Lorenzo Dominioni

Lung cancer in Teesside (UK) and Varese (Italy): a comparison of management and survival

Background: The survival of lung cancer patients in the UK is lower than in other similar European countries. The reasons for this are unclear. Methods: Two areas were selected with a similar incidence of lung cancer: Teesside in Northern England and Varese in Northern Italy. Data were collected prospectively on all new cases of lung cancer diagnosed in the year 2000. Comparisons were made of basic demographic characteristics, management, and survival. Results: There were 268 cases of lung cancer in Teesside and 243 in Varese. Patients in Teesside were older (p<0.05), were more likely to have smoked (p<0.001), had a higher occupational risk (p<0.001), higher co-morbidity (p<0.05), and poorer performance status (p<0.001). Fewer patients in Teesside presented as an incidental finding (p<0.001) and the histological confirmation rate was lower than in Varese (p<0.01). In Teesside there were more large cell carcinomas (p<0.001), more small cell carcinomas (p<0.05), and fewer early stage non-small cell lung cancers (p<0.05). The resection rate was lower in Teesside (7% v 24%; p<0.01) and more patients received no specific anti-cancer treatment (50% v 25%; p<0.001). Overall 3 year survival was lower in Teesside (7% v 14%; p<0.001). Surgical resection was the strongest multivariate survival predictor in Varese (HR = 0.46) and Teesside (HR = 0.31). Co-morbidity in Teesside resulted in a significantly lower resection rate (p<0.001). Conclusions: Patients with lung cancer in Teesside presented at a later stage, with more aggressive types of tumour, and had higher co-morbidity than patients in Varese. As a result, the resection rate was significantly lower and survival was worse.

Atrial fibrillation after pulmonary lobectomy for lung cancer affects long-term survival in a prospective single-center study.

BackgroundAtrial fibrillation (AF) after thoracic surgery is a continuing source of morbidity and mortality. The effect of postoperative AF on long-term survival however has not been studied. Our aim was to evaluate the impact of AF on early outcome and on survival > 5 years after pulmonary lobectomy for lung cancer.MethodsFrom 1996 to June 2009, 454 consecutive patients undergoing lobectomy for lung cancer were enrolled and followed-up until death or study end (October 2010). Patients with postoperative AF were identified; AF was investigated with reference to its predictors and to short- and long-term survival (> 5 years).ResultsHospital mortality accounted for 7 patients (1.5%), while postoperative AF occurred in 45 (9.9%). Independent AF predictors were: preoperative paroxysmal AF (odds ratio [OR] 5.91; 95%CI 2.07 to 16.88), postoperative blood transfusion (OR 3.61; 95%CI 1.67 to 7.82) and postoperative fibro-bronchoscopy (OR 3.39; 95%CI 1.48 to 7.79). Patients with AF experienced higher hospital mortality (6.7% vs. 1.0%, p = 0.024), longer hospitalization (15.3 ± 10.1 vs. 12.2 ± 5.2 days, p = 0.001) and higher intensive care unit admission rate (13.3% vs. 3.9%, p = 0.015). The median follow-up was 36 months (maximum: 179 months). Among the 445 discharged subjects with complete follow-up, postoperative AF was not an independent predictor of mortality; however, among the 151 5-year survivors, postoperative AF independently predicted poorer long-term survival (HR 3.75; 95%CI 1.44 to 9.08).ConclusionAF after pulmonary lobectomy for lung cancer, in addition to causing higher hospital morbidity and mortality, predicts poorer long-term outcome in 5-year survivors.

Evidence for a glutamatergic modulation of the cholinergic function in the human enteric nervous system via NMDA receptors.

Several reports suggest that enteric cholinergic neurons are subject to a tonic inhibitory modulation, whereas few studies are available concerning the role of facilitatory pathways. Glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), has recently been described as an excitatory neurotransmitter also in the guinea-pig enteric nervous system (ENS). The present study aimed at investigating the presence of glutamatergic neurons in the ENS of the human colon. At this level, the presence of ionotropic glutamate receptors of the NMDA type, and their possible interaction with the enteric cholinergic function was also studied. In the human colon, L-glutamate and NMDA concentration dependently enhance spontaneous endogenous acetylcholine overflow in Mg2+-free buffer, both effects being significantly reduced by the antagonists, (+/-)-2-amino-5-phosphonopentanoic acid (+/- AP5) and 5,7-diCl-kynurenic acid. In the presence of Mg2+, the facilitatory effect of L-glutamate changes to inhibition, while the effect of NMDA is significantly reduced. In addition, morphological investigations reveal that glutamate- and NR1-immunoreactivities are present in enteric cholinergic neurons and glial cells in both myenteric and submucosal plexus. These findings suggest that, as described for the guinea-pig ileum, glutamatergic neurons are present in enteric plexuses of the human colon. Modulation of the cholinergic function can be accomplished through NMDA receptors.

High-Dose Intravenous IgG for Treatment of Severe Surgical Infections

113 severely septic surgical patients, with an initial sepsis score ≧ 17 (mean: 23 ± 4) were prospectively randomized to receive either high-dose intravenous IgG (IVIG group) or placebo (control group

Targeting α7-nicotinic receptor for the treatment of pleural mesothelioma

Human malignant pleural mesothelioma (MPM) is a dreadful disease and there is still no standard therapy available for a consistent therapeutic approach. This research is aimed at the evaluation of the potential therapeutic effect of a specific nicotinic receptor (nAChR) antagonist, namely alpha-Cobratoxin (alpha-CbT). Its effectiveness was tested in mesothelioma cell lines and in primary mesothelioma cells in vitro, as well as in vivo, in orthotopically xenotransplanted NOD/SCID mice. Cells showed alpha7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-CbT [IC(80-90)]. Apoptosis was characterised by: change in mitochondrial potential, caspase-3 cleavage, down-regulation of mRNA and protein for survivin, XIAP, IAP1, IAP2 and Bcl-XL, inhibition by caspase-3 inhibitor. In vivo, the alpha-CbT acute LD(50) was 0.15 mg/kg. The LD(100) [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg alpha-CbT (1/1000 of LD(10)) were done in 53 xenotransplanted mice, inhibiting tumour development as confirmed by chest X-ray examinations, autopsy and microscopical findings. The growth of human proliferating T lymphocytes and of mesothelial cells in primary culture was not affected by alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use.

Peri-operative complications of video-assisted thoracoscopic surgery (VATS)

Video-assisted thoracoscopic surgery (VATS) has multiple indications for diagnosis and treatment of many different thoracic diseases; the commonest are lung wedge resection, pleural and mediastinal biopsy, treatment of pneumothorax, and pleurectomy. Moreover, in recent years a few surgeons have performed routinely major lung anatomic resections by VATS approach, including segmentectomy, lobectomy and pneumonectomy. In our experience VATS constitutes about one-third of all thoracic surgical procedures. In the reviewed literature as in the most frequent complications after VATS procedures are: prolonged air leak, bleeding, infection, postoperative pain, port site recurrence and the need to convert the access in thoracotomy. The complication and mortality rates are generally very low and VATS procedures are considered safe and effective. It is recommended that all thoracic surgery departments audit their VATS procedures for peri-operative morbidity and mortality to compare results and outcomes.

Lung cancer screening and the surgical oncologist: the controversy.

Although screening for lung cancer is not currently recommended, randomized trials consistently demonstrate that chest x-ray screening is associated with significant advantages in stage distribution, resectability, and long-term survival. Because these advantages have not been accompanied by a reduction in lung cancer mortalities a because an excess number of lung cancers were detected in experimental populations in two studies, it has been suggested that screening leads to the detection of clinically unimportant lung cancers. This hypothesis, known as overdiagnosis, is the only obstacle to the conclusion that chest x-ray screening saves lives. However, abundant evidence convincingly demonstrates that the overdiagnosis hypothesis is myth with regard to chest x-ray screening for lung cancer. With more than one million deaths from lung cancer on a worldwide basis every year, public policy regarding screening for lung cancer is in urgent need of reconsideration.

Infections in 346 Consecutive Video-Assisted Thoracoscopic Procedures

BACKGROUND Postoperative infections, as related to risk factors, in patients undergoing video-assisted thoracoscopic surgery (VATS) procedures have been studied infrequently. MATERIALS AND METHODS We evaluated 346 consecutive patients who underwent VATS procedures between October 1996 and June 2002 at our center. Patients preoperatively were free of chest infections and were divided into two groups: Group A (n = 139) who underwent lung wedge resection; group B (n = 207), who underwent pleural biopsy (n = 183) or biopsy of a mediastinal mass (n = 24). We recorded prospectively the following preoperative infection risk parameters: Hemoglobin concentration, hematocrit, serum albumin concentration, lymphocyte count, length of preoperative stay, duration of surgery, blood transfusion, age, comorbidity, and chronic obstructive pulmonary disease specifically (COPD, measured as FEV(1) <70% of expected). Short-term antibiotic prophylaxis was given to 94% of patients in group A and to 90% of patients in group B. As outcome measures we recorded the occurrence of postoperative infections within 30 days (surgical site infection, pneumonia, empyema) and the final patient outcome. RESULTS Patients who developed postoperative infections (all the above types included) were 17/346 (4.9%), the difference between group A (5.0%) and group B (4.8%) being not significant. The overall surgical site infection rate was 1.7%. Groups A and B showed a similar incidence of surgical site infection (2.8% vs. 1.0%; p = NS), of pneumonia (2.8% vs. 3.4%; p = NS), and of empyema (0.7% vs. 2.0%; p = NS). Among assessed infection risk parameters, a FEV(1) <70% of expected was the only parameter associated with a significantly increased incidence of surgical site infection (p < 0.05). CONCLUSIONS This prospective study confirms that the wound infection rate is low (1.7%) after minimally invasive VATS procedures. The cumulative incidence of postoperative infections (including wound infection, pneumonia, empyema) was similar after lung wedge resection and after pleural or mediastinal mass biopsy procedures. Among the infection risk parameters, COPD was the only parameter associated with a significantly increased incidence of postoperative infection. Our results suggest that patients with COPD who undergo VATS for lung wedge resections and for pleural/mediastinal biopsy should receive antibiotic prophylaxis to prevent surgical site infection.

Self-Selection Effects in Smokers Attending Lung Cancer Screening: A 9.5-Year Population-Based Cohort Study in Varese, Italy

Background: We hypothesize that mortality risk profile of participants and nonparticipants in nonrandomized lung cancer (LC) screening of smokers may be different. Methods: In 1997, a population-based cohort of 5815 smokers of Varese Province was invited to nonrandomized LC screening by annual chest x-ray examination for 4 years. LC risk factors and screening participation rate were recorded. Except for screening, the whole cohort received usual care. After 9.5-year observation, we compared mortality of participants versus nonparticipants by assessing age-standardized all-cause mortality rate ratio (MRR) and disease group-specific MRR with 95% confidence intervals (95% CI). Results: Self-selected screening participants were 21% of cohort. Participants were younger (p < 0.001), were more frequently current smokers (p = 0.019), had more pack-years of smoking (p < 0.0001), and had higher rate of LC family history (p < 0.0001) and of occupational LC risk (p < 0.0001) relative to nonparticipants. In logistic regression analysis familial LC, occupational risk and pack-years smoked were significant predictors of participation in screening and of developing LC. Participants displayed a healthy effect, as shown by all-cause MRR = 0.67 (95% CI, 0.53–0.84), all cancers except LC MRR = 0.61 (95% CI, 0.41–0.91), cardiovascular diseases MRR = 0.38 (95% CI, 0.22–0.63), and noncancer disease other than cardiovascular or respiratory MRR = 0.57 (95% CI, 0.34–0.92). The LC mortality (MRR = 1.40; 95% CI, 1.03–1.91) was higher in participants relative to nonparticipants (p = 0.031). Conclusion: The selection effect in LC screening participants was dual: healthy effect and higher LC mortality. In assessing the overall effectiveness of LC screening on a population level, a higher LC mortality risk in participants should be considered.

A comparison between quantitative PCR and droplet digital PCR technologies for circulating microRNA quantification in human lung cancer

BackgroundSelected microRNAs (miRNAs) that are abnormally expressed in the serum of patients with lung cancer have recently been proposed as biomarkers of this disease. The measurement of circulating miRNAs, however, requires a highly reliable quantification method. Quantitative real-time PCR (qPCR) is the most commonly used method, but it lacks reliable endogenous reference miRNAs for normalization of results in biofluids. When used in absolute quantification, it must rely on the use of external calibrators. Droplet digital PCR (ddPCR) is a recently introduced technology that overcomes the normalization issue and may facilitate miRNA measurement. Here we compared the performance of absolute qPCR and ddPCR techniques for quantifying selected miRNAs in the serum.ResultsIn the first experiment, three miRNAs, proposed in the literature as lung cancer biomarkers (miR-21, miR-126 and let-7a), were analyzed in a set of 15 human serum samples. Four independent qPCR and four independent ddPCR amplifications were done on the same samples and used to estimate the precision and correlation of miRNA measurements obtained with the two techniques. The precision of the two methods was evaluated by calculating the Coefficient of Variation (CV) of the four independent measurements obtained with each technique. The CV was similar or smaller in ddPCR than in qPCR for all miRNAs tested, and was significantly smaller for let-7a (p = 0.028). Linear regression analysis of the miRNA values obtained with qPCR and ddPCR showed strong correlation (p < 0.001).To validate the correlation obtained with the two techniques in the first experiment, in a second experiment the same miRNAs were measured in a larger cohort (70 human serum samples) by both qPCR and ddPCR. The correlation of miRNA analyses with the two methods was significant for all three miRNAs. Moreover, in our experiments the ddPCR technique had higher throughput than qPCR, at a similar cost-per-sample.ConclusionsAnalyses of serum miRNAs performed with qPCR and ddPCR were largely concordant. Both qPCR and ddPCR can reliably be used to quantify circulating miRNAs, however, ddPCR revealed similar or greater precision and higher throughput of analysis.