Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

Impact of choice of volumetry software and nodule management guidelines on recall rates in lung cancer screening.

PURPOSE: Appropriate lung nodule management is essential to minimizing unnecessary patient recall in lung cancer screening. Two European guidelines provide differing recommendations in that participants with nodules ≥100 mm3 or ≥80 mm3 respectively should be recalled, at baseline. Nodule size estimation is known to vary between volumetry software packages (VSPs). The aim of this study was to examine the impact of choice of VSP on participant recall rates, when applying different European nodule management guidelines. An additional aim was to compare recall rates between 7 VSPs and manual diameter measurements. METHODS: 156 small-sized lung nodules (50-150 mm3) from the UK Lung Screening trial were measured using 7 different VSPs (VSP1-7) and also using manual diameter. The type of VSP used in the NELSON study (VSP1), on which European nodule management guidelines are based, provided the reference standard. Nodule size was compared using Bland Altman, and recall rates by Mcnemar's test. RESULTS: Compared to the reference standard, a 100 mm3 threshold for recall, resulted in no difference in recall rates only for VSP 5 & 7. Using an 80mm3 threshold resulted in no difference in recall rates for VSP2 & 6. Recall rates were significantly higher for VSP 4 regardless of threshold and when using manual diameter measurements. CONCLUSIONS: Appropriate nodule size thresholds for recall in screening depend on the type of volumetry software used. The results highlight the importance of benchmarking of volumetry packages.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Presentation of lung cancer in primary care.

Survival from lung cancer has seen only modest improvements in recent decades. Poor outcomes are linked to late presentation, yet early diagnosis can be challenging as lung cancer symptoms are common and non-specific. In this paper, we examine how lung cancer presents in primary care and review roles for primary care in reducing the burden from this disease. Reducing rates of smoking remains, by far, the key strategy, but primary care practitioners (PCPs) should also be pro-active in raising awareness of symptoms, ensuring lung cancer risk data are collected accurately and encouraging reluctant patients to present. PCPs should engage in service re-design and identify more streamlined diagnostic pathways-and more readily incorporate decision support into their consulting, based on validated lung cancer risk models. Finally, PCPs should ensure they are central to recruitment in future lung cancer screening programmes-they are uniquely placed to ensure the right people are targeted for risk-based screening programmes. We are now in an era where treatments can make a real difference in early-stage lung tumours, and genuine progress is being made in this devastating illness-full engagement of primary care is vital in effecting these improvements in outcomes.

Association between smoking and health outcomes in an economically deprived population: the Liverpool Lung Project.

BACKGROUND: The association between smoking and several health outcomes among those from the most deprived communities in the UK has not previously been detailed. The aim of this study is to examine the impact of smoking on health outcomes specifically among a particularly deprived population in a developed country (Liverpool; one of the most deprived local authorities in England). METHODS: The Liverpool Lung Project recruited a prospective cohort of 8753 participants from across Liverpool, aged 45-79 years between 1998 and 2008. Participants were followed annually through the Hospital Episode Statistics until 31 January 2013. Logistic regression models were used to identify health outcomes of smoking. RESULTS: From our study population, 5195 were smokers and 3558 were non-smokers. Smoking was associated with male gender (OR 1.62, 95% CI 1.48 to 1.77), pneumonia (1.28, 95% CI 1.10 to 1.49), chronic obstructive pulmonary disease (1.30, 95% CI 1.14 to 1.48), emphysema (5.46, 95% CI 3.48 to 8.55), bronchitis (1.85, 95% CI 1.65 to 2.07), other cancers (1.69, 95% CI 1.44 to 1.99), lung cancer (6.0, 95% CI 3.72 to 9.69), diabetes (1.21, 95% CI 1.02 to 1.43) and cardiovascular disease (1.45, 95% CI 1.25 to 1.67). CONCLUSIONS: Smokers from deprived backgrounds in Liverpool showed increased risk of developing pneumonia, emphysema, chronic obstructive pulmonary disease, bronchitis, lung cancer, other types of cancer, cardiovascular disease and diabetes. These findings are in line with the literature and may help to inform public health policies and ultimately work towards addressing smoking-related health inequalities.

Use of substitute Nonidet P-40 nonionic detergents in intracellular tubulin polymerization assays for screening of microtubule targeting agents.

Shell Chemical Company Nonidet P-40 has been used for decades in many biochemical assays as a nonionic, nondenaturing detergent; however, Shell no longer manufactures this product. Four commercially available substitutes were investigated and their activities titrated in an intracellular tubulin polymerization assay. Although claimed by the supply companies to be identical to the Shell Nonidet P-40, all four substitutes were about 10-fold more potent and needed to be diluted accordingly. As microtubule targeting drugs are a major class of anticancer agent, and many researchers use the intracellular tubulin polymerization assay, this information is important to help troubleshoot assay development with the new substitutes. As the Shell Nonidet P-40 has been used in many biochemical buffers, these results will be of general interest to the biochemical, cell, and molecular research community.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

CT screening for lung cancer: Is the evidence strong enough?

The prevailing questions at this time in both the public mind and the clinical establishment is, do we have sufficient evidence to implement lung cancer Computed Tomography (CT) screening in Europe? If not, what is outstanding? This review addresses the twelve major areas, which are critical to any decision to implement CT screening and where we need to assess whether we have sufficient evidence to proceed to a recommendation for implementation in Europe. The readiness level of these twelve categories in 2015 have been with colour coded, where green indicates we have sufficient evidence, amber is borderline evidence and red requires further evidence. Recruitment from the 'Hard to Reach' community still remains at red, while mortality data, cost effectiveness and screening interval are all categorised as amber. The integration of smoking cessation into CT screening programmes is still considered to be category amber. The US Preventive Services Task Force have recommended that CT screening is implemented in the USA utilising the NLST criteria, apart from continuing screening to 80 years of age. The cost effectiveness of the NLST was calculated to be $81,000/QALY, however, its well recognised that the costs of medical care in the USA, is far higher than that of Europe. Medicare have agreed to cover the cost of screening but have stipulated a number of stringent requirements for inclusion. To date we do not have good CT screening mortality data available in Europe and eagerly await the publication of the NELSON trial data in 2016 and then the pooled UKLS and NELSON data thereafter. However in the meantime we should start planning for implementation in Europe, especially in the areas of the radiological service provision and accreditation, as well as identifying novel mechanisms to recruit from the hardest to reach communities.

Surgeons' and trainees' perceived self-efficacy in operating theatre non-technical skills.

BACKGROUND: An important factor that may influence an individual's performance is self-efficacy, a personal judgement of capability to perform a particular task successfully. This prospective study explored newly qualified surgeons' and surgical trainees' self-efficacy in non-technical skills compared with their non-technical skills performance in simulated scenarios. METHODS: Participants undertook surgical scenarios challenging non-technical skills in two simulation sessions 6 weeks apart. Some participants attended a non-technical skills workshop between sessions. Participants completed pretraining and post-training surveys about their perceived self-efficacy in non-technical skills, which were analysed and compared with their performance in surgical scenarios in two simulation sessions. Change in performance between sessions was compared with any change in participants' perceived self-efficacy. RESULTS: There were 40 participants in all, 17 of whom attended the non-technical skills workshop. There was no significant difference in participants' self-efficacy regarding non-technical skills from the pretraining to the post-training survey. However, there was a tendency for participants with the highest reported self-efficacy to adjust their score downwards after training and for participants with the lowest self-efficacy to adjust their score upwards. Although there was significant improvement in non-technical skills performance from the first to second simulation sessions, a correlation between participants' self-efficacy and performance in scenarios in any of the comparisons was not found. CONCLUSION: The results suggest that new surgeons and surgical trainees have poor insight into their non-technical skills. Although it was not possible to correlate participants' self-belief in their abilities directly with their performance in a simulation, in general they became more critical in appraisal of their abilities as a result of the intervention.

Using the STarT Back Tool: Does timing of stratification matter?

It is likely that individuals with nonspecific LBP (nsLBP) constitute a heterogenic group and targeting treatment appropriately to those most likely to respond is of major relevance. The STarT Back Tool (SBT) has been developed to stratify patients into risk groups to aid management choices. However, there is controversy over its generalisability and uncertainty as to the timing of use. This study investigated whether SBT categorisation early in a course of treatment would prove more prognostic than categorising patients at baseline. Seven hundred and forty nine patients over the age of 16 were recruited at 11 chiropractic clinics within the UK. The SBT was used to categorise these patients at presentation and 2 days following initial treatment with patient characteristics and condition specific markers also collected at baseline. The primary outcome was the Patient Global Impression of Change (PGIC) collected at 14, 30 and 90 days following the initial visit. In this population undergoing chiropractic care, patients had similar outcomes irrespective of their STarT back risk ranking. Multivariate prognostic models included only the post initial visit SBT as an independent predictor of favourable outcome for the medium risk group but only at 30 days. Follow up improvement was dominated by previous improvement in 30 and 90-day models. Over one third of patients swapped SBT risk groups in the 2 day period between initial stratification and post initial visit although there was little difference in eventual improvement at follow-up. Understanding the impact of timing of SBT stratification is indicated.

Unique volatolomic signatures of TP53 and KRAS in lung cells.

BACKGROUND: Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRAS(V12) mutation, knockdown of TP53 or both with parental HBEC cells. METHODS: VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS) or sensor array with discriminant factor analysis (DFA). RESULTS: In TD-GC-MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80-100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%. CONCLUSIONS: Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC-MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

Translation of research results to simple estimates of the likely effect of a lung cancer screening programme in the United Kingdom.

BACKGROUND: There is considerable interest in the possibility of provision of lung cancer screening services in many developed countries. There is, however, no consensus on the target population or optimal screening regimen. METHODS: In this paper, we demonstrate the use of published results on lung cancer screening and natural history parameters to estimate the likely effects of annual and biennial screening programmes in different risk populations, in terms of deaths prevented and of human costs, including screening episodes, further investigation rates and overdiagnosis. RESULTS: Annual screening with the UK Lung Screening Study eligibility criteria was estimated to result in 956 lung cancer deaths prevented and 457 overdiagnosed cancers from 330,000 screening episodes. Biennial screening would result in 802 lung cancer deaths prevented and 383 overdiagnosed cancers for 180,000 screening episodes. INTERPRETATION/CONCLUSION: The predictions suggest that the intervention effect could justify the human costs. The evidence base for low-dose CT screening for lung cancer pertains almost entirely to annual screening. The benefit of biennial screening is subject to additional uncertainty but the issue merits further empirical research.

A new laboratory-based surveillance system (Respiratory DataMart System) for influenza and other respiratory viruses in England: results and experience from 2009 to 2012.

During the 2009 influenza A(H1N1) pandemic, a new laboratory-based virological sentinel surveillance system, the Respiratory DataMart System (RDMS), was established in a network of 14 Health Protection Agency (now Public Health England (PHE)) and National Health Service (NHS) laboratories in England. Laboratory results (both positive and negative) were systematically collected from all routinely tested clinical respiratory samples for a range of respiratory viruses including influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza virus, adenovirus and human metapneumovirus (hMPV). The RDMS also monitored the occurrence of antiviral resistance of influenza viruses. Data from the RDMS for the 2009­2012 period showed that the 2009 pandemic influenza virus caused three waves of activity with different intensities during the pandemic and post pandemic periods. Peaks in influenza A(H1N1)pdm09 positivity (defined as number of positive samples per total number of samples tested) were seen in summer and autumn in 2009, with slightly higher peak positivity observed in the first post-pandemic season in 2010/2011. The influenza A(H1N1)pdm09 virus strain almost completely disappeared in the second postpandemic season in 2011/2012. The RDMS findings are consistent with other existing community-based virological and clinical surveillance systems. With a large sample size, this new system provides a robust supplementary mechanism, through the collection of routinely available laboratory data at minimum extra cost, to monitor influenza as well as other respiratory virus activity. A near real-time, daily reporting mechanism in the RDMS was established during the London 2012 Olympic and Paralympic Games. Furthermore, this system can be quickly adapted and used to monitor future influenza pandemics and other major outbreaks of respiratory infectious disease, including novel pathogens.

A systematic review of the characteristics associated with recall rates, detection rates and positive predictive values of computed tomography screening for lung cancer.

BACKGROUND: Low-dose computed tomography (LDCT) screening has been shown to reduce mortality from lung cancer but at a substantial cost in diagnostic activity. The objective of this study was to investigate the characteristics of screening programmes associated with recall rates, detection rates and positive predictive values (PPVs). DESIGN: We conducted a systematic review of randomised trials and observational studies on LDCT screening for lung cancer. A meta-regression using random-effect logistic regressions was carried out to assess factors influencing recall rates for further investigation, cancer detection rates and PPVs of recall. RESULTS: We used data from 63 372 prevalent screens from 16 studies of LDCT screening for lung cancer and 79 302 incident screens from nine studies. In univariable analysis, the use of a cut-off size to define nodules warranting further investigation at prevalent screens reduced recall rates [odds ratio (OR) = 0.44, 95% confidence interval (CI) 0.24-0.82 and OR = 0.42, 95% CI 0.21-0.84 for cut-off sizes of 3-4 and 5-8 mm, respectively], without significant changes in detection rates and PPVs. The number of readers (1 or ≥2) was not associated with changes in recall rates, detection rates and PPVs at prevalent and incident screens. Using the volumetry software at incident screens significantly increased the PPV (OR = 5.02, 95% CI 1.65-15.28) as a result of a decrease in recall rates (OR = 0.25, 95% CI 0.12-0.51), without significant changes in detection rates. CONCLUSION: These results highlight the value of using a cut-off size for nodules warranting further investigation with lower recall rates at prevalent screens, whereas the volumetric assessment software at incident screens results in lower recall rates and higher PPVs. The presence of positron emission tomography in the work-up protocol might be associated with lower rates of surgical procedures for benign findings, although this hypothesis deserves further investigation.

A microRNA-based prediction algorithm for diagnosis of non-small lung cell carcinoma in minimal biopsy material.

BACKGROUND: Diagnosis is jeopardised when limited biopsy material is available or histological quality compromised. Here we developed and validated a prediction algorithm based on microRNA (miRNA) expression that can assist clinical diagnosis of lung cancer in minimal biopsy material to improve clinical management. METHODS: Discovery utilised Taqman Low Density Arrays (754 miRNAs) in 20 non-small cell lung cancer (NSCLC) tumour/normal pairs. In an independent set of 40 NSCLC patients, 28 miRNA targets were validated using qRT-PCR. A prediction algorithm based on eight miRNA targets was validated blindly in a third independent set of 47 NSCLC patients. The panel was also tested in formalin-fixed paraffin-embedded (FFPE) specimens from 20 NSCLC patients. The genomic methylation status of highly deregulated miRNAs was investigated by pyrosequencing. RESULTS: In the final, frozen validation set the panel had very high sensitivity (97.5%), specificity (96.3%) and ROC-AUC (0.99, P=10(-15)). The panel provided 100% sensitivity and 95% specificity in FFPE tissue (ROC-AUC=0.97 (P=10(-6))). DNA methylation abnormalities contribute little to the deregulation of the miRNAs tested. CONCLUSION: The developed prediction algorithm is a valuable potential biomarker for assisting lung cancer diagnosis in minimal biopsy material. A prospective validation is required to measure the enhancement of diagnostic accuracy of our current clinical practice.

Outcomes of oral squamous cell carcinoma arising from oral epithelial dysplasia: rationale for monitoring premalignant oral lesions in a multidisciplinary clinic.

Surveillance of oral epithelial dysplasia results in a number of newly diagnosed cases of oral squamous cell carcinoma (SCC). The clinical stage of oral SCC at diagnosis influences the magnitude of treatment required and the prognosis. We aimed to document the stage, treatment, and outcome of oral SCC that arose in patients who were being monitored for oral epithelial dysplasia in a dedicated multidisciplinary clinic. Those with histologically diagnosed lesions were enrolled on an ethically approved protocol and molecular biomarker study. Details of clinical and pathological TNM, operation, radiotherapy, recurrence, second primary tumour, and prognosis, were recorded in patients whose lesions underwent malignant transformation. Of the 91 patients reviewed (median follow-up 48 months, IQR 18-96), 23 (25%) had malignant transformation. All were presented to the multidisciplinary team with stage 1 disease (cT1N0M0). Of these, 21 were initially treated by wide local excision, 2 required resection of tumour and reconstruction, and 2 required adjuvant radiotherapy. At follow-up 3 had local recurrence, one had regional recurrence, one had metachronous lung cancer, and 5 had second primary oral SCC. There were further diagnoses of oral dysplasia in 5 during follow-up, and it is estimated that 76% of patients will have one or other event in 5 years. Disease-specific survival was 100% and overall survival was 96% (22/23). Median follow-up after diagnosis of oral SCC was 24 months (IQR 11-58). Specialist monitoring of oral epithelial dysplasia by a multidisciplinary team allows oral SCC to be detected at an early stage, and enables largely curative treatment with simple and usually minor surgical intervention. The high incidence of second primary oral SCC in high-risk patients with oral epithelial dysplasia further supports intensive targeted surveillance in this group.