Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AIMS: Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo. METHODS AND RESULTS: We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans. CONCLUSION: Combined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes.

RATIONALE: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. OBJECTIVE: To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. METHODS AND RESULTS: In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type; P<0.01), because of sarcoplasmic reticulum Ca(2+) ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na(+)/Ca(2+) exchanger current is the main driver in translating Ca(2+) fluctuations into RA. CONCLUSIONS: In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.

Effect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart.

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.

Endobronchial ultrasound-guided transbronchial needle aspiration prevents mediastinoscopies in the diagnosis of isolated mediastinal lymphadenopathy: a prospective trial.

RATIONALE: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer. OBJECTIVE: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML. METHODS: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy. MEASUREMENTS AND MAIN RESULTS: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient. CONCLUSIONS: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854).

A governing equation for rotor and wavelet number in human clinical ventricular fibrillation: Implications for sudden cardiac death.

BACKGROUND: Ventricular fibrillation (VF) is characterized by multiple wavelets and rotors. No equation to predict the number of rotors and wavelets observed during fibrillation has been validated in human VF. OBJECTIVE: The purpose of this study was to test the hypothesis that a single equation derived from a Markov M/M/∞ birth-death process could predict the number of rotors and wavelets occurring in human clinical VF. METHODS: Epicardial induced VF (256-electrode) recordings obtained from patients undergoing cardiac surgery were studied (12 patients; 62 epochs). Rate constants for phase singularity (PS) (which occur at the pivot points of rotors) and wavefront (WF) formation and destruction were derived by fitting distributions to PS and WF interformation and lifetimes. These rate constants were combined in an M/M/∞ governing equation to predict the number of PS and WF in VF episodes. Observed distributions were compared to those predicted by the M/M/∞ equation. RESULTS: The M/M/∞ equation accurately predicted average PS and WF number and population distribution, demonstrated in all epochs. Self-terminating episodes of VF were distinguished from VF episodes requiring termination by a trend toward slower PS destruction, slower rates of PS formation, and a slower mixing rate of the VF process, indicated by larger values of the second largest eigenvalue modulus of the M/M/∞ birth-death matrix. The longest-lasting PS (associated with rotors) had shorter interactivation time intervals compared to shorter-lasting PS lasting <150 ms (∼1 PS rotation in human VF). CONCLUSION: The M/M/∞ equation explains the number of wavelets and rotors observed, supporting a paradigm of VF based on statistical fibrillatory dynamics.

Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans.

BACKGROUND: Diffuse myocardial fibrosis is a final end point in most cardiac diseases. It is missed by the cardiovascular magnetic resonance (CMR) late gadolinium enhancement technique. Currently, quantifying diffuse myocardial fibrosis requires invasive biopsy, with inherent risk and sampling error. We have developed a robust and noninvasive technique, equilibrium contrast CMR (EQ-CMR) to quantify diffuse fibrosis and have validated it against the current gold standard of surgical myocardial biopsy. METHODS AND RESULTS: The 3 principles of EQ-CMR are a bolus of extracellular gadolinium contrast followed by continuous infusion to achieve equilibrium; a blood sample to measure blood volume of distribution (1-hematocrit); and CMR to measure pre- and postequilibrium T1 (with heart rate correction). The myocardial volume of distribution is calculated, reflecting diffuse myocardial fibrosis. Clinical validation occurred in patients undergoing aortic valve replacement for aortic stenosis or myectomy in hypertrophic cardiomyopathy (n=18 and n=8, respectively). Surgical biopsies were analyzed for picrosirius red fibrosis quantification on histology. The mean histological fibrosis was 20.5+/-11% in aortic stenosis and 17.1+/-7.4% in hypertrophic cardiomyopathy. EQ-CMR correlated strongly with biopsy histological fibrosis: aortic stenosis, r(2)=0.86, Kendall Tau coefficient (T)=0.71, P<0.001; hypertrophic cardiomyopathy, r(2)=0.62, T=0.52, P=0.08; combined r(2)=0.80, T=0.67, P<0.001. CONCLUSIONS: We have developed and validated a new technique, EQ-CMR, to measure diffuse myocardial fibrosis as an add-on to a standard CMR scan, which allows for the noninvasive quantification of the diffuse fibrosis burden in myocardial diseases.

Failure to recapture cardioprotection with high-dose atorvastatin in coronary artery bypass surgery: a randomised controlled trial.

The acute administration of atorvastatin has been reported to reduce myocardial infarct size in animal studies. However, this cardioprotective effect is lost with the chronic administration of atorvastatin, although it can be recaptured by administering an acute high-dose of atorvastatin. We hypothesised that pre-treatment with high-dose atorvastatin, on a background of chronic standard 'statin' therapy, would reduce myocardial injury in patients undergoing elective coronary artery bypass graft (CABG) surgery. One hundred and one consenting patients undergoing elective CABG surgery at a single tertiary cardiac centre were recruited into two randomised controlled, single-blinded clinical studies. Study 1: 45 patients were randomised to receive either 160 mg of atorvastatin 2 h preoperatively and 24 h following surgery or their standard statin therapy. Study 2: 56 patients were randomised to receive either 160 mg of atorvastatin 12 h preoperatively and 24 h following surgery or their standard statin therapy. Blood samples for troponin T and creatine kinase were taken prior to surgery and then at 6, 12, 24, 48 and 72 h post-surgery. Cardiac enzyme levels at each time point and the total area-under curve (AUC) were calculated. The group characteristics and surgical methods were well matched. High-dose atorvastatin was not associated with any significant side effects. There was no significant difference in serum troponin T or creatine kinase in either study at each time point or over 72 h. Study 1: AUC, troponin T: atorvastatin 29.6 ± 34.8 µg/L versus control 25.0 ± 22.0 µg/L:P > 0.05. Creatine kinase: atorvastatin 33,544 ± 20,063 IU/L versus control 30,620 ± 10,776 IU/L:P > 0.05. Study 2: AUC, troponin T: atorvastatin 21.8 ± 14.3 µg/L versus control 20.9 ± 8.7 µg/L:P > 0.05. Creatine kinase: atorvastatin 36,262 ± 28,821 IU/L versus control 33,448 ± 14,984:P > 0.05. There were no differences in postoperative outcomes. We report that the administration of high-dose atorvastatin to low risk patients undergoing elective CABG surgery, who are already on standard dose 'statin' therapy is safe, but does not further reduce perioperative myocardial injury.

Maintaining safe lung cancer surgery during the COVID-19 pandemic in a global city.

BACKGROUND: SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection. METHODS: This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up. FINDINGS: 352 patients underwent anatomical lung resection with a median age of 69 (IQR: 35-86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively (MIS), compared to 59.9% pre pandemic. Median LOS was 6 days with a 30-day survival of 98.3% (comparable to a median LOS of 6 days and 30-day survival of 98.4% pre-pandemic). Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3-4) and 12 there were re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%). INTERPRETATION: SARS-CoV-2 infection significantly increases morbidity and mortality in patients undergoing elective anatomical pulmonary resection. However, surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients. FUNDING: This work did not receive funding.

The insidious presentation and challenging management of esophageal perforation following diagnostic and therapeutic interventions.

Diagnostic and therapeutic interventions on the esophagus or adjacent organs are responsible for nearly half of all esophageal perforations. If not recognized at the time of the injury, iatrogenic esophageal perforations can present insidiously and lead to delay in diagnosis, thereby increasing morbidity and mortality. Acute clinical awareness is vital for prompt diagnosis, which is usually confirmed with contrast esophagography and contrast-enhanced computed tomography. After establishment of diagnosis, treatment should be promptly initiated and include fluid-volume resuscitation, cessation of oral intake, nasogastric tube insertion, broad-spectrum antibiotics and analgesia. Primary repair, when feasible, is the treatment of choice. Additional procedures beyond primary repair, such as relief of concomitant obstruction, may be necessary if there is underlying esophageal pathology. Drainage alone can be performed for perforations of the cervical esophagus that cannot be visualized. Esophageal T-tube placement or exclusion and diversion techniques are appropriate in clinically unstable patients and in cases where primary repair is precluded either due to preexisting esophageal disease or extensive esophageal damage. Esophagectomy should be performed in patients with malignancy, end-stage benign esophageal disease or extensive esophageal damage that precludes repair. Endoscopic techniques, including stenting, clipping or vacuum therapy, can be used in select cases. Finally, nonoperative management should be reserved for patients with contained esophageal perforations, limited extraluminal soilage and no evidence of systemic inflammation.

Carcinoma of unknown primary abuts left clavicle: Case report and review of the literature.

INTRODUCTION: Carcinoma of unknown primary is a well-recognized clinical syndrome which accounts for the 3-5% of all the malignancies. Patients with carcinoma of unknown primary usually present with late stage disease without having identified the primary source of the tumour despite an extensive diagnostic work-up. PRESENTATION OF CASE: A 60 years old male presented to the clinic complaining of a neck mass to the left lateral neck. Patient's history was unremarkable without evidence of any malignant disease. Clinical and radiological examination revealed a cystic mass extending from the lower one third of the neck to the left clavicle causing periostal reaction. Mass biopsy and PET-CT was unspecific for the primary origin of the mass. However in the context of tumour immunohistochemistry, HPV status, neck location and basaloid cell differentiation, the tumour mass was considered as carcinoma of unknown primary with possible oropharyngeal primary location. The patient underwent surgical resection of the mass, left clavicle and the first rib. One year after the operation the patient is disease free. DISCUSSION: Although CUP usually presents with cervical lyphadenopathy, in our case there was no evidence of lymph node tissue infiltration in the neck region. Surgical resection of the mass showed that the location was extending within the cervical soft tissues and upper thorax. Taking into consideration the absence of lymphadenopathy this is an uncommon location of carcinoma of unknown primary in the neck. CONCLUSION: This is an uncommon location of CUP with possible implications in survival and management.

A cohort study of 30 day mortality after NON-EMERGENCY surgery in a COVID-19 cold site.

BACKGROUND: Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems. METHODS: During the peak of the pandemic in the United Kingdom, we set up a multicentre cancer network amongst 14 National Health Service institutions, performing urological, thoracic, gynaecological and general surgical urgent and cancer operations at a central COVID-19 cold site. This is a cohort study of 500 consecutive patients undergoing surgery in this network. The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days. RESULTS: 500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male, 60% had a known diagnosis of cancer and 61% of surgeries were considered complex or major. No patient died from COVID-19 at 30-days. 30-day all-cause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19. CONCLUSION: It is safe to continue cancer and urgent surgery during the COVID-19 pandemic with appropriate service reconfiguration.

The divergent roles of protein kinase C epsilon and delta in simulated ischaemia-reperfusion injury in human myocardium.

Experimental studies suggest that cardioprotection can be achieved through either the activation of PKC-epsilon prior to the index ischaemic episode or the inhibition of PKC-delta at the onset of reperfusion. However, whether these PKC isoforms exert such divergent roles in human myocardium, subjected to simulated ischaemia-reperfusion injury, is unclear. Human atrial trabeculae were isolated from right atrial appendages harvested from patients undergoing elective cardiac surgery. These were subjected to 90 min of hypoxia followed by 120 min of reoxygenation, at the end of which the recovery of baseline contractile function was determined. Atrial trabeculae were randomised to receive various treatment protocols comprising a peptide activator of PKC-epsilon, a peptide inhibitor of PKC-delta and their respective inactive control peptides. Administering the PKC-delta peptide inhibitor at reoxygenation improved the recovery of function at all the concentrations tested (39.3+/-1.4% at 5 nM, 52.4+/-2.9% at 50 nM and 46.8+/-2.9% at 500 nM versus the control group, 27.5+/-1.4%: N > or = 6/group: P<0.02). Preconditioning with the PKC-epsilon peptide activator improved the recovery of function (40.0+/-0.8% at 50 nM and 49.7+/-3.1% at 500 nM versus the control group 27.5+/-1.4%: N > or = 6/group: P<0.02). This cardioprotective effect was comparable to that achieved by a standard hypoxic preconditioning protocol (52.3+/-3.2%). Interestingly, administering the PKC-epsilon activator (500 nM) at the onset of reperfusion also improved the recovery of contractile function (40.7+/-2.1% versus 27.5+/-1.5%: N > or = 6/group: P < 0.05). In human myocardium, cardioprotection can be achieved by either inhibiting PKC-delta or activating PKC-epsilon at the onset of reperfusion. In addition, PKC-epsilon activation offers cardioprotection when administered as a preconditioning strategy.

Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.

BACKGROUND: Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS: 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS: Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION: We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia.

The surgical management of non-malignant aerodigestive fistula.

BACKGROUND: Acquired aerodigestive fistula (ADF) are rare, but associated with significant morbidity. Surgery affords the best prospect of cure. We present our experience of the surgical management of ADFs at a specialist unit, highlighting operative techniques, challenges and assess clinical outcomes following intervention. We also illustrate findings of a Hospital Episodes Statistics search for ADFs. METHODS: A prospectively-maintained database was searched to identify all patients diagnosed with an ADF who were managed at our institution. Of 48 patients with an ADF, eight underwent surgical intervention. RESULTS: Four patients underwent an exploration of the ADF with primary repair of the defect. Two of these patients had proximal ADFs, amenable to repair through a neck incision, and two required a thoracotomy. Two patients suffered fistulae secondary to endoscopic therapy and underwent oesophageal exclusion surgery, with subsequent staged reconstruction. Two patients with previous Tuberculosis had a lung segmentectomy and lobectomy respectively, and a further patient in remission after treatment for lymphoma underwent oesophageal resection with synchronous reconstruction. Three patients suffered a complication, with one post-operative mortality. The remaining seven patients all achieved normal oral alimentation, with no evidence of ADF recurrence at a median follow-up of 32 months. CONCLUSIONS: Surgery to manage ADFs is effective in restoring normal alimentation and alleviates soiling of the airway, with a very low risk of recurrence. Several operative techniques can be utilised dependent on the features of the ADF. Early referral to specialist units is advocated, where the expertise to facilitate the complete management of patients is present, within a multi-disciplinary setting.

Spatio-temporal Organization During Ventricular Fibrillation in the Human Heart.

In this paper, we present a novel approach to quantify the spatio-temporal organization of electrical activation during human ventricular fibrillation (VF). We propose three different methods based on correlation analysis, graph theoretical measures and hierarchical clustering. Using the proposed approach, we quantified the level of spatio-temporal organization during three episodes of VF in ten patients, recorded using multi-electrode epicardial recordings with 30 s coronary perfusion, 150 s global myocardial ischaemia and 30 s reflow. Our findings show a steady decline in spatio-temporal organization from the onset of VF with coronary perfusion. We observed transient increases in spatio-temporal organization during global myocardial ischaemia. However, the decline in spatio-temporal organization continued during reflow. Our results were consistent across all patients, and were consistent with the numbers of phase singularities. Our findings show that the complex spatio-temporal patterns can be studied using complex network analysis.

Evidence for multiple mechanisms in human ventricular fibrillation.

BACKGROUND: The mechanisms that sustain ventricular fibrillation (VF) in the human heart remain unclear. Experimental models have demonstrated either a periodic source (mother rotor) or multiple wavelets as the mechanism underlying VF. The aim of this study was to map electrical activity from the entire ventricular epicardium of human hearts to establish the relative roles of these mechanisms in sustaining early human VF. METHODS AND RESULTS: In 10 patients undergoing cardiac surgery, VF was induced by burst pacing, and 20 to 40 seconds of epicardial activity was sampled (1 kHz) with a sock containing 256 unipolar contact electrodes connected to a UnEmap system. Signals were interpolated from the electrode sites to a fine regular grid (100x100 points), and dominant frequencies (DFs) were calculated with a fast Fourier transform with a moving 4096-ms window (10-ms increments). Epicardial phase was calculated at each grid point with the Hilbert transform, and phase singularities and activation wavefronts were identified at 10-ms intervals. Early human VF was sustained by large coherent wavefronts punctuated by periods of disorganized wavelet behavior. The initial fitted DF intercept was 5.11 +/- 0.25 (mean +/- SE) Hz (P < 0.0001), and DF increased at a rate of 0.018 +/- 0.005 Hz/s (P < 0.01) during VF, whereas combinations of homogeneous, heterogeneous, static, and mobile DF domains were observed for each of the patients. Epicardial reentry was present in all fibrillating hearts, typically with low numbers of phase singularities. In some cases, persistent phase singularities interacted with multiple complex wavelets; in other cases, VF was driven at times by a single reentrant wave that swept the entire epicardium for several cycles. CONCLUSIONS: Our data support both the mother rotor and multiple wavelet mechanisms of VF, which do not appear to be mutually exclusive in the human heart.