Modeling diffusion-weighted imaging lesion expansion between 2 and 24 h after endovascular thrombectomy in acute ischemic stroke.

PURPOSE: Diffusion-weighted imaging (DWI) lesion expansion after endovascular thrombectomy (EVT) is not well characterized. We used serial diffusion-weighted magnetic resonance imaging (MRI) to measure lesion expansion between 2 and 24 h after EVT. METHODS: In this single-center observational analysis of patients with acute ischemic stroke due to large vessel occlusion, DWI was performed post-EVT (< 2 h after closure) and 24-h later. DWI lesion expansion was evaluated using multivariate generalized linear mixed modeling with various clinical moderators. RESULTS: We included 151 patients, of which 133 (88%) had DWI lesion expansion, defined as a positive change in lesion volume between 2 and 24 h. In an unadjusted analysis, median baseline DWI lesion volume immediately post-EVT was 15.0 mL (IQR: 6.6-36.8) and median DWI lesion volume 24 h post-EVT was 20.8 mL (IQR: 9.4-66.6), representing a median change of 6.1 mL (IQR: 1.5-17.7), or a 39% increase. There were no significant associations among univariable models of lesion expansion. Adjusted models of DWI lesion expansion demonstrated that relative lesion expansion (defined as final/initial DWI lesion volume) was consistent across eTICI scores (0-2a, 0.52%; 2b, 0.49%; 2c-3, 0.42%, p = 0.69). For every 1 mL increase in lesion volume, there was 2% odds of an increase in 90-day mRS (OR: 1.021, 95%CI [1.009, 1.034], p < 0.001). CONCLUSION: We observed substantial lesion expansion post-EVT whereby relative lesion expansion was consistent across eTICI categories, and greater absolute lesion expansion was associated with worse clinical outcome. Our findings suggest that alternate endpoints for cerebroprotectant trials may be feasible.

Spirometry performed as part of the Manchester community-based lung cancer screening programme detects a high prevalence of airflow obstruction in individuals without a prior diagnosis of COPD.

BACKGROUND: COPD is a major cause of morbidity and mortality in populations eligible for lung cancer screening. We investigated the role of spirometry in a community-based lung cancer screening programme. METHODS: Ever smokers, age 55-74, resident in three deprived areas of Manchester were invited to a 'Lung Health Check' (LHC) based in convenient community locations. Spirometry was incorporated into the LHCs alongside lung cancer risk estimation (Prostate, Lung, Colorectal and Ovarian Study Risk Prediction Model, 2012 version (PLCOM2012)), symptom assessment and smoking cessation advice. Those at high risk of lung cancer (PLCOM2012 ≥1.51%) were eligible for annual low-dose CT screening over two screening rounds. Airflow obstruction was defined as FEV1/FVC<0.7. Primary care databases were searched for any prior diagnosis of COPD. RESULTS: 99.4% (n=2525) of LHC attendees successfully performed spirometry; mean age was 64.1±5.5, 51% were women, 35% were current smokers. 37.4% (n=944) had airflow obstruction of which 49.7% (n=469) had no previous diagnosis of COPD. 53.3% of those without a prior diagnosis were symptomatic (n=250/469). After multivariate analysis, the detection of airflow obstruction without a prior COPD diagnosis was associated with male sex (adjOR 1.84, 95% CI 1.37 to 2.47; p<0.0001), younger age (p=0.015), lower smoking duration (p<0.0001), fewer cigarettes per day (p=0.035), higher FEV1/FVC ratio (<0.0001) and being asymptomatic (adjOR 4.19, 95% CI 2.95 to 5.95; p<0.0001). The likelihood of screen detected lung cancer was significantly greater in those with evidence of airflow obstruction who had a previous diagnosis of COPD (adjOR 2.80, 95% CI 1.60 to 8.42; p=0.002). CONCLUSIONS: Incorporating spirometry into a community-based targeted lung cancer screening programme is feasible and identifies a significant number of individuals with airflow obstruction who do not have a prior diagnosis of COPD.

Analysis of lung cancer risk model (PLCOM2012 and LLPv2) performance in a community-based lung cancer screening programme.

INTRODUCTION: Low-dose CT (LDCT) screening of high-risk smokers reduces lung cancer (LC) specific mortality. Determining screening eligibility using individualised risk may improve screening effectiveness and reduce harm. Here, we compare the performance of two risk prediction models (PLCOM2012 and Liverpool Lung Project model (LLPv2)) and National Lung Screening Trial (NLST) eligibility criteria in a community-based screening programme. METHODS: Ever-smokers aged 55-74, from deprived areas of Manchester, were invited to a Lung Health Check (LHC). Individuals at higher risk (PLCOM2012 score ≥1.51%) were offered annual LDCT screening over two rounds. LLPv2 score was calculated but not used for screening selection; ≥2.5% and ≥5% thresholds were used for analysis. RESULTS: PLCOM2012 ≥1.51% selected 56% (n=1429) of LHC attendees for screening. LLPv2 ≥2.5% also selected 56% (n=1430) whereas NLST (47%, n=1188) and LLPv2 ≥5% (33%, n=826) selected fewer. Over two screening rounds 62 individuals were diagnosed with LC; representing 87% (n=62/71) of 6-year incidence predicted by mean PLCOM2012 score (5.0%). 26% (n=16/62) of individuals with LC were not eligible for screening using LLPv2 ≥5%, 18% (n=11/62) with NLST criteria and 7% (n=5/62) with LLPv2 ≥2.5%. NLST eligible Manchester attendees had 2.5 times the LC detection rate than NLST participants after two annual screens (≈4.3% (n=51/1188) vs 1.7% (n=438/26 309); p<0.0001). Adverse measures of health, including airflow obstruction, respiratory symptoms and cardiovascular disease, were positively correlated with LC risk. Coronary artery calcification was predictive of LC (adjOR 2.50, 95% CI 1.11 to 5.64; p=0.028). CONCLUSION: Prospective comparisons of risk prediction tools are required to optimise screening selection in different settings. The PLCOM2012 model may underestimate risk in deprived UK populations; further research focused on model calibration is required.

Attendees of Manchester's Lung Health Check pilot express a preference for community-based lung cancer screening.

Manchester's 'Lung Health Check' pilot utilised mobile CT scanners in convenient retail locations to deliver lung cancer screening to socioeconomically disadvantaged communities. We assessed whether screening location was an important factor for those attending the service. Location was important for 74.7% (n=701/938) and 23% (n=216/938) reported being less likely to attend an equivalent hospital-based programme. This preference was most common in current smokers (27% current smokers vs 19% former smokers; AdjOR 1.46, 95% CI 1.03 to 2.08, p=0.036) and those in the lowest deprivation quartile (25% lowest quartile vs 17.6% highest quartile; AdjOR 2.0, 95% CI 1.24 to 3.24, p=0.005). Practical issues related to travel were most important in those less willing to attend a hospital-based service, with 83.3% citing at least one travel related barrier to non-attendance. A convenient community-based screening programme may reduce inequalities in screening adherence especially in those at high risk of lung cancer in deprived areas.

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot.

We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

"To know or not to know ?" Push and pull in ever smokers lung screening uptake decision-making intentions.

BACKGROUND: In the United States, lung cancer screening aims to detect cancer early in nonsymptomatic current and former smokers. A lung screening pilot service in an area of high lung cancer incidence in the United Kingdom has been designed based on United States trial evidence. However, our understanding of acceptability and reasons for lung screening uptake or decline in a United Kingdom nontrial context are currently limited. OBJECTIVE: To explore with ever smokers the acceptability of targeted lung screening and uptake decision-making intentions. DESIGN: Qualitative study using semistructured focus groups and inductive thematic analysis to explore acceptability and uptake decision-making intentions with people of similar characteristics to lung screening eligible individuals. SETTING AND PARTICIPANTS: Thirty-three participants (22 ex-smokers; 11 smokers) men and women, smokers and ex-smokers, aged 50-80 were recruited purposively from community and health settings in Manchester, England. RESULTS: Lung screening was widely acceptable to participants. It was seen as offering reassurance about lung health or opportunity for early detection and treatment. Participant's desire to know about their lung health via screening was impacted by perceived benefits; emotions such as worry about a diagnosis and screening tests; practicalities such as accessibility; and smoking-related issues including perceptions of individual risk and smoking stigma. DISCUSSION: Decision making was multifaceted with indications that current smokers faced higher participation barriers than ex-smokers. Reducing participation barriers through careful service design and provision of decision support information will be important in lung screening programmes to support informed consent and equitable uptake.

Association of Clinical, Imaging, and Thrombus Characteristics With Recanalization of Visible Intracranial Occlusion in Patients With Acute Ischemic Stroke.

Importance: Recanalization of intracranial thrombus is associated with improved clinical outcome in patients with acute ischemic stroke. The association of intravenous alteplase treatment and thrombus characteristics with recanalization over time is important for stroke triage and future trial design. Objective: To examine recanalization over time across a range of intracranial thrombus occlusion sites and clinical and imaging characteristics in patients with ischemic stroke treated with intravenous alteplase or not treated with alteplase. Design, Setting, and Participants: Multicenter prospective cohort study of 575 patients from 12 centers (in Canada, Spain, South Korea, the Czech Republic, and Turkey) with acute ischemic stroke and intracranial arterial occlusion demonstrated on computed tomographic angiography (CTA). Exposures: Demographics, clinical characteristics, time from alteplase to recanalization, and intracranial thrombus characteristics (location and permeability) defined on CTA. Main Outcomes and Measures: Recanalization on repeat CTA or on first angiographic acquisition of affected intracranial circulation obtained within 6 hours of baseline CTA, defined using the revised arterial occlusion scale (rAOL) (scores from 0 [primary occlusive lesion remains the same] to 3 [complete revascularization of primary occlusion]). Results: Among 575 patients (median age, 72 years [IQR, 63-80]; 51.5% men; median time from patient last known well to baseline CTA of 114 minutes [IQR, 74-180]), 275 patients (47.8%) received intravenous alteplase only, 195 (33.9%) received intravenous alteplase plus endovascular thrombectomy, 48 (8.3%) received endovascular thrombectomy alone, and 57 (9.9%) received conservative treatment. Median time from baseline CTA to recanalization assessment was 158 minutes (IQR, 79-268); median time from intravenous alteplase start to recanalization assessment was 132.5 minutes (IQR, 62-238). Successful recanalization occurred at an unadjusted rate of 27.3% (157/575) overall, including in 30.4% (143/470) of patients who received intravenous alteplase and 13.3% (14/105) who did not (difference, 17.1% [95% CI, 10.2%-25.8%]). Among patients receiving alteplase, the following factors were associated with recanalization: time from treatment start to recanalization assessment (OR, 1.28 for every 30-minute increase in time [95% CI, 1.18-1.38]), more distal thrombus location, eg, distal M1 middle cerebral artery (39/84 [46.4%]) vs internal carotid artery (10/92 [10.9%]) (OR, 5.61 [95% CI, 2.38-13.26]), and higher residual flow (thrombus permeability) grade, eg, hairline streak (30/45 [66.7%]) vs none (91/377 [24.1%]) (OR, 7.03 [95% CI, 3.32-14.87]). Conclusions and Relevance: In patients with acute ischemic stroke, more distal thrombus location, greater thrombus permeability, and longer time to recanalization assessment were associated with recanalization of arterial occlusion after administration of intravenous alteplase; among patients who did not receive alteplase, rates of arterial recanalization were low. These findings may help inform treatment and triage decisions in patients with acute ischemic stroke.

The mediation of social influences on smoking cessation and awareness of the early signs of lung cancer.

BACKGROUND: Whilst there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present findings from a qualitative study involving in-depth interviews with patients who had been diagnosed with lung cancer (n = 11), and people who were at heightened risk of developing the disease (n = 14). METHODS: A grounded theory methodology was drawn upon to conduct thematic and narrative based approaches to analysis. RESULTS: The paper focuses on three main themes which emerged from the study: i) fatalism and resignation in pathways to help-seeking and the process of diagnosis; ii) Awareness of smoking risk and response to cessation information and advice. iii) The role of social and other networks on help-seeking. Key findings included: poor awareness among participants of the symptoms of lung cancer; ambivalence about the dangers of smoking; the perception of lung cancer as part of a homogenisation of multiple illnesses; close social networks as a key trigger in help-seeking. CONCLUSIONS: We suggest that future smoking cessation and lung cancer awareness campaigns could usefully capitalise on the influence of close social networks, and would benefit from taking a 'softer' approach.

Infarcts Due to Large Vessel Occlusions Continue to Grow Despite Near-Complete Reperfusion After Endovascular Treatment.

BACKGROUND AND PURPOSE: Infarcts in acute ischemic stroke (AIS) patients may continue to grow even after reperfusion, due to mechanisms such as microvascular obstruction and reperfusion injury. We investigated whether and how much infarcts grow in AIS patients after near-complete (expanded Thrombolysis in Cerebral Infarction [eTICI] 2c/3) reperfusion following endovascular treatment (EVT), and to assess the association of post-reperfusion infarct growth with clinical outcomes. METHODS: Data are from a single-center retrospective observational cohort study that included AIS patients undergoing EVT with near-complete reperfusion who received diffusion-weighted magnetic resonance imaging (MRI) within 2 hours post-EVT and 24 hours after EVT. Association of infarct growth between 2 and 24 hours post-EVT and 24-hour National Institutes of Health Stroke Scale (NIHSS) as well as 90-day modified Rankin Scale score was assessed using multivariable logistic regression. RESULTS: Ninety-four of 155 (60.6%) patients achieved eTICI 2c/3 and were included in the analysis. Eighty of these 94 (85.1%) patients showed infarct growth between 2 and 24 hours post-reperfusion. Infarct growth ≥5 mL was seen in 39/94 (41.5%) patients, and infarct growth ≥10 mL was seen in 20/94 (21.3%) patients. Median infarct growth between 2 and 24 hours post-reperfusion was 4.5 mL (interquartile range: 0.4-9.2 mL). Post-reperfusion infarct growth was associated with the 24-hour NIHSS in multivariable analysis (odds ratio: 1.16 [95% confidence interval 1.09-1.24], P<0.01). CONCLUSION: Infarcts continue to grow after EVT, even if near-complete reperfusion is achieved. Investigating the underlying mechanisms may inform future therapeutic approaches for mitigating the process and help improve patient outcome.

The cost-effectiveness of the Manchester 'lung health checks', a community-based lung cancer low-dose CT screening pilot.

BACKGROUND: Previous evaluations of low-dose CT (LDCT) lung cancer screening programmes have taken very different approaches in the design of the informative trials and the methods applied to determine cost-effectiveness. Therefore, it has not been possible to determine if differences in cost-effectiveness are due to different screening approaches or the evaluation methodology. This study reports the findings of an evaluation of the first round of a community-based, LDCT screening pilot Manchester, applying previously published methodology to ensure consistency. METHODS: Using the economic evaluation method reported in the UKLS trial, applying Manchester specific evidence where possible, we estimate the cost-effectiveness of LDCT for lung cancer. Estimates of the total costs and quality adjusted life years (QALYs) were calculated. RESULTS: The Manchester programme cost £663,076, diagnosed 42 patients with lung cancer resulting in a gain in population health of 88.13 discounted life years, equivalent to 65.85 QALYs. This implied an incremental cost-effectiveness ratio of £10,069/QALY. CONCLUSIONS: We found the Manchester programme to be a cost-effective use of limited NHS resources. The findings suggest that further research is now needed not as to whether LDCT screening is cost-effective but under what conditions can it improve patient health by the most while remaining cost-effective.

Smoking is associated with a decrease of O6-alkylguanine-DNA alkyltransferase activity in bronchial epithelial cells.

O6-alkylguanine-DNA alkyltransferase (MGMT) represents the first line of defense against the toxic, mutagenic and carcinogenic effects of O6-alkylguanine adducts in DNA. These adducts mediate the biological activity from a series of alkylating agents, such as the tobacco-specific nitrosamines, believed to contribute to the carcinogenicity of tobacco smoke. There have been conflicting reports on the effects of smoking on MGMT activity in lung and other tissues. Here, we investigate MGMT activity in peripheral blood mononuclear cells (PBMC) and lung bronchial epithelial cells (BEC), extracted by lung brushings, from smokers and nonsmokers attending a bronchoscopy clinic. MGMT activity was significantly lower in BECs (geometric mean; 95% confidence interval 1.02; 0.86-1.20 fmol/microg DNA) than in PBMCs (7.86; 6.70-9.59 fmol/microg DNA; p < 0.001), suggesting that bronchial epithelia may be particularly sensitive to alkylation damage. More importantly our results indicate that activity in BECs is significantly decreased in samples from current smokers (0.71; 0.54-0.93 fmol/microg DNA) compared to nonsmokers (1.25; 1.03-1.51 fmol/microg DNA; p = 0.002). This could represent an important contribution to the carcinogenicity of tobacco smoke.

Lessons in experimental ischemia for clinical stroke medicine.

PURPOSE OF REVIEW: This review covers experimental developments in the laboratory and their translation to clinical stroke trials over the year from 3 August 2001 to 2002. RECENT FINDINGS: Recent findings include novel observations in the areas of excitotoxicity, free radical injury, neuro-inflammation and apoptosis. A key clinical finding this year has been the translation of the effects of hypothermia in global ischemia to two successful trials in cardiac arrest with patients cooled within 4-8 h following resuscitation achieving good neurological outcomes, as compared with their normothermic controls. An era of molecular imaging in stroke research is presaged by the first reports of enhanced magnetic resonance or labeling with supramagnetic contrast agents. SUMMARY: Although none of the drugs in focal ischemia has translated from experimental models, for the first time there is evidence of cytoprotection for the brain that has been translated from the laboratory to man.