The Tuscany Mesothelioma Register (ARTMM) records pleural malignant mesothelioma cases of Tuscany residents, diagnosed by histological, cytological, or clinical (radiography or computerized tomography) examinations. The ARTMM began in... more
The Tuscany Mesothelioma Register (ARTMM) records pleural malignant mesothelioma cases of Tuscany residents, diagnosed by histological, cytological, or clinical (radiography or computerized tomography) examinations. The ARTMM began in 1988 and estimates mesothelioma incidence in Tuscany and collects information on past asbestos exposure of mesothelioma cases. The aim of this paper was to describe the incidence of pleural mesothelioma cases in Tuscany and to analyse their possible past asbestos exposures. We considered pleural mesothelioma cases recorded in ARTMM in the period 1988-2000 and interviews collected for these cases. In order to identify past asbestos exposure in the occupational and non-occupational history of patients, interviews were carried out using a standardised questionnaire. In the period 1988-2000, 494 pleural malignant mesothelioma cases were recorded in the ARTMM; 82% were males. In the periods 1988-1993, 1994-1997, 1998-2000 the incidence rates, standardised o...
Depletion of intracellular potassium ions (K+) is necessary for cells to shrink, induce DNA fragmentation and activate caspases, events which are features of apoptosis. We used 86Rb+ as a K+ analogue to evaluate the possibility of... more
Depletion of intracellular potassium ions (K+) is necessary for cells to shrink, induce DNA fragmentation and activate caspases, events which are features of apoptosis. We used 86Rb+ as a K+ analogue to evaluate the possibility of pharmacologically depleting human pulmonary mesothelioma (P31) and small cell lung cancer (U1690) cells of K+, for future use in studies of apoptosis induction. The Na+, K+, 2CI(-)-cotransport inhibitor bumetanide transiently inhibited 86Rb+ influx, but when combined with the Na+, K+, ATPase pump inhibitor ouabain there was a marked and lasting (up to 6 h) 86Rb+ influx inhibition. Cellular K+ efflux was augmented by amphotericin B, digitonin and nigericin. Amphotericin B was an effective 86Rb+ efflux stimulator with low cytotoxicity, whereas digitonin caused cell detachment and nigericin increased LDH release in the U1690 cell line, indicating considerable toxicity of the drugs. It is possible to efficiently reduce intracellular K+ by persistent K+ influx ...
To show the radiological manifestations of primary pleural tumors. we carried out a retrospective analysis of radiological findings in 62 patients with primary malignant tumor of pleura. Study included 39 male and 23 female patients.... more
To show the radiological manifestations of primary pleural tumors. we carried out a retrospective analysis of radiological findings in 62 patients with primary malignant tumor of pleura. Study included 39 male and 23 female patients. Malignant tumors were present in 92.7% of the patients and benign ones in 7.2%. The most common malignant tumor was mesothelioma (85.4%), and solitary fibrous tumor prevailed among benign tumors (9.7%). Diffuse malignant mesothelioma manifested on computed tomography (CT) as a pleural thickening and effusion in 67.4% of the patients, tumors and effusion in 11.7%, and only as an effusion in 9.8% cases. Thickening of the pleura appeared diffuse in 54% of patients and most often it had nodular pattern. Both localized malignant and all benign tumors presented as tumor-like changes with the signs of necrosis in 50%. The imaging methods have a key role in the diagnosis of pleural tumors. CT shows different morphologic features of pleural lesions that have been established as a useful tool for differentiating malignant from benign disease. However, magnetic resonance is preferred imaging method for assessing the extent and resectability of pleural tumors.
Approximately three million workers in the United States are estimated to be exposed to silica, man-made mineral fibers, and asbestos. The lung is the primary target organ of concern. Each of these substances is composed predominantly of... more
Approximately three million workers in the United States are estimated to be exposed to silica, man-made mineral fibers, and asbestos. The lung is the primary target organ of concern. Each of these substances is composed predominantly of silicon and oxygen; asbestos and silica are crystalline, and asbestos and man-made mineral fibers are fibers. Man-made mineral fibers and asbestos are used as insulating agents, with the former having generally replaced the latter in recent years. Silica is used in foundries, pottery, and brick making, and is encountered by miners. A meta-analysis of 16 of the largest studies with well-documented silica exposure and low probability of confounding by other occupational exposures, indicates a relative risk (RR) of 1.3 (95 percent confidence interval [CI] = 1.2-1.4). Lung cancer risks are highest and most consistent for silicotics, who have received the highest doses (RR = 2.3, CI = 2.2-2.4, across 19 studies). The data for mineral fibers continue to s...
Trapped lung is defined by the inability of the lung to expand and fill the thoracic cavity because of a restricting "peel." This restriction may be secondary to a benign inflammatory or fibrotic cortex or to a malignant... more
Trapped lung is defined by the inability of the lung to expand and fill the thoracic cavity because of a restricting "peel." This restriction may be secondary to a benign inflammatory or fibrotic cortex or to a malignant visceral pleural tumor. This condition has a significant impact on the patient's quality of life by causing dyspnea. This article discusses the role of surgery in relieving the trapped lung, including decortication in benign disease and pleurectomy in malignant disease. The surgical approaches of video-assisted thoracoscopy and thoracotomy are contrasted and the future potential for surgical trials in this condition is outlined.
To summarize the geographical and temporal variations in incidence of pleural mesothelioma in Europe, using the extensive data available from European general cancer registries, and consider these in light of recent trends in asbestos... more
To summarize the geographical and temporal variations in incidence of pleural mesothelioma in Europe, using the extensive data available from European general cancer registries, and consider these in light of recent trends in asbestos extraction, use and import in European countries. The data were extracted from the European Cancer Incidence and Mortality database (EUROCIM). The inclusion criteria was acceptance in Volume VII of Cancer Incidence in Five Continents. Truncated age-standardized rates per 100,000 for the ages 40-74 were used to summarise recent geographical variations. Standardized rate ratios and 95% confidence intervals for the periods 1986-1990 and 1991-1995 were compared to assess geographical variations in risk. To investigate changes in the magnitude of most recent trends, regression models fitted to the latest available 10-year period (1988-1997) were compared with trends in the previous decade. Fitted rates in younger (40-64) and older adults (65-74) in the most...
The aim of this study was to evaluate the prevalence, clinical meaning and diagnostic value of extrapleural and cardiophrenic nodes occasionally observed on computed tomography (CT) scans of the chest. We included 750 consecutive patients... more
The aim of this study was to evaluate the prevalence, clinical meaning and diagnostic value of extrapleural and cardiophrenic nodes occasionally observed on computed tomography (CT) scans of the chest. We included 750 consecutive patients who underwent CT of the chest for different clinical purposes (340 nonneoplastic patients, 270 with extrathoracic neoplasms, 120 with intrathoracic neoplasms, 20 with pleural metastasis) and 91 patients with histologically proven malignant pleural mesothelioma (MPM). For each group of patients, we analysed the presence of extrapleural and cardiophrenic nodes, their number (single or multiple) and their size. The prevalence of cardiophrenic nodes between 6 and 10 mm and >10 mm was significantly higher in patients with MPM (28.6 and 26.4 %, respectively) than in all other categories of patients, except for patients with pleural metastasis (30 and 25 %, respectively). The prevalence of extrapleural nodes, independently from their size, was significantly higher in patients with MPM (68 %) compared with all other groups, including patients with pleural metastasis (5 %; p < 0.0001). Cardiophrenic nodes >5 mm and extrapleural nodes of any size have a significant diagnostic value in malignant pleural disease, either primary or secondary, whereas they are extremely rare in other neoplastic or nonneoplastic diseases.
The objective of this paper is to investigate mortality among 1247 male asbestos-cement workers employed in an asbestos-cement plant located in Naples. The cohort included 1247 men hired between 1950 and 1986. The follow-up began on... more
The objective of this paper is to investigate mortality among 1247 male asbestos-cement workers employed in an asbestos-cement plant located in Naples. The cohort included 1247 men hired between 1950 and 1986. The follow-up began on January 1st 1965. The vital status and causes of death were ascertained up to December 31 2005. Cause-specific mortality rates of the Campania Region population were used as reference. Relative risks were estimated using Standardized Mortality Ratios (SMRs), and the confidence intervals were calculated at a 95% level (95% CI). A significant increase in mortality was observed for respiratory disease (81 deaths; SMR = 187; 95% CI = 149- 233), particularly for pneumoconiosis (42 deaths; SMR = 13 313; 95% CI = 9595-17 996) of which 41 deaths for asbestosis (SMR = 43 385; 95% CI = 31 134-58 857), for pleural cancer (24 deaths; SMR = 2617; 95% CI = 1677-3893), for lung cancer (84 deaths; SMR=153; 95% CI = 122-189) and for peritoneal cancer (9 deaths; SMR = 198...
Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there... more
Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy.
The accumulation of fluid in the pleural space is a common manifestation of a wide range of disease. This review provides a structured approach to the investigation of the patient with a pleural effusion. This should allow an accurate... more
The accumulation of fluid in the pleural space is a common manifestation of a wide range of disease. This review provides a structured approach to the investigation of the patient with a pleural effusion. This should allow an accurate diagnosis to be made with the minimum number of invasive and time-consuming investigations.
Epidemiologic studies of mesothelioma have focused primarily on occupational exposures to asbestos. Nonoccupational exposure to asbestos can be grouped into three main categories: paraoccupational (familial), neighborhood, and true... more
Epidemiologic studies of mesothelioma have focused primarily on occupational exposures to asbestos. Nonoccupational exposure to asbestos can be grouped into three main categories: paraoccupational (familial), neighborhood, and true environmental exposures. Elevated mesothelioma rates not attributable to occupational exposures have been observed in asbestos mining and manufacturing areas. Asbestos is one of the most dangerous environmental carcinogens because of the small dose known to cause mesothelioma and the rapid lethality of the disease once it develops. Further research is needed to characterize the contribution and risk profile for environmental asbestos and mesothelioma, and for the development of public health policy.
Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin... more
Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubule-disrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, αMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous...
Mesothelioma, the primary malignancy of mesothelial cells, still remains a public health concern since it is associated with occupational, domestic and environmental exposure to asbestos. Asbestos is the main etiological factor involved... more
Mesothelioma, the primary malignancy of mesothelial cells, still remains a public health concern since it is associated with occupational, domestic and environmental exposure to asbestos. Asbestos is the main etiological factor involved in the occurrence of this kind of tumour, which most often arises in the pleural cavities. Theses tumours often caused an increased secretion of the pleural fluid, and produced hyaluronic acid in excessive amounts. Therefore, the quantitative determination of hyaluronic acid content in the pleural effusion is a useful and suitable marker for malignant mesothelioma. Hyaluronic acid (also called hyaluronan) is a high molecular weight polymer, belonging to the glycosaminoglycan family. It is composed of characteristic repeating disaccharide units containing D-glucuronic acid and N-acetyl-D-glucosamine and joined by/31-4 linkages. These last decades, many various methods have been published for the determination of hyaluronic acid in the pleural fluid. A qualitative electrophoretic test combined with a quantitative measurement of hyaluronic acid after isolation by ion-exchange chromatography was firstly developed, easy to perform, and accurate. More recently, quantitative HPLC methods and specific radio assays or immunoenzymoassays have been proposed, sufficiently sensitive to qualify as useful diagnosis procedures. For most studies, the acid hyaluronic content in the pleural fluid can be considered as significant when higher than 50 mg/l (threeshold level). High levels of hyaluronic in pleural fluid combined with low levels of carcinoembryonic antigen should raise the suspicion of mesothelioma.
Objective: We sought to estimate the lifetime risk of asbestos-related cancer for residents of Lower Manhattan attributable to asbestos released into the air by the 9/11 attack on New York City's World Trade Center (WTC). Methods:... more
Objective: We sought to estimate the lifetime risk of asbestos-related cancer for residents of Lower Manhattan attributable to asbestos released into the air by the 9/11 attack on New York City's World Trade Center (WTC). Methods: Exposure was estimated from available data and reasoned projections based on these data. Cancer risk was assessed using an asbestos risk model that differentiates
Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166), is expressed on osteoblasts (OB) and hematopoietic stem cells (HSC) residing in the hematopoietic niche, and may have important regulatory roles in bone formation. Because HSC... more
Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166), is expressed on osteoblasts (OB) and hematopoietic stem cells (HSC) residing in the hematopoietic niche, and may have important regulatory roles in bone formation. Because HSC numbers are reduced 77% in CD166(-/-) mice, we hypothesized that changes in bone phenotype and consequently the endosteal niche may partially be responsible for this alteration. Therefore, we investigated bone phenotype and OB function in CD166(-/-) mice. Although osteoclastic measures were not affected by loss of CD166, CD166(-/-) mice exhibited a modest increase in trabecular bone fraction (42%), and increases in osteoid deposition (72%), OB number (60%), and bone formation rate (152%). Cortical bone geometry was altered in CD166(-/-) mice resulting in up to 81% and 49% increases in stiffness and ultimate force, respectively. CD166(-/-) OB displayed elevated alkaline phosphatase (ALP) activity and mineralization, and increased mRNA expression of Fra 1...
Helmut Sies established the concept of oxidative stress in 1985. However, it took some time to introduce this concept into pathology, where investigators count on formalin-fixed paraffin-embedded tissue sections. I sought out antigens for... more
Helmut Sies established the concept of oxidative stress in 1985. However, it took some time to introduce this concept into pathology, where investigators count on formalin-fixed paraffin-embedded tissue sections. I sought out antigens for this purpose based on an oxidative stress-induced rat renal carcinogenesis model, which revealed that 8-hydroxy-2′- deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins are ideal. These two monoclonal antibodies successfully revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis. Shigeru Okada established the aforementioned ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model, which thus far has answered many questions regarding the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also inhuman carcinogenesis. Furthermore, excess iron is amajor pathology in asbestosinduced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.
Well-differentiated papillary mesothelioma (WDPM) is a tumor of uncertain malignant potential that usually occurs as a multifocal lesion of the female peritoneum, and is incidentally found at the time of surgery. We present here a... more
Well-differentiated papillary mesothelioma (WDPM) is a tumor of uncertain malignant potential that usually occurs as a multifocal lesion of the female peritoneum, and is incidentally found at the time of surgery. We present here a multifocal case that had arisen from the lining of a hernia sac. To our knowledge, only four cases of this event have been previously described. A review of the five cases reported, including our case, revealed that the mean age of the patients was 56.6±8.35 years. There was predominance in men (4:1). In four cases, the lesion was incidental. Most tumors were found in inguinal hernias. Four cases presented with gross abnormalities in the hernia sac. All the five patients were alive with no evidence of WDPM after a mean follow-up of 38.6 months. Extensive sampling of this rare lesion helps to rule out an epithelial malignant mesothelioma and prevents overtreatment.