Introduction Pleural mesothelioma (PM) is often presaged by benign asbestos-associated pleural inflammation (AAPI), offering a unique window of opportunity for translational research. The PREDICT-Meso International Accelerator Network is leveraging this natural history to perform target identification and develop novel therapies for early-stage or pre-invasive disease. This requires assembly of a unique bioresource of longitudinal human tissue samples spanning the terminal stages of PM evolution, development of preclinical models for drug screening and reliable tools for risk prediction in patients presenting with AAPI.Methods and analysis Mesothelioma Observational study of Risk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy (Meso-ORIGINS) is a prospective, multicentre observational study, comprising two arms (A and B), with a nested MRI substudy in arm A. Arm A will recruit 300 AAPI patients and perform 6-monthly surveillance for 2 years. Suspicion of PM evolution will prompt repeat biopsy and banking, delivering a primary objective of ≥38 longitudinal AAPI-PM tissue pairs. This target reflects a projected PM evolution rate of 14% (95% CI 10.5 to 19.2) derived from a prior multicentre feasibility trial. Multiomic risk profiling will be performed in arm A, using blood proteomics, exhaled breath metabolomics and perfusion MRI. Arm B will recruit 300 patients with suspected PM, permitting collection of multiregion pleural biopsies in patients spanning AAPI and PM timepoints for evaluation of anatomical heterogeneity. Where possible, patients in arm B diagnosed with AAPI will be recruited to arm A for 2-year surveillance +/− repeat biopsy in subsequent PM evolution cases. Pleural fluid will be collected in arm B for cell-line generation and diagnostic biomarker evaluation. Exhaled breath will be collected in arm B for diagnostic biomarker evaluation.Ethics and dissemination The study has ethical approval (REC Ref 21/WS/0120). Results will be disseminated via peer-reviewed journals and national/international scientific conferences. Tissues, data and derived omics will be shared via the PREDICT-Meso Research Tissue Bank (REC Ref 21/WS/0011).Trial registration number ISRCTN22929761.

BACKGROUND:Bronchopulmonary carcinoids (BPCs) are classified into typical carcinoids (TC) and atypical carcinoids (AC), based on the mitotic count and absence/presence of necrosis on pathology specimens. There are limitations to accurate measurement of these criteria. It important to study other markers like Ki-67, to enhance the diagnostic accuracy of lung carcinoids. OBJECTIVE AND METHODOLOGY:Retrospective analysis of BPCs treated with surgery between 2012-2022, to examine the accuracy of Ki-67 on the diagnostic specimen, concordance of diagnostic and resection specimens, diagnostic accuracy of Positron Emission Tomography (PET) and concordance of clinical and pathological staging. RESULTS:205 patients were included in the analysis (final diagnosis TC 180, AC 25). Mean age 60.5 years and 68 % female. Ki-67 (<5% vs. 5-30 %) on diagnostic biopsy, available in 64 % (n = 131) of the cohort, had specificity (diagnose TC correctly) of 89.4 % (95 %CI 80.4 %-94.7 %) and sensitivity (diagnose AC correctly) of 77.8 % (40.2 %-96.1 %). This compared to 97.5 % (90.3 %-99.6 %) and 36.4 % (12.4 %-68.4 %) for mitotic count (<2mitoses/2mm2 vs. 2-10mitoses/2mm2) and 100 % (94.4 %-100 %) and 21.4 % (5.7 %-51.2 %) for necrosis (absence vs. presence). A pre-resection diagnosis of TC (including surgical biopsy) shows better concordance with final diagnosis on resection specimen (94.9 %, 95 %CI 88.7 %-97.9 %, n = 117) as compared to the diagnosis of AC 83.3 % (95 %CI 50.9 %-97.1 %, n = 12). Concordance for AC appears higher with image guided lung biopsy 80 % (95 % CI, 29.9 %-98.9 %) than bronchoscopy 50 % (9.5 %-90.5 %). SUVmax on 18FDG-PET was a modest predictor of BPC sub-type with an AUC of 0.684 (95 % CI: 0.545,0.823). The clinical and pathological staging were concordant in 46 % (85/184) cases. However, 27 % (50/184) were upstaged and 13 % (23/172) found to have occult nodal metastases on pathology review of the surgical specimens. CONCLUSION:The diagnosis and sub-typing of BPCs on diagnostic specimens is challenging. Our data suggest Ki-67 could increase diagnostic accuracy, but further research is needed to confirm this.

Introduction Although lung cancer screening is being implemented in the UK, there is uncertainty about the optimal invitation strategy. Here, we report participation in a community screening programme following a population-based invitation approach, examine factors associated with participation, and compare outcomes with hypothetical targeted invitations. Methods Letters were sent to all individuals (age 55–80) registered with a general practice (n=35 practices) in North and East Manchester, inviting ever-smokers to attend a Lung Health Check (LHC). Attendees at higher risk (PLCO m2012NoRace score≥1.5%) were offered two rounds of annual low-dose CT screening. Primary care recorded smoking codes (live and historical) were used to model hypothetical targeted invitation approaches for comparison. Results Letters were sent to 35 899 individuals, 71% from the most socioeconomically deprived quintile. Estimated response rate in ever-smokers was 49%; a lower response rate was associated with younger age, male sex, and primary care recorded current smoking status ( adj OR 0.55 (95% CI 0.52 to 0.58), p<0.001). 83% of eligible respondents attended an LHC (n=8887/10 708). 51% were eligible for screening (n=4540/8887) of whom 98% had a baseline scan (n=4468/4540). Screening adherence was 83% (n=3488/4199) and lung cancer detection 3.2% (n=144) over 2 rounds. Modelled targeted approaches required 32%–48% fewer invitations, identified 94.6%–99.3% individuals eligible for screening, and included 97.1%–98.6% of screen-detected lung cancers. Discussion Using a population-based invitation strategy, in an area of high socioeconomic deprivation, is effective and may increase screening accessibility. Due to limitations in primary care records, targeted approaches should incorporate historical smoking codes and individuals with absent smoking records.

Introduction: Single-station N2 (ssN2) versus multi-station N2 has been used as a selection criterion for treatment recommendations between surgical versus non-surgical multimodality treatment in stage III-N2 NSCLC. We hypothesized that clinical staging would be susceptible to upstaging on pathologic staging and, therefore, challenge this practice. Methods: A retrospective study of prospectively collected routine clinical data for patients with stage III-N2 NSCLC that had completed computed tomography (CT), positron emission tomography (PET), and staging endobronchial ultrasound (EBUS) and had been confirmed clinical stage III-ssN2 at multidisciplinary team discussion and went on to complete surgical resection as the first treatment to provide pathologic staging. The study was completed in two cohorts (A) across a single cancer alliance in England (Greater Manchester) January 1, 2015 to December 31, 2018 and (B) across five United Kingdom centers to validate the findings in part A January 1, 2016 to December 31, 2020. Results: A total of 115 patients met the inclusion criteria across cohort A (56 patients) and cohort B (59 patients) across 15 United Kingdom hospitals. The proportion of cases in which clinical stage III-ssN2 was upstaged to pathologic stage III-multi-station N2 was 34% (19 of 56) in cohort A, 32% in cohort B (19 of 59), and 33% across the combined study cohort (38 of 115). Most patients had a single radiologically abnormal lymph node on CT and PET (88%, 105 of 115). In the majority, the reasons for missed N2 disease on staging EBUS were due to inaccessible (stations 5, 6, 8, 9) N2 nodes at EBUS (34%, 13 of 38) and accessible lymph nodes not sampled during staging EBUS as not meeting sampling threshold (40%, 15 of 38) rather than false-negative sampling during EBUS (26%, 10 of 38). Conclusions: During multidisciplinary team discussions, clinicians must be aware that one-third of patients with stage III-ssN2 on the basis of CT, PET, and staging EBUS do not truly have ssN2 and this questions the use of this criterion to define treatment recommendations.

Circulating tumour DNA (ctDNA) can be detected in peripheral blood of cancer patients and tested for genomic alterations and could support the delivery of the Lung Cancer Optimal Pathway (LCOP).

Introduction On the back of recent randomised trials, there has been a paradigm shift in the management of primary spontaneous pneumothorax (PSP), towards conservative and ambulatory treatment options. Due to the clinical equipoise between different options, it is important that patients are actively involved in the management plan and have appropriate information resources available at the time to aid decision making. It is important to ensure patients are involved in the production of such information resources – Patient and Public Involvement and Engagement (PPIE). Therefore, the aim of this project was to co-produce patient information resource on PSP and related treatment options. Methods Pleural physicians and nursing staff from Manchester University NHS Foundation Trust and University Hospital of North Midlands NHS Trust worked in collaboration with the West Midlands Academic Health Science Network (WMAHSN) and NHS England Accelerated Access Collaborative (AAC). The initial draft leaflet was discussed with patients from both hospital sites via a focus group and online survey for those who could not attend; the feedback was then used to revise the leaflet. For greater utility across diverse patient populations, leaflet has been translated into Urdu, Arabic, Polish and Romanian as well as Easy Read format. These languages are a combination of the most commonly requested via interpreter services in the two Trusts. The key information from the leaflet was then used to produce an animated video. This involved scriptwriting, story-boarding, character design, background theme and voice over. Results The final product of this piece of work is co-produced patient information leaflets in multiple languages and Easy Read format, as well a 2-minute video animation exploring definitions, aetiology, symptoms, investigations and management options. All the resources are available for free for patients to access on the WMAHSN website (via the QR code). The leaflets can be viewed online or printed. Conclusion We successfully produced an online resource to help patients, who present to the hospital with primary spontaneous pneumothorax, to gain better understanding and aid decision making with support from treating clinicians.

Introduction: The PREDICT-Meso Accelerator Network (35 institutions, 8 countries) aims to define the biology driving malignant pleural mesothelioma (MPM) evolution and develop targeted therapies. We provide an update on Meso-ORIGINS (MO), the primary vehicle for prospective tissue collection and risk prediction. Aims: MO will generate a longitudinal cohort of patients with asbestos associated pleural inflammation (AAPI). The primary objective is to generate ≥ 63 benign-MPM tissue pairs (projected evolution rate 14% (95% CI 10.5-19.2) based on a prior feasibility trial). Secondary objectives are (a) generation of a multiomic risk prediction model (b) characterisation of intra-patient heterogeneity using multi-region thoracoscopic biopsies. Methods: Arm A will recruit 500 AAPI patients and perform 6-monthly surveillance for 2 yrs. Suspicion of MPM evolution will prompt repeat pleural biopsy and banking. Arm A includes baseline risk profiling via serum proteomics, exhaled breath metabolomics +/- perfusion MRI. Arm B will address heterogeneity by recruiting patients with suspected MPM undergoing thoracoscopy (n=39) Results: MO opened in July 2022 (planned 3.5yr recruitment). At submission, 17 UK centres are open (9 in setup). 37/500 and 26/39 patients have been recruited to Arms A and B, respectively. 2/30 Arm A cases with ≥ 1-month follow-up have evolved into MPM, making the current evolution rate 6.7% (95% CI 0.7-22.4). 5/26 Arm B cases have a confirmed MPM diagnosis with a mean (SD) of 5.2 (0.8) multi-region biopsies collected. Conclusions: MO is collecting paired tissues that are critical for downstream PREDICT-Meso work packages focused on target identification, pre-clinical models and drug development.

Introduction: Stage III/N2 Non-small cell lung cancer (NSCLC) is a complex disease with multi-modality therapeutic options. UK practice emphasizes the presence of single station N2 (ssN2) vs multi-station N2 disease (msN2) to determine treatment. A pilot study in Manchester, found 34% of patients with pre-operative ssN2 disease (based on CT, PET-CT and EBUS) were upstaged at pathological sampling (Craig, C. et al. Lung cancer, v156, S23). This study aims to investigate this correlation across multiple centres. Methods: We conducted a retrospective analysis across 6 UK sites over a 5-year period (01/01/2016-31/12/2020). Data was collected from patients with T1-4N2M0 NSCLC, who had pre-operative staging (CT, PET and EBUS-TBNA) and an MDT diagnosis of ssN2, who underwent surgical resection. Clinical and pathological staging was compared to describe the diagnostic accuracy of pre-operative staging. Statistical analysis was performed on variables between the 2 groups. Results: 59 patients were recruited, 19 (32%) had pathological staging of msN2. 37% of these patients had no evidence of N2 nodes on CT but 89% had a PET stage of ssN2. In the false ssN2: 58% had nodes not sampled due to EBUS characteristics and size, 4 were due to negative EBUS sampling and 4 due to inaccessible nodes. There was no statistically significant difference in tumour sub-typing, location, size or PET-SUV between the 2 groups. Median time from EBUS to surgery was 33 days. Conclusion: In stage III-N2 disease, pre-operative staging is unreliable at distinguishing between ssN2 and msN2 when compared to pathological stage. This should provide caution for centres which rely on this distinction to define treatment.

Introduction Greater Manchester (GM) has implemented a standardised, risk-stratified follow-up protocol after surgical resection of lung cancer (LNC-PATH protocol) which de-intensifies surveillance in low-risk patients and intensifies surveillance in high-risk patients.1 This evaluation assessed the clinical effectiveness of this protocol. Methods A prospective analysis of the LNC-PATH protocol at a single centre physician-led survivorship service. Clinical effectiveness was assessed by the overall proportion of disease recurrences, proportion of disease recurrences detected through the standardised protocol, the pattern of disease recurrence and the subsequent treatment delivered stratified by risk category in the period between 01/01/2016 and 31/12/2019. We also analysed the site of disease recurrence identified outside the protocol. Results 250 patients under risk stratified surveillance in the study period; 70% (176/250) of patients were low-risk, 22% (54/250) moderate-risk and 8% (20/250) high-risk (table 1). Overall, 15% (38/250) of patients were diagnosed with disease recurrence within the first two years of surgical resection; 8% (14/176) in the low-risk, 24% (13/54) in the moderate-risk and 55% in the high-risk group (11/20). The LNC-PATH protocol identified 71% (27/38) of disease recurrences through routine surveillance; 57% (8/14) in the low-risk, 69% (9/13) in the moderate-risk and 91% (10/11) in the high-risk groups. 56% (15/27) of patients with disease recurrence detected via LNC-PATH had isolated local or thoracic lymph node recurrence. A total of 56% (15/27) patients underwent curative-intent treatment of disease recurrence and 78% (21/27) of patients underwent any treatment for anti-cancer therapy. In the 11 patients (6/11, 4/11 and 1/11 in low, moderate and high-risk groups respectively) that presented with symptomatic disease recurrence outside of the LNC-PATH protocol, 55% (6/11) were intra-cranial recurrence and 45% (5/11) were visible on a CT chest and upper abdomen. Discussion The LNC-PATH protocol appears to accurately stratify patients into different categories of risk for disease recurrence allowing an appropriate de-intensification or intensification of surveillance and maximising the efficiency of healthcare utilisation. The protocol also appears to identify a high proportion of disease recurrence prior to symptomatic onset and facilitates access to anti-cancer treatment including curative-intent treatment. Reference https://gmcancer.org.uk/wp-content/uploads/2021/10/greater-manchester-risk-stratified-follow-up-after-lung-cancer-surgery-p....pdf

Lung cancer remains the most significant cause of cancer death, accounting for about 20% of all cancer-related mortality. A significant reason for this is delayed diagnosis, either due to lack of symptoms in early-stage disease or presentation with non-specific symptoms common with a broad range of alternative diagnoses. More is needed in terms of increasing public awareness, providing adequate healthcare professional education and implementing clinical pathways that improve the earlier diagnosis of symptomatic lung cancer. Low-dose computed tomography screening of high-risk, asymptomatic populations has been shown to reduce lung cancer mortality, with focus now shifting towards how best to implement lung cancer screening on a wider scale in a safe, efficient and cost-effective manner. For maximum benefit, efforts must be made to optimise uptake, especially among high-risk populations with significant socioeconomic deprivation, as well as successfully incorporate tobacco-dependency treatment. Quality assured programme management will be critical to minimising screening-related harms and adequately managing incidental findings. By undertaking the above, there can be optimism that lung cancer outcomes can be improved significantly in the near future.