Patient-derived and artificial ascites have minor effects on MeT-5A mesothelial cells and do not facilitate ovarian cancer cell adhesion.

The presence of ascites in the peritoneal cavity leads to morphological and functional changes of the peritoneal mesothelial cell layer. Cells loose cell-cell interactions, rearrange their cytoskeleton, activate the production of fibronectin, and change their cell surface morphology in a proinflammatory environment. Moreover, ovarian cancer cell adhesion has been shown to be facilitated by these changes due to increased integrin- and CD44-mediated binding sites. In this study, the biological responsiveness of the human pleural mesothelial cell line MeT-5A to patient-derived and artificial ascites was studied in vitro and adhesion of ovarian cancer cells, i.e. SKOV-3 cells, investigated. Changes were mainly observed in cells exposed to artificial ascites containing higher cytokine concentrations than patient-derived ascites. Interestingly, reduced cell-cell interactions were already observed in untreated MeT-5A cells and effects on tight junction protein expression and permeability upon exposure to ascites were minor. Ascites induced upregulation of CDC42 effector protein 2 expression, which affects stress fiber formation, however significant F-actin reorganization was not observed. Moreover, fibronectin production remained unchanged. Analysis of mesothelial cell surface characteristics showed upregulated expression of intercellular adhesion molecule 1, slightly increased hyaluronic acid secretion and decreased microvillus expression upon exposure to ascites. Nevertheless, the observed changes were not sufficient to facilitate adhesion of SKOV-3 cells on MeT-5A cell layer. This study revealed that MeT-5A cells show a reduced biological responsiveness to the presence of ascites, in contrast to published studies on primary human peritoneal mesothelial cells.

Lowered Cyclin E levels increase the efficiency and the specificity of capsaicin against cancerous cells of mesothelium.

Capsaicin is one of the most extensively studied phytochemicals and its cytotoxicity on various types of cancer has been demonstrated both in vitro and in vivo. The evaluation of its effect on mesothelioma, however, has remained quite limited. In this study, we investigated the anti-mesothelioma potential of capsaicin by observing its cytotoxicity on healthy, immortalized and cancerous cells of mesothelium in vitro and how this potential be affected by lowered Cyclin E levels, a key regulator of G1/S transition of cell cycle. For this purpose, we determined and compared the IC50 values of capsaicin in both FBS (Fetal Bovine Serum) containing and FBS-deprived medium of each cell population studied. Additionally, we examined the changes in both protein and mRNA levels of caspase-3 upon capsaicin exposure as well as conducted a series of experiments through which the relatively long term effect of capsaicin on the growth rate of the cells was assessed. As a result, the reduced Cyclin E obtained through the absence of FBS in growth medium was found not only to decrease IC50 values for all cell types dramatically (p<0.05) but also to cause a considerable difference between the values determined for cancerous and non-cancerous populations (p<0.05), which had not been observed in regular medium. Moreover, along with the fact that capsaicin exposure did not have an impact on the cell growth in long term in most cases, caspase-3 levels also remained the same when exposed to capsaicin, suggesting a mechanism of cell death independent of caspases.

Application of 3D Mass Spectrometry Imaging to TKIs.

Mass spectrometry imaging (MSI) allows visualization of endogenous and exogenous compound in tissue sections based on its molecular mass. The 3D reconstruction by MSI provides a more informative description of the tumor drug distribution compared to the high-performance liquid chromatography method, highlighting the heterogeneity of intratumor drug concentration. This additional information can be important in understanding chemoresistance to target agents. Here, we present the 3D visualization of the tyrosine kinase inhibitor (TKI), imatinib, in a xenograft model of resistant malignant pleural mesothelioma.

Eficacia y seguridad de pemetrexed en el tratamiento de primera línea del mesotelioma maligno pleural estadio clínico IV, y III no operable / Efficacy and safety of pemetrexed in the first-line treatment of malignant pleural mesothelioma clinical stage IV, and III not operable

INTRODUCCIÓN: El presente informe expone la evaluación de la combinación de pemetrexed con quimioterapia como tratamiento de primera línea en los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. El mesotelioma maligno pleural (MMP) es un raro tipo de neoplasia que se origina en las células mesoteliales que recubren la cavidad pleural. Más del 80% de los casos están relacionados con la exposición ocupacional a los asbestos; esta condición es significativamente más común en hombres, con una razón de hombre-mujer de 5:1. Con frecuencia la manifestación clínica y el diagnóstico aparecen en estadios avanzados, siendo muy pobre el pronóstico para la mayoría de los afectados. OBJETIVO: Comparar el efecto de la combinación de pemetrexed + cisplatino en la sobrevida global (SG) de los pacientes, respecto al uso de cisplatino solo. TECNOLOGÍA SANITARIA DE INTERÉS: Pemetrexed es un agente anti-folato que ejerce su acción antineoplásica por medio de la alteración de varios procesos metabólicos, dependientes de folato, esenciales de la división celular. Suprime la síntesis de purinas y pirimidinas, las cuales son claves en la formación de bloques de ADN y ARN. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de la combinación de pemetrexed con platino como tratamiento de primera línea de los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), The Canadian Agency for Drugs and Technologies in Health (CADTH) y The Scottish Medicines Consortium (SMC). Esta búsqueda se completó ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de la combinación de pemetrexed con cisplatino como tratamiento de primera línea de los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. La evidencia de mayor calidad disponible es el estudio EMPHACIS. Este estúdio fue un ECA de fase III, ciego simple, cuyo objetivo principal fue comparar el efecto de la combinación de pemetrexed + cisplatino en la sobrevida global (SG) de los pacientes, respecto al uso de cisplatino solo. El estudio EMPHACIS sugiere que pemetrexed + cisplatino puede ofrecer mayor beneficio comparado con cisplatino solo, en pacientes con enfermedad avanzada en términos de ganancia de aproximadamente 2.8 meses en la sobrevida. Se observó una diferencia significativa en la sobrevida a favor de la combinación de pemetrexed + cisplatino, respecto al uso de cisplatino solo. Al considerarse la población por intención a tratar, la mediana de SG fue 12.1 meses (IC 95% 10.0-14.4) en el brazo de pemetrexed + cisplatino, comparado con los 9.3 meses (IC 95% 7.8-10.7) en el brazo de cisplatino (HR=0.77; IC 95%, 0.61 - 0.96; p=0.02). El uso de pemetrexed suplementado con ácido fólico y vitamina B12 puede mejorar la sobrevida cuando es usada en combinación con cisplatino, pero en pacientes con buen funcionamiento general (ECOG 0-1). No obstante, aun seleccionando al paciente según este criterio, la decisión de tratar a un paciente con la combinación de pemetrexed con cisplatino debe también tomar em consideración la toxicidad asociada. En EsSalud, están disponibles vinorelbina y el régimen MVP (mitomicina C, vinblastina y cisplatino), que son los agentes que se han venido usando en el tratamiento del MMP, pero han mostrado ofrecer solo algún alivio de los sintomas con aceptable toxicidad y sin ninguna mejora en la tasa de respuesta ni en la sobrevida global. Actualmente, no hay evidencia de otro agente que haya logrado más allá de respuestas parciales sin ningún efecto en la sobrevida. La única combinación que mostró algún beneficio en la SG es la de pemetrexed con cisplatino. A pesar de las limitantes del estudio, el MMP es una enfermedad con una mediana de sobrevida de alrededor de 12 meses, por lo que, una ganancia en la sobrevida de 2.8 meses en pacientes seleccionados es de utilidad clínica. Por lo tanto, la combinación de pemetrexed con cisplatino puede ser recomendado como una opción para el tratamiento de MMP solamente si los pacientes tienen enfermedad avanzada y con puntuación ECOG 0-1, en quienes la cirugía no está recomendada. CONCLUSIÓN: el Instituto de Evaluación de Tecnologías en Salud e Investigación IETSI, aprueba el uso de pemetrexed + cisplatino con suplementación de ácido fólico y vitamina B12, en pacientes con diagnóstico de MMP estadio avanzado inoperable, estado de funcionamiento de ECOG 0-1, y para quienes la cirugía no está recomendada, según lo establecido en el Anexo N° 1 del presente Dictamen Preliminar, el que tiene una vigencia de dos años a partir de su fecha de publicación.

Third-line chemotherapy with carboplatin, gemcitabine and liposomised doxorubicin for malignant pleural mesothelioma.

There is no well-defined standard third-line chemotherapy for advanced malignant pleural mesothelioma (MPM). However, combination of carboplatin, liposomised doxorubicin (Caelyx) and gemcitabine (CCG regimen) has revealed noteworthy activity when used as first-line treatment. The aim of this study is to assess efficacy and toxicity profile for patients with MPM receiving CCG regimen as a third-line treatment. Carboplatin (AUC 5), Caelyx (30 mg/m(2)) and Gemcitabine (1,000 mg/m(2)) day 1, together with Gemcitabine (800 mg/m(2)) day 8, were given in up to six cycles. Patients were unresectable, PS 0-2, and had previously received a first-line platinum-based regimen and either vinorelbine or pemetrexed as second line. Response to treatment was assessed by CT scan using Modified RECIST criteria for mesothelioma. Forty-three patients were treated between 2010 and 2014. Median age was 67 years (47-82), 72 % males, and 79 % had previous asbestos exposure. Ninety per cent had PS 0-1, 58 % had epitheloid subtype and 63 % IMIG stage IV. First-line treatment was platinum and pemetrexed in 42 cases. Second-line treatment was vinorelbine in 42 cases and pemetrexed in one patient. Median lead time from cessation of second-line treatment to start of third CCG was 1 month. Twenty-eight per cent of the patients received six cycles, while treatment was postponed due to toxicities, mainly haematological, in 56 % of cases. No toxicity-related deaths occurred. Partial response (PR) occurred in 14 %, and disease control rate (DCR) was 60 %. Medians of overall survival (OS) from diagnosis and from start of CCG treatment were 25.2 months (18.4-31.5 months) and 6.8 months (5.4-8.4 months), respectively. Progression-free survival (PFS) was 4.1 months (1.7-4.5 months). Third-line CCG revealed a noteworthy efficacy with a DCR of 60.4 %. It was, however, associated with considerable haematological toxicity. Less toxic and more active treatment options are clearly needed.

Belmont Hyperthermia Pump in the conduct of intra-operative heated chemotherapy.

Intra-operative heated chemotherapy (IOHC) has been performed in the Thoracic surgical department of Brigham and Women's Hospital (BWH, Boston, MA, USA) for over a decade. A "home-grown" system was developed for this purpose with limited improvements made to it through the years. This technology is used for neo-adjuvant therapy in the conduct of extra-pleural pneumonectomy and pleurectomy for treatment of mesothelioma. Improvements to the traditional BWH system were sought due to the hazardous nature of the chemotherapy solution and the relative complexity of the IOHC circuit. Belmont Instrument (Belmont Instrument Corporation, Billerica, MA, USA) applied their proprietary infusion/warming technology to develop the Belmont Hyperthermia Pump. The Hyperthermia Pump was designed to recirculate large volumes of fluid while maintaining perfusate temperatures up to 46oC at a flow rate of up to 750 ml/min. Approval from the FDA for clinical use of this device was granted June 2007. Parameters were defined and investigated to determine if the Hyperthermia Pump would meet or exceed the performance characteristics of the traditional BWH system. Our investigation resulted in the replacement of the traditional BWH circuit. The Belmont Hyperthermia Pump is a compact, easy to use, extremely safe means to deliver intra-operative hyperthermic chemotherapy in the conduct of surgical treatment of mesothelioma.

Chemoimmunotherapy: an emerging strategy for the treatment of malignant mesothelioma.

Whether the immune system can recognize malignant and premalignant cells and eliminate them to prevent the development of cancer is still a matter of open debate, but in our view, the balance of evidence favours this concept. Nonetheless, the International Agency for Research on Cancer has now predicted that cancer will overtake heart disease as the leading cause of death worldwide by 2010, showing that this protective mechanism often fails. Malignant mesothelioma has traditionally been considered a relatively non-immunogenic cancer. However, mesothelioma cells do express a set of well-defined tumour antigens that have been shown to engage with the host immune system. Mesothelioma should therefore be considered a target for immunotherapy. A variety of anticancer immunotherapies have been investigated in mesothelioma and in other malignancies, although these have been largely ineffective when used in isolation. Over recent years, there has been increasing interest in the possibility of combining immunotherapy with chemotherapy in the fight against cancer. Here, we discuss the rationale behind combining these two, long considered antagonistic, treatment options in the context of malignant mesothelioma.

Pemetrexed como tratamiento de mesotelioma pleural / Pemetrexed as treatment of pleural mesothelioma

Se describe el caso de un varón de 63 años de edad sin antecedentes previos de interés, salvo contacto con asbesto que presenta un mesotelioma pleural maligno. En la ecografía torácica y la tomografía computarizada torácica se observa una gran masa pleural unida al diafragma además del derrame pleural en hemitórax derecho. El enfermó inició tratamientoquimioterápico con pemetrexed y cisplatino, observándose en la tomografía computarizada una clara disminución del tamaño de la masa pleural a los seis meses de iniciar este tratamiento. Este artículo describe la posible utilización de pemetrexed en pauta combinada con carboplatino como tratamiento quimioterápico válido de un mesotelioma pleural maligno que presenta masas pleurales al diagnóstico

A case of a 63-year-old male with no previous background of interest, except contact with asbestos who had a malignant pleural mesothelioma is described. The chest ultrasonography and chest computed tomography showed a large pleural mass joined to the diaphragm in addition to pleural effusion in the right hemothorax. The patient initiated chemotherapy with pemetrexed and cisplatin, a clear decrease in the size of the pleural mass being observed in the computed tomography at six months of initiating this treatment.This article describes the possible use of pemetrexed in regimes combined with carboplatin as valid chemotherapy treatment of a malignant pleural mesothelioma that has pleural masses on diagnosis

[Morphology of gastrointestinal stromal tumors in advanced stages of the disease: baseline findings before chemotherapy with imatinib]. / Morphologie gastrointestinaler Stromatumoren im fortgeschrittenen Stadium der Erkrankung: Ausgangsbefunde vor Chemotherapie mit Imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract with an increasing detection rate due to improved differentiating methods in current diagnostic pathology. This study evaluates the radiologic characteristics of these neoplasms to discover specific signs leading to an earlier diagnosis. MATERIALS AND METHODS: As part of a randomized phase III clinical trial of the European Organization for Research and Treatment of Cancer (EORTC), 72 patients with advanced stage GIST were treated with the selective tyrosine-kinase-inhibitor imatinib (Glivec, Novartis, Switzerland). For initial staging, 60 patients underwent MRI and 12 patients underwent CT. RESULTS: GISTs are mesenchymal tumors that grow submucosally and exophytically and become multiple, nodular or ovoid in the advanced stage. The predominant findings are peripheral solid structures with strong contrast enhancement and a central necrosis. Metastases are primarily located in the liver, where they appear as oval or round, sharply delineated solitary lesions with central necrosis. CT demonstrates the primary tumors and local recurrences as nearly isodense with the liver. On MRI, the lesions are hypointense on T 1 -weighted sequences and hyperintense on T 2 -weighted sequences, compared to the liver. CONCLUSION: Immunopathology now enables the exact histologic separation of GISTs from other mesenchymal tumors. The radiological morphology is not sufficiently specific to differentiate GISTs from other mesenchymal tumors. In view of new therapeutic options, cognizance of their typical manifestations is of increasing importance for radiologists.

Increased fatty acid synthase is a therapeutic target in mesothelioma.

Many common human cancer tissues express high levels of fatty acid synthase (FAS), the primary enzyme for the synthesis of fatty acids, and the differential expression of FAS between normal and neoplastic tissues has led to the consideration of FAS as a target for anticancer therapy. To investigate the potential of targeting FAS for the treatment of pleural mesothelioma, we first determined whether FAS is overexpressed in human mesothelioma. By immunohistochemistry, we found 22 of 30 human mesothelioma tissue samples tested to express significantly increased levels of FAS compared with normal tissues, including mesothelium. To further explore FAS as a therapeutic target in mesothelioma, we established a nude mouse xenograft model for human mesothelioma using the H-Meso cell line. The i.p. xenografts of this cell line have high levels of FAS expression and fatty acid synthesis pathway activity and grow along mesothelial surfaces in a manner similar to the growth pattern of human mesothelioma. Growth of these tumor xenografts was essentially abolished in mice treated with weekly i.p. injections of C75, a synthetic, small molecule inhibitor of FAS, at levels that resulted in no significant systemic toxicity except for reversible weight loss. These results suggest that FAS may be an effective target for pharmacological therapy in a high proportion of human mesotheliomas.

Mesotelioma pleural maligno: experiencia del Instituto Nacional de Cancerología (1935-1954)

Introducción: El mesotelioma pleural maligno (MPM) es una neoplasia casi invariablemente fatal, relaciónada la gran mayoría de las veces con la exposición a asbesto. La frecuencia de aparición de MPM es creciente en el mundo entero y, en nuestro país su aumento es alarmante. Sin embargo, hay pocos estudios que describan la experiencia con esta entidad en nuestro medio. Objetivo: Presentar la experiencia del Instituto Nacional de Cancerología de Santafé de Bogotá en MPM. Diseño: estudio observacional descriptivo (serie de casos) Pacientes y Métodos: se revisaron los registros de pacientes con diagnóstico de MPM entre 1935 y 1994. Se escogieron 32 que tuvieron la información requerida. Las variables seleccionadas fueron analizadas estadísticamente por los métods de chi cuadrado, T de student, Kaplan-Meier, Log-Rank-Test y Cox. Resultados: Se diagnósticaron 32 pacientes con Mesotelioma Pleural Maligno. Veintidós (69 por ciento), consultaron en los últimos 6 años; fueron 24 hombres y 8 mujeres (relación 3:1), con edad promedio de 46,5 años (rango 6-76 años). El tiempo promedio de evolución de los síntomas fue de 8 meses (rango 1-72 meses). Se presentó disnea en 22 (69 por ciento) pacientes, dolor torácico en 21 (66 por ciento)y tos en 17 (53 por ciento). Todos presentaron alteraciones radiológicas: 27 derrames pleurales, 24 engrosamientos pleurales y 9 masas. Se definió, si hubo o no exposición a asbesto en 18 pacientes; 14 estuvieron expuestos (78 por ciento). La broncospía y citología del líquido pleural nunca confirmaron el diagnóstico. La biopsia pleural ciega detectó malignidad, pero sólo confirmó el diagnóstico en 2 de 21 pacientes (9,5 por ciento). Las biopsias por toracoscopia o cirugía, siempre permitieron el diagnóstico. Histológicamente fueron 16 epiteliales (51,6 por ciento) 8 mixtos (25.8 por ciento) y 7 sarcomatosos (22,6 por ciento); Veintiocho (90,3 por ciento) fueron difusos. Diez pacientes se consideraron en estado I (34,5 por ciento) y 14 en estado II (48,3 por ciento). Cirugía radical se realizó en 11, con una mortalidad operatoria de 2 (8 por ciento), y una morbilidad de 4 (16 por ciento). Radioterapia se administró a 11 pacientes y quimioterapia a 7. El tiempo libre de enfermedad promedio fue 37,9 meses (rango 1-137), el cual se disminuye a 14,1 meses si excluimos al paciente que duró 137 meses. este tiempo fue influido si la cirugía fue o no...