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Hipertermia Induzida , Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Mesotelioma/terapia , Mesotelioma/patologia , Neoplasias Peritoneais/terapia , Técnicas de Apoio para a Decisão , Procedimentos Cirúrgicos de Citorredução , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Taxa de Sobrevida , Estudos RetrospectivosRESUMO
Diffuse primary malignant pericardial mesothelioma (PMPM) is an extremely rare and highly invasive tumor of pericardium. The tumor can infiltrate myocardium in part of cases, and will contribute to grave prognosis. Herein, we reported a 58-year-old man of diffuse PMPM with myocardial involvement, and summarized 39 cases of diffuse PMPM. Multimodal echocardiography, which combined conventional, tissue Doppler and speckle tracking echocardiography, was applied to diagnose diffuse PMPM with myocardial involvement, and assess the myocardial function. The common features were pericardial effusion, pericardial masses and thickened pericardium. The other echocardiographic characteristics were extensive and heterogenous echo, adhesion with pericardium and myocardium, reduced motion of adhered myocardium, and constriction performance. Diffuse PMPM with myocardial involvement revealed decreased LV diastolic function, and decreased LV and RV systolic function. Especially in systolic function, the unique strain features were reduced longitudinal strains from segmental to global and from epicardial to endocardial, relative 'septal sparing' pattern, and decreased transmural gradient of longitudinal strain. Our findings suggested that multimodal echocardiography not only can identify this disease, but also can provide detailed information of myocardial dysfunction, which provides a reference for clinicians to develop an optimal individualized treatment.
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Mesotelioma , Derrame Pericárdico , Humanos , Pessoa de Meia-Idade , Ecocardiografia , Miocárdio , Pericárdio/diagnóstico por imagem , Pericárdio/patologia , Derrame Pericárdico/diagnóstico por imagem , Derrame Pericárdico/etiologia , Derrame Pericárdico/patologia , Mesotelioma/diagnóstico por imagem , Mesotelioma/patologiaRESUMO
BACKGROUND: Considering the expanding industrial applications of carbon nanotubes (CNTs), safety assessment of these materials is far less than needed. Very few long-term in vivo studies have been carried out. This is the first 2-year in vivo study to assess the effects of double walled carbon nanotubes (DWCNTs) in the lung and pleura of rats after pulmonary exposure. METHODS: Rats were divided into six groups: untreated, Vehicle, 3 DWCNT groups (0.12 mg/rat, 0.25 mg/rat and 0.5 mg/rat), and MWCNT-7 (0.5 mg/rat). The test materials were administrated by intratracheal-intrapulmonary spraying (TIPS) every other day for 15 days. Rats were observed without further treatment until sacrifice. RESULTS: DWCNT were biopersistent in the rat lung and induced marked pulmonary inflammation with a significant increase in macrophage count and levels of the chemotactic cytokines CCL2 and CCL3. In addition, the 0.5 mg DWCNT treated rats had significantly higher pulmonary collagen deposition compared to the vehicle controls. The development of carcinomas in the lungs of rats treated with 0.5 mg DWCNT (4/24) was not quite statistically higher (p = 0.0502) than the vehicle control group (0/25), however, the overall incidence of lung tumor development, bronchiolo-alveolar adenoma and bronchiolo-alveolar carcinoma combined, in the lungs of rats treated with 0.5 mg DWCNT (7/24) was statistically higher (p < 0.05) than the vehicle control group (1/25). Notably, two of the rats treated with DWCNT, one in the 0.25 mg group and one in the 0.5 mg group, developed pleural mesotheliomas. However, both of these lesions developed in the visceral pleura, and unlike the rats administered MWCNT-7, rats administered DWCNT did not have elevated levels of HMGB1 in their pleural lavage fluids. This indicates that the mechanism by which the mesotheliomas that developed in the DWCNT treated rats is not relevant to humans. CONCLUSIONS: Our results demonstrate that the DWCNT fibers we tested are biopersistent in the rat lung and induce chronic inflammation. Rats treated with 0.5 mg DWCNT developed pleural fibrosis and lung tumors. These findings demonstrate that the possibility that at least some types of DWCNTs are fibrogenic and tumorigenic cannot be ignored.
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Neoplasias Pulmonares , Mesotelioma , Nanotubos de Carbono , Animais , Exposição por Inalação/efeitos adversos , Pulmão , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Nanotubos de Carbono/toxicidade , Pleura , RatosRESUMO
Although there is early support for schemes based on nuclear grade, necrosis and mitotic rate, there is currently no widely implemented grading system for diffuse pleural mesothelioma (DPM). We investigated current systems and propose a novel Mesothelioma Weighted Grading Scheme (MWGS). The MWGS assigns weighted scores from 0 to 10 based on age (≤74, >74 yrs: 0,1); histologic type (epithelioid, biphasic, sarcomatoid: 0,1,2); necrosis (absent, present: 0,2); mitotic count per 2 mm2 (≤1, 2 to 4, ≥5: 0,1,2); nuclear atypia (mild, moderate, severe: 0,1,2); and BRCA1-associated protein 1 (BAP1) expression (lost, retained: 0,1). A score of 0 to 3 is low grade, 4 to 6 intermediate grade, and 7 to 10 high grade. In 369 consecutive DPMs, median survival was 17.1, 10.1, and 4.1 months for low, intermediate, and high grades (P<0.0001). A progressive increase in score correlated with worsening overall survival (P<0.0001). Interobserver concordance was substantial (κ=0.588), with assessment of nuclear grade being the most subjective parameter (κ=0.195). We compared the MWGS to the 2-tiered system discussed in the World Health Organization (WHO) fifth edition. The WHO system predicted median survival in epithelioid (median 18.0 vs. 11.3 mo, P=0.003) and biphasic (16.2 vs. 4.2 mo, P=0.002), but not sarcomatoid DPM (5.4 vs. 4.7 mo, P=0.407). Interestingly, the WHO grading system was prognostic in cases with BAP1 loss (median survival 18.7 vs. 10.4 mo, P<0.0001), but not retained BAP1 expression (8.9 vs. 6.2 mo, P=0.061). In conclusion, the WHO scheme has merit in epithelioid/biphasic and BAP1-deficient DPM, however, the MWGS can be used for risk stratification of all DPMs, regardless of histologic subtype and BAP1 status.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Idoso , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Necrose , Gradação de Tumores , Neoplasias Pleurais/patologia , PrognósticoRESUMO
Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, Setting, and Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main Outcomes and Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.
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Predisposição Genética para Doença/epidemiologia , Neoplasias Renais/genética , Melanoma/genética , Mesotelioma/genética , Fator de Transcrição Associado à Microftalmia/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Melanoma/complicações , Melanoma/epidemiologia , Melanoma/patologia , Mesotelioma/complicações , Mesotelioma/epidemiologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Minnesota/epidemiologia , Proteínas Proto-Oncogênicas , Sistema de RegistrosRESUMO
A cluster of nine mesothelioma cases was observed among 341 registrants' deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.
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Neoplasias Pulmonares/etiologia , Mesotelioma/etiologia , Método de Monte Carlo , Neoplasias Induzidas por Radiação/etiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Urânio/intoxicação , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/patologia , Doenças Profissionais/patologia , Doses de Radiação , Sistema de Registros/estatística & dados numéricos , Urânio/análiseRESUMO
OBJECTIVES: The aim of this pilot study was to investigate the utility of haemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans in the assessment of tumour response to treatment in malignant pleural mesothelioma (MPM) patients. METHODS: The patient cohort included nine patients undergoing chemotherapy and five patients on observation. Each patient underwent two DCE-CT scans separated by approximately 2 months. The DCE-CT parameters of tissue blood flow (BF) and tissue blood volume (BV) were obtained within the dynamically imaged tumour. Mean relative changes in tumour DCE-CT parameters between scans were compared between the on-treatment and on-observation cohorts. DCE-CT parameter changes were correlated with relative change in tumour bulk evaluated according to the modified RECIST protocol. RESULTS: Differing trends in relative change in BF and BV between scans were found between the two patient groups (p = 0.19 and p = 0.06 for BF and BV, respectively). No significant rank correlations were found when comparing relative changes in DCE-CT parameters with relative change in tumour bulk. CONCLUSIONS: Differing trends in the relative change of BF and BV between patients on treatment and on observation indicate the potential of DCE-CT for the assessment of pharmacodynamic endpoints with respect to treatment in MPM. A future study with a larger patient cohort and unified treatment regimens should be undertaken to confirm the results of this pilot study. KEY POINTS: ⢠CT-derived haemodynamic parameters show differing trends between malignant pleural mesothelioma patients on treatment and patients off treatment ⢠Changes in haemodynamic parameters do not correlate with changes in tumour bulk as measured according to the modified RECIST protocol ⢠Differing trends across the two patient groups indicate the potential sensitivity of DCE-CT to assess pharmacodynamic endpoints in the treatment of MPM.
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Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/diagnóstico por imagem , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/irrigação sanguínea , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Neovascularização Patológica/diagnóstico por imagem , Projetos Piloto , Neoplasias Pleurais/irrigação sanguínea , Neoplasias Pleurais/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Tomografia Computadorizada Espiral/métodos , Resultado do TratamentoRESUMO
OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response. MATERIALS AND METHODS: The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers. RESULTS: Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors. CONCLUSION: Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Apoptose/genética , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Fenóis/farmacologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Pirazinas/farmacologia , Quinolonas/farmacologia , Interferência de RNA , Transdução de Sinais/genética , Sulfonamidas/farmacologia , Células Tumorais Cultivadas , Verteporfina/farmacologiaRESUMO
INTRODUCTION: Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. METHODS: The current de facto standard for the assessment of mesothelioma tumor response, "modified RECIST" (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented "modified RECIST 1.1 for mesothelioma" response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. RESULTS: These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. CONCLUSION: Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/diagnóstico por imagem , Mesotelioma/tratamento farmacológico , Mesotelioma Maligno , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/tratamento farmacológico , Taxa de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, whose incidence is increasing worldwide. Unfortunately, no effective therapies are currently available and the prognosis is extremely poor. Recently, the anti-helminthic drug pyrvinium pamoate has attracted a strong interest for its anti-cancer activity, which has been demonstrated in many cancer models. Considering the previously established inhibitory effect of pyrvinium pamoate on the Wnt/ß-catenin pathway and given the important role of this pathway in MM, we investigated the potential anti-tumor activity of this drug in MM cell lines. We observed that pyrvinium pamoate significantly impairs MM cell proliferation, cloning efficiency, migration, and tumor spheroid formation. At the molecular level, our data show that pyrvinium pamoate down-regulates the expression of ß-catenin and Wnt-regulates genes. Overall, our study suggests that the repurposing of pyrvinium pamoate for MM treatment could represent a new promising therapeutic approach.
Assuntos
Reposicionamento de Medicamentos , Mesotelioma/tratamento farmacológico , Compostos de Pirvínio/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Mesotelioma/genética , Mesotelioma/patologia , Compostos de Pirvínio/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Tempo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
BACKGROUND: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. METHODS: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). DISCUSSION: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK. TRIAL REGISTRATION: EudraCT Number: 2016-003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Mesotelioma/tratamento farmacológico , Recidiva Local de Neoplasia , Nivolumabe/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Ensaios Clínicos Fase III como Assunto , Análise Custo-Benefício , Método Duplo-Cego , Custos de Medicamentos , Feminino , Humanos , Masculino , Mesotelioma/economia , Mesotelioma/imunologia , Mesotelioma/patologia , Estudos Multicêntricos como Assunto , Nivolumabe/efeitos adversos , Nivolumabe/economia , Neoplasias Peritoneais/economia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Neoplasias Pleurais/economia , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Reino UnidoRESUMO
Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.
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Biomarcadores Tumorais/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Mutação , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Photosensitizer fluorescence excited by photodynamic therapy (PDT) treatment light can be used to monitor the in vivo concentration of the photosensitizer and its photobleaching. The temporal integral of the product of in vivo photosensitizer concentration and light fluence is called PDT dose, which is an important dosimetry quantity for PDT. However, the detected photosensitizer fluorescence may be distorted by variations in the absorption and scattering of both excitation and fluorescence light in tissue. Therefore, correction of the measured fluorescence for distortion due to variable optical properties is required for absolute quantification of photosensitizer concentration. In this study, we have developed a four-channel PDT dose dosimetry system to simultaneously acquire light dosimetry and photosensitizer fluorescence data. We measured PDT dose at four sites in the pleural cavity during pleural PDT. We have determined an empirical optical property correction function using Monte Carlo simulations of fluorescence for a range of physiologically relevant tissue optical properties. Parameters of the optical property correction function for Photofrin fluorescence were determined experimentally using tissue-simulating phantoms. In vivo measurements of photosensitizer fluorescence showed negligible photobleaching of Photofrin during the PDT treatment, but large intra- and inter-patient heterogeneities of in vivo Photofrin concentration are observed. PDT doses delivered to 22 sites in the pleural cavity of 8 patients were different by 2.9 times intra-patient and 8.3 times inter-patient.
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Éter de Diematoporfirina/uso terapêutico , Mesotelioma/tratamento farmacológico , Imagens de Fantasmas , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Pleurais/tratamento farmacológico , Radiometria/métodos , Ensaios Clínicos Fase II como Assunto , Fluorescência , Humanos , Mesotelioma/metabolismo , Mesotelioma/patologia , Método de Monte Carlo , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espectrometria de FluorescênciaRESUMO
Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making.
Assuntos
Mesotelioma/diagnóstico , Mesotelioma/epidemiologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/epidemiologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/epidemiologia , Diagnóstico Diferencial , Diagnóstico por Imagem/normas , Medicina Baseada em Evidências/normas , Humanos , Oncologia/normas , Mesotelioma/patologia , Estadiamento de Neoplasias , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/patologia , Guias de Prática Clínica como Assunto , Prevalência , Fatores de RiscoRESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome. METHODS: Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18-month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort. RESULTS: A total of 482 cases were included in the derivation cohort; the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C-statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic 0.68). CONCLUSIONS: We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.
Assuntos
Árvores de Decisões , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias Pleurais/diagnóstico , Idoso , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Modelos Estatísticos , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , PrognósticoRESUMO
Malignant pleural mesothelioma (MPM) is the most frequent pleural neoplasm, with asbestos exposure as one of the recognized carcinogen agents, causative in 80% of cases. The prognosis is poor; median survival of untreated cases is 6-9 months, with fewer than 5% of patients surviving 5 years. Sarcomatoid mesothelioma (SM) represents the subtype with the worst outcome and median survival ranging from 3.5 to 8 months. In the last few years, an accurate differentiation between the subtypes of MPM has become a crucial issue, due to differences in chemosensitivity and clinical outcome, and several studies have evaluated different immunohistochemical markers to better define the diagnosis. The different and worse outcome of patients with SM and, in general, nonepithelioid subtypes makes it intriguing to select these cases to better study the biomolecular profile in order to find factors linked to prognosis and/or predictive of therapeutic response. Considering recent studies on miRNA and genetic mapping, further investigation of this rare subtype might represent a field for basic and clinical-translational research providing for more tailored therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mesotelioma/diagnóstico , Mesotelioma/genética , MicroRNAs/análise , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/genética , Amianto/toxicidade , Carcinógenos/toxicidade , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Mesotelioma/tratamento farmacológico , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Estadiamento de Neoplasias , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Valor Preditivo dos Testes , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVES: An orthotopic rat tumour recurrence model for malignant pleural mesothelioma (MPM) provides clinical similarity to patients and is useful for drug testing combined with surgical intervention. Importantly, a reliable imaging method is required allowing for noninvasive and repetitive evaluation of the tumour load. We compared the tumour load assessed by bioluminescence and magnetic resonance imaging (MRI) to the macroscopic tumour volume as a reference standard. METHODS: A total of 500,000 syngeneic rat MPM cells transfected with luciferase were implanted underneath the parietal pleura of immunocompetent rats (n=13). From the second day after implantation, bioluminescence measurements of the tumour load expressed as the maximum bioluminescent intensity (photon/second) were performed daily after intraperitoneal injection of the luciferase substrate, d-luciferin, to observe the first occurrence of tumour. Six days after the first detection of tumour, bioluminescence, MRI and macroscopic tumour volume measurement were conducted. For MRI, a 4.7-Tesla small animal imager equipped with a 1H whole-body rat coil was employed using T2-weighted fast spin-echo sequences. Tumour burden (mm3) was quantified from magnetic resonance transverse images by two independent readers by manual segmentation. Finally, the tumour burden assessed by bioluminescence and MRI was correlated (Pearson's correlation) with the macroscopic measurement of tumour (ellipsoid) volume. RESULTS: In all rats, a single tumour nodule was found at the inoculation site with a median macroscopic volume of 46 mm3 (18-377 mm3). For tumour burden quantification of MRIs, we observed good interobserver correlation (R2=0.81, P<0.0001) as well as significant association with the macroscopic tumour volume (R2=0.59, P=0.002). However, the signal intensity of bioluminescence did not correspond to the macroscopic tumour volume (R2=0.01, P=0.76). CONCLUSIONS: MRI is a reliable and reproducible noninvasive in vivo imaging method for MPM tumour burden assessment for the present MPM model.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias Pleurais/diagnóstico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Medições Luminescentes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico , Mesotelioma/patologia , Mesotelioma Maligno , Transplante de Neoplasias , Pleura/patologia , Neoplasias Pleurais/patologia , Ratos , Ratos Endogâmicos F344 , Imagem Corporal Total/métodosRESUMO
PURPOSE: To evaluate the diagnostic accuracy of the visual assessment of malignant pleural mesothelioma (MPM) on magnetic resonance (MR) images by using two known visual markers (mediastinal pleural thickness and shrinking of the lung) and a newly introduced one (pleural pointillism). MATERIALS AND METHODS: With the approval of the local ethics committee, 100 consecutive patients (mean age, 61.4 years; age range, 18-87 years; 75 men, 25 women) suspected of having MPM pleural abnormalities underwent positron emission tomography/computed tomography and MR imaging, including diffusion-weighted (DW) MR imaging, followed by explorative thoracoscopy or guided biopsy with histopathologic confirmation. Because visual assessment is still the preferred method of image interpretation, the diagnostic accuracy of mediastinal pleural thickening, shrinking lung (hemithorax volume decrease due to fibrosis), and pleural pointillism were examined. Pleural pointillism was denoted by the presence of multiple, hyperintense pleural spots on high-b-value DW images. Histopathologic findings in the surgical specimen served as the reference standard. McNemar tests with Bonferroni correction were used to assess differences in accuracy among the three examined markers. RESULTS: Of 100 patients, 33 had benign pleural alterations, and 67 had malignant pleural diseases (MPDs); 57 of 67 had MPM. A total of 78 patients received a correct diagnosis (benign vs malignant) on the basis of mediastinal pleural thickening (sensitivity, 81%; specificity, 73%; accuracy, 78%); and 66 patients, on the basis of shrinking lung (sensitivity, 60%; specificity, 79%; accuracy, 66%). The correct diagnosis was indicated on the basis of pleural pointillism in 88 patients (sensitivity, 93%; specificity, 79%; accuracy, 88%). CONCLUSION: Visual assessment of pleural pointillism on high-b-value DW images is useful to differentiate MPD from benign alterations, performing substantially better than mediastinal pleural thickness and shrinking lung, and might obviate unnecessary invasive procedures for MPM.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Mesotelioma Maligno , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Pleural effusion often represents the first clinical symptom of lung carcinoma and malignant mesothelioma. As pleural punctation is performed quite early in the diagnostic procedure, effusion cytology frequently gives the first evidence about the presence of tumour cells and tumor histogenesis. In this study, we report on seven cases which were evaluated in our institution for the Employers' Liability Insurance Association, based solely on cytology findings.The mean age of the seven patients with a given long-term asbestos exposure during their working life was 81.7 years. On average eight smears per patient were investigated. In addition to routine cytology, immunocytochemistry, DNA image cytometry, AgNOR-analysis and fluorescence in situ hybridization were applied in a case-specific way. The results were interpreted against the clinical and occupational history of the respective patient.Definitive diagnosis could be made in six cases. In three of them, the diagnosis of malignant mesothelioma was made. Two cases were diagnosed as malignant effusion due to metastatic lung cancer. In one case, cells of high-grade Non-Hodgkin's lymphoma (NHL) were diagnosed and a malignant mesothelioma was excluded. In the last case, malignant mesothelioma could not be diagnosed unequivocally by cytology. In all seven cases, our interpretation was accepted by Employers' Liability Insurance Association. The five mesothelioma or lung cancer cases were accepted as asbestos-associated occupational disease, while the NHL case was rejected. In the last case, malignant mesothelioma was diagnosed later by autopsy, and the case was retroactively accepted as occupational disease.Cytology-based tumor diagnosis including adjuvant methods is a useful and reliable approach in cases of asbestos-associated tumours. Acceptance of occupational disease on the basis of cytological diagnoses even by the Employers' Liability Insurance Association helps avoid invasive pleural or lung biopsies in cases with an unequivocally positive effusion cytology of lung cancer or malignant mesothelioma.
Assuntos
Asbestose/complicações , Asbestose/patologia , Mesotelioma/complicações , Mesotelioma/patologia , Derrame Pleural/etiologia , Derrame Pleural/patologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Seguro de Acidentes , Neoplasias Pulmonares , Masculino , Doenças Profissionais/complicações , Doenças Profissionais/patologiaRESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Currently, the molecular mechanisms that induce MPM development are still unknown. The purpose of this study was to identify new molecular biomarkers for mesothelial carcinogenesis. METHODS: We analyzed a panel of 84 genes involved in extracellular matrix remodeling and cell adhesion by polymerase chain reaction (PCR) array in 15 samples of epithelioid mesothelioma and 10 samples of reactive mesothelial hyperplasia (MH; 3 of 25 samples were inadequate for mRNA analysis). To validate the differentially expressed genes identified by PCR array, we analyzed 27 more samples by immunohistochemistry, in addition to the 25 samples already studied. RESULTS: Twenty-five genes were differentially expressed in MPM and MH by PCR array. Of these we studied matrix metalloproteinase 7 (MMP7), MMP14, CD44, and integrin, alpha3 expression by immunohistochemistry in 26 epithelioid MPM and 26 MH samples from the entire series of 52 cases. We observed higher MMP14 and integrin, alpha3 expression in MPM samples compared with MH samples (p = 0.000002 and p = 0.000002, respectively). Conversely, CD44 expression was low in most (57.7%) mesothelioma samples but only in 11.5% of the MH samples (p = 0.0013). As regards MMP7, we did not observe differential expression between MH and MPM samples. CONCLUSIONS: We have extensively studied genes involved in cell adhesion and extracellular matrix remodeling in MPM and MH samples, gaining new insight into the pathophysiology of mesothelioma. Moreover, our data suggest that these factors could be potential biomarkers for MPM.