Nicholas Screaton

Guidelines on the radical management of patients with lung cancer.

A joint initiative by the British Thoracic Society and the Society for Cardiothoracic Surgery in Great Britain and Ireland was undertaken to update the 2001 guidelines for the selection and assessment of patients with lung cancer who can potentially be managed by radical treatment.

Airway Wall Thickening and Emphysema Show Independent Familial Aggregation in Chronic Obstructive Pulmonary Disease

RATIONALE It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families. OBJECTIVES To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD. METHODS Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema. MEASUREMENTS AND MAIN RESULTS A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD. CONCLUSIONS Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.

Nontuberculous mycobacteria in bronchiectasis: prevalence and patient characteristics

The aim of the current study was to investigate the prevalence and clinical associations of nontuberculous mycobacteria (NTM) in a well-characterised cohort of patients with adult-onset bronchiectasis. The sputum of all patients attending a tertiary referral bronchiectasis clinic between April 2002 and August 2003 was examined for mycobacteria as part of an extensive diagnostic work-up. NTM-positive patients subsequently had further sputa examined. A modified bronchiectasis scoring system was applied to all high-resolution computed tomography (HRCT) scans from NTM-positive patients, and a matched cohort without NTM. Out of 98 patients attending the clinic, 10 had NTM in their sputum on first culture; of those, eight provided multiple positive cultures. Three patients were treated for NTM infection. A higher proportion of NTM-positive than -negative patients were subsequently diagnosed with cystic fibrosis (two out of nine versus two out of 75). On HRCT scoring, more patients in the NTM-positive group had peripheral mucus plugging than in the NTM-negative group. In the current prospective study of a large cohort of patients with bronchiectasis, 10% cultured positive for nontuberculous mycobacteria in a random clinic sputum sample. Few clinical parameters were helpful in discriminating between groups, except for a higher prevalence of previously undiagnosed cystic fibrosis and of peripheral mucus plugging on high-resolution computed tomography in the nontuberculous mycobacteria group.

State-of-the-art chronic thromboembolic pulmonary hypertension diagnosis and management

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease caused by chronic obstruction of pulmonary artery branches following episodes of pulmonary embolism and incomplete thrombus resolution. The prognosis of patients with CTEPH is poor unless an early diagnosis is made and treatment is initiated. Chest radiography and echocardiography are used in the initial assessment of suspected pulmonary hypertension. A diagnosis of CTEPH may be confirmed by the presence of a mismatched wedge-shaped perfusion deficit during ventilation/perfusion scintigraphy or characteristic findings during multi-slice computed tomography (CT) angiography, including a mosaic perfusion pattern, dilatation of proximal pulmonary arteries and right heart chambers, and the presence of vascular stenosis or obstruction. Prior to possible surgery, pulmonary angiography remains the definitive diagnostic technique, indicating the site and accessibility of the obstruction. However, many centres utilise CT and magnetic resonance imaging following recent advances in these noninvasive techniques. Haemodynamic evaluation via right heart catheterisation is also mandatory, as pulmonary vascular resistance is the most important determinant of both prognosis and the risk associated with pulmonary endarterectomy surgery. Accurate CTEPH diagnosis and characterisation of its extent and distribution are imperative to allow the prompt initiation of treatment, particularly surgical pulmonary endarterectomy in eligible patients.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening

Background Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. Methods The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. Results 247 354 individuals aged 50–75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm3 or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm3 at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). Conclusions The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective—this needs to be confirmed using data on observed lung cancer mortality reduction. Trial registration ISRCTN 78513845.

Smoking related COPD and facial wrinkling: is there a common susceptibility?

Background: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. Methods: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell <IV) and 25 (16.8%) were wrinkled (Daniell score ⩾IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. Results: Forced expiratory volume in 1 second (FEV1) was significantly lower in those with wrinkles than in those without (mean difference in FEV1 % predicted −13.7%, 95% CI −27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). Conclusion: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Background: Activated phosphoinositide 3‐kinase &dgr; syndrome (APDS) is a recently described combined immunodeficiency resulting from gain‐of‐function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3‐kinase &dgr; (PI3K&dgr;). Objective: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3K&dgr; in the central nervous system; consistent with this, PI3K&dgr; is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3K&dgr; inhibitors offer new prospects for APDS treatment.

Idiopathic Pulmonary Fibrosis and Diffuse Parenchymal Lung Disease: Implications from Initial Experience with 18F-FDG PET/CT

The purpose of this study was to evaluate integrated 18F-FDG PET/CT in patients with idiopathic pulmonary fibrosis (IPF) and diffuse parenchymal lung disease (DPLD). Methods: Thirty-six consecutive patients (31 men and 5 women; mean age ± SD, 68.7 ± 9.4 y) with IPF (n = 18) or other forms of DPLD (n = 18) were recruited for PET/CT and high-resolution CT (HRCT), acquired on the same instrument. The maximal pulmonary 18F-FDG metabolism was measured as a standardized uptake value (SUVmax). At this site, the predominant lung parenchyma HRCT pattern was defined for each patient: ground-glass or reticulation/honeycombing. Patients underwent a global health assessment and pulmonary function tests. Results: Raised pulmonary 18F-FDG metabolism in 36 of 36 patients was observed. The parenchymal pattern on HRCT at the site of maximal 18F-FDG metabolism was predominantly ground-glass (7/36), reticulation/honeycombing (26/36), and mixed (3/36). The mean SUVmax in patients with ground-glass and mixed patterns was 2.0 ± 0.4, and in reticulation/honeycombing it was 3.0 ± 1.0 (Mann–Whitney U test, P = 0.007). The mean SUVmax in patients with IPF was 2.9 ± 1.1, and in other DPLD it was 2.7 ± 0.9 (Mann–Whitney U test, P = 0.862). The mean mediastinal lymph node SUVmax (2.7 ± 1.3) correlated with pulmonary SUVmax (r = 0.63, P < 0.001). Pulmonary 18F-FDG uptake correlated with the global health score (r = 0.50, P = 0.004), forced vital capacity (r = 0.41, P = 0.014), and transfer factor (r = 0.37, P = 0.042). Conclusion: Increased pulmonary 18F-FDG metabolism in all patients with IPF and other forms of DPLD was observed. Pulmonary 18F-FDG uptake predicts measurements of health and lung physiology in these patients. 18F-FDG metabolism was higher when the site of maximal uptake corresponded to areas of reticulation/honeycomb on HRCT than to those with ground-glass patterns.

Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy Results From the United Kingdom National Cohort

Background— Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA. Methods and Results— Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s−1·cm−5 at reassessment correlated with worse long-term survival. Conclusions— Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patients postsurgery.

The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.

The UK Lung Cancer Screening trial (UKLS) aims to evaluate low-dose computed tomography (LDCT) lung cancer population screening in the United Kingdom. In UKLS, a large population sample ages 50 to 75 years is approached with a questionnaire to determine lung cancer risk. Those with an estimated risk of at least 5% of developing lung cancer in the next 5 years (using the Liverpool Lung project risk model) are invited to participate in the trial. Here, we present demographic, risk, and response rate data from the first 88,897 individuals approached. Of note, 23,794 individuals (26.8% of all approached) responded positively to the initial questionnaire; 12% of these were high risk. Higher socioeconomic status correlated positively with response, but inversely with risk (P < 0.001). The 50- to 55-year age group was least likely to participate, and at lowest cancer risk. Only 5% of clinic attendees were ages ≤60 years (compared with 47% of all 88,897 approached); this has implications for cost effectiveness. Among positive responders, there were more ex-smokers than expected from population figures (40% vs. 33%), and fewer current smokers (14% vs. 17.5%). Of note, 32.7% of current smokers and 18.4% of ex-smokers were designated as high risk. Overall, 1,452 of 23,794 positive responders (6.1%) were deemed high risk and attended a recruitment clinic. UKLS is the first LDCT population screening trial, selecting high-risk subjects using a validated individual risk prediction model. Key findings: (i) better recruitment from ex- rather than current smokers, (ii) few clinic attendees ages early 50s, and (iii) representative number of socioeconomically deprived people recruited, despite lower response rates. Cancer Prev Res; 7(3); 362–71. ©2014 AACR.