PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial.

BACKGROUND: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. METHODS: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. RESULTS: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group. CONCLUSIONS: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.

Resolution and characterization of contributions of select protein and coupled solvent configurational fluctuations to radical rearrangement catalysis in coenzyme B12-dependent ethanolamine ammonia-lyase.

Coenzyme B12 (adenosylcobalamin) -dependent ethanolamine ammonia-lyase (EAL) is the signature enzyme in ethanolamine utilization metabolism associated with microbiome homeostasis and disease conditions in the human gut. The enzyme conducts a complex choreography of bond-making/bond-breaking steps that rearrange substrate to products through a radical mechanism, with themes common to other coenzyme B12-dependent and radical enzymes. The methods presented are targeted to test the hypothesis that particular, select protein and coupled solvent configurational fluctuations contribute to enzyme function. The general approach is to correlate enzyme function with an introduced perturbation that alters the properties (for example, degree of concertedness, or collectiveness) of protein and coupled solvent dynamics. Methods for sample preparation and low-temperature kinetic measurements by using temperature-step reaction initiation and time-resolved, full-spectrum electron paramagnetic resonance spectroscopy are detailed. A framework for interpretation of results obtained in ensemble systems under conditions of statistical equilibrium within the reacting, globally unstable state is presented. The temperature-dependence of the first-order rate constants for decay of the cryotrapped paramagnetic substrate radical state in EAL, through the chemical step of radical rearrangement, displays a piecewise-continuous Arrhenius dependence from 203 to 295K, punctuated by a kinetic bifurcation over 219-220K. The results reveal the obligatory contribution of a class of select collective protein and coupled solvent fluctuations to the interconversion of two resolved, sequential configurational substates, on the decay time scale. The select class of collective fluctuations also contributes to the chemical step. The methods and analysis are generally applicable to other coenzyme B12-dependent and related radical enzymes.

Randomised trial of indwelling pleural catheters for refractory transudative pleural effusions.

OBJECTIVE: Refractory symptomatic transudative pleural effusions are an indication for pleural drainage. There has been supportive observational evidence for the use of indwelling pleural catheters (IPCs) for transudative effusions, but no randomised trials. We aimed to investigate the effect of IPCs on breathlessness in patients with transudative pleural effusions when compared with standard care. METHODS: A multicentre randomised controlled trial, in which patients with transudative pleural effusions were randomly assigned to either an IPC (intervention) or therapeutic thoracentesis (TT; standard care). The primary outcome was mean daily breathlessness score over 12 weeks from randomisation. RESULTS: 220 patients were screened from April 2015 to August 2019 across 13 centres, with 33 randomised to intervention (IPC) and 35 to standard care (TT). Underlying aetiology was heart failure in 46 patients, liver failure in 16 and renal failure in six. In primary outcome analysis, the mean±sd breathlessness score over the 12-week study period was 39.7±29.4 mm in the IPC group and 45.0±26.1 mm in the TT group (p=0.67). Secondary outcomes analysis demonstrated that mean±sd drainage was 17 412±17 936 mL and 2901±2416 mL in the IPC and TT groups, respectively. A greater proportion of patients had at least one adverse event in the IPC group (p=0.04). CONCLUSION: We found no significant difference in breathlessness over 12 weeks between IPCs or TT. TT is associated with fewer complications and IPCs reduced the number of invasive pleural procedures required. Patient preference and circumstances should be considered in selecting the intervention in this cohort.

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

The influence of body composition on respiratory muscle, lung function and diaphragm thickness in adults with cystic fibrosis.

BACKGROUND: Weight loss and loss of fat-free mass (FFM) are associated with peripheral muscle wasting in cystic fibrosis (CF) although whether this co-exists with loss of diaphragm mass remains unclear. METHODS: FFM was determined by dual-energy X-ray absorptiometry and bioelectrical impedance in 40 adults with CF and 30 age-matched healthy subjects (HS). Diaphragm thickness at functional residual capacity (FRC) [TDIrel] and total lung capacity (TLC) [TDIcont] and thickening ratio (TR) were assessed by ultrasonography. Inspiratory muscle strength and work capacity were determined by maximal inspiratory pressure (PImax), and sustained PImax (SPImax); pulmonary function (RV, VC and TLC) and physical activity status (PAS) were also determined. RESULTS: When the CF patients were assessed as a group (low and normal FFM) they had similar age, weight, height and PAS compared to the HS, although patients had lower FFM (p<0.05), VC and TLC than the HS (p<0.01). In addition, although PImax, TDIrel, TDIcont and TR were similar between the patients and the HS, SPImax was lower in the patients (p<0.01). When analyses were made between patients with low versus normal FFM and between patients with low FFM and HS no significant differences were found between overall weight although TDIrel, TDIcont, TR and PAS were all reduced in patients with low FFM (p<0.01). CONCLUSIONS: PImax is relatively well preserved in adults with CF although there is a relationship between the loss of inspiratory muscle work capacity, FFM, PAS and pulmonary function. Furthermore loss of FFM is associated with loss of diaphragm muscle mass.

Cellular protein breakdown and systemic inflammation are unaffected by pulmonary rehabilitation in COPD.

BACKGROUND: Pulmonary rehabilitation can improve the functional capacity, but has a variable effect on the low fat-free mass (FFM) in patients with chronic obstructive pulmonary disease. HYPOTHESIS: Pulmonary rehabilitation would not affect catabolic drives such as systemic inflammation and also protein breakdown. METHODS: Patients (n = 40) were studied at the start of an 8-week in-patient pulmonary rehabilitation programme, at the end of the programme and 4 weeks later. FFM and functional capacity (quadriceps strength, handgrip strength and peak workload) were assessed. Pseudouridine (PSU) urinary excretion (cellular protein breakdown) and inflammatory status were determined. Healthy participants had a single baseline assessment (n = 18). RESULTS: PSU, (IL)-6 and soluble tumour necrosis factor (sTNF)alpha R75 were increased in patients compared with healthy participants, whereas FFM and functional capacity were reduced (all p < 0.01). PSU was inversely related to both FFM and skeletal muscle function. FFM and functional parameters increased with rehabilitation, but PSU and inflammatory status were unaffected. The gain in FFM was lost 4 weeks after the completion of rehabilitation (p < 0.01). CONCLUSION: The anabolic effect of pulmonary rehabilitation improved FFM, but it did not reverse the increased protein breakdown or systemic inflammation. Thus, on cessation of pulmonary rehabilitation the FFM gains were lost owing to a loss of anabolic drive.

The systemic inflammatory response to exercise in adults with cystic fibrosis.

Exercise is associated with release of inflammatory mediators in the circulation and there is evidence that the exercising muscles and tendons are sources of interleukin-6. Due to the catabolic effects of some cytokines, increased release in circulation might contribute to alterations in body composition in adults with cystic fibrosis. We hypothesised that exercise of moderate intensity would generate increased blood concentrations of some inflammatory mediators. We investigated the change in blood concentrations of interleukin-6, tumour necrosis factor alpha and their soluble receptors after a structured exercise (box stepping) of intensity similar to that encountered during activities of daily living in 12 adults with cystic fibrosis and mean (95% confidence interval) FEV1 55.6 (44.4, 66.8)% predicted, body mass index 23.0 (21.3, 24.6) kg/m2 and 12 healthy subjects. The increments post-exercise for all inflammatory mediators and lactate corrected for the work performed until voluntary exhaustion were greater for patients, while the total work was less for patients (all p<0.01). Daytime variability of the inflammatory mediators was assessed in eight patients and was less than the change due to exercise. We report greater increments in circulating concentrations of some cytokines with moderate exercise in adults with cystic fibrosis compared to healthy subjects.

Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma.

BACKGROUND: Previous research has demonstrated that fish oil supplementation has a protective effect on exercise-induced bronchoconstriction (EIB) in elite athletes, which may be attributed to its antiinflammatory properties. Since EIB in asthma involves proinflammatory mediator release, it is feasible that fish oil supplementation may reduce the severity of EIB in asthmatic subjects. STUDY OBJECTIVES: To determine the efficacy of fish oil supplementation on severity of EIB in subjects with asthma. DESIGN: Randomized, double-blind, crossover study. SETTING: Lung function and exercise testing in a university research laboratory. PATIENTS AND MEASUREMENTS: Sixteen asthmatic patients with documented EIB entered the study on their normal diet and then received either fish oil capsules containing 3.2 g of eicosapentaenoic acid and 2.0 g of docohexaenoic acid (fish oil diet, n = 8) or placebo capsules (placebo diet, n = 8) daily for 3 weeks. At the beginning of the study (normal diet) and at the end of each treatment phase, the following pre-exercise and postexercise measures were assessed: (1) pulmonary function; (2) induced sputum differential cell count percentage and proinflammatory eicosanoid metabolite (leukotriene C4 [LTC4]-leukotriene E4 [LTE4] and prostaglandin D2 [PGD2]) and cytokine (interleukin [IL]-1beta and tumor necrosis factor [TNF]-alpha) concentrations; and (3) eicosanoid metabolites leukotriene B4 (LTB4) and leukotriene B5 (LTB(5)) generation from activated polymorphonuclear leukocytes (PMNLs). RESULTS: On the normal and placebo diet, subjects exhibited EIB. However, the fish oil diet improved pulmonary function to below the diagnostic EIB threshold, with a concurrent reduction in bronchodilator use. Induced sputum differential cell count percentage and concentrations of LTC4-LTE4, PGD2, IL-1beta, and TNF-alpha were significantly reduced before and following exercise on the fish oil diet compared to the normal and placebo diets. There was a significant reduction in LTB4 and a significant increase in LTB5 generation from activated PMNLs on the fish oil diet compared to the normal and placebo diets. CONCLUSION: Our data suggest that fish oil supplementation may represent a potentially beneficial nonpharmacologic intervention for asthmatic subjects with EIB.

Inspiratory muscle training improves lung function and exercise capacity in adults with cystic fibrosis.

STUDY OBJECTIVES: To investigate the effects of high-intensity inspiratory muscle training (IMT) on inspiratory muscle function (IMF), diaphragm thickness, lung function, physical work capacity (PWC), and psychosocial status in patients with cystic fibrosis (CF). DESIGN: Twenty-nine adult patients with CF were randomly assigned to three groups. Two groups were required to complete an 8-week program of IMT in which the training intensity was set at either 80% of maximal effort (group 1; 9 patients) or 20% of maximal effort (group 2; 10 patients). A third group of patients did not participate in any form of training and acted as a control group (group 3; 10 patients). INTERVENTIONS: In all patients, baseline and postintervention measures of IMF were determined by maximal inspiratory pressure (Pimax), and sustained Pimax (SPimax); pulmonary function, body composition, and physical activity status were also determined. In addition, diaphragm thickness was measured at functional residual capacity (FRC) and total lung capacity (TLC) [TDIcont], and the diaphragm thickening ratio (TR) was calculated (TR = thickness during Pimax at FRC/mean thickness at FRC). Subjects also completed an incremental cycle ergometer test to exhaustion and two symptom-related questionnaires, prior to and following training. RESULTS: Following training, significant increases in Pimax and SPimax (p < 0.05), TDIcont (p < 0.05), TR (p < 0.05), vital capacity (p < 0.05), TLC (p < 0.05), and PWC (p < 0.05) were identified, and decreases in anxiety scores (p < 0.05) and depression scores (p < 0.01) were noted in group 1 patients compared to group 3 patients. Group 2 patients significantly improved Pimax and SPimax (both p < 0.05) only with respect to group 3 patients. No significant differences were observed in group 3 patients. CONCLUSION: An 8-week program of high-intensity IMT resulted in significant benefits for CF patients, which included increased IMF and thickness of the diaphragm (during contraction), improved lung volumes, increased PWC, and improved psychosocial status.

Cellular proteolysis and systemic inflammation during exacerbation in cystic fibrosis.

BACKGROUND: Weight loss indicates a poor prognosis in cystic fibrosis (CF). We hypothesised that fat-free mass (FFM) depletion and increased systemic inflammation would be associated with increased cellular proteolysis during an exacerbation of the respiratory symptoms. Patients were studied prospectively from the beginning of treatment with antibiotics when admitted to the Adults CF Centre. METHODS: Twenty six patients with CF were studied at the start and end of antibiotic treatment and 2 weeks later. Mean (95% CI) FEV1 when clinically stable was 54.1 (44.5, 62.6)% predicted. Urinary excretion of Pseudouridine (5-ribosyluracil, PSU) was determined as an indicator of cellular protein breakdown. Body composition was assessed by dual energy X-ray absorptiometry (DXA). RESULTS: Patients had increased concentrations of PSU at all assessments (p<0.01). Those with a low FFM had greater PSU (ratio to FFMI) than those with a normal FFM at all assessments. At the start of treatment, PSU was related to FFM, C-reactive protein (CRP) (p<0.05) and tumour necrosis factor (TNF)alpha soluble receptors (sr) I and II (p<0.01). Circulating inflammatory mediators were greater in patients than in healthy subjects at all assessments. CONCLUSION: Increased protein breakdown is associated with a low FFM and increased systemic inflammation and it may be a contributory mechanism of poor weight preservation in CF.

Hidden depletion of fat-free mass and bone mineral density in adults with cystic fibrosis.

BACKGROUND: Weight loss is associated with reduced survival in patients with cystic fibrosis (CF). OBJECTIVE: We hypothesized that some adult patients with a normal body mass index (BMI) have evidence of hidden fat-free mass (FFM) and bone mineral density (BMD) depletion that is linked to more severe disease. DESIGN: Fat mass (FM), FFM, and BMD were determined by dual-energy x-ray absorptiometry (DXA) and by bioelectric impedance in 56 adults in clinically stable condition and 20 age-matched healthy subjects. FM index and FFM index (FFMI) [kilograms per meter squared] of the right arm, leg, and trunk (ratio to height squared) were calculated. Lung function, including the maximum inspiratory pressure (MIP) and sustained MIP (SMIP), physical activity, serum C-reactive protein (CRP) and the number of exacerbations in the previous year were recorded. RESULTS: Patients had a lower total FFM than healthy subjects (p < 0.01), while FM was similar. Of the 56 patients, 30 patients had a normal BMI, of which 12 patients had a low FFM (hidden loss) by DXA. The right arm, leg, and trunk FFMI and BMD at hip sites were less in these patients than in those with a normal BMI and normal FFM (all p < 0.01). This group had a lower FEV(1), SMIP, more frequent exacerbations, and greater circulating CRP (all p < 0.05). CONCLUSIONS: In adults with CF, apparent or hidden loss of FFM, rather than weight loss, was related to overall disease severity. Hidden depletion of FFM was associated with increased loss of BMD and systemic inflammatory activity.

Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes.

In elite athletes, exercise-induced bronchoconstriction (EIB) may respond to dietary modification, thereby reducing the need for pharmacologic treatment. Ten elite athletes with EIB and 10 elite athletes without EIB (control subjects) participated in a randomized, double-blind crossover study. Subjects entered the study on their normal diet, and then received either fish oil capsules containing 3.2 g eicosapentaenoic acid and 2.2 g docohexaenoic acid (n-3 polyunsaturated fatty acid [PUFA] diet; n = 5) or placebo capsules containing olive oil (placebo diet; n = 5) taken daily for 3 weeks. Diet had no effect on preexercise pulmonary function in either group or on postexercise pulmonary function in control subjects. However, in subjects with EIB, the n-3 PUFA diet improved postexercise pulmonary function compared with the normal and placebo diets. FEV1 decreased by 3 +/- 2% on n-3 PUFA diet, 14.5 +/- 5% on placebo diet, and 17.3 +/- 6% on normal diet at 15 minutes postexercise. Leukotriene (LT)E4, 9alpha, 11beta-prostaglandin F2, LTB4, tumor necrosis factor-alpha, and interleukin-1beta, all significantly decreased on the n-3 PUFA diet compared with normal and placebo diets and after the exercise challenge. These data suggest that dietary fish oil supplementation has a markedly protective effect in suppressing EIB in elite athletes, and this may be attributed to their antiinflammatory properties.

Pulmonary function, body composition, and protein catabolism in adults with cystic fibrosis.

Increased survival in cystic fibrosis (CF) is associated with bone thinning and fat-free mass (FFM) loss. We hypothesized that the severity of lung disease would be associated with increased protein catabolism and systemic inflammatory status in clinically stable patients. Forty adults with CF and 22 age-matched healthy subjects were studied. Body composition was determined by dual-energy X-ray absorptiometry. Urinary pseudouridine (PSU), a marker of protein breakdown, and cross-linked N-telopeptides of type I collagen (NTx), a marker of bone connective tissue breakdown, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and their soluble receptors were measured. A 3-d food intake diary revealed 21 patients had a low energy intake. Excretion of PSU (p = 0.019) and NTx (p < 0.01) was increased in patients and was inversely related to FEV(1); PSU (r = - 0.53, p = 0.001) and NTx (r = - 0.43, p < 0.01). Increased excretion of PSU and NTx (p < 0.05 for both) was also related to a low FFM. All inflammatory mediators were greater in patients and were related to PSU and NTx. Clinically stable adults were catabolic with both cellular and connective tissue protein breakdown, which was related to lung disease severity, systemic inflammation, and body composition.