Andrew J. Ritchie

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis Effects of Telomerase and Oxidative Stress

Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated β-galactosidase [SAβG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAβG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.

Rupture of the Atherosclerotic Plaque. Does a Good Animal Model Exist

Abstract—By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability.

Cardiopulmonary exercise tests and lung cancer surgical outcome

STUDY OBJECTIVES Surgical resection remains the treatment of choice for anatomically resectable non-small cell lung cancer. However, the presence of associated comorbid conditions increases the risk of death and surgical complications. Several studies have evaluated the usefulness of preoperative exercise testing for predicting postoperative morbidity and mortality. The aim of this study was to establish whether exercise testing could predict poor surgical outcome in lung cancer surgery and whether the absolute value or percentage of predicted value is the better predictor of the surgical outcome. DESIGN The study was designed as a prospective study. PATIENTS AND SETTING One hundred thirty patients with potentially operable lung cancer at Papworth Hospital over 2 years were recruited; of these, 101 underwent curative surgery. INTERVENTIONS Spirometry and cardiopulmonary exercise tests were performed for every patient (n = 99), except for two patients with back problems. We also recorded the outcome of surgery, in particular, complications and mortality. MEASUREMENTS AND RESULTS Mean maximum oxygen transport at peak exercise (Vo(2)peak) was 18.3 mL/kg/min (SD, 4.7 mL/kg/min), and mean percentage of predicted Vo(2)peak value was 84.4% (SD, 30%). Poor surgical outcome was significantly related to Vo(2)peak percentage of predicted (p < 0.01) but not to the actual oxygen uptake value. CONCLUSIONS The use of the percentage of predicted Vo(2)peak value would be a better indicator of surgical outcome, since it predicts the surgical outcome better, and corrects for normal physiologic ranges. The threshold of Vo(2)peak for surgical intervention could be set between 50% and 60% of predicted without excess surgical mortality.

Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial

BACKGROUND Malignant pleural mesothelioma incidence continues to rise, with few available evidence-based therapeutic options. Results of previous non-randomised studies suggested that video-assisted thoracoscopic partial pleurectomy (VAT-PP) might improve symptom control and survival. We aimed to compare efficacy in terms of overall survival, and cost, of VAT-PP and talc pleurodesis in patients with malignant pleural mesothelioma. METHODS We undertook an open-label, parallel-group, randomised, controlled trial in patients aged 18 years or older with any subtype of confirmed or suspected mesothelioma with pleural effusion, recruited from 12 hospitals in the UK. Eligible patients were randomly assigned (1:1) to either VAT-PP or talc pleurodesis by computer-generated random numbers, stratified by European Organisation for Research and Treatment of Cancer risk category (high vs low). The primary outcome was overall survival at 1 year, analysed by intention to treat (all patients randomly assigned to a treatment group with a final diagnosis of mesothelioma). This trial is registered with ClinicalTrials.gov, number NCT00821860. FINDINGS Between Oct 24, 2003, and Jan 24, 2012, we randomly assigned 196 patients, of whom 175 (88 assigned to talc pleurodesis, 87 assigned to VAT-PP) had confirmed mesothelioma. Overall survival at 1 year was 52% (95% CI 41-62) in the VAT-PP group and 57% (46-66) in the talc pleurodesis group (hazard ratio 1·04 [95% CI 0·76-1·42]; p=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus ten (14%) of 73 patients who completed talc pleurodesis (p=0·019), as were respiratory complications (19 [24%] vs 11 [15%]; p=0·22) and air-leak beyond 10 days (five [6%] vs one [1%]; p=0·21), although not significantly so. Median hospital stay was longer at 7 days (IQR 5-11) in patients who received VAT-PP compared with 3 days (2-5) for those who received talc pleurodesis (p<0·0001). INTERPRETATION VAT-PP is not recommended to improve overall survival in patients with pleural effusion due to malignant pleural mesothelioma, and talc pleurodesis might be preferable considering the fewer complications and shorter hospital stay associated with this treatment. FUNDING BUPA Foundation.

Barrett's oesophagus: microsatellite analysis provides evidence to support the proposed metaplasia-dysplasia-carcinoma sequence.

The development of adenocarcinoma in Barretts oesophagus is proposed to occur via a stepwise progression recognised histologically as a metaplasia‐dysplasia‐carcinoma sequence. In order to identify chromosomal loci involved in the malignant transformation of Barretts epithelium and the development of oesophageal adenocarcinoma, microsatellite analysis was carried out on 17 cases of Barretts‐associated oesophageal adenocarcinoma. Samples of premalignant Barretts epithelium adjacent to adenocarcinoma were obtained from seven of these cases. Allelic imbalance was detected in >45% of informative cases of oesophageal adenocarcinoma on chromosome arms 3q (65%), 4q (71%), 5q (59%), 6q (59%), 9p (50%), 9q (47%), 12p (47%), 12q (65%), 17p (76%), and 18q (75%). Allelic imbalance at 4q, 17p, and 18q was significantly higher than the upper 95% confidence interval for background allelic imbalance. Allelic imbalance was detected at several loci in the premalignant epithelium from five of the seven cases studied. These loci included several chromosomal arms that had demonstrated high levels of allelic imbalance in oesophageal adenocarcinoma, namely, 4q (one case), 5q (two cases), 9 (three cases), 12q (five cases), 17p (four cases), and 18q (two cases). Novel microsatellite alleles were detected in both premalignant and malignant Barretts epithelium. In three cases, dysplastic Barretts epithelium and adjacent adenocarcinoma demonstrated the same pattern of novel microsatellite alleles at a number of loci. In conclusion, these data indicate chromosomal loci which may be specifically involved in the histological progression of Barretts epithelium. The detection of shared novel microsatellite alleles in premalignant and malignant Barretts epithelium is consistent with a process of clonal expansion underlying this progression. Genes Chromosomes Cancer 21:49–60, 1998.

Mesothelioma – VATS biopsy and lung mobilization improves diagnosis and palliation

OBJECTIVES Mesothelioma is an increasingly frequent malignancy in which diagnosis is often delayed and disease diagnosed at an advanced stage. Earlier diagnosis and therapeutic intervention that can control recurrent pleural effusion may improve outlook and survival. METHODS A prospective series of 25 patients in whom mesothelioma was suspected was referred for histological diagnosis by video assisted-thoracoscopy (VAT) after failure of other methods. At the same operative procedure drainage of pleural effusion, cytoreductive pleurectomy and lung mobilization was performed where possible. Complete follow-up was obtained. RESULTS All patients had a histological diagnosis (100%) from the material sent for biopsy. In 23 patients this was mesothelioma, in two patients chronic empyema. All patients undergoing drainage of effusion, cytoreductive pleurectomy and lung mobilization subsequently were diagnosed of having mesothelioma stages III to IV. Fifteen out of 21 who underwent lung mobilization had closure of the pleural space. Post operative air leak in this group was a mean of 5 days (2-12 days). Recurrent effusion occurred in only one patient. Eleven patients remain alive at 1-2 years post operation with no hospital admissions for recurrent pleural effusion. In the six out of 21 who did not have closure of the pleural space, one remained alive 9 months post surgery. Five died within 1-6 months of the procedure. The average number of further hospital admissions for repeat drainage of effusion was 3 (1-6). CONCLUSIONS VATs provides adequate tissue for histological diagnosis where other methods fail. At the same operative sitting it provides a therapeutic intervention that allows drainage of effusion cytoreductive pleurectomy and lung mobilization in a significant number of cases. Where the pleural space can be closed this results in significantly fewer hospital admissions and appears to improve quality of life and length of survival. The price is a longer hospital stay due to prolonged air leak.

Ventilation-perfusion scintigraphy to predict postoperative pulmonary function in lung cancer patients undergoing pneumonectomy

OBJECTIVE The American College of Chest Physicians (ACCP) recommends using quantitative perfusion scintigraphy to predict postoperative lung function in lung cancer patients with borderline pulmonary function tests who will undergo pneumonectomy. However, previous scintigraphic data were gathered on small cohorts more than a decade ago, when surgical populations were significantly different with respect to age and sex compared with typical lung cancer patients undergoing pneumonectomy in 2005. We therefore revisited the use of V/Q scintigraphy in pneumonectomy patients in predicting postoperative pulmonary function and the appropriateness of current clinical guidelines. CONCLUSION Contrary to ACCP guidelines, we found that ventilation scintigraphy alone provided the best correlation between the predicted and actual postoperative values and recommend its use to predict postoperative lung function. However, scintigraphic techniques may underestimate postoperative lung function, so caution is required before unnecessarily preventing a patient from undergoing surgery that offers a potential cure.

The management of deep sternal wound infections using vacuum assisted closure (V.A.C.) therapy

A group of international experts met in May 2006 to develop clinical guidelines on the practical application of vacuum assisted closure™ (V.A.C.®) † therapy in deep sternal wound infections. Group discussion and an anonymous interactive voting system were used to develop content. The recommendations are based on current evidence or, where this was not available, the majority consensus of the international group. The principles of treatment for deep sternal wound infections include early recognition and treatment of infection. V.A.C. therapy should be instigated early, following thorough wound irrigation and surgical debridement. V.A.C. therapy in deep sternal wound infections requires specialist surgical supervision and should only be undertaken by clinicians with adequate experience and training in the use of the technique.

Thoracoscopic thoracic duct ligation for traumatic chylothorax

Traumatic chylothorax requires surgical intervention when conservative medical management fails to reduce chyle leakage. This usually entails thoracotomy or laparotomy. We report a case in which successful ligation of a torn thoracic duct was achieved using a video-assisted thoracoscopic technique.

Prophylactic digitalization fails to control dysrhythmia in thoracic esophageal operations

A prospective, controlled, randomized study of 80 patients undergoing esophageal operations was undertaken, in which one group of patients was given digoxin and the other was not. The incidence of cardiac dysrhythmia was compared in each group. Twenty-six patients underwent operation for benign disease. Equal numbers were digitalized or not and no dysrhythmias occurred. Fifty-four patients underwent operation for malignant disease. Of 26 in the group digitalized, 12 suffered dysrhythmia (46%). Of 28 not digitalized, 9 suffered dysrhythmia (32%). Overall, 39% of patients with malignant disease suffered a dysrhythmia compared with none with benign disease (p < 0.002 by chi 2).