Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.     

Societal cost of cancer in Norway –Results of taking a broader cost perspective

BackgroundThe broader cost consequences of diseases may be of interest for a wide range of stakeholders. We aimed to estimate all relevant societal costs of cancer and to provide insight into the relative magnitude of the different cost categories.MethodWe used data from eight different health and work-related registries in Norway. Direct, indirect, and intangible costs (value of lost life years) were estimated over a period of one year with a combination of a top-down and a bottom-up costing approach.ResultsThe indirect costs (EUR 1,997 million per year) are almost as high as direct costs (EUR 2,154 million), and the value of lost life years and quality of life represents the greatest cost related to cancer (EUR 18,200 million). In addition, cancer is associated with other costs which are commonly omitted from cost-of-illness analyses, including informal nursing (EUR 306 million), patient time costs (EUR 85 million), and excess costs of using public funds (EUR 439 million). Breast and cervical cancer had relatively high work absenteeism costs, while pancreatic and lung cancer had relatively high production costs due to premature deaths.DiscussionDirect health care costs represent small proportions of the total societal costs of cancer. Costs commonly omitted in cost-of-illness analyses represent a significant cost and should be measured and valued in these analyses.     

Mediastinitis after coronary artery bypass grafting increases the incidence of left internal mammary artery obstruction

Mediastinitis after coronary artery bypass grafting (CABG) gives a longstanding chronic inflammation and has a detrimental negative effect on long‐term survival. For this reason, we aimed to study the effect of mediastinitis on graft patency after CABG. The epidemiologic design was of an exposed (mediastinitis, n = 41) versus non‐exposed (non‐mediastinitis, controls, n = 41) cohort with two endpoints: (i) obstruction of saphenous vein grafts (SVG) and (ii) obstruction of the internal mammary artery (IMA) grafts. The graft patency was evaluated with coronary CT‐angiography examination at a median follow‐up of 2·7 years. The number of occluded SVG in the mediastinitis group was 18·9% versus 15·5% in the control group. Using generalized estimating equations model with exchangeable matrix, and confounding effect of ischaemic time and patients age, we found no significant association between presence of mediastinitis and SVG obstruction [rate ratio (RR) = 0·96, 95% CI (0·52–2·67), P = 0·697]. The number of occluded IMA grafts was 10·5% in the mediastinitis group and 2·4% in the control group. Using the Poisson regression model, we estimated RR = 5·48, 95% CI (1·43–21·0) and P = 0·013. There was a significant association between mediastinitis and IMA graft obstruction, when controlling for the confounding effect of ischaemic time, body mass index, presence of diabetes mellitus and the number of diseased vessels. Presence of mediastinitis increases the risk of IMA graft obstruction. This may confirm the importance of inflammation as a major contributor to the pathogenesis of atherosclerosis and explain the negative effect of mediastinitis on a long‐term survival.     

Mediastinitis after coronary artery bypass grafting: the effect of vacuum‐assisted closure versus traditional closed drainage on survival and re‐infection rate

Mediastinitis is treated with either vacuum‐assisted closure (VAC) or traditional closed drainage (TCD) with irrigation. The aim of the study was to determine the effect of the two treatments on mortality and re‐infection rate in a source population, using 21 314 consecutive patients undergoing isolated coronary artery bypass grafting (CABG) from January 1997 to October 2010. Median observation time was 2·9 years in the VAC group and 8·0 years in the TCD group. The epidemiological design was of an exposed (VAC, n = 64) versus non‐exposed (TCD, n = 66) cohort with two endpoints: (1) mortality and (2) failure of sternal wound healing or re‐infection. The crude effect of treatment technique versus endpoint was estimated by univariate analysis. Stratification analysis by the Mantel–Haenszel method was performed to quantify confounders and to pinpoint effect modifiers. Adjustment for confounders was performed using Cox regression analysis. Mediastinitis was diagnosed 6–105 (median 14) days after primary operation in the VAC group and 13 (5–29) days in the TCD group. There was no difference between groups in long‐term survival. Failure of sternal wound healing or re‐infection occurred less frequently in the VAC group (6%) than in the TCD group (21%; relative risk = 0·29, 95% CI = 0·06–0·88, P = 0·01). There are concerns for increase in right ventricle rupture in VAC compared with TCD. There was no difference in survival after VAC therapy and TCD therapy of post‐CABG mediastinitis. Failure of sternal wound healing or re‐infection was more common after TCD therapy.     

The acetabulum in Perthes’ disease: Inter-observer agreement and reliability of radiographic measurements

Background and purpose

Perthes’ disease leads to radiographic changes in both the femoral head and the acetabulum. We investigated the inter-observer agreement and reliability of 4 radiographic measurements assessing the acetabular changes.

Patients and methods

We included 123 children with unilateral involvement, femoral head necrosis of more than 50%, and age at diagnosis of 6 years or older. Radiographs were taken at onset, and 1 year and 5 years after diagnosis. Sharp’s angle, acetabular depth-width ratio (ADR), lateral acetabular inclination (LAI), and acetabular retroversion (ischial spine sign, ISS) were measured by 3 observers. Before measuring, 2 of the observers had a consensus meeting.

Results

We found good agreement and moderate to excellent reliability for Sharp’s angle for all observers (intra-class correlation coefficient (ICC) > 0.80 with consensus, ICC = 0.46–0.57 without consensus). There was good agreement and substantial reliability for ADR between the observers who had had a consensus meeting (ICC = 0.62–0.89). Low levels of agreement and poor reliability were found for observers who had not had a consensus meeting. LAI showed fair agreement throughout the course of the disease (kappa = 0.28–0.52). The agreement between observations for ISS ranged from fair to good (kappa = 0.20–0.76).

Interpretation

Sharp’s angle showed the highest reliability and agreement throughout the course of the disease. ADR was only reliable and showed good agreement between the observers when landmarks were clarified before measuring the radiographs. Thus, we recommend both parameters in clinical practice, provided a consensus is established for ADR. The observations for LAI had only fair agreement and ISS showed inconclusive agreement in our study. Thus, LAI and ISS can hardly be recommended in clinical practice.Perthes’ disease leads to typical radiographic changes of the femoral head. Several authors have described simultaneous changes of the acetabular anatomy, such as hypertrophy, bicompartmental development, retroversion, and dysplastic changes (Yngve and Roberts 1985, Joseph 1989, Ezoe et al. 2006).Most measurements describing the radiographic changes of the acetabulum on anteroposterior (AP) pelvic radiographs have been validated in children with hip dysplasia. As the hip pathology and the morphological changes in Perthes’ disease are different from those in hip dysplasia, we wanted to assess inter-observer reliability and agreement of 4 commonly used acetabular measurements at the different stages of skeletal maturity in Perthes’ disease.