Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug ...resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133(+) SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133(+) cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting.
Summary Background Malignant pleural mesothelioma incidence continues to rise, with few available evidence-based therapeutic options. Results of previous non-randomised studies suggested that ...video-assisted thoracoscopic partial pleurectomy (VAT-PP) might improve symptom control and survival. We aimed to compare efficacy in terms of overall survival, and cost, of VAT-PP and talc pleurodesis in patients with malignant pleural mesothelioma. Methods We undertook an open-label, parallel-group, randomised, controlled trial in patients aged 18 years or older with any subtype of confirmed or suspected mesothelioma with pleural effusion, recruited from 12 hospitals in the UK. Eligible patients were randomly assigned (1:1) to either VAT-PP or talc pleurodesis by computer-generated random numbers, stratified by European Organisation for Research and Treatment of Cancer risk category (high vs low). The primary outcome was overall survival at 1 year, analysed by intention to treat (all patients randomly assigned to a treatment group with a final diagnosis of mesothelioma). This trial is registered with ClinicalTrials.gov , number NCT00821860. Findings Between Oct 24, 2003, and Jan 24, 2012, we randomly assigned 196 patients, of whom 175 (88 assigned to talc pleurodesis, 87 assigned to VAT-PP) had confirmed mesothelioma. Overall survival at 1 year was 52% (95% CI 41–62) in the VAT-PP group and 57% (46–66) in the talc pleurodesis group (hazard ratio 1·04 95% CI 0·76–1·42; p=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus ten (14%) of 73 patients who completed talc pleurodesis (p=0·019), as were respiratory complications (19 24% vs 11 15%; p=0·22) and air-leak beyond 10 days (five 6% vs one 1%; p=0·21), although not significantly so. Median hospital stay was longer at 7 days (IQR 5–11) in patients who received VAT-PP compared with 3 days (2–5) for those who received talc pleurodesis (p<0·0001). Interpretation VAT-PP is not recommended to improve overall survival in patients with pleural effusion due to malignant pleural mesothelioma, and talc pleurodesis might be preferable considering the fewer complications and shorter hospital stay associated with this treatment. Funding BUPA Foundation.
To re-examine the evidence for recommendations for complete dissection versus sampling of ipsilateral mediastinal lymph nodes during lobectomy for cancer.
We searched for randomized trials of ...systematic mediastinal lymphadenectomy versus mediastinal sampling. We performed a textual analysis of the authors' own starting assumptions and conclusion. We analysed the trial designs and risk of bias. We extracted data on early mortality, perioperative complications, overall survival, local recurrence and distant recurrence for meta-analysis.
We found five randomized controlled trials recruiting 1980 patients spanning 1989-2007. The expressed starting position in 3/5 studies was a conviction that systematic dissection was effective. Long-term survival was better with lymphadenectomy compared with sampling (Hazard Ratio 0.78; 95% CI 0.69-0.89) as was perioperative survival (Odds Ratio 0.59; 95% CI 0.25-1.36, non-significant). But there was an overall high risk of bias and a lack of intention to treat analysis. There were higher rates (non-significant) of perioperative complications including bleeding, chylothorax and recurrent nerve palsy with lymphadenectomy.
The high risk of bias in these trials makes the overall conclusion insecure. The finding of clinically important surgically related morbidities but lower perioperative mortality with lymphadenectomy seems inconsistent. The multiple variables in patients, cancers and available treatments suggest that large pragmatic multicentre trials, testing currently available strategies, are the best way to find out which are more effective. The number of patients affected with lung cancer makes trials feasible.
The global coronavirus disease 2019 (COVID-19) pandemic has caused major morbidity, mortality and socioeconomic disruption on an individual and collective level. Over 6 million COVID-19-related ...deaths have been reported, with total case numbers now well over 500 million worldwide 1. Whilst the prompt and efficient design of effective vaccines has restored varying degrees of normal activity to some parts of world, the effects of the pandemic will be long in duration and far-reaching.
Long implicated in the pathology of ageing, cancer and many other systemic diseases, cellular senescence is now emerging as a key factor in the pathogenesis of severe COVID-19, with implications for other viral illnesses.
https://bit.ly/3bbmOuT
Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative ...reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects.
To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening.
A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years).
Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire.
Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres.
A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria.
Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling.
A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality.
The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols.
The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation.
Current Controlled Trials ISRCTN78513845.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.
Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to ...affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
Chang and colleagues state that lobectomy with dissection or sampling of mediastinal lymph nodes (ie, intraoperative dissection of whole lymph nodes, either all that are accessible or those in ...specified anatomical locations) is the standard of care for operable, stage I, non-small-cell lung cancer.1 However, after surgical lobectomy--when all mediastinal nodes can be looked at under the microscope--some cases will be identified as non-stage-I cancers.4 But, in a cohort of patients treated with SABR, these cases would remain, thus systematically defeating the intention-to-treat principle and providing a golden opportunity to bias the analysis in favour of lobectomy.5 The clinical effectiveness of the addition of lymphadenectomy to lobectomy has not been proven.
Lung cancer 5-year survival has doubled over 15 years. Although the risk of second primary cancer is recognised, quantification over time is lacking. We describe the incidence of second and higher ...order smoking-related primary cancers in lung cancer survivors, identifying high-incidence groups and how incidence changes over time from first diagnosis.
Data on smoking-related primary cancers (lung, laryngeal, head and neck, oesophageal squamous cell carcinoma and bladder) diagnosed in England between 2000 and 2014 were obtained from Public Health England National Cancer Registration and Analysis Service. We calculated absolute incidence rates and standardised incidence rate ratios, both overall and for various subgroups of second primary cancer for up to 10 years from the initial diagnosis of lung cancer, using Poisson regression.
Elevated incidence of smoking-related second primary cancer persists for at least 10 years from first lung cancer diagnosis with those aged 50 and 79 at first diagnosis at particularly high risk. The most frequent type of second malignancy was lung cancer although the highest standardised incidence rate ratios were for oesophageal squamous cell carcinoma (2.4) and laryngeal cancers (2.8) and consistently higher in women than in men. Over the last decade, the incidence of second primary lung cancer has doubled.
Lung cancer survivors have increased the incidence of subsequent lung, laryngeal, head and neck and oesophageal squamous cell carcinoma for at least a decade from the first diagnosis. Consideration should be given to increasing routine follow-up from 5 years to 10 years for those at highest risk, alongside surveillance for other smoking-related cancers.
To investigate the sensitivity and accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for restaging the mediastinum after induction chemotherapy in patients with ...non-small-cell lung cancer (NSCLC).
One hundred twenty-four consecutive patients with tissue-proven stage IIIA-N2 disease who were treated with induction chemotherapy and who had undergone mediastinal restaging by EBUS-TBNA were reviewed. On the basis of computed tomography, 58 patients were classified as having stable disease and 66 were judged to have had a partial response. All patients subsequently underwent thoracotomy with attempted curative resection and a lymph node dissection regardless of EBUS-TBNA findings.
Persistent nodal metastases were detected by using EBUS-TBNA in 89 patients (72%). Of the 35 patients in whom no metastases were assessed by EBUS-TBNA, 28 were found to have residual stage IIIA-N2 disease at thoracotomy. The majority (91%) of these false negative results were due to nodal sampling error rather than detection error. Overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of EBUS-TBNA for mediastinal restaging after induction chemotherapy were 76%, 100%, 100%, 20%, and 77%, respectively.
EBUS-TBNA is a sensitive, specific, accurate, and minimally invasive test for mediastinal restaging of patients with NSCLC. However, because of the low negative predictive value, tumor-negative findings should be confirmed by surgical staging before thoracotomy.
Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma ...contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >10
informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
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