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Background Malignant mesothelioma (MM) is a rare tumor with a dismal prognosis. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients’ survival. Bortezomib (Bor) is a specific and reversible inhibitor of the chymotrypsin-like activity of the 20S core of the proteasome, currently approved for the treatment of multiple myeloma and mantle cell lymphoma. On the other hand, Bor appears to have limited clinical effects on solid tumors, because of its low penetration and accumulation into tumor tissues following intravenous administration. These limitations could be overcome in MM through intracavitary delivery, with the advantage of increasing local drug concentration and decreasing systemic toxicity. Methods In this study, we investigated the effects of Bor on cell survival, cell cycle distribution and modulation of apoptotic and pro-survival pathways in human MM cell lines of different histotypes cultured in vitro. Further, using a mouse MM cell line that reproducibly forms ascites when intraperitoneally injected in syngeneic C57BL/6 mice, we investigated the effects of intraperitoneal Bor administration in vivo on both tumor growth and the modulation of the tumor immune microenvironment. Results We demonstrate that Bor inhibited MM cell growth and induced apoptosis. Further, Bor activated the Unfolded Protein Response, which however appeared to participate in lowering cells’ sensitivity to the drug’s cytotoxic effects. Bor also affected the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors, including ERK1/2 and AKT. In vivo, Bor was able to suppress MM growth and extend mice survival. The Bor-mediated delay of tumor progression was sustained by increased activation of T lymphocytes recruited to the tumor microenvironment. Conclusions The results presented herein support the use of Bor in MM and advocate future studies aimed at defining the therapeutic potential of Bor and Bor-based combination regimens for this treatment-resistant, aggressive tumor.

Tumor-initiating cells (TICs), the subset of cells within tumors endowed with stem-like features, being highly resistant to conventional cytotoxic drugs, are the major cause of tumor relapse. The identification of molecules able to target TICs remains a significant challenge in cancer therapy. Using TIC-enriched cultures (MM1, MM3 and MM4), from 3 human malignant pleural mesotheliomas (MPM), we tested the effects of sorafenib on cell survival and the intracellular mechanisms involved. Sorafenib inhibited cell-cycle progression in all the TIC cultures, but only in MM3 and MM4 cells this effect was associated with induction of apoptosis via the down-regulation of Mcl-1. Although sorafenib inhibits the activity of several tyrosine kinases, its effects are mainly ascribed to Raf inhibition. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with EGF or bFGF causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt and STAT3 phosphorylation. These effects were significantly reduced by sorafenib in bFGF-treated cells, while a slight inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGFR inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib. \ud A different picture was observed in MM1 cells, which, releasing high levels of bFGF, showed an autocrine activation of FGFR1 and a constitutive phosphorylation/activation of MEK-ERK1/2. A powerful inhibitory response to sorafenib was observed in these cells, indirectly confirming the central role of sorafenib as FGFR inhibitor.\ud These results suggest that bFGF signaling may impact antiproliferative response to sorafenib of MPM TICs, which is mainly mediated by a direct FGFR targeting.

Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e., NCI-H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer.

Asbestos has been used extensively and, in spite of many countries having banned most of its uses, professional, domestic and environmental exposure has not ceased worldwide. Inhaled asbestos fibers can lead to malignant mesothelioma, lung cancer and non-cancerous conditions, while the substance persists indefinitely in the lung and pleural tissue, resulting in continuous damage. Exposed individuals may be offered medical surveillance or compensation, but nothing is currently being done to lower their specific cancer risk: chemoprevention seems a promising approach. A web search and a PubMed review of the literature on chemoprevention trials in individuals exposed to asbestos have been conducted. Forty-six articles on five projects were found and newly reviewed but, surprisingly, no novel trials have been set up for twenty years, although considerable advances have been gained in cancer chemoprevention. A re-consideration of possibilities offered by chemoprevention should be encouraged. New trials based on the most recently characterized molecules should be planned, taking into account specific issues such as the need for a very large number of participants and a long follow up or, alternatively, the use of biomarkers as surrogate endpoints. The long latency of asbestos related diseases may offer delayed intervention opportunities. The lack of chemoprevention trials for asbestos exposure highlights the urgent need for research in this field.

La enfermedad de reflujo gastroesofágico (ERGE) es una enfermedad recurrente relacionada con el flujo retrógrado del contenido gástrico al esófago, con o sin daño tisular a dicho nivel. La Hernia Hiatal (HH) se asocia con ERGE, y se ha relacionado con grados severos de la enfermedad (Esofagitis Erosiva Severa y Esófago de Barrett). Objetivo: Describir la presencia y las alteraciones a nivel de la mucosa esofágica reportadas endoscópicamente en los pacientes que consultan con síntomas de ERGE al servicio de Gastroenterología del Hospital Vargas. Pacientes y métodos: estudio descriptivo de corte transversal, en el cual se evaluaron hallazgos endoscópicos de pacientes que acudieron con síntomas de ERGE a las consultas del servicio de gastroenteologia del Hospital Vargas entre enero-mayo de 2007. Resultados: de 674 pacientes encuestados, 204 pacientes (59 hombres y 145 mujeres)presentaron síntomas de ERGE, a 60 de ellos se les realizó videogastroscopia de manera aleatoria, reportando 23,33% (14 pacientes) con ERGE erosiva, 1,66% (1paciente) con tu submucoso de esófago, 6,66% con esófago Barret y 75% (45 pacientes) sin alteraciones esofágicas. 23 (38,33%) con hernia hiatal, 8 de ellos con esofagitis erosiva. Conclusiones: Nuestro trabajo confirma el valor de la endoscopia digestiva superior en la evaluación de pacientes con síntomas cardinales de ERGE. Gastro-esophageal reflux disease (GERD) is a recurrent disease related with retrograde progression of gastric contents to the esophagus with or without mucosal damage at this level. Hiatal hernia is associated with GERD and it has been related with severe grades of the disease (severe erosive esophagitis and BarrettÊs esophagus). Aims: to describe the presence of endoscopic features in GERD patientss with cardinals symptoms attended at the Gastroenterology Division of the Vargas Hospital in Caracas. Patients and Methods: this was a descriptive, transversal cohort study in which endoscopic findings in patients with GERD symptoms were evaluated, at the Gastroenterology Service, between January and May 2007. Results: of 674 patients interviewed, 204 patients (59 men and 145 women) presented GERD symptoms; to 60 of them an upper endoscopy randomly was performed. 23,33% (14 patients) had erosive GERD, 1,66% (1 patient) a submucous esophageal tumor, 6,66 % with BarrettÊs esophagus and 75% (45 patients) without esophageal changes, 23 (38,33%) with hiatal hernia, 8 of them with erosive esophagitis. Conclusion: our study supports the importance of performing an upper endoscopy in patients with cardinals symptoms of GERD.

Desde hace dos décadas esta descrita la utilidad de las prótesis endoscópicas, en patología biliopancreática. Objetivo: Mostrar la experiencia del Servicio de Gastroenterología del Hospital Vargas de Caracas en la colocación de prótesis endoscópicas en la patología biliopancreática, describiendo características demográficas, patologías más frecuentes, tasa de éxito en su colocación y complicaciones. Pacientes y Métodos: Estudio descriptivo, retrospectivo. Se revisaron datos de los informes de CPRE de pacientes hospitalizados y ambulatorios evaluados en la institución desde enero 1998 hasta abril 2007. Resultados: Se incluyeron 248 procedimientos de 110 mujeres y 73 hombres, 242 correspondieron a colocación de prótesis biliares (234 de teflón o plástico y 8 autoexpansibles metálicas) y 6 prótesis pancreáticas. Las indicaciones mas frecuentes para la colocación de prótesis fueron: patologías neoplásicas (47%), lesiones de la vía biliar post-quirúrgicas o traumáticas (22%) y litiasis biliar (17%). El éxito de la colocación de la prótesis fue del 99,1%. Se reportaron complicaciones en 4% de los procedimientos, con mayor frecuencia la colangitis (2%) y una mortalidad del 0%. Conclusión: La colocación de prótesis endoscópicas en patologías biliopancreáticas es un procedimiento seguro, con un bajo porcentaje de complicaciones y mortalidad. The utility of the endoscopic stent have been described for two decades in the biliopancreatic diseases. Aims: To show the Gastroenterology Division of the Hospital Vargas de Caracas experience in placing endoscopic stents in biliopancreatic diseases, describing demographic characteristics more frequent diseases, success rates and complications. Patients and Methods: descriptive and retrospective trial. Features of the reports of PEPR of hospitalized and ambulatory patients seen in the institution from January 1998 to april 2007 were reviewed. Results: 248 procedures from 110 women and 73 men were included, 242 had a biliar stent (234 of Teflon or plastic and 8 metallic selfexpanded) and 6 had pancreatic stents. The more frequent indications for placing the stents were: Tumoral disease, (47%), traumatic or post-surgical lesions of the biliary tract (22%) and biliary stones (17%). The success rate of the placing of stents was 99.1%. The procedureÊs complication rate reported was 4%, being colangitis the most frequent with 2% and a 0% mortality. Conclusion: the placing of endoscopic stents in biliopancreatic diseases is a safe procedure, with a low rate of complications and mortality.

La enfermedad por reflujo gastroesofágico (ERGE) es uno de los trastornos gastrointestinales con mayor prevalencia; afecta del 10 a 15% de la población general constituyendo una causa frecuente de consulta. Sin embargo, existen pocos reportes acerca de la prevalencia de ERGE en la población general. Objetivos: Determinar la prevalencia de ERGE en la población general adulta del área metropolitana de Caracas y estudiar algunos factores asociados a esta enfermedad. Materiales y métodos: Estudio de corte transversal, realizado en la población general adulta del área metropolitana de Caracas en abril de 2007. Se utilizó una encuesta basada en criterios clínicos epidemiológicos de acuerdo a consensos latinoamericanos y europeos sobre la ERGE. Para el análisis de los resultados se calcularon promedios, medianas y porcentajes. Resultados: De 389 sujetos encuestados, 223 fueron mujeres (57,3%) y 166 hombres (42,7%). El promedio de edad fue 33,89 años. La prevalencia de síntomas cardinales en la ERGE fue 19,02%. En los sujetos con ERGE encontramos que 47,3% ingerían licor al menos un vez al mes, y 21,6% referían hábitos tabáquicos. Conclusión: Se determinó que la prevalencia de la ERGE en la población general adulta del área Metropolitana de Caracas fue de 19,02% encontrándose asociación con el hábito alcohólico. Gastroesophageal reflux disease (GERD) is one of the gastrointestinals problems with higher prevalence; it affects 10 to 15% of the general population being a frequent cause of medical visit. Nevertheless, there is low number of reports about GERD prevalence. Objectives: to determine GERD prevalence in adult population of the Caracas Metropolitan Area and study some related factors to this disease. Materials and methods: Study of transversal cut, made in adult population in Caracas Metropolitan Area in April 2007. A poll based in clinical and epidemiological criteria in accordance with a Latin- American and European consensus about GERD was used. To analize the results averages, medians and percentages were calculated. Results: of 389 subjects surveyed, 223 were women (57,3%) and 166 were men (42,7%). The mean age of the patients was 33 years old. The cardinals symptoms prevalence was 19,02%. In subjects with GERD we found that 47,3% drank alcohol at least once a week, and 21,6% were smokers. In Conclusion, we found that GERD prevalence in adult population of the Caracas Metropolitan Area was 19, 02% finding a relationship with alcoholic habit.

Introducción: La cápsula endoscópica (CE) y la enteroscopia de doble balón (EDB) fueron introducidas como nuevas modalidades endoscópicas para el estudio del intestino delgado. Objetivo: comparar el rendimiento diagnóstico de estos dos métodos en la evaluación de pacientes con patología del intestino delgado. Pacientes y métodos: estudio descriptivo de una muestra de 97 pacientes de ambos géneros mayores de 12 años, que acudieron al Servicio de Gastroenterología del Hospital Vargas de Caracas y Policlínica Metropolitana entre diciembre 2004 y mayo 2006, con indicación médica para evaluación del intestino delgado por cápsula endoscópica y/o enteroscopia doble balón. Resultados: a 30 pacientes se les realizó CE (12 mujeres, 18 hombres) edad promedio 58,95 años. Se encontraron hallazgos positivos en 72,41%. A 67 pacientes (36 mujeres, 31 hombres) se les realizó enteroscopia doble balón, edad promedio de 52,9 años. Hubo hallazgos positivos en 62,68%. Hubo 3 complicaciones menores (4,4%) tratadas médicamente. Conclusión: el rendimiento diagnóstico de la CE y EDB fue similar para detectar lesiones del intestino delgado. EDB permite realizar toma de biopsias y procedimientos terapéuticos. Introduction: Endoscopic Capsule (EC) and Double Balloon Enteroscopy (DBE), are new endoscopic modalities for the study of the small bowel. Objective: To compare the diagnostic yield of these two methods in the evaluation of patients with pathology of the small bowel. Patients and methods: Comparative study of a sample of 97 patients of both genders that attended the Hospital Vargas de Caracas and Metropolitan Policlinic, between December 2004-May 2006, with clinical indication for evaluation of the small bowel by EC and/or DBE. Results: EC was performed to 30 patients (12 women, 18 men) age average 58,95 years, with findings in 72,41%: DBE was performed to 67 patients (36 women, 31 men), age average 52,9 years. Positive findings: 62,68%. There were 3 complications (4,4%).Conclusion: The diagnostic yield of EC y DBE was similar to detect lesions of the small bowel. With DBE is possible to take biopsy samples and perform therapeutic procedures.

Introducción: los métodos descritos para el estudio del intestino delgado han sido de difícil realización y baja certeza diagnóstica. La cápsula endoscópica (CE) y enteroscopia doble balón (EDB), permiten obtener beneficio para el estudio y tratamiento del paciente con hemorragia digestiva oscura. Objetivo: determinar el rendimiento diagnóstico de la CE y EDB en pacientes con hemorragia digestiva oscura. Métodos y pacientes: se evaluaron 50 pacientes con hemorragia digestiva oscura, en 24 pacientes se realizó CE y en 26 pacientes EDB. Los hallazgos de las lesiones por cápsula endoscópica M2A Given Imaging y enteroscopia doble balón fueron comparados. Resultados: como causa de sangrado se encontraron lesiones en el 56,52% de los pacientes utilizando CE y en 42,30 % de los pacientes con EDB (p= 0,04). Ambos estudios fueron bien tolerados. No se reportó ningún efecto adverso. Biopsias (n: 1), coagulación con argón plasma (n: 7), esclerosis con adrenalina (n: 1) fueron realizados al utilizar EDB. Conclusión: el rendimiento diagnóstico de la CE y EDB fue similar para detectar las lesiones causantes de hemorragia oscura. La ventaja de la EDB es la posibilidad de aplicar procedimientos endoscópicos terapéuticos. Introduction: The methods described for the study of the small bowel have been of difficult accomplishment and low diagnostic certainty. The Endoscopic Capsule (EC) and Double Balloon Enteroscopy (DBE), can be helpful in the study and treatment of the patient with occult digestive bleeding. Objective: To determine the diagnostic yield of EC and DBE in patients with occult digestive bleeding. Methods and patients: 50 patients with occult digestive bleeding were evaluated, in 24 patients EC was the method of choice and in 26 patients DBE. Findings by means of endoscopic capsule M2A Given Imaging and double balloon enteroscopy were compared. Results: A cause of bleeding was found in 56.52% of patients using EC and in 42, 30% of patients with DBE (p=0,04). Both studies were well tolerated. No adverse effects were reported. Biopsies (n: 1), argon plasma coagulation (n: 7), sclerosis with adrenalin (n: 1) were performed when using DBE. Conclusion: The diagnostic yield of EC and DBE was similar in detecting injuries causing occult bleeding. The advantage of DBE is the possibility of applying therapeutic endoscopic procedures.

Deoxyribonucleic acid (DNA) oncoviruses can induce neoplastic transformation by interfering with proliferative proteins. Simian virus 40 (SV40) has been shown to induce brain tumors, osteosarcoma, lymphoid tumors and malignant mesothelioma in hamsters and SV40-like DNA sequences corresponding to the Rb-pocket binding domain of SV40 T-antigen (Tag) have been detected in the same human tumors. Since only a small percentage of people exposed to asbestos fibers develop a malignant mesothelioma, SV40 has been suspected to co-operate with the fibers in the neoplastic transformation or even to itself induce the onset of malignant mesothelioma in patients without expositive history. The mechanism that seems to be involved in the SV40-induced carcinogenesis process is mediated by interaction of Tag, both with p53 and Rb proteins, leading to their functional inactivation that is responsible for the removal of their inhibitory cell cycle effect which determines the increase of the number of cells entering the G1-S phase. Up to now the source of SV40 human infections has not yet been completely identified even though administration from 1957-1965 of SV40 contaminated polio vaccines is highly suspected. Horizontal infection by sexual transmission has been also hypothesized. Due to the important public health implications further investigations are required in order to establish both the source and the carcinogenetic role of simian virus 40 in humans.

The long latency period between asbestos exposure and the onset of malignant mesothelioma (MM) suggests that a multistep tumorigenesis process occurs whilst the capability of asbestos fibres to interfere directly with chromosomes focuses on the critical role of the chromosomal abnormalities in this neoplasm. The aim of our study was to identify any recurrent chromosomal changes in ten primary MM cell cultures derived from pleural effusions of patients with MM from the same geographic area and environmental and/or occupational exposure to asbestos fibers. Cytogenetic analysis was performed in accordance with International System for Human Cytogenetic Nomenclature. Our results confirmed a great number of cytogenetic abnormalities in MM cells. Recurrent loss of the long arms of chromosome 6 (6q-) was the most frequent abnormality detected (four epithelial and two mixed subtypes) while, on the whole, abnormalities of chromosome 6 were found in nine out of ten cases whereas chromosome 6 was normal only in the case with fibromatous subtype. Monosomy 13 and 17 was found in five cases, monosomy 14 in four cases and 22 in three cases. Since deletion of 6q- was detected even in relatively undisturbed karyotype, we hypothesize a multistep carcinogenic process in which deletion of 6q- is an early event in the development and progression of malignant mesothelioma.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a haematopoietic growth factor, has been shown to stimulate in vitro the production of interleukins 1, 6 and 8 (IL-1, IL-6 and IL-8), tumour necrosis factor-alpha (TNF-alpha) and GM-CSF by polymorphonuclear cells (PMNs), alveolar macrophages (AMs), fibroblasts and endothelial cells of the lung, and the growth and differentiation of resident alveolar macrophages. The aim of this study was to establish whether recombinant GM-CSF (rhGM-CSF), administered subcutaneously at a dose of 5 micrograms.kg-1 for 3 days in five patients with unresectable non-small cell lung cancer before starting chemotherapy, induces an increase in the alveolar cell count, and whether these cellular lung variations may be related to increases in the above-mentioned cytokines. In the bronchoalveolar lavage fluid (BALF) total cell count, polymorphonuclear cells, neutrophils, and alveolar macrophages increased significantly in comparison with the baseline, and the extent of variation of the BAL cell count was considerably greater than that of the circulating leucocytes. The mean levels of all the cytokines increased, but a significant difference with respect to the basal condition was observed only for IL-6 and IL-8. After rhGM-CSF treatment, significant correlations were found between neutrophil counts and the levels of IL-6 and IL-8. In conclusion, rhGM-CSF administration induces a cellular expansion in the lung, and the neutrophil increase appears to be related to increased levels of IL-8.

The effect of in vivo administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on neutrophils GM-CSF receptor, was investigated in patients with neoplastic diseases and normal hematopoiesis. Patients were divided into two groups. Group A received a single dose of rhGM-CSF (5 micrograms/kg/day) and receptor studies were performed 90 min and 48 h after treatment. Group B received three doses, administered subcutaneously every 24 h and receptor studies were performed 90 min after first injection and 24 h after the last. Before treatment neutrophils only displayed high-affinity receptors (KD 85 +/- 53 pM; number of receptors/cell 1318 +/- 567). The first injection of rhGM-CSF produced a transient leucopenia and the internalization of GM-CSF receptor on neutrophils in both groups of patients: 90 min after s.c. administration receptors could not be detected with conventional binding studies. In group A patients, 48 h after a single dose of rhGM-CSF, receptors, albeit with a decreased affinity (KD = 240 +/- 131 pM; number of receptors/cell 783 +/- 494) were again expressed. In group B patients, 24 h after the last rhGM-CSF injection, low intermediate affinity receptors not present before treatment appeared (KD 720 +/- 175 pM; number of receptor/cell 1222 +/- 179). They were associated with a low number of high affinity receptors (KD = 9 +/- 4 pM; number of receptors/cell 106 +/- 44). These observations indicate that more than one type of GM-CSF receptor may exist on neutrophils. It may be suggested that in vivo the regulation of the GM-CSF receptor is different from that in vitro and is related to the presence of the cytokine in patient blood.