Relationship between pulmonary function and lung cancer surgical outcome.

The British Thoracic Society and American College of Chest Physician guidelines outline criteria for investigating patients for lung cancer surgery. However, the guidelines are based on relatively old studies. Therefore, the relationship between pulmonary function test results and surgical outcome were studied prospectively in a large cohort of lung cancer patients. From January 2001 to December 2003, 110 patients underwent surgery for lung cancer. All underwent full lung function testing in order to predict post-operative lung function. The hospital mortality rate was 3% and major complication rate 22%. There was poor overall outcome in 13%. Mean pre-operative lung function values were: forced expiratory volume in one second (FEV1) 2.0 L (79.4% of the predicted value), and carbon monoxide diffusing capacity of the lung (D(L,CO)) 73.6% pred. The mean post-operative lung function values were: FEV1 1.4 L (55.6% pred), and D(L,CO) 51.3% pred. All lung function values were better predictors of poor surgical outcome when expressed as a percentage of the predicted value. Using a threshold of pre-operative FEV1 of 47% pred resulted in the most useful positive and negative predictive probabilities, 0.90 and 0.67, respectively. Lung function values expressed as a percentage of the predicted value are more useful predictors of post-operative outcome than absolute values. The threshold of predicted forced expiratory volume in one second for surgical intervention could be lower (45-50% pred) than is currently accepted without increased mortality.

Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma.

AIMS: Malignant mesothelioma is increasing in incidence and no current therapy significantly prolongs survival. Previous surgical strategies involved high-risk open procedures without achieving histologically clear resection margins. We present the results of VATS debulking pleurectomy-decortication in advanced disease. METHODS: A consecutive series of patients with suspected malignant mesothelioma underwent thoracoscopic assessment to determine the feasibility of decortication, where this was not possible a biopsy alone was taken. Post-operative radiotherapy was administered to port sites, but no other adjuvant therapy was given. The two groups (biopsy only and pleurectomy-decortication) were composed of patients with histologically confirmed mesothelioma [28 and 51 patients, respectively]. The primary endpoint was comparison of actuarial patient survival. Secondary endpoints included post-operative air leak and duration of hospital stay. RESULTS: The overall actuarial survival was 288 days and 67% of patients had died at the time of data analysis. The groups were matched for patient and tumour-related characteristics including age (66, 64 years, p=0.39) and tumour stage (median IMIG stage 3 [IQR 2-3] both groups, p=0.54). The biopsy only group had fewer air leaks (57, 84%, p=0.01) and a shorter hospital stay (4, 8 days, p=0.03). However, the pleurectomy-decortication group had favourable actuarial survival relative to the biopsy only group (416, 127 days, p<0.001). Multivariate analysis showed early stage (p<0.001), absence of pre-operative fever (p=0.03) and pleurectomy-decortication (p<0.001) as independent predictors of survival. CONCLUSION: VATS pleurectomy-decortication is feasible in the majority of cases and independently improves survival for patients with advanced malignant mesothelioma.

Effect of lung cancer surgery on quality of life.

BACKGROUND: Health related quality of life (HRQOL) after surgery is important, although very limited data are available on the QOL after lung cancer surgery. METHODS: The effect of surgery on HRQOL was assessed in a prospective study of 110 patients undergoing potentially curative lung cancer surgery at Papworth Hospital, 30% of whom had borderline lung function as judged by forced expiratory volume in 1 second. All patients completed the EORTC QLQ-C30 and LC13 lung cancer module before surgery and again at 1, 3 and 6 months postoperatively. RESULTS: On average, patients had high levels of functioning and low levels of symptoms. Global QOL had deteriorated significantly 1 month after surgery (p = 0.001) but had returned to preoperative levels by 3 months (p = 0.93). Symptoms had worsened significantly at 1 month after surgery but had returned to baseline levels by 6 months. Low values on the preoperative HRQOL scales were not significantly associated with poor surgical outcome. However, patients with low preoperative HRQOL functioning scales and high preoperative symptom scores were more likely to have poor postoperative (6 months) QOL. The only lung function measurement to show a marginally statistically significant association with quality of life at 6 months after surgery was percentage predicted carbon monoxide transfer factor (Tlco). CONCLUSION: Although surgery had short term negative effects on quality of life, by 6 months HRQOL had returned to preoperative values. Patients with low HRQOL functioning scales, high preoperative symptom scores, and preoperative percentage predicted Tlco may be associated with worse postoperative HRQOL.

The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone inhibits T-cell differentiation and cytokine production by a mechanism involving an early step in T-cell activation.

The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) has been reported to have immunomodulatory activity in several systems, although the mechanism of that activity remains to be fully characterized. We demonstrate here, using a defined in vitro model of antigen responses by T-cell receptor (TCR)-transgenic mouse splenic CD4 T cells, that the effect of OdDHL on activation and cytokine production is complete within 4 h of antigen or mitogen stimulation and does not depend on the insertion of OdDHL in the cell membrane, despite a previous report that immunosuppression by homoserine lactones required a minimum acyl chain length of 11 carbons (S. R. Chhabra, C. Harty, D. S. W. Hooi, M. Daykin, B. W. Bycroft, P. Williams, and D. Pritchard, J. Med. Chem. 46:97-104, 2003). We also demonstrate that while OdDHL can have toxic effects on nonlymphoid leukocytes, it does not induce significant cell death in T cells at the concentrations (< or =10 microM) used in these experiments. In addition, we show that primary and secondary antigen-specific cytokine responses are equally susceptible to inhibition by OdDHL and that the compound inhibits the differentiation of both Th1 and Th2 cells. However, the precise balance of cytokine production by CD4 T cells stimulated in the presence of OdDHL varies with both the antigen concentration and its affinity for the transgenic TCR. Thus, conflicting reports of the nature of the immunosuppression by OdDHL may be due in part to the differences in antigen affinity and concentration in different models.

Acute hydrothorax in CAPD. Eearly thoracoscopic (VATS) intervention allows return to peritoneal dialysis.

BACKGROUND/AIMS: Hydrothorax is a complication of continuous ambulatory peritoneal dialysis (CAPD) occurring due to pleuroperitoneal fistulae. Several treatments exist with no consensus as to best management. We report on the largest series of video-assisted thoracoscopic surgery (VATS) treated pleuroperitoneal fistulae yet available. METHODS: Between 1995 and 2000, we treated 6 CAPD patients for acute right hydrothoraces using VATS. Data pertaining to size and sterility of hydrothoraces, presence of diaphragmatic defects, surgical procedures performed, morbidity and return to CAPD were obtained. RESULTS: Hydrothoraces were drained in all patients and there were no significant growths on subsequent culture. Fistulae were directly identified and closed in three patients. In the remaining patients, endoclips were placed across the base of small diaphragmatic blebs (the presumed site of communication). Parietal pleurectomy was performed uneventfully in all patients. There was no morbidity, all patients returned to haemodialysis and there have been no recurrences. CONCLUSIONS: Pleuroperitoneal fistulae produce symptomatic hydrothoraces in CAPD patients. A variety of approaches to the problem have been described. This is the largest series of VATS available and shows the usefulness of this approach in both closing the defect and producing an effective pleurectomy to prevent recurrence.

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.

Effect of the blood substitute diaspirin crosslinked hemoglobin in rat mesenteric and human radial collateral arteries.

The actions of the blood substitute diaspirin crosslinked hemoglobin (DCLHb) were investigated in rat (small mesenteric artery) and human (radial collateral artery) resistance vessels mounted in a wire myograph for isometric tension recording. DCLHb did not contract resting vessels from rats, but vasoconstrictor responses were observed in isolated arteries and perfused mesenteric beds prestimulated with threshold concentrations of methoxamine. The DCLHb contractile responses were greatly attenuated by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or endothelial removal, whereas BQ-123 (endothelin A receptor antagonist), prazosin (alpha1-adrenoceptor antagonist), or indomethacin (cyclooxygenase inhibitor) had no effect. Endothelium-dependent relaxations to carbachol in both rat mesenteric and human radial collateral artery were inhibited by DCLHb. Relaxations to carbachol were studied in the presence of L-NAME or 25 mM KCl to investigate the effect of DCLHb on endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide, respectively. In both rat and human vessels, EDHF-mediated relaxations were not affected by DCLHb preincubation, whereas the nitric oxide component of carbachol-induced relaxations was practically abolished. In conclusion, inhibition of the effects of basal nitric oxide release underpins the vasoconstrictor effects of DCLHb. DCLHb effectively abolishes the nitric oxide component of carbachol-induced relaxation, with no effect on the EDHF-mediated component in both isolated rat mesenteric and human radial collateral arteries.

Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin.

Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb3) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-alpha) upregulates Gb3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-alpha treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb3 levels. Differential expression of Gb3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS.

The action of diaspirin cross-linked haemoglobin blood substitute on human arterial bypass conduits.

BACKGROUND: Immediately available blood substitutes could transform medicine. In coronary artery surgery, vasoconstriction induced by some of these agents could have serious implications. We have examined some of the vasoactive effects of one of these blood substitute, diaspirin cross-linked haemoglobin (DCLHb), on isolated rings of human arterial conduits. METHODS: Sections of human left internal mammary artery (LIMA) and radial artery (RA) were cut into 3-mm rings, mounted in individual organ baths containing aerated (95% O(2)/5% CO(2)) Krebs-Heinseleit solution at 37 degrees C and attached to isometric strain gauge for measurements of tension. All rings were tested for the presence of endothelium by addition of carbachol to rings pre-contracted with phenylephrine. The relative importance of nitric oxide (NO) in contraction mediated by the addition of DCLHb was studied. RESULTS: Carbachol relaxed phenylephrine precontracted LIMA by 72.3+/-1.7% and RA by 97+/-0.7% confirming the presence of a functional endothelium. Sodium nitroprusside (SNP) caused complete relaxation of LIMA with an EC(50) value of 2.0+/-0.1x10(-8) M and RA with an EC(50) value of 1. 9+/-0.1x10(8) M. In the presence of DCLHb (10(-7) M), carbachol-induced relaxation was significantly reduced to 46.3+/-0. 7% (P<0.01) and the BC(50) value for SNP relaxation increased to 1. 2+/-0.1x10(-7) M (P<0.01). DCLHb caused rings to contract in the absence of phenylephrine with EC(50) values of 1.6+/-0.1x10(-7) M (LIMA) and 1.8+/-0.1x10(-7) M (RA). Presence of L-NAME (300 microM) caused no alteration in DCLHb-induced contraction. CONCLUSION: In this study of isolated rings of human vessels, DCLHb causes a significant reduction in relaxation mediated by carbachol and SNP, which is likely to be due to its ability to bind NO. However, it is possible that other mechanisms might contribute to the vasoconstrictor effects of DCLHb and these might be amenable to anti-vasospastic strategies.

Videothoracoscopic drainage of mediastinal abscess: an alternative to thoracotomy.

A late-presenting high esophageal perforation that resulted in a massive mediastinal abscess and bronchopleural fistula in an elderly moribund patient unfit for radical surgery was successfully drained using a videothoracoscopic technique.

Clinical versus actual outcome in cardiac surgery: a post-mortem study.

BACKGROUND: Clinical attribution of the cause of death can be misleading, with the only true outcome measure being post-mortem analysis. Despite this there is very little published data on post-mortems following cardiac surgery. METHODS: Prospective consecutive post-mortem data were collected on 167 patients (84.4% of all in-hospital cardiac surgical deaths) in a single institution. Clinical diagnoses were compared with post-mortem findings. RESULTS: The mean age at death was 69.8 with 67.6% male. The proportion undergoing coronary artery bypass graft (CABG) alone was 52.1%, valve surgery 18.6%, valve+CABG 19.2% and other procedures 10.1%. The mean time to death was 7.9 days (range 0-87). The causes of death were cardiac 67.7%, gastrointestinal 9.6%, respiratory 8.4%, haemorrhage/technical failure 4.8%, stroke (cerebrovascular accident) 3.6%, multiorgan failure 3.0%, sepsis 1.8%, malignancy 0. 6% and trauma 0.6%. Post-mortem revealed an unsuspected cause of death in 19 (11.4%). These were gastrointestinal (infarction nine, perforation two), cardiac three, adult respiratory distress syndrome two, technical two and pulmonary embolus one. In addition, an unsuspected lung cancer was found in 1 patient who died of cardiac causes. When cardiac deaths were compared with non-cardiac causes the Parsonnet score was higher 20.0 (+/-1.4) vs. 15.3 (+/-1.6), P=0. 07; and a greater proportion tended to have poor ejection fractions (34 vs. 15%), P=0.12. There was no significant difference between the groups in terms of age, sex, operation, hypertension, diabetes, creatinine and body mass. CONCLUSIONS: Post-mortem can determine unsuspected diagnoses in a significant proportion of cases. Pre-operative risk factors do not correlate with eventual cause of death. Post-mortem still has an important role to play in cardiac surgery.

Inhibitory effects of glibenclamide on the contraction of human arterial conduits used in coronary artery bypass surgery.

Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated. Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37 degrees C. Contractions were obtained by either the use of a thromboxane analogue (U46619), L-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2+/-0.17 (n = 7) for LIMA and 3.26+/-0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 microM) caused the concentration-response curves for U46619 and L-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 microM) also had an inhibitory effect on Ca2+-induced tension in radial artery. These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.

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.

Current practice in thoracic sympathectomy.

Thoracic sympathectomy has been performed for many years. With the recent development of video assisted thoracic surgical techniques the indications for surgery have increased, and the outcome is much better.

Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers.

BACKGROUND: Advanced glycation endproducts (AGEs) arise from the spontaneous reaction of reducing sugars with the amino groups of macromolecules. AGEs accumulate in tissue as a consequence of diabetes and aging and have been causally implicated in the pathogenesis of several of the end-organ complications of diabetes and aging, including cataract, atherosclerosis, and renal insufficiency. It has been recently proposed that components in mainstream cigarette smoke can react with plasma and extracellular matrix proteins to form covalent adducts with many of the properties of AGEs. We wished to ascertain whether AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers. MATERIALS AND METHODS: Lens and coronary artery specimens from nondiabetic smokers and nondiabetic nonsmokers were examined by immunohistochemistry, immunoelectron microscopy, and ELISA employing several distinct anti-AGE antibodies. In addition, lenticular extracts were tested for AGE-associated fluorescence by fluorescence spectroscopy. RESULTS: Immunoreactive AGEs were present at significantly higher levels in the lenses and lenticular extracts of nondiabetic smokers (p < 0.003). Anti-AGE immunogold staining was diffusely distributed throughout lens fiber cells. AGE-associated fluorescence was significantly increased in the lenticular extracts of nondiabetic smokers (p = 0.005). AGE-immunoreactivity was significantly elevated in coronary arteries from nondiabetic smokers compared with nondiabetic nonsmokers (p = 0.015). CONCLUSIONS: AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers than in nonsmokers, irrespective of diabetes. In view of previous reports implicating AGEs in a causal association with numerous pathologies, these findings have significant ramifications for understanding the etiopathology of diseases associated with smoking, the single greatest preventable cause of morbidity and mortality in the United States.

Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia.

This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.

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

The development of adenocarcinoma in Barrett's 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 Barrett's epithelium and the development of oesophageal adenocarcinoma, microsatellite analysis was carried out on 17 cases of Barrett's-associated oesophageal adenocarcinoma. Samples of premalignant Barrett's 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 Barrett's epithelium. In three cases, dysplastic Barrett's 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 Barrett's epithelium. The detection of shared novel microsatellite alleles in premalignant and malignant Barrett's epithelium is consistent with a process of clonal expansion underlying this progression.

Allelotype analysis of adenocarcinoma of the gastric cardia.

To identify chromosomal loci involved in the development of proximal gastric adenocarcinoma, this study delineated the pattern of allelic imbalance in a series of 38 adenocarcinomas arising in the gastric cardia. A total of 137 microsatellite markers covering all autosomal arms, excluding acrocentric arms, were analysed. A mean of 35 out of a total of 39 chromosomal arms studied were informative for each patient. The tumour group demonstrated a high level of allelic imbalance, with an observed median fractional allelic imbalance of 0.47 for the 29 intestinal-type adenocarcinomas and 0.54 for the nine diffuse-type adenocarcinomas. Allelic imbalance was detected in >50% of informative cases in both histological subtypes on a number of chromosomal arms. In the intestinal subtype, these included, 3p (61%), 4q (71%), 5q (59%), 8p (60%), 9p (65%), 9q (83%), 12q (52%), 13q (52%), 17p (78%) and 18q (70%). A higher incidence of allelic imbalance was detected on chromosome 16q in tumours of the diffuse type relative to those of the intestinal type. A more detailed mapping on chromosomes 4q and 6q identified a number of cases with subchromosomal breakpoints. In conclusion, this analysis has indicated regions of the genome potentially involved in the development of proximal gastric carcinomas.