Common Pathogenic Mechanisms Between Idiopathic Pulmonary Fibrosis and Lung Cancer.

Abundant epidemiologic evidence supports an association between idiopathic pulmonary fibrosis (IPF) and lung cancer. Lung tumors in patients with IPF develop preferentially in the periphery immediately adjacent to fibrotic areas, with different histologic distribution and immunohistochemical features compared with non-IPF-associated lung tumors. In this context, evidence indicates that IPF and lung cancer share many pathogenic similarities including genetic and epigenetic markers. It has been suggested that specific germline mutations predispose toward both IPF and lung cancer, leading to imbalance between oncogenes and tumor suppressor genes and ultimately carcinogenesis within fibrotic lungs. Aberrant epigenetic regulation due to methylation, histone modifications, and mainly deregulation of common noncoding RNAs represents a possible pathogenic link between the two disease paradigms. Genetic and epigenetic alterations lead to abnormal activation of common transduction pathways, including Wnt/ß-catenin and phosphoinositide 3-kinase/protein kinase B, mediating metaplasia and hyperproliferation in alveolar type II epithelial cells. Cellular transformations in the mesenchymal phenotype represent a common link between lung fibrosis and carcinogenesis. In this review we summarize current data on common cellular and molecular pathogenic mechanisms between IPF and lung cancer and highlight promising therapeutic targets for this disease combination.

Activin A and follistatin in patients with asthma. Does severity make the difference?

BACKGROUND AND OBJECTIVE: Activin A is a pleiotropic cytokine holding a fundamental role in inflammation and tissue remodelling. Follistatin can modulate the bioactivity of activin. We aimed to measure activin A and follistatin in sputum supernatants and bronchoalveolar lavage (BAL) of asthmatic patients and to determine the possible associations with severity as well as with inflammatory and remodelling indices. METHODS: A total of 58 asthmatic patients (33 with severe refractory asthma (SRA)) and 10 healthy controls underwent sputum induction for % cells, activin A, follistatin, eosinophilic cationic protein (ECP), transforming growth factor beta 1 (TGF-ß1), IL-13 and IL-8 measurements. In 22 asthmatic patients, BAL and bronchial biopsies were also performed for the assessment of the above-mentioned variables, measurement of remodelling indices and immunostaining for different activin A receptors. RESULTS: Sputum activin A (pg/mL) was higher in patients with SRA (median (interquartile ranges): 76 (33-185)) compared to mild-to-moderate asthma (44 (18-84); P = 0.005), whereas follistatin did not differ between the two groups. BAL activin A (pg/mL) was higher in patients with SRA compared to those with mild-to-moderate disease. A significant association was observed between activin A and TGF-ß1, eosinophils in sputum and/or in BAL, while reticular basement membrane (RBM) thickness was significantly associated with BAL activin levels only. No difference in immunostaining for activin receptor type IB was observed between patients with SRA and those with mild-to-moderate asthma. CONCLUSION: Sputum and BAL levels of activin A are higher in SRA. The association of activin A with TGF-ß1, eosinophils and RBM thickness may indicate a role of this cytokine in the inflammatory and remodelling process in SRA.

Prolonged occupational exposure leads to allergic airway sensitization and chronic airway and systemic inflammation in professional firefighters.

BACKGROUND AND OBJECTIVES: Little data exist on short- and long-term effects of occupational exposure on airway and systemic inflammation in professional firefighters. We aimed to characterize airway and systemic inflammation in training firefighters with a maximum occupational exposure of 1 year compared to the long-term exposure of professional firefighters. METHODS: A questionnaire for symptoms and exposure, pulmonary function, atopy, bronchial hyper-responsiveness, and markers of inflammation in induced sputum, serum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies were assessed in a total of 92 firefighters (63 full-time professionals and 29 trainees). RESULTS: Professional firefighters showed allergic bronchial sensitization documented by the presence of atopy, and eosinophilia in induced sputum, BAL and bronchial biopsies. IL-8, ECP, VEGF, and TNF-α levels were statistically significantly higher in the sputum supernatants of professional firefighters compared to the trainees (p = 0.04, p = 0.02, p = 0.04, and p = 0.02, respectively). Serum IL-8 and TNF-α levels were also statistically significantly higher in the group of professional firefighters (p = 0.04, p = 0.03, respectively). Finally, there was a linear correlation between the duration of the occupation in Service and the degree of airway and systemic inflammation. CONCLUSIONS: These results indicate a "dose-response" effect of chronic exposure to a polluted environment on bronchial and systemic inflammation in professional firefighters.

Immunohistochemical expression of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins in urothelial bladder carcinoma: correlation with clinicopathological parameters.

PURPOSE: To reevaluate the expression levels of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins and their potential association with standard clinicopathological parameters, including tumor stage and grade, in urothelial bladder carcinoma (UBC). METHODS: Immunohistochemistry was performed in 100 transurethral resection specimens obtained from prospectively identified patients with primary UBC. RESULTS: Overall, 26, 41 and 75% of the cases showed positive staining for p53, p63 and c-myc, respectively, while p21(WAF1/cip1) and p27(kip1) expression levels were altered in 75 and 88% of the cases, respectively. Positive staining for p53 was associated with increased tumor stage (pT2) (p=0.037), while altered expression of p27(kip1) was strongly associated with male gender (p=0.009). CONCLUSION: The results of our study imply that p53 overexpression may be a useful marker of tumor invasion in UBC. In contrast, we failed to demonstrate any statistically significant correlation between the remaining markers evaluated and tumor stage or grade.

The clinical significance of cytology versus histology-based diagnosis in small cell lung cancer: a retrospective study.

OBJECTIVES: The aim of this study was to investigate the clinical significance of cytology versus histology-based diagnosis among patients diagnosed with small cell lung cancer (SCLC). MATERIALS AND METHODS: Retrospective analysis of medical records of 443 patients with histologically or cytologically confirmed small cell lung carcinoma (SCLC) was performed. All patients received platinum-based chemotherapy regimens. Survival data (overall survival) were compared between patients with histology or cytology-based diagnosis in the overall study population as well as after stratification of patients according to disease stage (limited or extensive) at the time of diagnosis. RESULTS: Distribution of demographics and clinicopathological characteristics among the two groups ("histology" and "cytology") was similar. No statistically significant differences in the survival curves between the "histology" and "cytology" groups were found in the overall study population (log rank test, p=0.237), as well as in the subgroup of patients with limited disease (log rank test, p=0.474). In contrast, patients with histology-based diagnosis had a statistically significant longer survival as compared to those with cytology-based diagnosis in the extensive disease subgroup (log rank test, p=0.031), but this association was not retained after adjusting the analysis for demographics and clinical characteristics via a Cox regression model (HR=1.18, 95% CI: 0.96-1.44, p=0.110). CONCLUSION: The results of our study suggest that the type of diagnostic modality employed (histology or cytology-based) for the establishment of a diagnosis of SCLC may not have a significant effect on the overall survival of patients. Further studies are warranted to further investigate this important, yet rather unexplored, issue.

Necrosis and apoptotic index as prognostic factors in non-small cell lung carcinoma: a review.

Necrosis and apoptosis represent two pathogenetically distinct types of cell death. Necrosis is associated with pathologic conditions while apoptosis is a physiological process of programmed cell death, which is associated with normal tissue growth and is frequently impaired in various forms of cancer. Tumor necrosis and apoptotic index (AI) have been previously evaluated as prognostic biomarkers in lung cancer, but their exact clinical value remains unclear. The aim of this study was to perform a systematic review of the MEDLINE literature on the prognostic significance of these histopathological markers in patients with non-small cell lung carcinoma (NSCLC). Although a substantial body of evidence suggests that tumor necrosis may be a strong predictor of aggressive tumor behavior and reduced survival in patients with NSCLC, the independent prognostic value of this biomarker remains to be firmly established. Furthermore, previous data on the prognostic significance of apoptotic index in NSCLC are relatively limited and largely controversial. More prospective studies are necessary in order to further validate tumor necrosis and AI as prognostic markers in NSCLC.

Wedge resection and segmentectomy in patients with stage I non-small cell lung carcinoma.

The use of sublobar resections as definitive management in stage I non-small cell lung carcinoma is a controversial topic in the medical community. We intend to report the latest developments and trends in relative indications for each of the above-mentioned surgical approaches for the treatment of stage I non-small cell lung carcinoma as well as the results of studies regarding local recurrence, disease-free survival and five-year survival rates. We reviewed 45 prospective and retrospective studies conducted over the last 25 years listed in the Pubmed and Scopus electronic databases. Trials were identified through bibliographies and a manual search in journals. Authors, citations, objectives and results were extracted. No meta-analysis was performed. Validation of results was discussed. Segmentectomies are superior to wedge resections in terms of local recurrences and cancer-related mortality rates. Sublobar resections are superior to lobectomy in preserving the pulmonary parenchyma. High-risk patients should undergo segmentectomy, whereas lobectomies are superior to segmentectomies only for tumors >2 cm (T2bN0M0) in terms of disease-free and overall 5-year survival. In most studies no significant differences were found in tumors <2 cm. Disease-free surgical margins are crucial to prevent local recurrences. Systematic lymphadenectomy is mandatory regardless of the type of resection used. In sublobar resections with less thorough nodal dissections, adjuvant radiotherapy can be used. This approach is preferable in case of prior resection. In pure bronchoalveolar carcinoma, segmentectomy is recommended. Sublobar resections are associated with a shorter hospital stay. The selection of the type of resection in T1aN0M0 tumors should depend on characteristic of the patient and the tumor. Patient age, cardiopulmonary reserve and tumor size are the most important factors to be considered. However further prospective randomized trials are needed to investigate the efficacy of minimal resections in early lung cancer patients.

Computed tomography-guided needle aspiration and biopsy of pulmonary lesions: a single-center experience in 1000 patients.

BACKGROUND: Computed tomography (CT)-guided fine needle aspiration (FNA) and biopsies are well-established, minimally invasive diagnostic tools for pulmonary lesions. PURPOSE: To analyze retrospectively the results of 1000 consecutive lung CT-guided FNA and/or core needle biopsies (CNB), the main outcome measures being diagnostic yield, and complication rates. MATERIAL AND METHODS: Patients considered eligible were those referred to our department for lung lesions. The choice of FNA, CNB, or both was based upon the radiologist's judgment. Diagnostic yield was defined as the probability of having a definite result by cytology/histology. RESULTS: The study included 733 male patients and 267 female patients, with a mean (SD) age of 66.4 (11.4) years. The mean (SD) lesion size was 3.7 (2.4) cm in maximal diameter. Six hundred and forty-one (64%) patients underwent an FNA procedure, 245 (25%) a CNB, and 114 (11%) had been subjected to both. The diagnostic yield was 960/994 (96.6%); this decreased significantly with the use of CNB only (odds ratio [OR] 0.32; 95% CI 0.12-0.88; P = 0.03), while it increased with lesion size (OR 1.35; 95% CI 1.03-1.79; P = 0.03 per cm increase). In 506 patients (52.7%), a malignant process was diagnosed by cytopathology/histology. The complication rate reached 97/1000 (9.7%); complications included: hemorrhage, 62 (6.2%); pneumothorax, 28 (2.8%); hemorrhage and pneumothorax, 5 (0.5%); and hemoptysis, 2 (0.2%). It was not significantly affected by the type of procedure or localization of the lesion. The overall risk for complications was three times higher for lesions <4 cm (OR 3.26; 95% CI 1.96-5.42; P < 0.001). CONCLUSION: CT-guided lung biopsy has a high diagnostic yield using FNA, CNB, or both. The CNB procedure alone will not suffice. Complication rates were acceptable and correlated inversely with lesion size, not localization or type of procedure.

Multi-organ failure with atypical liver granulomas following intravesical Bacillus Calmette-Guerin instillation.

Bacillus Calmette-Guerin (BCG) intravesical instillation has been adopted in the treatment of patients with superficial bladder cancer. BCG-induced disseminated infection, though rare, has been associated with the histological finding of epithelioid granulomas in different organs, including the liver. We report the case of an adult patient with multi-organ failure, who developed sepsis, acute respiratory failure and acute hepatic failure with encephalopathy whose liver biopsy confirmed the presence of atypical, granulomatous-like lesions. Recovery was observed only after empirical therapy for Mycobacterium bovis with isoniazid, rifampicin, ethambutol and steroids was introduced. This case highlights the importance of a thorough patient assessment in order to exclude other more common causes of hepatic granulomas and to confirm diagnosis. Histological findings may be non-specific when the liver is involved in BCG-induced disseminated infection.

Hepatic involvement in Wegener's granulomatosis: a case report.

INTRODUCTION: We report the case of a 58-year-old Caucasian Greek man who presented with dry cough, fever, bilateral alveolar infiltrates and acute hepatitis. CASE PRESENTATION: After a lung biopsy, the patient was diagnosed with Wegener's granulomatosis. The diagnosis was supported by the presence of anti-proteinase-3 anti-neutrophil cytoplasmic antibodies. A liver biopsy demonstrated the presence of mild non-specific lobular hepatitis and periodic acid-Schiff positive Lafora-like inclusions in a large number of his liver cells. The patient was treated with prednisone and cyclophosphamide, which was followed by subsequent remissions of chest X-ray findings and liver function studies. CONCLUSION: What makes this case worth reporting is the coexistence of liver inflammation with a biochemical profile of severe anicteric non-viral, non-drug induced hepatitis coinciding with the diagnosis of Wegener's granulomatosis. Our paper may be the first report of hepatic involvement in a patient diagnosed with Wegener's granulomatosis. The aetiological link between the two diseases is supported by the reversion of hepatitis after the immunosuppression of Wegener's granulomatosis. We favor the hypothesis that hepatic vasculitis may be the cause of acute hepatocellular necrosis.

Helicobacter pylori infection in diabetic patients: prevalence and endoscopic findings.

BACKGROUND: In patients with diabetes mellitus, chronic infections are frequent and severe, due to the impairment of their immune status. However, data on the prevalence of Helicobacter pylori (H. pylori) infection in diabetics are scanty and contradictory. The aim of our study was to assess the prevalence of H. pylori infection in diabetic patients and to evaluate the association between endoscopic features and H. pylori colonization of the gastric mucosa in diabetes mellitus. METHODS: A cross-sectional study of 172 dyspeptic patients (67 diabetics and 105 nondiabetic subjects) was designed. In all cases, an upper gastrointestinal endoscopy was performed, gastroduodenal lesions were noted, and the presence of gastritis and H. pylori was assessed by histopathological examination. Differences between diabetic patients and nondiabetic subjects were evaluated. RESULTS: The difference of H. pylori prevalence between diabetics (37.3%) and nondiabetics (35.2%) was not significant (P=0.78). Nor did the prevalence of gastritis and peptic ulcer differ significantly between the two groups (59.7% vs. 49.5%, P=0.19; and 32.8% vs. 40.9%, P=0.08, respectively). Studying only H. pylori-positive patients, we found no difference between diabetics and nondiabetics with regard to the prevalence of either gastritis (80% vs. 72.9%, P=0.71) or peptic ulcer (91.8% vs. 76%, P=0.09). CONCLUSIONS: Our data do not support an association between H. pylori infection and diabetes mellitus. This is confirmed by the lack of difference between diabetics and nondiabetics with regard to the prevalence of both H. pylori infection and H. pylori-related gastroduodenal disorders.