National working group meeting on ALK diagnostics in lung cancer

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.

Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Visual function and the ageing visual system

The population is ageing. Globally, the number of older adults (aged 60 years or over) is expected to more than double, from 841 million people in 2013 to more than 2 billion in 2050.1 In light of the increasing size of the older adult population, there is a pressing need to better identify the nature of, and mechanisms underlying, age-related vision impairment and the functional impact it has on the performance of everyday activities in older adults. The content of this feature issue reflects the diversity of research currently being undertaken on the topic of the ageing visual system and the important visual challenges that this presents for our ageing patient population. The scope is broad and includes topics relating to three main related themes: 1) The treatment of age-related ocular disorders and diseases and their consequences, including presbyopia and AMD; 2) The impact of age-related visual changes on everyday activities in older people, including mobility, driving and falls, and; 3) The interaction of age-related visual impairments and other age-related impairments including hearing and cognitive changes.

Theoretical modelling of momentum transfer function of bi-disperse porous media

The aim of this paper is to obtain the momentum transfer coefficient between the two phases, denoted by f and p, occupying a bi-disperse porous medium by mapping the available experimental data to the theoretical model proposed by Nield and Kuznetsov. Data pertinent to plate-fin heat exchangers, as bi-disperse porous media, were used. The measured pressure drops for such heat exchangers are then used to give the overall permeability which is linked to the porosity and permeability of each phase as well as the interfacial momentum transfer coefficient between the two phases. Accordingly, numerical values are obtained for the momentum transfer coefficient for three different fin spacing values considered in the heat exchanger experiments.

Comparison of ocular modulation transfer function determined by a ray-tracing aberrometer and a double-pass system in early cataract patients

BACKGROUND: The evaluation of retinal image quality in cataract eyes has gained importance and the clinical modulation transfer functions (MTF) can obtained by aberrometer and double pass (DP) system. This study aimed to compare MTF derived from a ray tracing aberrometer and a DP system in early cataractous and normal eyes. METHODS: There were 128 subjects with 61 control eyes and 67 eyes with early cataract defined according to the Lens Opacities Classification System III. A laser ray-tracing wavefront aberrometer (iTrace) and a double pass (DP) system (OQAS) assessed ocular MTF for 6.0 mm pupil diameters following dilation. Areas under the MTF (AUMTF) and their correlations were analyzed. Stepwise multiple regression analysis assessed factors affecting the differences between iTrace- and OQAS-derived AUMTF for the early cataract group. RESULTS: For both early cataract and control groups, iTrace-derived MTFs were higher than OQAS-derived MTFs across a range of spatial frequencies (P < 0.01). No significant difference between the two groups occurred for iTrace-derived AUMTF, but the early cataract group had significantly smaller OQAS-derived AUMTF than did the control group (P < 0.01). AUMTF determined from both the techniques demonstrated significant correlations with nuclear opacities, higher-order aberrations (HOAs), visual acuity, and contrast sensitivity functions, while the OQAS-derived AUMTF also demonstrated significant correlations with age and cortical opacity grade. The factors significantly affecting the difference between iTrace and OQAS AUMTF were root-mean-squared HOAs (standardized beta coefficient = -0.63, P < 0.01) and age (standardized beta coefficient = 0.26, P < 0.01). CONCLUSIONS: MTFs determined from a iTrace and a DP system (OQAS) differ significantly in early cataractous and normal subjects. Correlations with visual performance were higher for the DP system. OQAS-derived MTF may be useful as an indicator of visual performance in early cataract eyes.

Cold water immersion enhances recovery of submaximal muscle function after resistance exercise

We investigated the effect of cold water immersion (CWI) on the recovery of muscle function and physiological responses following high-intensity resistance exercise. Using a randomized, cross-over design, 10 physically active men performed high-intensity resistance exercise, followed by one of two recovery interventions: 10 min of cold water immersion at 10°C, or 10 min active recovery (low-intensity cycling). After the recovery interventions, maximal muscle function was assessed after 2 h and 4 h by measuring jump height and isometric squat strength. Submaximal muscle function was assessed after 6 h by measuring the average load lifted during six sets of 10 squats at 80% 1RM. Intramuscular temperature (1 cm) was also recorded, and venous blood samples were analyzed for markers of metabolism, vasoconstriction and muscle damage. CWI did not enhance recovery of maximal muscle function. However, during the final three sets of the submaximal muscle function test, the participants lifted a greater load (p<0.05; 38%; Cohen’s d 1.3) following CWI compared with active recovery. During CWI, muscle temperature decreased 6°C below post-exercise values, and remained below pre-exercise values for another 35 min. Venous blood O2 saturation decreased below pre-exercise values for 1.5 h after CWI. Serum endothelin-1 concentration did not change after CWI, whereas it decreased after active recovery. Plasma myoglobin concentration was lower, whereas plasma interleukin-6 concentration was higher after CWI compared with active recovery. These results suggest that cold water immersion after resistance exercise allow athletes to complete more work during subsequent training sessions, which could enhance long-term training adaptations.

Effect of tocopherol on atherosclerosis, vascular function and inflammation in Apolipoprotein E knockout mice with subtotal nephrectomy

Background/Aims: Inflammation and endothelial dysfunction contribute to cardiovascular disease, prevalent in chronic kidney disease (CKD). Antioxidant supplements such as tocopherols may reduce inflammation and atherosclerosis. This study aimed to investigate the effect of tocopherol supplementation on vascular function, aortic plaque formation, and inflammation in apolipoprotein E−/− mice with 5/6 nephrectomy as a model of combined cardiovascular and kidney disease. Methods: Nephrectomized mice were assigned to a normal chow diet group (normal chow), a group receiving 1000 mg/kg diet of α-tocopherol supplementation or a group receiving 1000 mg/kg diet mixed-tocopherol (60% γ-tocopherol). Results: Following 12 weeks, in vitro aortic endothelial-independent relaxation was enhanced with both α-tocopherol and mixed-tocopherol (P < 0.05), while mixed-tocopherol enhanced aortic contraction at noradrenaline concentrations of 3 × 10−7 M to 3 × 10−5 M (P < 0.05), when compared to normal chow. Supplementation with α- and mixed-tocopherol reduced systemic concentrations of IL-6 (P < 0.001 and P < 0.001, respectively) and IL-10 (P < 0.05 and P < 0.001, respectively), while α-tocopherol also reduced MCP-1 (P < 0.05) and tumor necrosis factor (TNF)-α (P < 0.05). Aortic sinus plaque area was significantly reduced with α-tocopherol supplementation when compared to normal chow (P < 0.01). Conclusion: Tocopherol supplementation favorably influenced vascular function and cytokine profile, while it was also effective in reducing atherosclerosis in the apolipoprotein E−/− mouse with CKD.

Head-of-bed elevation improves end-expiratory lung volumes in mechanically ventilated subjects : a prospective observational study

BACKGROUND: Head-of-bed elevation (HOBE) has been shown to assist in reducing respiratory complications associated with mechanical ventilation; however, there is minimal research describing changes in end-expiratory lung volume. This study aims to investigate changes in end-expiratory lung volume in a supine position and 2 levels of HOBE. METHODS: Twenty postoperative cardiac surgery subjects were examined using electrical impedance tomography. End-expiratory lung impedance (EELI) was recorded as a surrogate measurement of end-expiratory lung volume in a supine position and at 20° and then 30°. RESULTS: Significant increases in end-expiratory lung volume were seen at both 20° and 30° HOBE in all lung regions, except the anterior, with the largest changes from baseline (supine) seen at 30°. From baseline to 30° HOBE, global EELI increased by 1,327 impedance units (95% CI 1,080–1,573, P < .001). EELI increased by 1,007 units (95% CI 880–1,134, P < .001) in the left lung region and by 320 impedance units (95% CI 188–451, P < .001) in the right lung. Posterior increases of 1,544 impedance units (95% CI 1,405–1,682, P < .001) were also seen. EELI decreased anteriorly, with the largest decreases occurring at 30° (−335 impedance units, 95% CI −486 to −183, P < .001). CONCLUSIONS: HOBE significantly increases global and regional end-expiratory lung volume; therefore, unless contraindicated, all mechanically ventilated patients should be positioned with HOBE.

Acoustic identification of 12 species of echolocating bat by discriminant function analysis and artificial neural networks

We recorded echolocation calls from 14 sympatric species of bat in Britain. Once digitised, one temporal and four spectral features were measured from each call. The frequency-time course of each call was approximated by fitting eight mathematical functions, and the goodness of fit, represented by the mean-squared error, was calculated. Measurements were taken using an automated process that extracted a single call from background noise and measured all variables without intervention. Two species of Rhinolophus were easily identified from call duration and spectral measurements. For the remaining 12 species, discriminant function analysis and multilayer back-propagation perceptrons were used to classify calls to species level. Analyses were carried out with and without the inclusion of curve-fitting data to evaluate its usefulness in distinguishing among species. Discriminant function analysis achieved an overall correct classification rate of 79% with curve-fitting data included, while an artificial neural network achieved 87%. The removal of curve-fitting data improved the performance of the discriminant function analysis by 2 %, while the performance of a perceptron decreased by 2 %. However, an increase in correct identification rates when curve-fitting information was included was not found for all species. The use of a hierarchical classification system, whereby calls were first classified to genus level and then to species level, had little effect on correct classification rates by discriminant function analysis but did improve rates achieved by perceptrons. This is the first published study to use artificial neural networks to classify the echolocation calls of bats to species level. Our findings are discussed in terms of recent advances in recording and analysis technologies, and are related to factors causing convergence and divergence of echolocation call design in bats.

A hybrid quality function deployment and cybernetic analytic network process model for project manager selection

Identifying appropriate decision criteria and making optimal decisions in a structured way is a complex process. This paper presents an approach for doing this in the form of a hybrid Quality Function Deployment (QFD) and Cybernetic Analytic Network Process (CANP) model for project manager selection. This involves the use of QFD to translate the owner's project management expectations into selection criteria and the CANP to weight the expectations and selection criteria. The supermatrix approach then prioritises the candidates with respect to the overall decision-making goal. A case study is used to demonstrate the use of the model in selecting a renovation project manager. This involves the development of 18 selection criteria in response to the owner's three main expectations of time, cost and quality.

Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans

The authors used data collected from 1995 to 1999, from an on-going cancer case–control study in greater Johannesburg, to estimate the importance of tobacco and alcohol consumption and other suspected risk factors with respect to cancer of the oesophagus (267 men and 138 women), lung (105 men and 41 women), oral cavity (87 men and 37 women), and larynx (51 men). Cancers not associated with tobacco or alcohol consumption were used as controls (804 men and 1370 women). Tobacco smoking was found to be the major risk factor for all of these cancers with odds ratios ranging from 2.6 (95% CI 1.5–4.5) for oesophageal cancer in female ex-smokers to 50.9 (95% CI 12.6–204.6) for lung cancer in women, and 23.9 (95% CI 9.5–60.3) for lung cancer and 23.6 (95% CI 4.6–121.2) for laryngeal cancer in men who smoked 15 or more grams of tobacco a day. This is the first time an association between smoking and oral and laryngeal cancers has been shown in sub-Saharan Africa. Long-term residence in the Transkei region in the southeast of the country continues to be a risk factor for oesophageal cancer, especially in women (odds ratio=14.7, 95% CI 4.7–46.0), possibly due to nutritional factors. There was a slight increase in lung cancer (odds ratio=2.9, 95% CI 1.1–7.5) in men working in ‘potentially noxious’ industries. ‘Frequent’ alcohol consumption, on its own, caused a marginally elevated risk for oesophageal cancer (odds ratio=1.7, 95% CI 1.0–2.9, for women and odds ratio=1.8, 95% CI 1.2–2.8, for men). The risks for oesophageal cancer in relation to alcohol consumption increased significantly in male and female smokers (odds ratio=4.7, 95% CI=2.8–7.9 in males and odds ratio=4.8, 95% CI 3.2–6.1 in females). The above results are broadly in line with international findings.

Lung sickness in Murri kids : a cohort study in urban Indigenous children

QLD, 4Murri Health Group, Caboolture, QLD Introduction Respiratory illnesses with cough as a symptom are predominant causes of morbidity in young Australian Indigenous children. With the exception of ear disease, there are limited studies that have addressed burden and outcome. Also, there are no studies that are specific to urban Indigenous children. Aim: We aim to comprehensively investigate the incidence, aetiology, risk factors for and outcomes of acute respiratory illnesses (ARIs) in this population. Methods A cohort study of Indigenous children aged less than 5 years registered with an urban Indigenous primary health care service. Comprehensive baseline data are collected and children are followed monthly for 12 months to capture ARI events. ARI events are subsequently followed weekly for 4 weeks to determine cough outcomes, with review by a paediatric respiratory physician if cough has not resolved within 28 days. Results To date, 58 children (57% female) have been enrolled and 46 ARIs have been captured over 907 child weeks of observation (5.1 events per 100 child weeks, 95%CI 3.7–6.8). 13 ARIs (28.3%) have resulted in persistent cough for >28 days following onset. Conclusion Our early findings suggest an excess incidence of ARI in this population. The proportion of ARIs resulting in persistent cough for more than 4 weeks is the highest yet reported. Key Words: Indigenous, acute respiratory illness, paediatric.