Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a ...molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.
Sex is an essential biological variable that influences the development, progression and response to treatment in cancer. Despite this, early-phase cancer clinical trials frequently neglect to ...consider sex as a variable, creating a barrier to the development of personalised medicine. This article argues that failure to identify and infer sex differences in early-phase clinical trials may result in suboptimal dosing, underestimation of toxicity, and the failure to identify potential sex-specific responses to new systemic anticancer therapies. There should be a greater focus on sex as a biological variable in drug development so that thoughtful and deliberate study design can bring precision to the development of new systemic cancer therapies.
Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are ...inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.
Our aim was to develop a validated Patient Reported Experience Measure (PREM) to capture patient and carer experience during participation in experimental cancer medicine trials (ECM): called ...PREM-ECM.
Mixed method design, consisting of four stages. Questionnaire items were produced for both patients and carers using interviews, focus groups, and cognitive interviews with patients and carers separately. For both patient and carer PREMs, a cross-sectional questionnaire study was conducted to identify final items for inclusion using hierarchical item reduction and Rasch analysis. Questionnaire validity and reliability were assessed, including administration feasibility.
Initial interview participants suggested the need for three PREMs, two specific to patients: (i) a 'prior' questionnaire that captured experiences of trial introduction, screening, consenting, and early trial experience (< 6 weeks post consent); and (ii) 'on-trial' that captured experiences of ongoing consent and trial participation; and (iii) a PREM specific for carers. The draft 25-item 'prior' questionnaire was completed by 162 patients and 162 patients completed the draft 35-item 'on-trial' questionnaire. Hierarchical and Rasch analysis produced a 14-item 'prior' list and a 15-item list for 'on-trial'. Both patient PREM's demonstrated a good fit to the Rasch model following Bonferroni correction (X
p = 0.008). The carer 34-draft item questionnaire was completed by 102 participants. Hierarchical and Rasch analysis produced a 13-item list for PREM-ECM-Carer, with good fit to the Rasch model ( X
p = 0.62). The pilot testing demonstrated the feasibility of all the PREMs in capturing patient and caregiver experiences in routine clinical settings.
The three PREM-ECM questionnaires will be the first validated experience measures for ECM trial patients and their carers. These questionnaires may be used to assess patients' and their carers' experiences of ECM and enable robust comparisons across cancer trial units highlighting areas for service improvement.
Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined ...by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.
Developing country vaccine manufacturers (DCVMs) supply over half of the vaccines used in developing country immunisation programs. Decisions by developing countries to establish vaccine ...manufacturing should be based on economic viability, however reliable assessments of vaccine production costs are lacking. This study aimed to quantify the cost of establishing vaccine manufacturing facilities and producing vaccines in developing countries.
This study estimates vaccine production costs in developing countries based on twelve vaccines produced by eight DCVMs. The results were based on estimates of the capital and operating costs required to establish vaccine manufacturing facilities under three hypothetical scenarios of production scale and scope. Cost patterns were then compared to vaccine prices paid by countries in both industrialized and developing country markets.
The cost of producing vaccines in developing countries was estimated to be on average US$ 2.18 per dose, ranging between US$ 0.98 and US$ 4.85 for different vaccine types and formulations. Vaccine costs-per-dose decrease as production scale and scope increase. Cost-per-dose is mainly driven by fixed costs, but at a scale of production over 20 million doses per year it becomes driven by variable costs. Under the three hypothetical scenarios used, costs-per-dose of vaccines produced by developing countries were around 47% lower than vaccine prices in developing-country markets and 84% lower than prices in industrialized-country markets.
This study has found that local production of vaccines in developing countries exhibits both economies of scale and economies of scope. The lower costs relative to prices suggests that a producer surplus and potential profits may be attainable in both developing and developed country markets, supporting sustainable production.
Small cell lung cancer (SCLC) has a particularly poor prognosis despite the high initial response to first-line systemic therapy, and there is a well-recognised lack of meaningful treatments beyond ...the second line. A number of reasons have been put forward to explain this, including a lack of common, easily-druggable genetic mutations in SCLC and rarity of high-quality tissue samples due to late presentation. Liquid biopsies, including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are increasingly used as surrogates for tumour tissue and have the advantage of being easily obtained serially to inform on the biology of disease progression and acquired chemoresistance, and may provide a pathway to improve care in this notoriously refractory disease. Here we discuss the current evidence behind these liquid biopsy methods in SCLC, and how they could be employed in future clinical care.
BackgroundAs doctors, we are increasingly aware of the financial implications of our practice. The need to work in a more conscientious, efficacious and cost-effective manner is greater than ever ...before. Environmental and financial benefits can be seen through employing the use of low-flow anaesthesia.AimsThis quality improvement project aimed to make anaesthetic practice more environmentally friendly and to reduce departmental spending. This could be achieved by promoting the use of low-flow anaesthesia and by encouraging isoflurane use where appropriate.MethodsAll anaesthetic consultants and trainees were invited to fill out an initial questionnaire relating to their personal preferences and practices when conducting anaesthesia. There were specific questions relating to low-flow anaesthesia and isoflurane use. Our main measure of improvement was any decrease in the number of bottles of volatile agent ordered by the department from pharmacy. Monthly spot audits were conducted to assess gas flow rates and volatile agent use in theatre. Departmental spending figures relating to the purchase of volatile agent bottles were obtained from pharmacy. Information was then disseminated to anaesthetists on a monthly basis via a ‘low-flow board’, which showed pictorial and graphical representations of differing gas flows and volatile agent usage in relation to cost.ResultsOur project showed a trend for the increased use of low-flow anaesthesia within the department. We also showed a decrease in the number of bottles of volatile agent ordered: 18% fewer bottles ordered compared with the same period the previous year. This represented a 25% decrease in total departmental expenditure on volatile agents despite an increase in theatre activity.ConclusionIncreasing awareness regarding anaesthetic choices and promoting low-flow anaesthesia and isoflurane use, translated into an overall decreased departmental spend on volatile agents without affecting patient care.
ObjectivesThe study aimed to explore patients’ experiences of experimental cancer medicine (ECM) clinical trials.DesignThe study’s design was qualitative. Two focus groups with patients were ...undertaken followed by semistructured interviews, to explore patients’ experiences of ECM clinical trials. Interviews and focus groups were audiorecorded and transcribed verbatim. Data were analysed using thematic analysis.SettingA regional cancer centre (tertiary care) in North-West England.ParticipantsTwelve patients (aged 52–79) participated in one of the two focus groups and 22 patients (aged 42–83) participated in interviews.Primary outcome measurePatients’ experiences of an ECM trial.ResultsFour main themes were identified from the analysis: decision making, information needs, the experience of trial participation and impact of trial participation. Subthemes are presented in the manuscript.ConclusionTo make fully informed decisions about trial participation, patients required the simplification of trial information and wanted more information about side effects, their response to trial treatment and the overall trial progress throughout the trial. Patients highlighted the need for improvement for the support provided to their family and friends.
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