RESUMO
Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials.
Assuntos
Neoplasias Hepáticas , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/patologia , Linfócitos T , Microambiente TumoralRESUMO
Asbestos and zeolites are silicate-based minerals, linked inextricably via paradoxical similarities and differences which have emanated from different geological epochs. Both have been employed in the service of humanity through millennia: asbestos, for its "inextinguishable" quality of being an insulator against heat and fire; zeolite, a "boiling stone" with its volcanic and marine sedimentary rock origins, for its propensity to adsorb water and remove metals and toxins. Serious adverse health effects observed in asbestos miners as long ago as the 1st Century AD did not halt the rising popularity of asbestos. As the miracle material of the 1900s, asbestos production and consumption exploded, culminating in its ubiquity in ships, vehicles, homes, commercial buildings, and over 3000 different industrial and household products. Through the 1940s and 1950s, epidemiological studies concluded that asbestos was a likely cause of asbestosis, lung cancer, and malignant mesothelioma, and it is now banned in many but far from all countries. The long latency between exposure to asbestos and the occurrence of cancer has obscured the deadly consequences of asbestos exposure for centuries. Even today, a considerable part of the world population is insufficiently aware of the dangers of asbestos, and millions of tons of this carcinogen continue to be mined and used worldwide. Zeolites, both natural and synthetic, are microporous aluminosilicate minerals commonly used in a myriad of processes, in the petrochemical industry, in domestic appliances and cleaning agents, as commercial adsorbents and exchangers for toxins and pollutants, and as catalysts. Zeolites are found in agriculture, veterinary science, and human health. More recently, new materials such as carbon nanotubes are being employed in materials requiring durability and thermal and electrical conductivity, yet nanotubes are now joining the ranks of more established particulates such as asbestos and silica, in causing human disease. In this review, we compare and contrast the similarities and differences of these two groups of silicate minerals and their waxing and waning use in the employ of humanity.
Assuntos
Amianto/efeitos adversos , Zeolitas/efeitos adversos , Amianto/metabolismo , Humanos , Nanotubos de Carbono/efeitos adversos , Zeolitas/metabolismoRESUMO
Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFß or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
Assuntos
Fator de Crescimento Epidérmico/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Mesotelioma/metabolismo , Mesotelioma Maligno , Neoplasias Pleurais/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3â+â3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5â×â109, 7â×â109, and 9â×â109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1â×â109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. FINDINGS: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5â×â109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5â×â109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5â×â109 TargomiRs once weekly. We established that 5â×â109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. INTERPRETATION: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING: Asbestos Diseases Research Foundation.
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Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , MicroRNAs/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Segurança do Paciente , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Austrália , Biópsia por Agulha , Institutos de Câncer , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Infusões Intravenosas , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Mesotelioma/diagnóstico por imagem , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Seleção de Pacientes , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM. METHODS: We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed. RESULTS: We identified 910 patients (67% residing in major cities; 92% <50 km from MDT). Median overall survival was 10.0 months. On multivariate analysis, age >70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months; P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months; P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8%; P = 0.001). CONCLUSION: This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.
Assuntos
Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Mesotelioma/diagnóstico , Mesotelioma/epidemiologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/epidemiologia , Adulto , Idoso , Feminino , Humanos , Incidência , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/terapia , Mesotelioma Maligno , Pessoa de Meia-Idade , Análise Multivariada , New South Wales/epidemiologia , Neoplasias Pleurais/terapia , Pneumonectomia , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores SocioeconômicosRESUMO
BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.
Assuntos
Perfilação da Expressão Gênica/métodos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Pleurais/genética , Regiões 3' não Traduzidas , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Mesotelioma MalignoRESUMO
BACKGROUND: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). METHODS: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. RESULTS: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. CONCLUSIONS: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Osteonectina/metabolismo , Neoplasias Pleurais/metabolismo , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Espectrometria de Massas , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Pessoa de Meia-Idade , Análise Multivariada , Transplante de Neoplasias , Neoplasias Pleurais/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteômica , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
Australia is known to have had the highest per-capita asbestos consumption level of any nation, reaching a peak in the 1970s. Although crocidolite was effectively banned in the late 1960s, and amosite use ceased in the mid 1980s, a complete asbestos ban was not implemented until 2003. This resulted in an epidemic of asbestos-related disease, which has only now reached its peak. Between 1982 and 2011, 13,036 individuals were newly diagnosed with malignant mesothelioma, with 690 diagnosed in 2011. A further 778 cases were identified between 1945 and 1981 from retrospective searches and the first 2 years of the Australian Mesothelioma Program. The age-standardized malignant mesothelioma incidence rate has leveled off in the last 10 years (2.8 per 100,000 in 2011). There has been a marked increase over time in the age-specific incidence rates for individuals aged 75 years or older. Data from the current Australian Mesothelioma Registry on asbestos exposure history in Australia is available for 449 subjects diagnosed between July 1, 2010, and April 1, 2015. This asbestos exposure history data show that 60% (n = 268) of cases had probable or possible occupational asbestos exposure, with trade-based jobs being the most frequent sources of occupational asbestos exposure. In addition, out of the 449 cases, 377 were recorded as having probable or possible nonoccupational asbestos exposure. Continuous vigilance toward changes over time in the settings in which people are exposed to asbestos and in the descriptive epidemiology of malignant mesothelioma is recommended to enable a comprehensive understanding of the current and future impact of asbestos-related diseases in Australia.
Assuntos
Amianto/toxicidade , Exposição Ambiental , Neoplasias Pulmonares/epidemiologia , Mesotelioma/epidemiologia , Fatores Etários , Austrália/epidemiologia , Geografia , Humanos , Incidência , Neoplasias Pulmonares/induzido quimicamente , Mesotelioma/induzido quimicamente , Mesotelioma Maligno , Exposição Ocupacional , Fatores SexuaisRESUMO
BACKGROUND: Australia is known to have had one of the highest per-capita asbestos consumption rates, yet there are few contemporary reports on malignant mesothelioma trends. METHODS: Data on 10â 930 people with malignant pleural mesothelioma (MPM) and 640 people with malignant peritoneal mesothelioma diagnosed in Australia during 1982-2009 were analysed. Observed incidence rate trends were quantified. Incidence rates were projected up to 2030 using observed incident cases during 1982-2012. The relative per-decade change in excess mortality during 1999-2009 was estimated. RESULTS: During 1982-2009, acceleration in MPM age-standardised incidence rates were highest for women and those aged 75â years and above, with average annual percentage changes of +4.9 (95% CI 3.6 to 6.2) and +7.2 (95% CI 5.4 to 9.0), respectively. Age-standardised incidence rates for men with MPM aged 0-64â years decelerated rapidly during 2003-2009, an average annual percentage change of -5.1% (95% CI -7.6% to -2.5%). Overall, male age-specific MPM incidence rates in the age group of 65-74â year during 2010-2030 are projected to decline with rates projected to increase for older men and women with MPM. There was a statistically significant 16% relative reduction in the excess mortality rate (EMR) up to 5 years postdiagnosis for people diagnosed with malignant pleural and peritoneal mesothelioma combined in 2009 compared with those diagnosed in 1999, an EMR ratio of 0.84 (95% CI 0.77 to 0.92). CONCLUSIONS: Australia's malignant mesothelioma incidence rates appear to have reached maximum levels but with differences over time by age, gender and tumour location. Improvements over time in survival provide a glimpse of hope for this almost invariably fatal disease.
Assuntos
Amianto/efeitos adversos , Carcinógenos , Exposição Ambiental , Neoplasias Pulmonares/epidemiologia , Mesotelioma/epidemiologia , Neoplasias Peritoneais/epidemiologia , Neoplasias Pleurais/epidemiologia , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma/mortalidade , Mesotelioma Maligno , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidade , Peritônio/patologia , Neoplasias Pleurais/mortalidade , Adulto JovemRESUMO
BACKGROUND: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies. METHODS: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively. RESULTS: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)). CONCLUSIONS: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Mesotelioma/diagnóstico , Mesotelioma/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Derrame Pleural/metabolismo , PrognósticoRESUMO
Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Sequência de Bases , Proteínas de Ligação a Calmodulina/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Éxons , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Proteínas do Tecido Nervoso/genética , Receptores Proteína Tirosina Quinases/genética , Análise de Sequência de RNARESUMO
All six fiber types called asbestos can cause all the diseases related to exposure, including lung cancer. Known to the ancients, the modern history of asbestos hazards started in the 1890s with more and more data accumulating over time. Use increased exponentially in the middle of the 20th century with major use coming in construction and ship building. The recognition of asbestos as causing lung cancer dates to the early 1940s.
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Amianto , Neoplasias Pulmonares , Amianto/efeitos adversos , Humanos , História do Século XX , Neoplasias Pulmonares/história , Neoplasias Pulmonares/etiologia , História do Século XIX , História do Século XXI , Exposição Ocupacional/efeitos adversos , Asbestose/história , Asbestose/etiologiaRESUMO
Asbestos-Related Lung Cancer (ARLC) presents ongoing diagnostic challenges despite improved imaging technologies. The long latency period, coupled with limited access to occupational and environmental data along with the confounding effects of smoking and other carcinogens adds complexity to the diagnostic process. Compounding these challenges is the absence of a specific histopathologic or mutational signature of ARLC. A correlation between PD-L1 expression and response to immune checkpoint inhibition has not yet been proven. Thus, new biomarkers are needed to allow accurate diagnoses of ARLC, to enable prognostication and to offer personalized treatments. Liquid biopsies, encompassing circulating DNA and circulating tumor cells (CTCs), have gained attention as novel diagnostic methods in lung cancer to screen high-risk populations including those exposed to asbestos. CTCs can be enumerated and molecularly profiled to provide predictive and prognostic information. CTC studies have not been undertaken in populations at risk of ARLC to date. The potential of CTCs to provide real-time molecular insight into ARLC biology may significantly improve the diagnosis and management of ARLC patients.
Assuntos
Amianto , Biomarcadores Tumorais , Detecção Precoce de Câncer , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Humanos , Amianto/efeitos adversos , Detecção Precoce de Câncer/métodos , Biópsia Líquida/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/etiologia , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , PrognósticoRESUMO
Asbestos, a group of class I (WHO) carcinogenic fibers, is the main cause of mesothelioma. Asbestos inhalation also increases the risk to develop other solid tumours with lung cancer as the most prominent example [91]. The incidence of asbestos-related lung cancer (ARLC) is estimated to be to six times larger than the mesothelioma incidence thereby becoming an important health issue [86]. Although the pivotal role of asbestos in inducing lung cancer is well established, the precise causal relationships between exposures to asbestos, tobacco smoke, radon and 'particulate' (PM2.5) air pollution remain obscure and new knowledge is needed to establish appropriate preventive measures and to tailor existing screening practices[22,61,65]. We hypothesize that a part of the increasing numbers of lung cancer diagnoses in never-smokers can be explained by (historic and current) exposures to asbestos as well as combinations of different forms of air pollution (PM2.5, asbestos and silica).
Assuntos
Amianto , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/epidemiologia , Amianto/efeitos adversos , Exposição Ambiental/efeitos adversos , Incidência , Poluição do Ar/efeitos adversos , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversosRESUMO
Small cell lung cancer (SCLC) is a highly aggressive cancer with a dismal 5-year survival of < 7%, despite the addition of immunotherapy to first-line chemotherapy. Specific tumor biomarkers, such as delta-like ligand 3 (DLL3) and schlafen11 (SLFN11), may enable the selection of more efficacious, novel immunomodulating targeted treatments like bispecific T-cell engaging monoclonal antibodies (tarlatamab) and chemotherapy with PARP inhibitors. However, obtaining a tissue biopsy sample can be challenging in SCLC. Circulating tumor cells (CTCs) have the potential to provide molecular insights into a patient's cancer through a "simple" blood test. CTCs have been studied for their prognostic ability in SCLC; however, their value in guiding treatment decisions is yet to be elucidated. This review explores novel and promising targeted therapies in SCLC, summarizes current knowledge of CTCs in SCLC, and discusses how CTCs can be utilized for precision medicine.
RESUMO
PURPOSE: Malignant pleural mesothelioma (MPM) is a highly aggressive and symptomatic disease. We examined the relationship between health-related quality of life (HRQoL) and inflammatory markers, and the prognostic role of HRQoL in MPM patients. METHODS: MPM patients from two parallel phase II studies (thalidomide alone or thalidomide with chemotherapy) were included. HRQoL was assessed at baseline using the modified Lung Cancer Symptom Scale (LCSS). Baseline inflammatory markers and cytokines were measured. Spearman correlation was used to examine the relationship between inflammatory markers and HRQoL measures. The prognostic value of the HRQoL domains was examined using Cox proportional hazard model. RESULTS: Sixty-three patients were included: median age 61 years (range 44-79); 82% male; 77% Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 44% epithelial histology subtype. Baseline systemic symptoms of anorexia and fatigue, the summation symptoms of overall symptomatic distress, interference with normal activity and global QoL and the aggregate score of total LCSS score were all associated with elevated neutrophil-to-lymphocyte ratio, C-reactive protein and vascular endothelial growth factor levels at baseline (rho ≥ 0.25; p < 0.05). Baseline anorexia, fatigue, cough, dyspnoea, pain, overall symptomatic distress, interference with normal activity, global QoL and total LCSS score were all significantly related to survival (p < 0.05) after adjusting for established prognostic factors (age, gender, histological subtype and performance status) and treatment effect. CONCLUSIONS: In conclusion, HRQoL seems to relate to a patient's systemic inflammatory status and is associated with survival in MPM patients.
Assuntos
Inflamação/patologia , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Feminino , Seguimentos , Humanos , Linfócitos/metabolismo , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neoplasias Pleurais/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estatísticas não Paramétricas , Taxa de Sobrevida , Talidomida/administração & dosagem , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: Malignant pleural mesothelioma (MPM) is considered a treatment-resistant disease. We determined the proportion of patients who received treatment in the last month of life and potential factors associated with use of chemotherapy at the end of life. METHODS: Consenting MPM patients compensated by the Dust Diseases Board (DDB) were included. Patient, treatment and outcome details were obtained through the DDB, treating physicians and Medicare Australia. The association between potential factors (age, gender, geographical location, disease stage, histological subtype, palliative care referral, length of first line chemotherapy and lines of treatment) and chemotherapy use in the last month of life was determined. RESULTS: A total of 147 MPM patients were included in the analysis: 78 received chemotherapy, 50 had radiotherapy and 116 had surgery (77 received more than one treatment modality whilst 56 received one treatment modality). Twenty-one patients received treatment in their last month of life: nine received chemotherapy; six, radiotherapy and six had surgery. Those who were treated with second or subsequent lines of chemotherapy were more at risk of receiving chemotherapy until the end of life (six of 19 patients, i.e., 32 %) compared to those who were only treated with first-line therapy (three of 59 patients, i.e., 5 %; p < 0.01). Patients who received chemotherapy at the end of life had shorter survival compared to those who did not receive chemotherapy at the end of life (5.3 vs. 12.5 months, respectively; p = 0.01). CONCLUSIONS: Chemotherapy utilisation in the last month of life is not uncommon in this series of MPM patients. Patients who failed previous chemotherapy were more likely to receive chemotherapy near the end of life. More careful consideration of when to cease chemotherapy needs to be made as patients who received chemotherapy at the end of life had poorer survival outcome.
Assuntos
Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Cuidados Paliativos/métodos , Neoplasias Pleurais/terapia , Assistência Terminal/métodos , Idoso , Austrália , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.