Y disruption, autosomal hypomethylation and poor male lung cancer survival.

Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA-IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40-10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P = 1.2 × 10-10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small-cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.

A centralised respiratory diagnostic service for primary care: a 4-year audit.

BACKGROUND: The literature shows that delayed or erroneous diagnosis of respiratory conditions may be common in primary care due to underuse of spirometry or poor spirometric technique. The Community Respiratory Assessment Unit (CRAU) was established to optimise diagnosis and treatment of respiratory disease by providing focused history-taking, quality-assured spirometry, and evidence-based guideline-derived management advice. AIMS: To review the service provided by the CRAU to primary care health professionals. METHODS: Data from 1,156 consecutive GP referrals over 4 years were analysed. RESULTS: From the 1,156 referrals, 666 were referred for one of five common reasons: suspected asthma, confirmed asthma, suspected chronic obstructive pulmonary disease (COPD), confirmed COPD, or unexplained breathlessness. COPD was the most prevalent referral indication (445/666, 66.8%), but one-third of suggested diagnoses of COPD by the GP were found to be incorrect (161/445, 36%) with inappropriate prescribing of inhaled therapies resulting from this misdiagnosis. Restrictive pulmonary defects (56/666, 8% of referrals) were overlooked and often mistaken for obstructive conditions. The potential for obesity to cause breathlessness may not be fully appreciated. CONCLUSIONS: Misdiagnosis has significant financial, ethical, and safety implications. This risk may be minimised by better support for primary care physicians such as diagnostic centres (CRAU) or alternative peripatetic practice-based services operating to quality-controlled standards.

Surgical management of Gynaecomastia: outcomes from our experience.

The study aims to assess the morbidity and outcomes associated with gynaecomastia surgery. Between 1998 and 2007, 748 males with a mean age 44.67 years (10-90) were referred to us with breast-related symptoms. From these only 65 patients (102 breasts), with a median age of 26 years (11-82) had an operation for gynaecomastia. We considered for the purpose of the study each operated breast as an individual case. Overall, 42 cases of grade I gynaecomastia, 40 with grade II and 20 with grade III were treated mainly with subcutaneous mastectomies, 22 with skin reduction. Acute major complications requiring intervention occurred in 12 cases. Twenty-three cases required a late corrective operation for unsatisfactory results. The surgical approach appears to be the most important determinant of good cosmesis with the circumareolar approach to give the better results. The majority of the patients can be managed conservatively. Surgical candidates should be made aware of the significant morbidity.