Sridhar Rathinam

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.)

Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis

Background and aim: Aberrant angiogenesis and defective epithelial repair are key features of idiopathic pulmonary fibrosis (IPF). Endostatin is an antiangiogenic peptide with known effects on endothelial cells. This study aimed to establish the levels of endostatin in the bronchoalveolar lavage fluid (BALF) in IPF and to investigate its actions on distal lung epithelial cells (DLEC) and primary type II cells. Methods: 20 patients with IPF and 10 controls underwent BAL. Endostatin was measured by ELISA. BALF cytokines and matrix metalloproteinase (MMP)-3 were measured by Luminex array. Primary DLEC monolayers were wounded and treated with endostatin. Apoptosis and cell viability were assessed. Results: Endostatin was elevated in the BALF and plasma of patients with IPF compared with normal controls. There was a negative correlation between endostatin, forced vital capacity and gas transfer. Endostatin correlated with a number of proinflammatory cytokines and MMP3. Physiological endostatin doses inhibited DLEC wound repair by 44% in an effect that was partially FasL and caspase dependent. Endostatin increased apoptosis rates by 8% and reduced their viability by 34%. Similar effects of endostatin were seen in primary type II cells in terms of inhibition of wound repair and proliferation. Conclusions: Elevated BALF endostatin levels correlated with a number of elevated cytokines, MMP3 and lung function in IPF. Endostatin is a novel inhibitor of DLEC wound repair, inducing apoptosis and reducing cell viability in a FasL and caspase dependent manner. Endostatin may play a role in aberrant epithelial repair in IPF.

The Effects of Increased Provision of Thoracic Surgical Specialists on the Variation in Lung Cancer Resection Rate in England

Introduction: There is a wide variation in the lung cancer resection rate in England. We assessed the effect of the regional provision of thoracic surgery service on the variation in lung cancer resection rate. Methods: A retrospective observational study correlating National Lung Cancer Audit data with thoracic surgery workforce data was performed to review the lung cancer resection rate in England in 2008 and 2009. Results: In 2008, there was a sixfold variation in resection rate, with a higher resection rate in hospitals where surgeons were based (base hospitals) than in peripheral hospitals (20.0% versus 11.6%, p < 0.001). The resection rate was also higher in cancer networks, which were served by two or more specialist thoracic surgeons (14.6% versus 12.7%, p = 0.028), and where surgeons were present in more than two-thirds of the lung cancer multidisciplinary team meetings (14.4% versus 12.0%, p = 0.046). In 2009, the overall resection rate increased from 14.5% to 18.4%. Four units increased their number of specialist thoracic surgeons and had a significantly higher increase in resection rate than units without expansion (relative rise 66.3% versus 19.2%; p = 0.022). Conclusions: The large variation in the resection rate seems, in part, to be related to the local availability of specialist thoracic surgeons. The greatest improvement in the resection rate was in units with expansion of specialist thoracic surgeons. We suggest the expansion of specialist thoracic surgeons will improve the resection rate and thereby the overall survival of lung cancer in England. This has significant implications for the future of training in cardiothoracic surgery and organization of cancer services.

Excision of sympathetic ganglia and the rami communicantes with histological confirmation offers better early and late outcomes in Video assisted thoracoscopic sympathectomy

BackgroundVideo-Assisted Thoracoscopic Sympathectomy (VATS) is an established minimally invasive procedure for thoracic sympathetic blockade in patients with hyperhidrosis, facial flushing and intractable angina. Various techniques using clips, diathermy and excision are used to perform sympathectomy. We present our technique of excision of the sympathetic chain with histological proof and the analysis of the early and late outcomes.MethodsWe evaluated 200 procedures in 100 consecutive patients, who underwent Video Assisted Thoracoscopic Sympathectomy by a single surgeon in our centre between September 1996 to March 2007. All patients had maximum medical therapy prior to surgery and were divided into 3 groups based on indications, Group 1(hyperhidrosis: 48 patients), Group 2 (facial flushing: 26 patients) and Group 3(intractable angina: 26 patients). The demography and severity of symptoms for each group were analysed. The endpoints were success rate, 30 day mortality, complications and patients satisfaction.Results99 patients had bilateral VATS sympathectomy and 1 had unilateral sympathectomy. The conversion rate to open was 1(1%). All patients had successful removal of ganglia proven histologically with no perioperative mortality in our series. The complications included pneumothorax (5%), acute coronary syndrome (2%), transient Horners syndrome (1%), transient paraesthesia (1%), wound infection (4%), compensatory hyperhidrosis (18%), residual flushing (3%) and wound pain (5%). There were five late deaths in the intractable angina group at a mean follow up of 36.7 months. Overall success rates of abolishing the symptoms were 96.3%, 87.5% and 95.2% for Group 1, 2 and 3 respectively.ConclusionExcision of the sympathetic chain with histological confirmation during VATS sympathectomy is a safe and effective method in treating hyperhidrosis, facial flushing and intractable angina with good long term results and satisfaction.

The role of the emphysema multidisciplinary team in a successful lung volume reduction surgery programme

OBJECTIVES Lung volume reduction surgery (LVRS) for advanced emphysema is well established, with strong evidence from the National Emphysema Treatment Trial. However, there is still reluctance to offer the procedure, and many have looked for alternative, unproven treatments. The multidisciplinary approach has been well established in treatment of lung cancer and, more recently, in coronary artery surgery. We reviewed our practice to validate the role of our multidisciplinary team approach in our LVRS programme. METHODS Our multidisciplinary approach employs respiratory physicians, radiologists and surgeons involved in case selection, who meet on a regular basis. Cases are selected on the basis of clinical presentation, imaging (radionuclide lung perfusion and computerized tomography) and respiratory physiology. Retrospective analysis of prospectively collected data on 633 patients referred for lung volume reduction surgery between July 1995 and July 2013. RESULTS Six hundred and thirty-three patients (422 male) were referred for LVRS, of whom 253 [178 male; median age 61 years (range 37-79 years)] underwent 292 LVRS procedures.There were 268 video-assisted thoracoscopic surgical procedures, of which 13 were one-stage bilateral procedures and 37 required a staged second side. Overall median hospital stay was 13 (4-197) days, during which 11 patients died. Prolonged hospital stay was associated with increasing age and with duration of air leak, which in turn was associated with diffusion capacity and forced expiratory volume in 1 s. CONCLUSIONS The outcomes of a successful LVRS programme are not only dependent on good surgical technique and post-operative care. Case selection and work-up by a dedicated multidisciplinary approach for emphysema patients plays an invaluable and integral part in an LVRS programme.

BioGlue and Peri-strips in lung volume reduction surgery: pilot randomised controlled trial

BackgroundBoth tissue sealants and buttressing have been advocated to reduce alveolar air leaks from staple lines following Lung Volume Reduction Surgery (LVRS). However, the long term detrimental effects of buttressing material are increasingly apparent. We performed a pilot prospective randomised self controlled trial in patients undergoing LVRS comparing BioGlue and Peri-strips as adjuncts in preventing alveolar air-leaks.MethodsA pilot prospective self controlled clinical trial was conducted in patients undergoing LVRS. Each patient was treated with BioGlue on one side and pericardial buttress on the other side as an adjunct to the staple line. The sides were randomised for adjuncts with each patient acting as his own control. Duration of air leak, intercostal drainage and time to chest drain removal were the study end points.Results10 patients undergoing the procedure were recruited between December 2005 and October 2007. There were 6 men and the mean age was 59.8 ± 4.9 years. There was one mortality due to multi-organ failure. The BioGlue treated side had a shorter mean duration of air-leak (3.0 ± 4.6 versus 6.5 ± 6.9 days), lesser chest drainage volume (733 ± 404 ml versus 1001 ± 861) and shorter time to chest drain removal (9.7 ± 10.6 versus 11.5 ± 11.1 days) compared with Peri-strips.ConclusionThis study demonstrates comparable efficacy of BioGlue and Peri-strips, however there is a trend favouring the BioGlue treated side in terms of reduction in air-leak, chest drainage volumes, duration of chest drainage and significant absence of complications. A larger sample size is needed to validate this result.

Bullous herniation of the lung through an intercostal drain site

Intercostal herniation of pulmonary bulla is very rare. A 75-year-old man with emphysema and previous persistent right-sided pneumothorax (Fig. 1) treated with an apical drain, presented with herniation of a bulla through the apical drain site (Fig. 2). It was confirmed as a bulla by chest radiographs and computed tomography scan (the films of which were lost after operation during transfer to parent hospital). In view of the co-morbidities including emphysema and ischaemic heart disease, the bulla was ligated with a vicryl suture at the neck of the sac under local anaesthesia. There was no air leak, and no form of drainage was used. The patient did well postoperatively. European Journal of Cardio-thoracic Surgery 23 (2003) 240

A randomised controlled trial comparing Mediwrap® heat retention and forced air warming for maintaining normothermia in thoracic surgery

Hypothermia is one of the common complications in the perioperative period. Currently, normothermia is maintained with forced air warming (FAW) or passive heat retention methods. We compared the efficacy of the Mediwrap blanket with FAW in maintaining normothermia during intra-operative period in thoracic surgery in a prospective randomised controlled trial on 30 patients. Core temperature was measured at 30-min intervals in the perioperative period and the time taken to attain baseline in the postoperative periods in the two groups was compared. There was no difference in core temperatures between the groups during pre- and intra-operative period, with mean+/-S.D. final core temperatures of 36.2+/-0.6 degrees C with Mediwrap and 36+/-0.9 degrees C with the FAW blanket. However, the postoperative core temperatures were significantly higher in the Mediwrap group. The time required to reach baseline temperature was lower in the Mediwrap group with a mean+/-S.D. of 66+/-66 min as compared to 161+/-108 min in the FAW group. The Mediwrap blanket is as effective as the FAW blanket in maintaining core body temperature during thoracotomy when applied thirty minutes before the surgery.

Individualised risk in patients undergoing lung volume reduction surgery (LVRS): The Glenfield BFG Score

Lung volume reduction surgery (LVRS) has been shown to be beneficial in patients with chronic obstructive pulmonary disease, but there is low uptake, partly due to perceived concerns of high operative mortality. We aimed to develop an individualised risk score following LVRS. This was a cohort study of patients undergoing LVRS. Factors independently predicting 90-day mortality and a risk prediction score were identified. Reliability of the score was tested using area under the receiver operating characteristic curve (AUROC). 237 LVRS procedures were performed. The multivariate analysis factors associated independently with death were: body mass index (BMI)<18.5 kg·m−2 (OR 2.83, p=0.059), forced expiratory volume in 1 s (FEV1)<0.71 L (OR 5.47, p=0.011) and transfer factor of the lung for carbon monoxide (TLCO) <20% (OR 5.56, p=0.031). A risk score was calculated and total score assigned. AUROC for the risk score was 0.80 and a better predictor than individual components (p<0.01). The score was stratified into three risk groups. Of the total patients, 46% were classified as low risk. Similar improvements in lung function and health status were seen in all groups. The score was introduced and tested in a further 71 patients. AUROC for 90-day mortality in this cohort was 0.84. It is possible to provide an individualised predictive risk score for LVRS, which may aid decision making for both clinicians and patients. An individualised risk score for lung volume reduction surgery may aid decision making around surgery http://ow.ly/4lxm30b3n05

Inflammatory myofibroblastic tumour at the pacemaker site.

Inflammatory myofibroblastic tumour (IMT) or inflammatory pseudotumour is a histologically distinctive lesion occurring primarily in the viscera and soft tissue of children and young adults. We report an unusual case of IMT which had undergone malignant transformation in the chest wall at the pacemaker site. A 64-year-old male presented with a history of high fever, loss of appetite and weight loss of three months duration. He had a dual chamber pacemaker reinserted in the left infraclavicular region in the previous year. This was followed by a gradually enlarging hard swelling at the insertion site. The CT-scan showed a soft tissue mass encasing the pacing box, without intrathoracic extension. The trucut biopsy was suspicious of soft tissue sarcoma. A well encapsulated hard mass, with pacemaker embedded within it was resected en-bloc ensuring wide resection margins. Histology revealed fascicles of spindle cell proliferation with prominent inflammatory component, occasional spindle cells with prominent nucleoli and scattered atypical mitotic figures, with areas of focal necrosis. The lesional cells were negative for CD21, smooth muscle actin, ckit, cytokeratins and anaplastic lymphoma kinase 1. A diagnosis of IMT with malignant transformation i.e. inflammatory fibrosarcoma was made. He had adjuvant radiotherapy and uneventful recovery.