Giorgio Cavallesco

COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma

Background: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. Methods: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. Results: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. Conclusions: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.

Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease.

Aims:  To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD).

Interleukin‐13 and ‐4 expression in the central airways of smokers with chronic bronchitis

The aim of this study was to determine whether the T‐helper 2‐type cytokines interleukin (IL)‐13 and ‐4 are involved in mucus hypersecretion, the hallmark of chronic bronchitis (CB). Surgical specimens were examined from 33 subjects undergoing lung resection for localised peripheral malignant pulmonary lesions: 21 smokers with symptoms of CB, 10 asymptomatic smokers (AS) and two nonsmokers with normal lung function. The number of IL‐4 and ‐13 positive (+) cells in the central airways was quantified. To better assess the cytokine profile, a count was also made of IL‐5+ and interferon (IFN)‐γ+ cells. Compared to AS, the CB group had an increased number of IL‐13+ and ‐4+ cells in the bronchial submucosa, while the number of IL‐5+ and IFN‐γ+ cells were similar in all the groups. No significant associations were found between the number of cells expressing IL‐13 or ‐4 and the number of inflammatory cells. Double labelling showed that 13.2 and 12.9% of IL‐13+ cells were also CD8+ and CD4+, whereas 7.5 and 5% of IL‐4+ cells were CD8+ and CD4+, respectively. In conclusion, T‐helper‐2 and ‐1 protein expression is present in the central airways of smokers and interleukin‐4 and ‐13 could contribute to mucus hypersecretion in chronic bronchitis.

Mechanisms involved in lung cancer development in COPD.

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality.

MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients.

Aims:  Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups.

Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids.

Bronchial carcinoids (BCs) are rare tumors originating from endocrine cells dispersed in the respiratory epithelium. It has been previously demonstrated that everolimus, or RAD001, an mTOR inhibitor, has potent antiproliferative effects in human endocrine tumors. Our aim was to evaluate the possible antiproliferative effects of everolimus in human BCs in primary culture. We collected 24 BCs that were dispersed in primary cultures, treated without or with 1 nM-1 muM everolimus, 10 nM SOM230 (pasireotide, a somatostatin receptor multiligand), and/or 50 nM IGF1. Cell viability was evaluated after 48 h, and chromogranin A (CgA) as well as vascular endothelial growth factor (VEGF) secretion was assessed after 8 h incubation. Somatostatin receptors, mTOR, and AKT expression were investigated by quantitative PCR. We found that in 15 cultures (67.5%), everolimus significantly reduced cell viability (by approximately 30%; P<0.05 versus control), inhibited p70S6K activity (-30%), and blocked IGF1 proliferative effects. Everolimus also significantly reduced CgA (by approximately 20%) and VEGF (by approximately 15%) secretion. Cotreatment with SOM230 did not exert additive effects on cell viability and secretory activity. AKT expression was similar in responder and nonresponder tissues, while mTOR expression was significantly higher in the responder group, which was characterized by higher CgA plasma levels and bigger tumors with higher mitotic index and angiogenesis. Our data demonstrate that everolimus reduces VEGF secretion and cell viability in BCs with a mechanism likely involving IGF1 signaling, suggesting that it might represent a possible medical treatment for BCs.

Vasoactive intestinal peptide receptors in the airways of smokers with chronic bronchitis

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the regulation of airway mucus secretion. The biological functions of VIP are mediated through two receptors, the vasoactive intestinal peptide receptor type 1 (VPAC1R) and type 2 (VPAC2R). The aim of this study was to quantify the expression of both VPAC1R and VPAC2R in the central airways of smokers with chronic bronchitis. Surgical specimens were obtained from 33 smokers undergoing thoracotomy for localised pulmonary lesions: 23 smokers with symptoms of chronic bronchitis and 10 asymptomatic smokers with normal lung function. By using immunohistochemical and microscopic analysis, an increased expression of VPAC1R, but not VPAC2R, was found in bronchial epithelium, bronchial glands and vessels of smokers with symptoms of chronic bronchitis compared with asymptomatic smokers. Smokers with symptoms of chronic bronchitis also had an increased number of mononuclear cells positive for both VPAC1R and VPAC2R in the bronchial submucosa. In conclusion, the expression of type 1 and type 2 vasoactive intestinal peptide receptors is increased in the central airways of smokers with chronic bronchitis, suggesting their possible involvement in the pathogenesis of chronic bronchitis.

A totally mini-invasive approach for colorectal laparoscopic surgery

AIM To study the short-term outcome of patients treated with laparoscopic right colectomy and how intracorporeal anastomosis has improved the outcome. METHODS We retrospectively examined all patients affected by colorectal cancer who underwent a laparoscopic right colectomy between January 2006 and December 2010 in our department. Our evaluation criteria were: diagnosis of colorectal carcinoma at presurgical biopsy, elective surgery, and the same surgeon. We excluded: emergency surgery, conversions from laparotomic colectomy, and other surgeons. The endpoints we examined were: surgical time, number of lymph nodes removed, length of stay (removal of nasogastric tube, bowel movements, gas evacuation, solid and liquid feeding, hospitalization), and major complications. Seventy-two patients were divided into two groups: intracorporeal anastomosis (39 patients) and extracorporeal anastomosis (33 patients). RESULTS Significant differences were observed between intracorporeal vs extracorporeal anastomosis, respectively, for surgical times (186.8 min vs 184.1 min, P < 0.001), time to resumption of gas evacuation (3 d vs 3.5 d, P < 0.001), days until resumption of bowel movements (3.8 d vs 4.9 d, P < 0.001), days until resumption of liquid diet (3.5 d vs 4.5 d, P < 0.001), days until resuming a solid diet (4.6 d vs 5.7 d, P < 0.001), and total hospitalization duration (7.4 d vs 8.5 d, P < 0.001). In the intracorporeal group, on average, 19 positive lymph nodes were removed; in the extracorporeal group, on average, 14 were removed P < 0.001). Thus, intracorporeal anastomosis for right laparoscopic colectomy improved patient outcome by providing faster recovery of nutrition, faster recovery of intestinal function, and shorter hospitalization than extracorporeal anastomosis. CONCLUSION Short-term outcomes favor intracorporeal anastomosis, confirming that a less traumatic surgical approach improves patient outcome.

P2X7 targeting inhibits growth of human mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor refractory to anti-blastic therapy. MPM cells show several genetic and biochemical defects, e.g. overexpression of oncogenes, downregulation of onco-suppressor genes, dysregulation of microRNA, or alteration of intracellular Ca2+ homeostasis and of apoptosis. No information is as yet available on purinergic signalling in this tumor. Signalling via the P2×7 (P2RX7 or P2×7R) purinergic receptor is attracting increasing attention as a pathway involved in cancer cell death or proliferation. In this report we show that the P2×7R is expressed by three MPM cell lines established from MPM patients but not by mesothelial cells from healthy subjects (healthy mesothelial cells, HMCs). MPM cell proliferation was inhibited by in vitro incubation in the presence of selective P2×7R antagonists, as well as by stimulation with the P2×7R agonist BzATP. Systemic administration of the selective P2×7R blocker AZ10606120 inhibited in vivo growth of MPM tumors whether implanted subcutaneously (s.c.) or intraperitoneally (i.p.). Our findings suggest that the P2×7R might be a novel target for the therapy of mesothelioma.

Primary Pulmonary Epithelioid Hemangioendothelioma: A Rare Cause of PET-Negative Pulmonary Nodules

We report here a case of primary pulmonary epithelioid hemangioendothelioma diagnosed in a 67-year-old Caucasian man, presenting with exertion dyspnoea, dry cough, and multiple bilateral pulmonary nodules revealed by computed tomography. At the 18F-fluorodeoxyglucose positron emission tomography, these nodules were negative. The histopathological diagnosis was made on a pulmonary wedge resection (performed during video-thoracoscopic surgery).