbon framework consisting of three fused seven-membered rings surrounding a central nitrogen. Read the full text of the article at 10.1002/chem.202203954.

Azatriseptanes: Strained Framework Analogs of [7,7,7]Circulenes.

The synthesis and characterization of heptagon-embedded polycyclic aromatic compounds are essential for understanding the effect of negative curvature on carbon allotropes such as fullerenes and graphenes that have applications in functional organic materials. However, owing to the synthetic difficulties in functionalizing and embedding seven-membered rings, these strain-challenged structures are relatively unexplored. We report here the synthesis, characterization, and properties of a triarylamine core bridged with ethano chains at the 2,2'-positions. In doing so, we provide access to the first heterocycle containing three fused heptagon rings with a nitrogen at its core (BATA-NHAc). X-ray crystallographic analysis and DFT calculations revealed a remarkably strained structure wherein two of the bridged aryl units approach coplanarity, while the third ring is twisted out of plane at 70°. UV-vis and emission spectroscopies identify red-shifted absorption and concentration-dependent emission profiles, respectively, as a result of the unique conformation and self-assembly properties of BATA-NHAc. Furthermore, cyclic voltammetry shows a decrease in the oxidation potential for BATA-NHAc in comparison to the non-bridged analog. This study opens new avenues in understanding the structure-property relationships of curved π-aromatics and the construction of π-frameworks of increasing complexity.

Patient advocacy group involvement in health technology assessments: an observational study.

BACKGROUND: In some jurisdictions, patients and patient groups may be invited to provide input when Health Technology Assessment (HTA) is used to inform decisions about which medicines should be subsidised or funded. This input can help frame the evidence from a patient perspective, address uncertainties in the evidence and interpret it for the local setting. However, there is currently no evidence linking patient involvement with positive reimbursement decisions. AIM: We aimed to understand the expectations of patient involvement in the reimbursement process, especially among cancer patient advocacy groups (PAGs) in New Zealand (Aotearoa), South Korea and Taiwan. METHODS: We developed an online survey to help understand the role that cancer PAGs play in reimbursement processes and identify knowledge gaps about the processes that might impact the efforts of PAGs. The survey elicited the views of staff and patients affiliated with PAGs (n = 43) on current practices and how the assessment and reimbursement of new cancer drugs might be improved. RESULTS: There was variability in knowledge of the HTA assessment processes and in experience of being involved in them. Those with HTA experience were more likely to have confidence in the process. Those who had not been involved tended to have little awareness of, or frustration with, decision-making processes. Most identified cost, finances and economic assessments as key considerations in current processes. Some respondents had clear ideas about how their knowledge and involvement could improve processes to determine the value of new medicines. However, for many, a lack of information about the basis for decision making and opportunities to be involved was a barrier to identifying process improvement. CONCLUSIONS: HTA is implemented primarily in countries seeking to have fair and equitable processes for funding medicines. PAGs often recognise the financial challenges of funding new medicines and share the desire for procedural fairness. The connection PAGs make between patient involvement and improved access to new medicines may be based on the belief they can add information to the evidence base, help solve problems, ensure fairness through transparency and/or influence the culture towards increased access to medicines they value.

WHAT ARE HEALTH TECHNOLOGY ASSESSMENTS?: Health technologies are medicines, devices and services used to prevent, diagnose or treat medical conditions. A Health Technology Assessment (HTA) considers the value of a health technology to help governments make fair decisions about which treatments to fund or subsidise. Patients and Patient Advocacy Groups (PAGs) may be invited to provide input into this process. WHAT DID OUR STUDY LOOK AT?: We surveyed staff and patients from cancer PAGs in New Zealand (Aotearoa), South Korea and Taiwan to understand their experiences and expectations of involving patients in HTA. A total of 43 people completed our survey. WHAT WERE THE RESULTS?: Overall, 20 of the 43 surveyed people (47%) were aware of the assessment process used to decide which medicines were funded in their country. (27 of these 50 people were PAG staff members.) Patients from South Korea and New Zealand were rarely included in the assessment process. Patient involvement was more commonly reported in Taiwan. The impact of input from patients on HTA was rated low by patients in both South Korea and New Zealand and average in Taiwan. A general lack of transparency, feedback on the process, and support from assessment agencies was also reported. Many of the patients surveyed wanted to see more patient involvement in the assessment processes. WHAT IS THE MAIN TAKE-HOME MESSAGE FROM THIS STUDY?: With improved guidance and feedback from assessment agencies, PAGs and patients believe their involvement can improve decision making on treatment funding and increase fairness through transparency.

The validity of a clinical test for the diagnosis of lumbar spinal stenosis.

BACKGROUND: The diagnosis and management of acquired lumbar spinal stenosis (ALSS) is an area of growing interest with an increase in its prevalence and detection in the older population. OBJECTIVES: To investigate the diagnostic accuracy of a modified extension test (MExT) for diagnosing ALSS in subjects aged fifty or over. METHODS: Symptomatic response of the bi-component MExT was evaluated and compared against magnetic resonance imaging (MRI) findings in 30 subjects. Estimates of sensitivity, specificity, likelihood ratios (LRs) and post-test probabilities were all calculated, and the capability of the test to discriminate between grade and location of stenosis was also appraised. RESULTS: MExT sensitivity was high at 92% (95% confidence intervals (CI), 72-99%) leading to a significant negative likelihood ratio at -LR 0.2 (95% CI, 0.03-1.36); conversely, specificity was low at 40% (95% CI, 7-82%) with only a small positive likelihood ratio of +LR 1.53 (95% CI, 0.74-3.16). All correlations between the MExT and concurrent grade, or location of stenosis appeared weak and insignificant. CONCLUSIONS: The MExT was found to demonstrate acceptable criterion validity in relation to ruling-out a diagnosis when a negative result was observed; however, further validation appears warranted.