Giovanni Vicidomini

Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target

Background The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets. Methodology We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002). Conclusions Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma.

Impact of positive pleural lavage cytology on survival in patients having lung resection for non-small-cell lung cancer: An international individual patient data meta-analysis

OBJECTIVES Pleural lavage cytology is the microscopic study of cells obtained from saline instilled into and retrieved from the chest during surgery for non-small-cell lung cancer. The aims of this study were to collate multi-institutional individual patient data for meta-analysis to determine independence as a prognostic marker and to characterize the impact of positive results on stage-adjusted survival. METHODS We identified 31 publications from 22 centers/research groups that performed pleural lavage cytology during surgery for non-small-cell lung cancer and invited submission of individual patient data. Actuarial survival was calculated using Kaplan-Meier methods, and comparisons were performed using the log-rank test. Cox proportional hazards regression was used to ascertain the covariates associated with survival. RESULTS By January 1, 2008, submissions were received internationally from 11 centers with individual data from 8763 patients. In total, 511 (5.8%) patients had a positive pleural lavage cytology result, and this was shown to be an independent predictor of adverse survival associated with a hazard ratio of 1.465 (1.290-1.665; P < .001) compared with a reference hazard ratio of 1 for a negative result. On statistical modeling, the best adjustment for patients with a positive pleural lavage cytology result was a single increase in the T category assigned to the case, up to a maximum of T4. Correction for differences in survival were obtained in stages IB (P = .315) and IIB (P = .453), with a degree of correction in stage IIIA (P = .07). CONCLUSIONS Pleural lavage cytology should be considered in all patients with non-small-cell lung cancer suitable for resection. A positive result is an independent predictor of adverse survival, and the impact on survival suggests that it may be appropriate to upstage patients by 1 T category.

Prognostic significance of cyclooxygenase-2 (COX-2) and expression of cell cycle inhibitors p21 and p27 in human pleural malignant mesothelioma

Background: A study was undertaken to analyse the potential prognostic value of the immunohistochemical expression of cyclooxygenase-2 (COX-2) and p27 in 29 malignant mesotheliomas already screened for the expression of p21 and p53. Methods: Immunohistochemistry was used to determine the expression of COX-2 and p27. The correlation with survival of these factors and of p21 and p53 expression was assessed by univariate and multivariate analyses. Results: A positive statistically significant correlation was found between p27 and p21 expression (p<0.0001), but there was a negative correlation between COX-2 expression and both p27 (p = 0.001) and p21 (p<0.0001). No statistically significant correlation was recorded between p53 and all the other immunohistochemical parameters. Univariate analysis showed that overall survival was strongly influenced by p21, p27, and COX-2 expression, but multivariate Cox regression analysis showed that the only immunohistochemical parameter to influence overall survival of patients with mesothelioma was COX-2. Conclusions: These findings suggest that COX-2 expression may be a useful prognostic parameter for mesothelioma.

Endobronchial treatment of giant emphysematous bullae with one-way valves: a new approach for surgically unfit patients

OBJECTIVE We aimed to evaluate the feasibility and short-term efficacy of endobronchial treatment with one-way valves for giant emphysematous bulla in surgically unfit patients. METHODS Nine consecutive patients with giant emphysematous bulla were enrolled in the last 3 years. Endobronchial valves were placed in the segmental bronchi to functionally isolate the airway that supplied the bulla, favouring the deflation of the bulla and its atelectasis. Mean value ± standard deviation of forced expiratory volume in 1s (FEV1), preoperative forced vital capacity (FVC) and residual volume (RV) were: 1.0 ± 0.2l (35 ± 9.9%), 1.5 ± 0.5l (42 ± 12%) and 5.5 ± 0.7 l (23 1 ± 32%), respectively; and the values for diffusion capacity for carbon monoxide was 31 ± 4.6% and for the 6-min walk test (6 MWT) was 156 ± 92 m); all patients required supplemental oxygen at rest. The St. Georges Respiratory Questionnaire (SGRQ) score was 85 ± 4.6. RESULTS At 24-48 h after the procedure, the mean value of FEV1 (from 35% to 47%, p < 0.01), FVC (from 42% to 52%, p < 0.01), diffusion lung capacity for carbon monoxide (DLCO) (from 31% to 33%, p < 0.05) and 6 MWT (from 156 m to 281 m, p < 0.01) significantly improved with respect to baseline value. Conversely, mean value of total lung capacity (TLC) (from 157% to 123%, p < 0.01) RV (from 231% to 158%, p < 0.01) and SGRQ score (from 85 to 37, p < 0.01) was significantly lower than baseline data; these changes were preserved during the entire follow-up. CONCLUSION Our preliminary data confirm the feasibility and the potential efficacy of this strategy with significantly immediate improvement of respiration and quality of life, which remains stable during 6 months of follow-up.

SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer

Purpose: Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype. Experimental Design: Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non–small cell lung cancer (NSCLC) cell lines. Results: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity. In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy. Conclusions:This result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer. Clin Cancer Res; 21(20); 4686–97. ©2015 AACR.

Vascular endothelial growth factor in pleural fluid for differential diagnosis of benign and malignant origin and its clinical applications

Our goal was to determine the role of vascular endothelial growth factor (VEGF) in diagnosing of pleural effusion (PE) in order to select patients deserving of more aggressive procedures. Seventy-nine consecutive patients with undiagnosed unilateral PE were enrolled. Pleural VEGF levels, measured using enzyme-linked immunosorbent assay (ELISA), were correlated to etiology of PEs and other markers (protein, lactic dehydrogenase, amylase, glucose). The median level of VEGF in exudates (n=65) was significantly higher than that in transudates (P=0.0001) and among exudates, it was significantly higher in malignant (n=49) than that in benign exudates (P=0.005). No significant differences were observed between malignant effusions due to lung cancer (n=11) and other malignant effusions [mesothelioma (n=13) and/or extra-thoracic cancer]. Among all variables evaluated, logistic regression found that only VEGF was significantly correlated with the presence of malignant disease (P=0.002). Analysis of the receiver operating characterists (ROC) curves showed that the areas under the curve of VEGF were significantly larger than that of amylase (P=0.02), glucose (P=0.01), lactic dehydrogenase (P=0.001) and protein (P=0.01). VEGF increased the diagnostic rate of cytological examination by 24%. VEGF may represent a helpful adjunct to conventional diagnostic tools in ruling out malignancy as a probable diagnosis, thus guiding the selection of patients who might benefit from further invasive procedures.

Iatrogenic Air Leak Successfully Treated by Bronchoscopic Placement of Unidirectional Endobronchial Valves

This report describes a patient with persistent air leak after inadvertent placement of a chest drain in a bulla. Chest drain and suction failed to stop the air leak, whereas the surgical repair was judged to be excessively aggressive. In closure, two large endobronchial valves were sequentially positioned in the superior and inferior division of the left upper lobe to completely close it. The result was the collapse of bulla with closure of fistula and complete lung expansion.

A simple technique to control placement of Dumon stent in subglottic tracheal stenosis

Airway stenting is the chosen treatment for patients affected by subglottic tracheal stenosis and unfit for surgery. Among the different types of prostheses, the Dumon stent is a valid option especially in patients without tracheotomy. Insertion is usually achieved by pushing the stent off from a loader using a prosthesis pusher. If the stent is expelled below the stenosis, rigid forceps grasping the proximal end of the stent retract it above the stenosis. However, in difficult cases such as rigid stenosis with a luminal diameter smaller than the profile of the stent, such a manoeuvre may be difficult in non-expert hands. Thus, we proposed a simple and safe technique to facilitate the placement of a Dumon stent. We passed a long thread from outside to the inside of the stent. After the dilatation of the stenosis, the stent was pushed and, if needed, easily retracted with the thread into the proper position to ensure airway patency and to avoid migration. In addition, our procedure could be useful also to rapidly remove the stent if its size turned out to be inaccurate for the stenosis. With such a simple method we successfully treated 7 consecutive patients affected by complex subglottic stenosis and unfit for surgery.

Pre-emptive local analgesia in video-assisted thoracic surgery sympathectomy.

OBJECTIVE Our goal is to determine whether infiltration with a short-acting local anaesthetic such as lidocaine before the surgical incision has a pre-emptive effect on postoperative pain intensity and on incidence of paraesthesia in patients undergoing standard thoracoscopic sympathectomy for palmar hyperhidrosis. MATERIAL AND METHODS This prospective study includes a consecutive series of 18 patients undergoing bilateral standard thoracoscopic sympathectomy for palmar hyperhidrosis during January 2005-December 2007. Each patient enrolled in the study was randomised to receive pre-incisional lidocaine with epinephrine infiltration of the wounds on the one side, and normal saline solution on the other. The identical surgery was performed on each side to allow patients to act as their own controls. Then, the side which received local analgesia was compared with the control side with regard to pain control and paraesthesia after 4, 24 and 168 h postoperatively. The patients and investigators were both blinded concerning the side randomised to receive pre-emptive local analgesia (PLA). RESULTS We found that patients reported significantly less pain on the side treated with pre-emptive local anaesthesia in contrast to the control side 4 and 24h after surgery (p=0.001 and p=0.004, respectively). However, that difference decreased with time and was no longer significant 168 h following surgery (p=0.156). Regarding the paraesthesia, the incidence was higher in the control side than the PLA side at 4, 24 and 168 h postoperatively, but the difference was not statistically significant. A total of 17 of 18 (94%) patients noted a change in palmar hyperhidrosis status after surgery. CONCLUSION Our study shows that the pre-injection of local anaesthetic before standard thoracoscopic sympathectomy suppresses the local pain mediators, hence resulting in significantly less pain in the first postoperative 24 h but not thereafter. The clinical impact of the procedure is the possibility of early discharge to home and early return to work with potential economical benefits. However, because of the small number of patients, further studies are needed to corroborate our results.

Does cannabis smoking predispose to lung bulla formation

Objective The data of a consecutive series of habitual marijuana smokers were retrospectively evaluated and compared with that of non-marijuana smokers to assess differences between the 2 groups. Methods 13 consecutive habitual marijuana smokers were referred for treatment of spontaneous pneumothorax. The demographic, clinical, radiological, and pathological findings of these patients were reviewed and compared with 140 non-marijuana smokers treated for the same pathology at the same time. Results Bullae were seen in 8/13 (62%) and 110/140 (78%) of marijuana smokers and non-marijuana smokers, respectively. However, when patients less than 35-years old were considered, the incidence of bulla was higher in marijuana smokers than non-marijuana smokers (7/10 vs. 3/10, p < 0.05). The pathological findings showed a greater presence of inflammatory cells in specimens from marijuana smokers than those of non-marijuana smokers (8/11 vs. 2/42, respectively, p < 0.05). No significant differences in hospital stay and clinical outcome were registered between the 2 groups. Conclusions Despite the fact that we were unable to demonstrate that marijuana had a causal role in the development of emphysema, our study showed that marijuana smokers had a higher incidence of inflammatory cells in pathological specimens, which may favor lung injury, thus predisposing to bulla formation.