Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma.

Background: The combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts. Methods: The discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database. Results: Most patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients [hazard ratio (HR), 3.42 (1.15-10.16)] with low tumor mesothelin levels [HR, 2.58 (1.09-6.10)] and high PD-L1 and low infiltration of T cells CD4+ [HR, 3.81 (1.58-9.18)]. In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival. Conclusion: Tumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.

Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications.

Background: Malignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression. Methods: In a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome. Results: Epithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm2) for epithelioid MM. Conclusion: Differential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.

Malignant mesothelioma of the tunica vaginalis testis: A rare cause of hydrocele.

Mesotheliomas of the tunica vaginalis testis are very uncommon tumors, with rare cases published in the literature. This report demonstrates a case in with such a tumor was diagnosed in a 50-year-old man who presented to the emergency room with mild, acute scrotal pain and swelling, without previously known scrotal pathology. It is noted that sonographers should be aware of the typical characteristics that allow for suspecting malignancy in scrotal sonography performed in the emergency setting; this was particularly important in this case. Surgical pathology analysis of the right radical orchiectomy specimen confirmed the diagnosis.

The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma.

BACKGROUND: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM. METHODS: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up. RESULTS: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm2 had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm2 had a high risk of death (P=0.03) and a median survival time of 34 months. CONCLUSIONS: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.

Different histological patterns of type-V collagen levels confer a matrices-privileged tissue microenvironment for invasion in malignant tumors with prognostic value.

Previous studies have reported a close relationship between type V collagen (Col V) and tumor invasion and motility in both breast cancer (BC) and lung cancer (LC). The present work aims to determine whether the extracellular-matrix (ECM)-defined microenvironment influences patient clinical outcome and investigate to which extent histological patterns of Col V expression in malignant cells have a prognostic effect in patients. To that end, we examined the expression of Col V in the tissues of 174 primary tumors (MM, N = 82; LC, N = 41; and BC, N = 46) by immunohistochemistry. We found: (1) diffuse strong green birefringence in membrane and cytoplasm individualizing malignant cells in MM; (2) a focal and weak birefringence mainly in cytoplasmic membrane involving groups of malignant cells in LC and BC; (3) higher average H-score of Col V in MM than in LC and BC samples; (4) a direct correlation between Col V histologic pattern and TNM stage IV, status and median overall survival; (5) patients with LC in TNM stage I, and Col V ≤ 41.7 IOD/mm2 had a low risk of death and a median survival time more than 20 months; (6) patients with MM in TNM stage IV and Col V > 41.7 IOD/mm2 presented a high risk of death and a median survival time of just 20 months. These findings suggest that high levels of Col V individualizing malignant cells, as observed in MM, and low levels grouping malignant cells, as observed in LC and BC, confers different immune-privileged tissue microenvironment for tumor invasion with impact on prognosis of the patients.

Sarcomatoid Type of Paratesticular Malignant Mesothelioma in a Dry-Cleaning Worker Exposed to Asbestos and Diagnostic Value of WT-1.

Of the 3 major histologic types of malignant paratesticular mesothelioma (MPM) (epithelial, sarcomatoid, and biphasic), many cases of epithelial and biphasic mesothelioma have been reported in the literature. Pure sarcomatoid MPM is the least common but the most aggressive of the 3 major histologic types of mesothelioma cells. It is limited to only 2 cases in the literature The sarcomatoid type of MPM can be confused clinically and histologically with true sarcomas because it is rarely seen. We present a case who had been exposed to asbestos for years due to his involvement in the dry-cleaning industry and who was diagnosed with the sarcomatoid type of MPM but had a relatively prolonged survival not usually seen with this tumor. This report also emphasizes the significance of an immunohistochemical examination, focusing especially on the diagnostic role of WT-1.

Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. RESULTS: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. CONCLUSIONS: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Análise da qualidade de um registro de base populacional ao notificar casos de câncer potencialmente relacionados ao amianto / Analysis of the quality of a Population-Based Registry in reporting cases of cancer potentially related to asbestos

Esta pesquisa teve como objetivos analisar se os casos de câncer potencialmente relacionados ao amianto estão de acordo com o diagnóstico apresentado no Registro de Câncer de Base Populacional e verificar a sensibilidade e especificidade dos dados e relacionados às notificações e declarações de óbito. Trata-se de um estudo descritivo, retrospectivo e transversal, realizado em um registro de câncer de base populacional e em 11 fontes notificadoras, compreendendo hospitais, clínicas de anatomia patológica, unidade básica de saúde e no sistema de informação de mortalidade na cidade de Curitiba, Paraná. A amostra foi composta por 270 notificações de pacientes adultos com câncer de topografia C38 e C48. A coleta de dados foi referente às notificações de diagnóstico de câncer do período de janeiro de 1998 a dezembro de 2012. Para as análises estatísticas foi utilizado o software Stata 14®. Os resultados evidenciaram que, entre os cânceres estudados, 40,3% eram de peritônio e retroperitônio, 24,5% de mediastino e 11,5% de pleura e mesotelioma maligno. A média de idade dos pacientes com câncer de pleura e mesotelioma maligno foi de 66,3 anos, sete (70%) eram do sexo masculino, nove (90%) não possuíam registro sobre ocupação no prontuário e o tempo médio entre a data do diagnóstico e o óbito foi de 11,6 meses. Quanto à sensibilidade do registro com a notificação de câncer de pleura e mesotelioma maligno, esta foi de 100% e 50%, respectivamente. Em relação à especificidade, o registro apresentou 90% de concordância das notificações. Referente às notificações dos meios diagnósticos, os dados frequentes foram: histologia de tumor primário com 71,9% (n=194) e por declarações de óbito com 20,4% (n=55). Esses resultados expressam que não houve subnotificação para casos de mesotelioma maligno. Contudo, uma alta sobre a estimativa foi observada nas notificações de cânceres de pleura, decorrente da codificação equívoca da descrição da doença por parte do registro. Os resultados da pesquisa foram parcialmente de boa qualidade.

Esta investigación tuvo como objetivos, analizar si los casos de cáncer potencialmente relacionados con el amianto están de acuerdo con el diagnóstico presentado en el Registro de Cáncer de Base Poblacional, verificar la sensibilidad y especificidad de los datos y relacionarlos con las notificaciones y declaraciones de óbito. Se trata de un estudio descriptivo, retrospectivo y transversal, realizado en un registro de cáncer de base poblacional, con 11 fuentes de notificación que abarca hospitales, clínicas de anatomía patológica, unidad básica de salud y el sistema de información de mortalidad en la ciudad de Curitiba, Paraná. La muestra estuvo conformada por 270 notificaciones de pacientes adultos con cáncer de topografía C38 y C48. La recopilación de datos se refiere a las notificaciones de diagnóstico de cáncer durante el período comprendido entre enero de 1998 y diciembre de 2012. Para los análisis estadísticos se utilizó el software Stata 14®. Los resultados evidenciaron que entre los cánceres estudiados, 40,3% eran de peritoneo y retroperitoneo, 24,5% de mediastino y 11,5% de pleura y mesotelioma maligno. El promedio de edad de los pacientes con cáncer de pleura y mesotelioma maligno fue de 66,3 años, siete (70%) eran del sexo masculino, nueve (90%) no tenían registro sobre ocupación en la historia clínica. El tiempo promedio entre la fecha del diagnóstico y el óbito fue 11,6 meses. Con relación a la sensibilidad del registro con la notificación de cáncer de pleura y mesotelioma maligno, esta fue de 100% y 50% respectivamente. Con relación a la especificidad, el registro presentó 90% de concordancia de las notificaciones. En lo referente a las notificaciones de los medios diagnósticos, los datos frecuentes fueron: histología de tumor primario con 71,9% (n=194) y por declaraciones de óbito con 20,4% (n=55). Esos resultados expresan que no hubo subnotificación para casos de mesotelioma maligno. Sin embargo, se observó una alta sobrevaloración en las notificaciones de cánceres de pleura, resultante de la codificación equívoca de la descripción de la enfermedad por parte del registro. Los resultados de la investigación fueron parcialmente de buena calidad.

This research had as its objectives to analyze if the cancer cases are potentially related to asbestos according to the presented diagnosis by the registry of Cancer and Population Bases, and to verify the sensitivity and specificity of the data related to the notifications and statements of death. This is a descriptive, retrospective, and crosssectional study carried out in a population-based cancer registry and in 11 notifying sources such as hospitals, clinics of pathological anatomy, basic health units and in the mortality data system from the city of Curitiba located in the state of Paraná. The sample was composed by 270 notifications of adult patients with C38 and C48 topography cancer. The data collection had been done by searching for cases rated as cancer diagnosis reported from January 1998 to December 2012. Stata 14® software was used for the statistical analysis. The results clearly has shown that among the studied cases 40.3% were of peritoneum and retroperitoneum, 24.5% of mediastinum and 11, 5% of pleura and malignant mesothelioma. The average age of patients with pleural cancer and malignant mesothelioma was 66.3 years, seven (70%) were male, nine (90%) had no record of occupation on their medical records and the average time between the diagnostic and the death was 11.6 months. About the sensitivity from the registry with a notification of cancer of pleura and malignant mesothelioma, it was of 100% and 50% respectively. Regarding the specificity, the registry presented 90% an agreement of the notifications. Referring to the reports of the diagnostic ways, the frequent data has shown a histology of primary tumor with 71.9% (n = 194) and death declarations with 20.4% (n = 55). These results express that there was not underreporting for the cases of malignant mesothelioma. However, a high over estimate was noticed in reports of pleural cancers, as a result of the wrong coding of the disease description by the registry. The results of the survey were partially from good quality.

Estudo retrospectivo dos registros de mesotelioma maligno no período de 1995 a 2015 / Retrospective study of malignant mesothelioma records from 1995 to 2015

RESUMO : O objetivo deste estudo foi analisar os casos registrados de mesotelioma maligno em um hospital oncológico do Paraná no período de 1995 a 2015. Foram analisados 142 prontuários do Registro Hospitalar de Câncer de um Centro de Alta Complexidade em Oncologia de Curitiba, Paraná, registrados com os códigos topográficos C38 e C48. A coleta de dados ocorreu na instituição entre agosto de 2016 e julho de 2017, com a utilização de instrumento elaborado para a pesquisa. Para a manipulação dos dados e análises estatísticas utilizou-se o software Stata 14®. Foram identificados 16 casos de mesotelioma maligno, com 11 casos pleurais e cinco casos peritoneais. Foi observada maior prevalência em homens brancos, casados, com mais de 50 anos de idade, procedentes de Curitiba e com segundo grau de escolaridade. As ocupações relatadas na admissão foram variadas, com relato de exposição ocupacional ao amianto de apenas um paciente. Não foi possível estabelecer o perfil ocupacional devido à ausência de informações complementares. Em sete Declarações de Óbito as causas básicas dos óbitos eram diferentes dos diagnósticos registrados nas evoluções. Os principais sintomas relatados na busca por atendimento foram emagrecimento, dispneia e dor. Em 68,8% dos casos o tumor apresentava estádio IV, o que denota busca tardia por assistência. O tratamento utilizado foi paliativo multimodal, sendo a quimioterapia o tratamento de eleição em 68,8%. A Sensibilidade dos registros da doença foi de 81%, uma vez que três casos foram notificados com topografias inadequadas. A Especificidade foi de 97%. Divergências encontradas entre alguns diagnósticos estabelecidos em prontuários e os repassados ao Sistema de Informação de Mortalidade e Registro Hospitalar de Câncer apontam para a possibilidade de subnotificação e a necessidade de treinamentos sobre completude de registros e o uso de códigos de classificação de doenças.

Abstract: The objective of this study was to describe the reported cases of Malignant Mesothelioma at a cancer hospital in Paraná between 1995 and 2015. A total of 142 medical records of a Hospital Registry of Cancer of the Center of High Complexity in Oncology in Curitiba. Were analyzed, in which 142 were registered with the topographic codes C38 and C48. Data collection took place between August 2016 and July 2017, with the use of an instrument developed by the researcher. For the manipulation of the data and statistical analysis was used the software Stata 14®. Sixteen cases of Malignant Mesothelioma were identified, with 11 pleural cases and five peritoneal cases. It was observed a higher prevalence in white men, married, over 50 years old, coming from Curitiba and with a second degree of education. The occupations reported on admission were varied, with reports of occupational exposure to asbestos from only one patient. It was not possible to establish the occupational profile due to the lack of complementary information. In seven death certificates the basic causes of death were different from the diagnoses recorded in the evolutions. The main symptoms reported in the search of care were weight loss, dyspnea and pain. In 68.8% of the cases the tumor presented stage IV, denoting a late search by the patient for assistance. The treatment used was multimodal palliative, with chemotherapy being the treatment of choice in 68.8%. The sensitivity of the disease records was 81%, since three cases were reported with inadequate topographies. Specificity was 97%. Divergences were found between some diagnoses established in medical records and those passed on to the Mortality Information System and Cancer Hospital Registry pointed to the possibility of underreporting and the need for training on completeness of registries and use of disease classification codes.

RESUMEN: El objetivo de este estudio fue describir los casos registrados de mesotelioma maligno en un hospital oncológico del Paraná entre 1995 y 2015. Se analizaron 142 historias clínicas de un Registro Hospitalar de Cáncer de un Centro de Alta Complejidad en Oncología de Curitiba, que fueron registrados con los códigos topográficos C38 y C48. La colecta de datos se realizó entre agosto de 2016 y julio de 2017, con utilización de instrumento elaborado por la investigadora. Para la manipulación de los datos y el análisis estadístico se utilizó el software Stata 14®. Se identificaron 16 casos de mesotelioma maligno,11 casos pleurales y cinco peritoneales. Se observó mayor prevalencia en hombres blancos, casados, de más de 50 años de edad, procedentes de Curitiba, con escolaridad correspondiente a la enseñanza secundaria. Las ocupaciones relatadas en la admisión fueron variadas, solamente un paciente relató exposición ocupacional al amianto. No fue posible establecer el perfil ocupacional debido a la ausencia de informaciones complementarias. En siete Declaraciones de Óbito las causas básicas de estos óbitos eran diferentes de los diagnósticos registrados en las evoluciones. Los principales síntomas relatados al buscar atendimiento fueron adelgazamiento, dispneia y dolor. En 68,8% de los casos el tumor presenta estadio IV, lo que denota búsqueda de asistencia tardía. El tratamiento utilizado fue paliativo multimodal, siendo la quimioterapia el tratamiento elegido en 68,8% de los casos. La Sensibilidad de los registros de la enfermedad fue de 81%, ya que tres casos fueron notificados con topografías inadecuadas. La Especificidad fue de 97%. Divergencias encontradas entre algunos diagnósticos establecidos en historias clínicas y los enviados al Sistema de Información de Mortalidad y Registro Hospitalar de Cáncer indican posible subnotificación y necesidad de capacitación sobre completitud de registros y uso de códigos de clasificación de enfermedades.

Closing faucets: the role of anti-angiogenic therapies in malignant pleural diseases.

Malignant pleural effusion (MPE) represents 15-35 % of pleural effusions and markedly worsens the prognosis and quality of life of patients with cancer. Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE. Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patient life. Since angiogenesis plays a key role in MPE development, the potential role of bevacizumab and other anti-angiogenic therapies have been explored in this review. No relevant phase III trials have specifically analysed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE. However, small retrospective series reported 71.4-93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination. Being approved for the first-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE. In addition, further studies in this are recommended. In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary endpoints in two phase II trials. However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM. To date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM. However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation.

The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma.

Malignant Mesothelioma (MM) is a very aggressive cancer with low survival rates and often diagnosed at an advanced stage. Several players have been implicated in the development of this cancer, such as asbestos, erionite and the simian virus 40 (SV40). Here, we have reviewed the involvement of erionite, SV40, as well as, the role of several genes (p16(INK4a), p14(ARF), NF2, LATS2, SAV, CTNNB1 and among others), the pathways (RAS, PI3K, Wnt, BCL and Hippo), and their respective roles in the development of MM.

[Malignant mesothelioma risk factors: experience in the General Hospital of Mexico]. / Mesotelioma maligno: factores de riesgo, experiencia en el Hospital General de México.

BACKGROUND: Malignant mesothelioma is a neoplasm of bad prognosis, it is linked with asbestos contact, but there are cases without this antecedent. OBJECTIVE: To investigate the relationship of asbestos exposition and other factors with malignant mesothelioma. METHODS: Retrospective analysis of histologic confirmed cases of malignant mesothelioma, neoplasic familiar history, tobacco smoking, exposure to wood smoke and to asbestos, were annotated in a paired case/control study 1: 1-3 with logistic regression model to identify risk factors for OR. RESULTS: 61 cases of malignant mesothelioma were confirmed by histopathologic study, 41 male and 20 female. Mean age was 56 years ± 13 years; 56 cases (91.8%) correspond to epithelial malignant mesothelioma, three sarcomatous (4.9%) one desmoplastic and one biphasic. One in eight (13.1%) had exposure to asbestos. Model of logistic regression with four variables: history of familiar cancer, tobacco smoking, wood smoke and asbestos exposition, the the last one with an OR= 3.083 and p > 0.05. No other variables found to be a risk factor for malignant mesothelioma. CONCLUSIONS: Exposure to asbestos is a risk factor for malignant mesothelioma, which is confirmed in this study, however it is important to extend the investigation of other possible causal factors of this disease.

Antecedentes: el mesotelioma maligno es un tumor de mal pronóstico relacionado con el contacto con asbesto; sin embargo, existen numerosos casos sin este antecedente. Objetivo: describir la relación entre la exposición al asbesto y otros factores con el mesotelioma maligno. Material y métodos: estudio retrospectivo de casos y controles pareado 1: 1-3 por edad y sexo de pacientes con diagnóstico de mesotelioma maligno. Se registraron: la exposición al asbesto, tabaco, humo de leña y antecedentes familiares de cáncer. Se empleó regresión logística para razones de momios (ORs). Resultados: se estudiaron 61 casos con mesotelioma maligno, 41 hombres y 20 mujeres. La edad promedio fue 56 ± 13 años; 56 casos fueron mesotelioma maligno epitelial (91.8%), tres sarcomatosos (4.9%), uno desmoplásico y uno bifásico. Sólo en 8 (13.1%) se identificó exposición al asbesto. En el modelo de regresión logística el asbesto tuvo una razón de momios de 3.083 p > 0.05. Ninguna otra variable resultó ser un factor de riesgo para mesotelioma maligno. Conclusiones: la exposición al asbesto es un factor de riesgo para mesotelioma maligno, lo que se confirma en este estudio; sin embargo, es importante ampliar la investigación de otros posibles factores causales de esta enfermedad.

Mesotelioma Maligno Testicular / Malignant Testicular Mesothelioma

El mesotelioma maligno es un tumor adenomatoide de la línea de células no germinales, una neoplasia testicular muy rara, tan solo unos 100 casos han sido reportados en la literatura y la mayoría de los pacientes con este problema son mayores de 50 años. Más del 50% tienen el antecedente de exposición a los asbestos. Todos los pacientes con sospecha de un tumor maligno testicular deben someterse a una orquiectomía radical para evitar recidivas. Presentamos el caso clínico de un paciente de sexo masculino de 69 años de edad que acudió a consulta con un cuadro de 6 meses de evolución con aumento de volumen del escroto izquierdo y drenaje de líquido serohemático a través de un orificio fistuloso. Al paciente se le realizó el tratamiento quirúrgico mediante orquiectomía radical más hemiescrotectomía izquierda y finalmente el examen histopatológico evidenció un mesotelioma maligno testicular mixto.

Malignant mesothelioma is an adenomatoid tumor of non-germ line cells, a very rare testicular tumor, only about 100 cases have been reported in the literature and most patients with this condition are over 50 years. Over 50% had a history of asbestos exposure. All patients with suspected testicular malignancy should get a radical orchiectomy to prevent recurrences. We report a clinic case of a male patient of 69 years who consulted with a disease of 6 months duration with increased volume of left scrotum and serohematic fluid drainage through a fístula. The patient received surgical treatment with a radical orchiectomy and left hemiescrotectomy, histopathological examination revealed a mixed testicular malignant mesothelioma.