The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Video-Assisted Thoracoscopic Versus Robotic-Assisted Thoracoscopic Thymectomy: Systematic Review and Meta-analysis.

OBJECTIVE: Minimally invasive thoracic surgical procedures, performed with or without the assistance of a robot, have gained popularity over the last decade. They have increasingly become the choice of intervention for a number of thoracic surgical operations. Minimally invasive surgery decreases postoperative pain, hospital stay and leads to a faster recovery in comparison with conventional open methods. Minimally invasive techniques to perform a thymectomy include video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS). In this study, we aim to systematically review and interrogate the literature on minimally invasive thymectomy and draw a meta-analysis on the outcomes between the two approaches. METHODS: An extensive electronic health database search was performed on all articles published from inception to May 2015 for studies describing outcomes in VATS and RATS thymectomy. RESULTS: A total of 350 patients were included in this study, for which 182 and 168 patients underwent RATS and VATS thymectomy, respectively. There were no recorded in-hospital deaths for either procedure. There was no statistical difference in conversion to open, length of hospital stay, or postoperative pneumonia. Operational times for RATS thymectomy were longer. CONCLUSIONS: The VATS and RATS thymectomy offer good and safe operative and perioperative outcomes. There is little difference between the two groups. However, there is poor evidence basis for the long-term outcomes in minimally invasive procedures for thymectomy. It is imperative that future studies evaluate oncological outcomes both short and long term as well as those related to safety.

Cardiac comorbidity is not a risk factor for mortality and morbidity following surgery for primary non-small cell lung cancer.

OBJECTIVE: We examined the effect of cardiac comorbidity on mortality and postoperative complications following surgery for primary non-small cell lung cancer. METHODS: Between October 2001 to December 2005, 1067 consecutive patients underwent lung resection for primary cancer within a single centre; patient data was collected prospectively. Two hundred and seventy-one patients had a history of cardiac comorbidity, which included 196 angina, 118 myocardial infarction, 36 revascularisation, 10 congestive cardiac failure and 19 rhythm disorders (numbers not mutually exclusive). To account for differences in case-mix we used logistic regression to develop a propensity score for cardiac comorbidity group membership and then performed a propensity-matched analysis. Kaplan-Meier curves were used to assess follow-up mortality. RESULTS: Patients with cardiac comorbidity were more likely to be hypertensive, have severe dyspnoea, diabetes, current or ex-smokers and were older. After performing propensity matching to account for these differences we successfully matched 199 patients with cardiac comorbidity to 398 patients with no cardiac history. There was no difference in in-hospital mortality (2.5% vs 3%, p=0.73), myocardial infarction (0.5% vs 0.3%, p>0.99), arrhythmia (15.6% vs 14.1%, p=0.62), renal failure (2% vs 1.5%, p=0.65), stroke (0.5% vs 0.3%, p>0.99), respiratory insufficiency (4% vs 3.3%, p=0.64), reintubation (1% vs 2.5%, p=0.35), tracheostomy (4% vs 7.8%, p=0.08), intensive care readmission (8.5% vs 6.5%, p=0.37) and length of stay (8 days vs 8 days, p=0.98). Three-year survival was similar (61.4% vs 56.2%, p=0.39). No differences in outcomes existed with different cardiac conditions. CONCLUSION: With careful assessment and patient selection, patients with cardiac comorbidity were not found to be at increased risk of mortality and morbidity following lung resection for primary non-small cell lung cancer in a propensity-matched population.

Attenuation of receptor-dependent and -independent vasoconstriction in the human radial artery.

BACKGROUND: Vasodilator strategies used to treat bypass grafts in the operating theatre, such as nitrates, phosphodiesterase inhibitors and calcium channel antagonists have a broad but short-lived effect against a variety of vasoconstrictor stimuli. Treatments that react irreversibly with proteins modulating vasoconstriction have the advantage that their effects can last well into the postoperative period. In addition systemic effects are avoided as the treatment is localised to the treated graft. This study investigated the use of two clinically applied drugs; fluphenazine (SKF7171A, HCl), an irreversible calmodulin antagonist and minoxidil sulphate, an irreversible potassium channel opener. Treatments were tested against receptor and non-receptor-mediated contraction in the human radial artery. METHOD: Isometric tension was measured in response to angiotensin II, KCl and vasopressin in 108 radial artery rings (taken from 31 patients undergoing coronary artery bypass grafting). Control responses were compared with rings pretreated with fluphenazine or minoxidil sulphate. Vasopressin responses were also compared in the presence of glyceryl trinitrate or the reversible Rho kinase inhibitor Y27632. RESULTS: Fluphenazine pretreatment significantly suppressed vasoconstriction to all agonists tested. Maximal responses to angiotensin II, vasopressin and KCl were reduced by 42+/-19%, 35+/-8% and 48+/-15% respectively, without any measurable effect on the EC(50). Minoxidil sulphate showed no discernable effect. Vasopressin-induced contraction was also reduced by high levels of glyceryl trinitrate (220 microM; 50 microg/ml) or 10 microM Y27632. CONCLUSIONS: The irreversible calmodulin antagonist fluphenazine has potential to be developed as an inhibitor of contraction in arterial graft vessels. The involvement of Rho kinase indicates that other vasoconstrictors and surgical stress can sensitize radial artery to vasopressin-induced contraction. Strategies targeting this pathway also have future potential.

Intrapleural instillation of autologous blood in the treatment of prolonged air leak after lobectomy: a prospective randomized controlled trial.

BACKGROUND: The aim of this study was to assess the value of instilling autologous blood into the pleural cavity to seal prolonged air leaks after lobectomy. METHODS: Of 319 lobectomies performed over an 18-month period, 22 patients (6.9%) experienced prolonged air leak (more than 5 days after surgery). Twenty patients consented to be randomly assigned to one of two treatment pathways. The study group received instillation of 120 mL autologous blood into their apical chest drain on the fifth postoperative day, and again if the air leak persisted on days 7 and 9 respectively. No anticoagulation was used for this blood. The control group continued to be treated by tube thoracostomy alone, but if the air leak was still present on the 10th postoperative day they "crossed over" and underwent intrapleural installation of blood as in the study group. RESULTS: After instillation of blood, the air leak was sealed by the next day in 58.6% of treatments. The median length of air leak was 5 days in the study group and 11 days in the control group (p < 0.001). Time to chest drain removal (median 6.5 days versus 12 days) and hospital discharge (median 8 days versus 13.5 days) were both significantly (p < 0.001) shorter in the study group. CONCLUSIONS: This technique is effective in sealing air leaks after lobectomy. It allows earlier chest drain removal and shortens hospital stay.

Surgical treatment of anastomotic leaks after oesophagectomy.

OBJECTIVE: To determine the optimum management of anastomotic leaks after oesophagectomy. METHODS: We undertook a retrospective review of 23 patients who developed anastomotic leakage, out of 389 patients undergoing oesophagectomy with gastric interposition. The presentation, diagnosis, and treatment of the leaks, and patient outcomes are analysed. RESULTS: Leaks occurred from 3 to 23 (median=7.5) days after surgery. Clinical features included fever (57%), leucocytosis (52%), dysphagia (4%), coughing bile (4%), wound infection (13%), pneumothorax (35%), pleural effusion (70%) and septicaemia (70%). All but one leak was due to variable degree of gastric tip necrosis. Contrast swallow showed leakage in only 14 (61%) patients, whereas oesophagoscopy confirmed all the leaks. Surgical treatment (resection of necrotic stomach and either immediate or staged re-anastomosis, or end-oesophageal exteriorisation) was the primary treatment in 17 patients of whom 15 survived to discharge. Two out of the 6 patients treated non-surgically died. CONCLUSIONS: Diagnosis of anastomotic leakage after oesophagectomy is difficult due to its variable presentation and the unreliability of contrast swallow. Gastric tip necrosis is by far the most common cause. We feel our preferred strategy of immediate surgical treatment of symptomatic leaks is justified by the favourable outcome in the majority of patients.

Left internal mammary artery use in patients with poor left ventricular ejection fraction: a propensity-matched analysis of mid-term survival.

We aimed to determine whether the use of left internal mammary artery (LIMA) to the left anterior descending (LAD) artery during coronary artery bypass grafting (CABG) confers an improved survival benefit to patients with an impaired preoperative left ventricular ejection fraction (LVEF). Between April 1997 and March 2004, 7198 consecutive patients underwent first time CABG to the LAD. There were 627 patients who had an LVEF <30% and of these, 548 patients (87.4%) received a LIMA graft, while 79 patients (12.6%) did not. A propensity-matched analysis was performed to provide matched cohorts for analysis of deaths occurring over time, which were described using Kaplan-Meier techniques. Propensity-matching produced two cohorts of 77 patients with or without the use of LIMA. Patient characteristics were reasonably matched between the groups. Forty-six (29.9%) deaths occurred in the propensity-matched groups. Freedom from death in patients with LIMA used at 4-years was 77.1%, compared with 60.7% for the patients with no LIMA used (P=0.026). The use of the LIMA as a bypass conduit is not contraindicated in patients with a poor preoperative LVEF. The usage of LIMA markedly improves survival.

Phenoxybenzamine treatment is insufficient to prevent spasm in the radial artery: the effect of other vasodilators.

OBJECTIVES: After its reintroduction as an arterial graft in coronary artery surgery, the radial artery is now established as an alternative arterial conduit, with good early and midterm patency. However, because of the concern about its vasospasticity, numerous vasodilator strategies have been used. Recently the use of the irreversible alpha-adrenergic antagonist phenoxybenzamine has been proposed. Although this treatment is effective in eliminating the vasoconstriction mediated by noradrenaline, the contribution of other circulating vasoconstrictors to vasospasm could be as important. This study investigates the response of radial arteries treated with phenoxybenzamine to vasoconstrictor stimuli and possible preventative strategies. METHODS: In vitro, sections of radial artery, pretreated with phenoxybenzamine after harvesting, were stimulated with maximal concentrations of the vasoconstrictors noradrenaline, vasopressin, angiotensin II, KCl, and endothelin-1. In matched segments of artery, vasoconstrictor responses were recorded in the presence of diltiazem, glyceryl trinitrate, and papaverine and compared with phenoxybenzamine-treated samples. RESULTS: Phenoxybenzamine-treated radial artery failed to respond to noradrenaline but did respond to vasopressin, angiotensin II, endothelin-1, and KCl. Diltiazem was largely ineffective against contractile stimuli apart from KCl. Glyceryl trinitrate and papaverine significantly reduced responses to all of the vasoconstrictors tested. CONCLUSION: In phenoxybenzamine-treated sections of radial artery, circulating vasoconstrictor agonists may still contribute to the induction of spasm. Additional vasodilator strategies may be required to completely prevent vasospasm.

Preoperative beta-blocker therapy in coronary artery bypass surgery: a propensity score analysis of outcomes.

Preoperative beta-blockade in patients undergoing coronary artery bypass grafting (CABG) has recently been shown to be beneficial in improving the early outcomes after surgery. We aimed to quantify the effect of preoperative beta-blockade on outcomes in our own patient population. We performed a retrospective analysis on CABG patients identified from our prospectively collected cardiac surgery database. Logistic regression was used to adjust in-hospital outcomes for differences in patient and disease characteristics. Treatment selection bias was controlled by deriving a propensity score for beta-blocker therapy. Consecutive patients (4381) underwent CABG on cardiopulmonary bypass between 1 April 1997 and 31 March 2002, with 2836 (64.7%) on preoperative beta-blocker therapy. After adjustment with the propensity score, beta-blocker therapy was significantly associated with a reduction in post-operative stroke (adjusted OR 0.59, p=0.011). The incidence of atrial arrhythmia was significantly increased in patients who had received preoperative beta-blockers (adjusted OR 1.21, p=0.011). There were no significant differences in operative mortality or other morbidity outcomes. Preoperative beta-blocker therapy significantly reduces the incidence of post-operative cerebrovascular events in patients undergoing on-pump coronary artery bypass surgery.