Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.249
Filtrar
1.
Lancet Oncol ; 21(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888453

RESUMO

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão
2.
Anticancer Res ; 40(9): 4913-4919, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878779

RESUMO

BACKGROUND/AIM: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. MATERIALS AND METHODS: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. RESULTS: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 µM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). CONCLUSION: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Quinase 1 de Adesão Focal/metabolismo , Imidazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Estrutura Molecular , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Fosforilação/efeitos dos fármacos , Tiadiazóis/síntese química , Tiadiazóis/química , Células Tumorais Cultivadas
4.
PLoS One ; 15(7): e0236475, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726334

RESUMO

A historical cohort study in workers occupationally exposed to chrysotile was set up in the town of Asbest, the Russian Federation, to study their cause-specific mortality, with a focus on cancer. Chrysotile has different chemical and physical properties compared with other asbestos fibres; therefore it is important to conduct studies specifically of chrysotile and in different geographical regions to improve the knowledge about its carcinogenicity. Setting was the town of Asbest, Sverdlovsk oblast, the Russian Federation. Participants were all current and former employees with at least one year of employment between 1/1/1975 and 31/12/2010 in the mine, enrichment factories, auto-transport and external rail transportation departments, the central laboratory, and the explosives unit of the company. Of the 35,837 cohort members, 12,729 (35.5%) had died (2,373 of them of cancer, including 10 of mesothelioma), 18,799 (52.5%) were known to be alive at the end of the observation period (2015), and 4,309 (12.0%) were censored before the end of 2015. Mean follow-up duration was 21.7 years in men and 25.9 years in women. The mean age at death was 59.4 years in men and 66.5 years in women. This is the largest occupational cohort of chrysotile workers to date, and the only one with a large proportion of exposed female workers.


Assuntos
Asbestos Serpentinas/efeitos adversos , Neoplasias Pulmonares/epidemiologia , Mesotelioma/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Adulto , Asbestos/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/induzido quimicamente , Mesotelioma/patologia , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/patologia , Federação Russa/epidemiologia
5.
Am J Surg Pathol ; 44(9): 1259-1265, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496433

RESUMO

The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma using immunohistochemistry is improving. However, immunohistochemical markers with high sensitivity and specificity have yet to be identified. In this study, we investigated the utility of sex-determining region Y box 6 (SOX6) as a novel immunohistochemical marker, identified by analyzing previous gene expression data. Immunohistochemically, SOX6 expression was present in 53 of 54 (98%) cases of epithelioid mesothelioma, compared with its expression in only 5 of 69 (7%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma and lung adenocarcinoma were 98% and 93%, respectively. SOX6 expression showed similar sensitivity and far better specificity than those of calretinin or podoplanin (D2-40). In addition, SOX6 expression was more sensitive than Wilms' tumor 1 expression. The combination of SOX6 with other markers showed comparable or better sensitivity and specificity relative to other combinations. In particular, the sensitivity of positivity for both SOX6 and calretinin (96%) and the specificity of positivity for both SOX6 and Wilms' tumor 1 (93%) were higher than those of the other combinations. In conclusion, SOX6 is a novel candidate immunohistochemical marker for differentiating epithelioid mesothelioma from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/química , Biomarcadores Tumorais/análise , Células Epitelioides/química , Imuno-Histoquímica , Neoplasias Pulmonares/química , Mesotelioma/química , Fatores de Transcrição SOXD/análise , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Células Epitelioides/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Transcrição SOXD/genética
6.
Nanotoxicology ; 14(7): 947-967, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574520

RESUMO

Multi-walled carbon nanotubes (MWCNTs) are one of the most widely used types of novel nano-fiber materials. The aim of this study was to establish an experimental system based on actual exposure dosage and environments and explore the roles and mechanisms of inflammation in the malignant transformation of pleural mesothelial cells induced by MWCNTs after low doses and long-term exposure. Here, we established an in vitro system by co-culturing macrophages and mesothelial cells and exposing these cells to high aspect ratio MWCNTs (0.1 µg/mL) for three months. Results indicated that IL-1ß, secreted by macrophages stimulated by MWCNTs, may significantly enhance the release of inflammatory cytokines, such as IL-8, TNF-α, and IL-6, from mesothelial cells. Results obtained from proliferation, migration, invasion, colony formation, and chromosomal aberration studies indicated that MWCNTs may promote malignant transformation of mesothelial cells after long-term and low-dose exposure via inflammation. Furthermore, the obtained results demonstrated that the NF-κB/IL-6/STAT3 pathway was active in the malignant transformation of Met 5A cells, induced by MWCNTs, and played an important role in the process. In conclusion, our results showed that the NF-κB (p65)/IL-6/STAT3 molecular pathway, which was mediated by inflammation, played an important role in the malignant transformation of pleural mesothelial cells induced by MWCNTs. These findings also provide novel ideas and references for the treatment of mesothelioma and offers options for the occupational safety of nanomaterial practitioners.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Mesotelioma/imunologia , Nanotubos de Carbono/toxicidade , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Células Epiteliais/imunologia , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Inflamação , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Células THP-1 , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Cancer Invest ; 38(6): 356-364, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32468861

RESUMO

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.


Assuntos
Adenosina Desaminase/genética , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias/diagnóstico , Neoplasias Pleurais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/genética , Mesotelioma/patologia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Toracoscopia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/genética , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia
8.
Jpn J Clin Oncol ; 50(8): 920-925, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32463095

RESUMO

BACKGROUND: Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting. METHODS: This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1-14 months), and median of 8 cycles (range: 2-32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed. CONCLUSION: Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Mesotelioma/tratamento farmacológico , Mesotelioma/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento
9.
Anticancer Res ; 40(4): 1867-1874, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234874

RESUMO

BACKGROUND/AIM: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. MATERIALS AND METHODS: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. RESULTS: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. CONCLUSION: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Indazóis/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Mutação/genética , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
10.
Cancer Sci ; 111(6): 2016-2027, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248600

RESUMO

Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos. To explore the pathogenesis of MM, peritoneal MM was induced in rats by the repeated intraperitoneal injection of iron saccharate and nitrilotriacetate. In the present study, we used microarray techniques to screen the microRNA (miR) expression profiles of these MM. We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR-199/214 is a distinctive feature of iron saccharate-induced sarcomatoid mesothelioma (SM). Twist1, a transcriptional regulator of the epithelial-mesenchymal transition, has been shown to activate miR-199/214 transcription; thus, the expression level of Twist1 was examined in iron-induced and asbestos-induced mesotheliomas in rats. Twist1 was exclusively expressed in iron saccharate-induced SM but not in the epithelioid subtype. The Twist1-miR-199/214 axis is activated in iron saccharate-induced and asbestos-induced SM. The expression levels of miR-214 and Twist1 were correlated in an asbestos-induced MM cell line, suggesting that the Twist1-miR-199/214 axis is preserved. MeT5A, an immortalized human mesothelial cell line, was used for the functional analysis of miR. The overexpression of miR-199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells. These results indicate that miR-199/214 may affect the aggressive biological behavior of SM.


Assuntos
Neoplasias Pulmonares/patologia , Mesotelioma/patologia , MicroRNAs/biossíntese , Neoplasias Peritoneais/patologia , Proteína 1 Relacionada a Twist/biossíntese , Animais , Asbestos/toxicidade , Linhagem Celular , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ferro/toxicidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Ratos
12.
Pediatr Blood Cancer ; 67(6): e28286, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277799

RESUMO

BACKGROUND: Malignant and multicystic peritoneal mesotheliomas are extremely rare tumors in children, developing from mesothelial cells. No specific guidelines are available at this age. METHODS: We performed a retrospective analysis of all identified children (< 18-year-old) treated in France from 1987 to 2017 for a diffuse malignant peritoneal mesothelioma (DMPM) or a multicystic peritoneal mesothelioma (MCPM). RESULTS: Fourteen patients (5 males and nine females), aged 2.2 to 17.5 years, were included. The most frequent presenting symptoms were abdominal pain, ascitis, and alteration in the general condition. Eight patients had epithelioid mesothelioma, three had biphasic mesothelioma, and three had MCPM. Eight patients with DMPM diagnosis received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Among them, six patients had neoadjuvant systemic chemotherapy, one patient, post-operative chemotherapy, and one patient CRS and HIPEC only. Three patients received only systemic chemotherapy. All patients with MCPM had only surgery. After a median follow-up of seven years (2-15), six patients (6/11; one death) with DMPM and two patients (two/three) with MCPM had a local and distant recurrences. CONCLUSION: Peritoneal mesothelioma in children is a rare condition with difficult diagnosis and high risk of recurrence. Worldwide interdisciplinary collaboration and networking are mandatory to help diagnosis and provide harmonious treatment guidelines.


Assuntos
Quimioterapia Adjuvante/mortalidade , Cistos/terapia , Procedimentos Cirúrgicos de Citorredução/mortalidade , Hipertermia Induzida/mortalidade , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Terapia Neoadjuvante/mortalidade , Neoplasias Peritoneais/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Cistos/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Neoplasias Peritoneais/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Anticancer Res ; 40(3): 1307-1314, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132027

RESUMO

BACKGROUND/AIM: Malignant pleural mesothelioma (MPM) is an intractable cancer, and causes of its malignant transformation are not well known. Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that converts adenosine into inosine in double-stranded RNAs potentially involved in malignant development. MATERIALS AND METHODS: To examine the role of ADAR1 and ADAR2 in MPM, small interfering RNAs (siRNAs) against ADAR1 or ADAR2 were used. RESULTS: Transfection of siRNA against ADAR2 suppressed proliferation, motility, and invasiveness of MPM cells expressing both ADAR1 and ADAR2; however, siRNA against ADAR1 did not affect these cellular activities. Overexpression of ADAR2, that was incapable of binding to RNA, suppressed growth, motility, and invasion of MPM cells. However, overexpression of ADAR2 that had no enzyme activity did not alter the malignant properties of MPM cells. CONCLUSION: Enhancement of the malignant characteristics of cultured MPM cells via ADAR2 was independent of RNA-editing activity.


Assuntos
Adenosina Desaminase/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , Edição de RNA , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Mesotelioma/enzimologia , Mesotelioma/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Transfecção
14.
Am J Surg Pathol ; 44(8): 1143-1148, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32205484

RESUMO

Malignant mesothelioma can be difficult to distinguish from other malignancies, particularly non-small cell lung carcinomas (NSCLCs), without immunohistochemistry. However, conventional markers of mesothelial lineage all have variable degrees of cross-reactivity with other neoplasms, including NSCLCs, necessitating the use of multiple mesothelioma and carcinoma markers in every case for accurate diagnosis. A recently described monoclonal HEG homolog 1 (HEG1) antibody was proposed to be a specific marker for mesothelioma. Here we performed a large scale assessment of the SKM9-2 HEG1 antibody using tissue microarrays containing 69 epithelioid mesotheliomas, 32 sarcomatoid mesotheliomas, 167 NSCLCs, and 17 ovarian high-grade serous carcinomas. Strong membrane staining, usually diffuse, for HEG1 was seen in 65/69 (94%) epithelioid mesotheliomas, 0/60 pulmonary squamous cell carcinomas, 0/73 pulmonary adenocarcinomas, and 0/13 pulmonary large cell carcinomas. HEG1 showed staining in 14/32 (44%) sarcomatoid mesotheliomas compared with 0/21 sarcomatoid pulmonary carcinomas. Three of 17 (18%) high-grade serous carcinomas demonstrated membrane staining. Ten B3 thymoma whole sections were negative. On the microarrays, the conventional mesothelial markers calretinin, WT1, D2-40, and CK5/6 had sensitivities for epithelioid mesothelioma of 94%, 90%, 96%, and 91%, respectively. We conclude that HEG1 SKM9-2 antibody offers sensitivity comparable to conventional markers for epithelioid mesotheliomas, but provides considerably better specificity, such that the diagnosis of epithelioid mesothelioma versus NSCLC potentially could be confirmed with a combination of HEG1 and a suitable broad spectrum carcinoma marker such as claudin-4. HEG1 is specific but insensitive for separating sarcomatoid mesotheliomas from sarcomatoid lung carcinomas.


Assuntos
Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/imunologia , Células Epitelioides/imunologia , Imuno-Histoquímica , Neoplasias Pulmonares/imunologia , Proteínas de Membrana/imunologia , Mesotelioma/imunologia , Especificidade de Anticorpos , Diagnóstico Diferencial , Células Epitelioides/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Análise Serial de Tecidos
15.
ESMO Open ; 4(Suppl 2)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32156681

RESUMO

Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected patients may benefit from aggressive surgical management, also as part of a multimodal approach. In advanced disease, the combination of pemetrexed and platinum remains the only established treatment, while efficacy evidence of second line chemotherapy is lacking. Thus, a deeper knowledge of biology of the disease and more effective treatments are urgently needed. Refer to specialised centres with multidisciplinary expertise is mandatory, as well as inclusion of patients in clinical trials is advisable whenever possible. In all stages of disease focus on symptoms control is paramount.


Assuntos
Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mesotelioma/patologia , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Humanos
16.
Cancer Sci ; 111(4): 1180-1192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32080953

RESUMO

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.


Assuntos
Asbestos/toxicidade , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Animais , Amiantos Anfibólicos/toxicidade , Asbesto Crocidolita/toxicidade , Asbestos Serpentinas/toxicidade , Hibridização Genômica Comparativa , Homozigoto , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Mesotelioma/induzido quimicamente , Mesotelioma/patologia , Ratos , Fatores de Risco , Deleção de Sequência/genética
17.
PLoS One ; 15(2): e0229299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32069313

RESUMO

INTRODUCTION: The maximum standardized uptake value (SUVmax) in 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may be of prognostic significance for patients with malignant pleural mesothelioma (MPM). This retrospective study aimed to investigate the prognostic value of the SUVmax in patients with MPM. MATERIALS AND METHODS: Medical records were retrospectively reviewed for the patients who were diagnosed with histopathologically proven MPM between 2009 and 2018 at Samsung Medical Center. For each patient, SUVmax was calculated for the primary lesion on PET/CT. To determine optimal cutoff values for predicting mortality, receiver operating characteristic curves were used. RESULTS: Among the 54 study patients, 34 (63.0%) had epithelioid subtype, 13 (24.1%) had sarcomatoid or biphasic subtype, and 7 (13.0%) had mesothelioma, not otherwise specified (NOS). The median overall survival (OS) was 8.7 months, and the median SUVmax was 9.9. The median values of SUVmax were 5.5 in patients with epithelioid subtype, 11.7 in those with sarcomatoid/biphasic subtype, and 13.3 in those with NOS subtype (P = 0.003). The optimal cutoff values of SUVmax to predict mortality were 10.1 in all patients, and 8.5 in patients with epithelioid subtype. In multivariate analysis, SUVmax was significantly associated with overall survival in all patients (P = 0.003) and in patients with epithelioid subtype (P = 0.012), but not in those with non-epithelioid subtype. CONCLUSIONS: SUVmax in PET/CT is an independent prognostic factor in patients with MPM, especially those with epithelioid subtype. The histologic subtype of MPM should be considered when evaluating the prognostic significance of SUVmax.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Idoso , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/terapia , Pessoa de Meia-Idade , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/terapia , Prognóstico , Curva ROC , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Taxa de Sobrevida
19.
J Thorac Cardiovasc Surg ; 159(6): 2512-2520.e1, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32087959

RESUMO

OBJECTIVE: Diffuse chest wall invasion (DCWI) is a common finding in patients undergoing intended resection for malignant pleural mesothelioma. We sought to determine the incidence and preoperative predictors of this finding, and to test our anecdotal impression that contraction of the ipsilateral hemithorax is associated with DCWI. METHODS: This was a single-institution retrospective study of 170 patients undergoing intended macroscopic complete resection for malignant pleural mesothelioma from 2014-2018. A novel metric of thoracic cage volume was calculated by preoperative chest computed tomography. Univariable analyses were performed to determine associations of preoperative variables with DCWI. RESULTS: Macroscopic complete resection was achieved by pleurectomy/decortication in 104 patients (61%) and by extrapleural pneumonectomy in 39 patients (23%). Unresectable disease was discovered at thoracotomy in 27 (16%) of patients; 24 (14%) by DCWI and 3 (2%) by intrathoracic organ invasion. In univariable analysis, decreased ipsilateral thoracic cage volume demonstrated the strongest association with unresectability by DCWI (P = .009) with >5% decrease in thoracic cage volume representing the optimal cutoff (P = .014; area under the curve, 0.67). Other preoperative variables associated with DCWI included preoperative chest pain requiring opioids (P = .028), prior pleurodesis (P = .036), decreased forced vital capacity (P = .023), decreased ipsilateral lung perfusion by ventilation/perfusion lung scan (P = .007), and magnetic resonance imaging findings of chest wall invasion (P = .035). CONCLUSIONS: Preoperative identification of DCWI will avoid unnecessary thoracotomy and accelerate initiation of nonsurgical therapy in malignant pleural mesothelioma. Our data suggest that contraction of thoracic cage volume has merit in predicting malignant pleural mesothelioma unresectability and should be validated in prospective studies.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Mesotelioma/diagnóstico por imagem , Neoplasias Pleurais/diagnóstico por imagem , Parede Torácica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Feminino , Humanos , Imageamento Tridimensional , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/patologia , Mesotelioma/terapia , Pessoa de Meia-Idade , Invasividade Neoplásica , Seleção de Pacientes , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Valor Preditivo dos Testes , Estudos Retrospectivos , Parede Torácica/patologia , Parede Torácica/cirurgia , Toracotomia , Procedimentos Desnecessários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA