Impact on quality of life from multimodality treatment for lung cancer: a randomised controlled feasibility trial of surgery versus no surgery as part of multimodality treatment in potentially resectable stage III-N2 NSCLC (the PIONEER trial).

INTRODUCTION: Optimal treatment for 'potentially resectable' stage III-N2 non-small cell lung cancer (NSCLC) requires multimodality treatment: local treatment (surgery or radiotherapy) and systemic anticancer therapy. There is no clear evidence of superiority for survival between the two approaches and little research has explored quality of life (QOL). This study will inform the design of a phase III randomised trial of surgery versus no surgery as part of multimodality treatment for stage III-N2 NSCLC with QOL as a primary outcome. METHODS AND ANALYSIS: Patient participants will be randomised to receive multimodality treatment (1) with surgery OR (2) without surgery. The Quintet Recruitment Intervention will be used to maximise recruitment. Eligible patients will have 'potentially resectable' N2 NSCLC and have received a multidisciplinary team recommendation for multimodality treatment. Sixty-six patients and their carers will be recruited from 8 UK centres. Patient/carer QOL questionnaires will be administered at baseline, weeks 6, 9, 12 and month 6. Semistructured interviews will be conducted. Quantitative data will be analysed descriptively and qualitative data will be analysed using framework analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Results will be disseminated via publications, national bodies and networks, and patient and public involvement groups. TRIAL REGISTRATION: NCT04540757.

Simultaneous Detection of Carbon Monoxide and Viscosity Changes in Cells.

A new family of robust, non-toxic, water-compatible ruthenium(II) vinyl probes allows the rapid, selective and sensitive detection of endogenous carbon monoxide (CO) in live mammalian cells under normoxic and hypoxic conditions. Uniquely, these probes incorporate a viscosity-sensitive BODIPY fluorophore that allows the measurement of microscopic viscosity in live cells via fluorescence lifetime imaging microscopy (FLIM) while also monitoring CO levels. This is the first example of a probe that can simultaneously detect CO alongside small viscosity changes in organelles of live cells.

Identification of CD24 as a marker of Patched1 deleted medulloblastoma-initiating neural progenitor cells.

High morbidity and mortality are common traits of malignant tumours and identification of the cells responsible is a focus of on-going research. Many studies are now reporting the use of antibodies specific to Clusters of Differentiation (CD) cell surface antigens to identify tumour-initiating cell (TIC) populations in neural tumours. Medulloblastoma is one of the most common malignant brain tumours in children and despite a considerable amount of research investigating this tumour, the identity of the TICs, and the means by which such cells can be targeted remain largely unknown. Current prognostication and stratification of medulloblastoma using clinical factors, histology and genetic profiling have classified this tumour into four main subgroups: WNT, Sonic hedgehog (SHH), Group 3 and Group 4. Of these subgroups, SHH remains one of the most studied tumour groups due to the ability to model medulloblastoma formation through targeted deletion of the Shh pathway inhibitor Patched1 (Ptch1). Here we sought to utilise CD antibody expression to identify and isolate TIC populations in Ptch1 deleted medulloblastoma, and determine if these antibodies can help classify the identity of human medulloblastoma subgroups. Using a fluorescence-activated cell sorted (FACS) CD antibody panel, we identified CD24 as a marker of TICs in Ptch1 deleted medulloblastoma. CD24 expression was not correlated with markers of astrocytes or oligodendrocytes, but co-labelled with markers of neural progenitor cells. In conjunction with CD15, proliferating CD24+/CD15+ granule cell precursors (GCPs) were identified as a TIC population in Ptch1 deleted medulloblastoma. On human medulloblastoma, CD24 was found to be highly expressed on Group 3, Group 4 and SHH subgroups compared with the WNT subgroup, which was predominantly positive for CD15, suggesting CD24 is an important marker of non-WNT medulloblastoma initiating cells and a potential therapeutic target in human medulloblastoma. This study reports the use of CD24 and CD15 to isolate a GCP-like TIC population in Ptch1 deleted medulloblastoma, and suggests CD24 expression as a marker to help stratify human WNT tumours from other medulloblastoma subgroups.

Predicting survival following surgical resection of lung cancer using clinical and pathological variables: The development and validation of the LNC-PATH score.

INTRODUCTION: The aim of this study was to develop and validate a simple prognostic scoring system using readily available clinical and pathological variables that could stratify patients according to the risk of death following lung cancer resection. We hypothesized that by using additional pathological variables not accounted for by pathological stage alone coupled with markers of overall fitness a new prognostic tool could be developed. METHODS: Multivariable logistic regression analysis of pathological and other clinical variables from patients undergoing surgical resection of non-small cell lung cancer (NSCLC) were used to determine factors independently associated with 2-year overall survival and so derive the scoring system. The model was then validated in an external multi-centre dataset. RESULTS: Using multivariable logistic regression on a large dataset (n = 1,421) the 'LNC-PATH' (Lymphovascular invasion, N-stage, adjuvant Chemotherapy, Performance status, Age, T-stage, Histology) prognostic score was devised and then validated using an external dataset (n = 402). This can be used to risk stratify patients into low, moderate and high-risk groups with a statistically significant difference between the three groups in their survival distributions. 83.8% of patients in the low-risk group survived two years after surgery compared to 55.6% in the moderate-risk group and 26.2% in the high-risk group. The score was shown to perform moderately well with an Area Under the Receiver Operating Characteristic curve (AUROC) value of 0.76 (95% CI: 0.73-0.79) and 0.70 (95% CI: 0.64-0.76) in the derivation and validation cohorts respectively. DISCUSSION: The LNC-PATH score predicts 2-year overall survival after surgery for NSCLC. This may allow the development of risk stratified follow-up protocols in survivorship clinics which could be the subject of future prospective studies.

EORTC QLQ-C30 summary score reliably detects changes in QoL three months after anatomic lung resection for Non-Small Cell Lung Cancer (NSCLC).

INTRODUCTION: We tested the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) summary score (SumSC) to detect changes in the HRQOL after Non-small-cell lung cancer (NSCLC) surgery and compared its performance to the traditional scales. METHOD: EORTC QLQ-C30 data was obtained from 326 consecutive pre-operative patients submitted for anatomical lung resections for NSCLC.66 patients completed post-operative assessments 3 months after surgery. The data was analysed to evaluate the ability of the SumSC compared to the traditional scales to [1] preoperatively differentiate between clinical groups [2]; detect post-op changes and to [3] compare pre and post-op changes in clinically different groups.The importance of perioperative changes was measured by calculating the effect size (ES). RESULTS: Of the 326 patients, those older than 70 years, with higher DLCO value and Performance Status (PS) ≤1 had a significantly better preoperative SumScore. Physical function (PF) showed a large and significant decline (ES 0.91). Role and social function also showed a significant and medium decline (ES 0.62 and 0.41). Postoperatively some symptoms scales showed significant increases in the values, implying worse symptoms with the largest increase in dyspnoea (ES -0.88). The change in General Health score (GH) was not significant after surgery (ES 0.26, p = 0.062). The SumSc, decreased significantly postoperatively. In particular, medium or large postoperative declines of SumSc were observed in both males and females, in patients with lower FEV1, lower performance score, and in those older than 70 years. Interestingly the decline of SumSc was observed irrespective of the preoperative DLCO level. DISCUSSION: The Summary Score was more sensitive to changes in subjects' HRQOL, than the GH score. The SumSc can be used as a parsimonious and easy to interpreted patient-reported-outcome measure in multi-institutional database and future clinical trials.

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain.

Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR-/- mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR-deficient neural stem cells are impaired in their self-renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRΔbrain ) show low penetrance of cortical degeneration compared to EGFR-/- mice despite genetic recombination of the conditional allele. Adult EGFRΔ mice establish a proper blood-brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid-induced epileptic seizures. EGFR-deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region-specific neurodegeneration observed in EGFR-deficient brains.

Lung cancer stage-shift following a symptom awareness campaign.

BACKGROUND: Lung cancer outcomes in the UK are worse than in many other developed nations. Symptom awareness campaigns aim to diagnose patients at an earlier stage to improve cancer outcomes. METHODS: An early diagnosis campaign for lung cancer commenced in Leeds, UK in 2011 comprising public and primary-care facing components. Rates of community referral for chest X-ray and lung cancer stage (TNM seventh edition) at presentation were collected from 2008 to 2015. Linear trends were assessed by χ2 test for trend in proportions. Headline figures are presented for the 3 years pre-campaign (2008-2010) and the three most recent years for which data are available during the campaign (2013-2015). FINDINGS: Community-ordered chest X-ray rates per year increased from 18 909 in 2008-2010 to 34 194 in 2013-2015 (80.8% increase). A significant stage shift towards earlier stage lung cancer was seen (χ2(1)=32.2, p<0.0001). There was an 8.8 percentage point increase in the proportion of patients diagnosed with stage I/II lung cancer (26.5% pre-campaign vs 35.3% during campaign) and a 9.3% reduction in the absolute number of patients diagnosed with stage III/IV disease (1254 pre-campaign vs 1137 during campaign). INTERPRETATION: This is the largest described lung cancer stage-shift in association with a symptom awareness campaign. A causal link between the campaign and stage-shift cannot be proven but appears plausible. Limitations of the analysis include a lack of contemporary control population.

Increased visceral tissue perfusion with heated, humidified carbon dioxide insufflation during open abdominal surgery in a rodent model.

Tissue perfusion during surgery is important in reducing surgical site infections and promoting healing. This study aimed to determine if insufflation of the open abdomen with heated, humidified (HH) carbon dioxide (CO2) increased visceral tissue perfusion and core body temperature during open abdominal surgery in a rodent model. Using two different rodent models of open abdominal surgery, visceral perfusion and core temperature were measured. Visceral perfusion was investigated using a repeated measures crossover experiment with rodents receiving the same sequence of two alternating treatments: exposure to ambient air (no insufflation) and insufflation with HH CO2. Core body temperature was measured using an independent experimental design with three treatment groups: ambient air, HH CO2 and cold, dry (CD) CO2. Visceral perfusion was measured by laser speckle contrast analysis (LASCA) and core body temperature was measured with a rectal thermometer. Insufflation with HH CO2 into a rodent open abdominal cavity significantly increased visceral tissue perfusion (2.4 perfusion units (PU)/min (95% CI 1.23-3.58); p<0.0001) compared with ambient air, which significantly reduced visceral blood flow (-5.20 PU/min (95% CI -6.83- -3.58); p<0.0001). Insufflation of HH CO2 into the open abdominal cavity significantly increased core body temperature (+1.15 ± 0.14°C) compared with open cavities exposed to ambient air (-0.65 ± 0.52°C; p = 0.037), or cavities insufflated with CD CO2 (-0.73 ± 0.33°C; p = 0.006). Abdominal visceral temperatures also increased with HH CO2 insufflation compared with ambient air or CD CO2, as shown by infrared thermography. This study reports for the first time the use of LASCA to measure visceral perfusion in open abdominal surgery and shows that insufflation of open abdominal cavities with HH CO2 significantly increases visceral tissue perfusion and core body temperature.

Patient reported outcomes following video assisted thoracoscopic (VATS) resection or stereotactic ablative body radiotherapy (SABR) for treatment of non-small cell lung cancer: protocol for an observational pilot study (LiLAC).

BACKGROUND: Lung cancer is increasingly a disease of the elderly and frail population with a median age of 70 years at diagnosis. Therefore, consideration of the impact of interventions on health-related quality of life (HRQOL) and not only absolute survival is especially important. For non-small cell lung cancer (NSCLC), video-assisted thoracoscopic surgery (VATS) has been gaining popularity over the last few decades, replacing traditional open lobectomies. For high-risk patients who are not deemed suitable for surgery, stereotactic ablative body radiotherapy (SABR) provides a potentially curative alternative. However, little is known about how VATS and SABR affect HRQOL measured using patient reported outcome measures (PROMs). The LiLAC study (Life after Lung Cancer) aims to explore HRQOL following intervention with VATS or SABR using validated PROMs and to pilot the use of an online questionnaire system (QTool) in this setting. We hope the results will aid both patients and clinicians in decision making and improve the management of post-intervention problems. METHODS: In total, 300 patients (150 VATS and 150 SABR) patients will be recruited over the study period. Patients will be approached prior to intervention and asked to complete baseline HRQOL questionnaires. They will be given access to the QTool online system and then in the 12 months following intervention will be asked to complete questionnaires (paper or online) at 4-time points. Answers will available for patients and clinicians to view throughout the study period. Clinical information (age, gender, co-morbidity, current medications and smoking status along with treatment-specific information) will also be collected. Primary outcome will be to detect changes of PROs (HRQOL and patient satisfaction) after VATS lung resections or SABR in early stage lung cancer patients. Secondary outcomes include correlation of patient's clinical data with HRQOL results to identify predictors of poor outcomes and exploration of patient and clinician views on the usefulness of QOL measurements. DISCUSSION: (I) This first study will primarily compare multiple patients reported outcomes for 12 months after VATS lobectomy and SABR in early stages NSCLC patients. We will explore the acceptability of an online assessment of the HRQOL in NSCLC patients. (II) The study is also focused on the patients' opinion during the shared decision-making process, which has rarely been investigated in surgical lung cancer patients. (III) This is not a randomised trial. As a consequence, inherent cohort selection bias and unknown or unaccounted confounders correlated with the outcome of interest may influence the results of the comparison between the treatment groups. (IV) LILAC is not looking at a direct comparison, but to depict the trajectory of recovery post-treatments and preservation or improvement of the HRQOL. This study has received ethical approval from NRES Yorkshire and the Humber- Leeds East Research Ethics Committee (REC Ref: 16/YH/0407). Results of this study will be shared with participating hospitals and made available to the academic community through submission for publication in international peer-reviewed journals and presentation at relevant national and international conferences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02882750.

Poor preoperative patient-reported quality of life is associated with complications following pulmonary lobectomy for lung cancer.

Objectives: To assess whether quality of life (QOL) was associated with cardiopulmonary complications following pulmonary lobectomy for lung cancer. Methods: Retrospective analysis of 200 consecutive patients who had pulmonary lobectomy for lung cancer (September 2014-October 2015). QOL was assessed by the self-administration of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire within 2 weeks before the operation. The individual QOL scales were tested for a possible association with cardiopulmonary complications along with other objective baseline and surgical parameters by univariable and multivariable analyses. Results: Forty-three patients (21.5%) developed postoperative cardiopulmonary complications; 4 of them died within 30 days (2%). Univariable analysis showed that, compared to patients without complications, those with complications reported a lower global health status (GHS) [59.1; standard deviation (SD) 27.2 vs 69.6; SD 20.6, P = 0.02], were older (71.2; SD 8.4 vs 67.7; SD 9.4, P = 0.03), had lower values of forced expiratory volume in one second (FEV1) (83.9; SD 27.2 vs 91.4; SD 20.9), P = 0.06) and carbon monoxide lung diffusion capacity (DLCO) (67.9; SD 20.9 vs 74.2; SD 17.6, P = 0.02) and higher performance score (0.76; SD 0.63 vs 0.53; SD 0.64, P = 0.02). Stepwise logistic regression analysis showed that factors independently associated with cardiopulmonary complications were age [odds ratio (OR) 1.04, 95% CI 1.0-1.09, P = 0.02] and patient-reported GHS [OR 0.98, 95% confidence interval (CI) 0.96-0.99, P = 0.006], whereas other objective parameters (i.e. FEV1, DLCO) were not. The best cut-off value for GHS to discriminate patients with complications after surgery was 50 (c-index 0.65, 95% CI 0.58-0.72). Conclusions: A poor GHS perceived by the patient was associated with postoperative cardiopulmonary morbidity. Patient perceptions and values should be included in the risk stratification process to tailor cancer treatment.

Occult nodal disease in patients with non-small-cell lung cancer who are suitable for stereotactic ablative body radiation.

INTRODUCTION: Stereotactic ablative body radiotherapy is a therapeutic option for patients with peripheral stage I NSCLC in whom surgical resection is considered high risk. Patients receiving SABR do not undergo systematic nodal dissection and any occult nodal metastases will therefore go undetected. Our aim was to determine what proportion of cases this might represent. MATERIALS AND METHODS: We retrospectively studied patients who underwent lung resections for presumed stage I NSCLC between 2008 and 2011 at a United Kingdom teaching hospital. We reviewed postoperative pathological lymph node staging and analyzed a subset of these patients in whom SABR would have been be technically possible. RESULTS: We reviewed 128 cases of presumed NSCLC preoperatively staged as T1/2a N0 M0. Of 89 cases with peripheral tumor location, 8 patients (8.9%) had nodal involvement at surgical resection. CONCLUSION: Our data show that approximately 1 in 11 patients with peripheral stage I NSCLC will have occult mediastinal/hilar nodal involvement. Although this is a relatively small proportion, routine use of EBUS-TBNA for nodal staging in patients undergoing SABR might identify a greater proportion of patients with nodal disease compared with a strategy of nodal staging directed according to positron emission tomography-computed tomography findings.