Hesitancy around low-dose CT screening for lung cancer.

Lung cancer is the leading cause of cancer death worldwide. The absence of symptoms in early-stage (I/II) disease, when curative treatment is possible, results in >70% of cases being diagnosed at late stage (III/IV), when treatment is rarely curative. This contributes greatly to the poor prognosis of lung cancer, which sees only 16.2% of individuals diagnosed with the disease alive at 5 years. Early detection is key to improving lung cancer survival outcomes. As a result, there has been longstanding interest in finding a reliable screening test. After little success with chest radiography and sputum cytology, in 2011 the United States National Lung Screening Trial demonstrated that annual low-dose computed tomography (LDCT) screening reduced lung cancer-specific mortality by 20%, when compared with annual chest radiography. In 2020, the NELSON study demonstrated an even greater reduction in lung cancer-specific mortality for LDCT screening at 0, 1, 3 and 5.5 years of 24% in men, when compared to no screening. Despite these impressive results, a call to arms in the 2017 European position statement on lung cancer screening (LCS) and the widespread introduction across the United States, there was, until recently, no population-based European national screening programme in place. We address the potential barriers and outstanding concerns including common screening foes, such as false-positive tests, overdiagnosis and the negative psychological impact of screening, as well as others more unique to LDCT LCS, including appropriate risk stratification of potential participants, radiation exposure and incidental findings. In doing this, we conclude that whilst the evidence generated from ongoing work can be used to refine the screening process, for those risks which remain, appropriate and acceptable mitigations are available, and none should serve as barriers to the implementation of national unified LCS programmes across Europe and beyond.

The potential of breath analysis to improve outcome for patients with lung cancer.

Lung cancer remains the most common cause of cancer related death in both the UK and USA. Development of diagnostic approaches that have the ability to detect lung cancer early are a research priority with potential to improve survival. Analysis of exhaled breath metabolites, or volatile organic compounds (VOCs) is an area of considerable interest as it could fulfil such requirements. Numerous studies have shown that VOC profiles are different in the breath of patients with lung cancer compared to healthy individuals or those with non-malignant lung diseases. This review provides a scientific and clinical assessment of the potential value of a breath test in lung cancer. It discusses the current understanding of metabolic pathways that contribute to exhaled VOC production in lung cancer and reviews the research conducted to date. Finally, we highlight important areas for future research and discuss how a breath test could be incorporated into various clinical pathways.

In vivo implantation of a tissue engineered stem cell seeded hemi-laryngeal replacement maintains airway, phonation, and swallowing in pigs.

Laryngeal functional impairment relating to swallowing, vocalisation, and respiration can be life changing and devastating for patients. A tissue engineering approach to regenerating vocal folds would represent a significant advantage over current clinical practice. Porcine hemi-larynx were de-cellularised under negative pressure. The resultant acellular scaffold was seeded with human bone marrow derived mesenchymal stem cells and primary human epithelial cells. Seeded scaffolds were implanted orthotopically into a defect created in the thyroid cartilage in 8 pigs and monitored in vivo for 2 months. In vivo assessments consisted of mucosal brushing and bronchoscopy at 1, 2, 4, and 8 weeks post implantation followed by histological evaluation post termination. The implanted graft had no adverse effect on respiratory function in 6 of the 8 pigs; none of the pigs had problems with swallowing or vocalisation. Six out of the 8 animals survived to the planned termination date; 2 animals were terminated due to mild stenosis and deep tissue abscess formation, respectively. Human epithelial cells from mucosal brushings could only be identified at Weeks 1 and 4. The explanted tissue showed complete epithelialisation of the mucosal surface and the development of rudimentary vocal folds. However, there was no evidence of cartilage remodelling at the relatively early censor point. Single stage partial laryngeal replacement is a safe surgical procedure. Replacement with a tissue engineered laryngeal graft as a single procedure is surgically feasible and results in appropriate mucosal coverage and rudimentary vocal fold development.

Reliability and Validity of the HD-PRO-TriadTM, a Health-Related Quality of Life Measure Designed to Assess the Symptom Triad of Huntington's Disease.

BACKGROUND: Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. OBJECTIVES: The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. METHODS: Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. RESULTS: Internal reliability for all domains and the total HD-PRO-TRIADTM was excellent (all Cronbach's α >0.93). Convergent and discriminant validity were supported by significant associations between the HD-PRO-TRIADTM domains, and other patient reported outcome measures as well as clinician-rated measures. Known groups validity was supported as the HD-PRO-TRIADTM differentiated between stages of the disease. Floor and ceiling effects were generally within acceptable limits. There were small effect sizes for 12-month change over time and moderate effect sizes for 24-month change over time. CONCLUSIONS: Findings support excellent internal reliability, convergent and discriminant validity, known groups validity, and responsiveness to change over time. The current study supports the clinical efficacy of the HD-PRO-TRIADTM. Future research is needed to assess the test-retest reliability of this measure.

Pulmonary nodules and CT screening: the past, present and future.

Lung cancer screening has come a long way since the early studies with chest X-ray. Advancing technology and progress in the processing of images have enabled low dose CT to be tried and tested, and evidence suggests its use can result in a significant mortality benefit. There are several issues that need refining in order to successfully implement screening in the UK and elsewhere. Some countries have started patchy implementation of screening and there is increased recognition that the appropriate management of pulmonary nodules is crucial to optimise benefits of early detection, while reducing harm caused by inappropriate medical intervention. This review summarises and differentiates the many recent guidelines on pulmonary nodule management, discusses screening activity in other countries and exposes the present barriers to implementation in the UK.

Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study.

In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

Smoking is associated with pessimistic and avoidant beliefs about cancer: results from the International Cancer Benchmarking Partnership.

BACKGROUND: Smoking cessation is the key cancer prevention behaviour for smokers; nonetheless, smokers can still benefit from earlier diagnosis of cancer. However, fewer smokers participate in screening despite their increased risk, which may reflect different beliefs about cancer. METHODS: A UK population-representative sample of ⩾50 year-olds (n=6965) was surveyed using the Awareness and Beliefs about Cancer measure. These analyses examine six items on cancer beliefs (e.g., 'cancer can often be cured'), and four on help-seeking barriers (e.g., 'I would be too embarrassed'). RESULTS: Smokers were more likely to hold pessimistic cancer beliefs than never-smokers or former-smokers on four of six items. For example, 34% agreed 'a cancer diagnosis is a death sentence', compared with 24% of non/former-smokers (P<0.001). More smokers (18%) than non/former-smokers (11%) would not want to know if they had cancer (P<0.01). The only barrier to symptomatic help-seeking differing by smoking status was 'worry about what the doctor might find' (36% vs 28%, P<0.01). Associations were independent of demographics, self-rated health and cancer experience. CONCLUSIONS: Smokers held more pessimistic and avoidant beliefs about cancer, which could deter early-detection behaviour. A better understanding of these beliefs is needed to increase engagement in early diagnosis by this high-risk group.

Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma.

Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment, which contributes to tumor initiation, development, severity and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further antitumor effects of MSCs engineered to overexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSCs) or human (hMSC) MSCs were administered either systemically (intravenously or intraperitoneally) at various times following tumor inoculation. Both mMSCs and hMSCs localized at the sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. MSC-TRAIL exposure induced apoptosis of TRAIL-sensitive MM cells in vitro, and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover, human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma.

Airway stem cells and lung cancer.

Lung cancer is the biggest cancer killer in the UK and despite recent therapeutic advances there is a desperate need for new therapies to improve outcomes from this devastating disease. Through defining the spatial location of the airway epithelial stem or progenitor cell populations and their mechanisms of maintenance and repair of the epithelium it is becoming clear that these populations are situated at areas corresponding to those involved in lung cancer initiation. We explore the evidence for stem cells being the cancer initiator cell and for a 'lung cancer stem cell' within tumours that may be the cause of resistance to current therapies.

Impact of EBUS-TBNA on modalities for tissue acquisition in patients with lung cancer.

BACKGROUND: The impact of the introduction of Endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) on the use of diagnostic modalities for tissue acquisition in patients with lung cancer is unknown. METHODS: A retrospective review of 328 consecutive patients diagnosed with lung cancer at a university teaching hospital, where they first presented in London in 2007, 2009 and 2011. EBUS was introduced in 2008. RESULTS: In total, 316 patients were included in the analysis. Comparing 2007 with 2011 data, there has been a significant reduction in standard bronchoscopy (P < 0.0001) and mediastinoscopy (P = 0.02). The proportion of cases diagnosed by EBUS-TBNA significantly increased from 0% in 2007 to 26.7% in 2009 and 25.4% in 2011 (P < 0.0001). In the same period there has also been an increased trend in the proportion of patients going directly to surgery without pathological confirmation with a 9.6% increase in diagnoses obtained at thoracotomy (P = 0.0526). CONCLUSION: The use of diagnostic modalities that provide information on diagnosis and staging in a single intervention are increasing. At our hospital, the use of EBUS-TBNA for providing a lung cancer diagnosis is increasing and this has led to a significant reduction in standard bronchoscopies and mediastinoscopies. These changes in practice may have implications for future service provision, training and commissioning.

Imaging the paediatric lung: what does nanotechnology have to offer?

This review will provide an overview of current research into lung imaging with nanoparticles, with a focus on the use of nanoparticles as molecular imaging agents to observe pathological processes and to monitor the effectiveness of nanoparticulate drug delivery systems. Various imaging modalities together with their advantages and limitations for lung imaging will be discussed. We will also explore the range of nanoparticles used, as well as active or passive targeting of nanoparticles.

TRAIL-expressing mesenchymal stem cells kill the putative cancer stem cell population.

BACKGROUND: Tumours contain stem-like, side population (SP) cells, which have increased tumorigenic potential, resistance to traditional therapies and may be responsible for treatment failures and relapse in patients. METHODS: Mesenchymal stem cells (MSCs) were engineered to express the apoptotic ligand, TNF-related apoptosis-inducing ligand (TRAIL). Squamous (H357) and lung (A549) cancer cell lines were sorted into side and non-side populations (non-SP) by Hoechst flow cytometry. The survival and growth of both SP and non-SP cancer populations, in conjunction with TRAIL-expressing MSCs and mitoxantrone chemotherapy, were assessed by flow cytometry and colony forming ability. RESULTS: Mesenchymal stem cells expressing TRAIL migrate to tumours and reduce the growth of primary cancers and metastases. This report demonstrates that these cells cause apoptosis, death and reduced colony formation of the SP of squamous and adenocarcinoma lung cancer cells and are synergistic when combined with traditional chemotherapy in apoptosis induction. CONCLUSIONS: The sensitivity of putative cancer stem cells to TRAIL-expressing MSCs, suggests their possible role in the prevention of cancer relapse.

More trouble ahead; is gene therapy coming of age?

BACKGROUND: A recent incident, the halting of a Phase I/II trial utilising an adeno-associated vector, highlights the fact that there are more hurdles to overcome prior to a full realisation of gene therapy in the clinical arena. METHODS: The sources of information used to prepare the paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agency websites. RESULTS/CONCLUSION: Over the years, two fatal incidents associated with viral vector usage have been reported. Viral vectors used as carriers for gene therapy have failed in safety trials on two occasions. Also, the human immune response and the oncogenic property of the vectors have restricted the advancement of gene therapy as a therapeutic tool. Nonetheless, gene therapy has now progressed from its infancy 'proof of concept' stage, to the next stage in which we try to overcome the problems associated with therapeutic application. However, this progression has been slow as more and more setbacks have occurred. This calls for a new perspective and radical thinking about future vector development.

Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade.

Cancers are a heterogeneous mix of cells, some of which exhibit cancer stem cell-like characteristics including ATP-dependent drug efflux and elevated tumorigenic potential. To determine whether aerodigestive squamous cell carcinomas (SCCs) contain a subpopulation of cancer stem cell-like cells, we performed Hoechst dye efflux assays using four independent cell lines. Results revealed the presence of a rare, drug effluxing stem cell-like side population (SP) of cells within all cell lines tested (SCC-SP cells). These cells resembled previously characterised epithelial stem cells, and SCC-SP cell abundance was positively correlated with overall cellular density and individual cell quiescence. Serial SCC-SP fractionation and passaging increased their relative abundance within the total cell population. Purified SCC-SP cells also exhibited increased clonogenic potential in secondary cultures and enhanced tumorigenicity in vivo. Despite this, SCC-SP cells remained chemotherapeutically sensitive upon ATP-dependent transporter inhibition. Overall, these findings suggest that the existence of ATP transporter-dependent cancer stem-like cells may be relatively common, particularly within established tumours. Future chemotherapeutic strategies should therefore consider coupling identification and targeting of this potential stem cell-like population with standard treatment methodologies.