RESUMEN
Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer deaths. Lung cancer screening (LCS) reduces NSCLC mortality; however, a lack of diversity in LCS studies may limit the generalizability of the results to marginalized groups who face higher risk for and worse outcomes from NSCLC. Identifying sources of inequity in the LCS pipeline is essential to reduce disparities in NSCLC outcomes. The authors searched 3 major databases for studies published from January 1, 2010 to February 27, 2020 that met the following criteria: 1) included screenees between ages 45 and 80 years who were current or former smokers, 2) written in English, 3) conducted in the United States, and 4) discussed socioeconomic and race-based LCS outcomes. Eligible studies were assessed for risk of bias. Of 3721 studies screened, 21 were eligible. Eligible studies were evaluated, and their findings were categorized into 3 themes related to LCS disparities faced by Black and socioeconomically disadvantaged individuals: 1) eligibility; 2) utilization, perception, and utility; and 3) postscreening behavior and care. Disparities in LCS exist along racial and socioeconomic lines. There are several steps along the LCS pipeline in which Black and socioeconomically disadvantaged individuals miss the potential benefits of LCS, resulting in increased mortality. This study identified potential sources of inequity that require further investigation. The authors recommend the implementation of prospective trials that evaluate eligibility criteria for underserved groups and the creation of interventions focused on improving utilization and follow-up care to decrease LCS disparities.
Asunto(s)
Detección Precoz del Cáncer , Disparidades en Atención de Salud , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Humanos , Factores Raciales , Factores Socioeconómicos , Estados UnidosRESUMEN
BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.
Asunto(s)
Cuidadores , Ejercicio Físico , Neoplasias Pulmonares , Calidad de Vida , Humanos , Anciano , Neoplasias Pulmonares/cirugía , Masculino , Femenino , Teléfono , Atención Perioperativa/métodosRESUMEN
Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract.
Asunto(s)
Neoplasias Pulmonares , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Peptidasa Específica de Ubiquitina 7/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Neoplasias Pulmonares/patología , Histonas/metabolismo , Transducción de Señal , Línea Celular TumoralRESUMEN
BACKGROUND: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. METHODS: A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. RESULTS: Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 Alpha/Beta (TFAP2A/2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2α and AP2ß are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target: Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. CONCLUSION: Our findings indicate AP2α and AP2ß are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer. Video Abstract.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Factor de Transcripción AP-2/metabolismo , Factor de Transcripción Activador 3/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclina D1/metabolismo , Expresión Génica , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Neoplasias Pulmonares/patología , ARN Interferente Pequeño , Tioléster Hidrolasas/genética , Tioléster Hidrolasas/metabolismo , Factor de Transcripción AP-2/genética , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) pandemic and associated restrictions have altered the delivery of surgical care. The purpose of this study was to explore the impact of COVID-19 on care delivery and quality of life (QOL) from the perspectives of lung cancer surgery patients, family caregivers (FCGs), and thoracic surgery teams. METHODS: Patients/FCGs enrolled in a randomized trial of a self-management intervention for lung cancer surgery preparation/recovery were invited to participate in this qualitative study. Patients/FCGs data were collected separately 1-month postdischarge. Interviews were also conducted with thoracic surgery team members. Content analysis approaches were used to develop themes. RESULTS: Forty-one respondents including 19 patients, 18 FCGs, three thoracic surgeons, and one nurse practitioner participated in the study. Patient themes included isolation, psychological distress, delayed/impacted care, and financial impact. FCGs themes included caregiving challenges, worry about COVID-19, financial hardship, isolation, and physical activity limitations. Surgical team themes included witnessing patient/FCG's distress, challenges with telehealth, communication/educational challenges, and delays in treatment. CONCLUSIONS: COVID-19 had a varied impact on care delivery and QOL for lung cancer surgery dyads. Some dyads reported minimal impact, while others experienced added psychological distress, isolation, and caregiving challenges. Surgical teams also experienced challenges in the approach used to provide care.
Asunto(s)
COVID-19 , Neoplasias Pulmonares , Cuidados Posteriores , COVID-19/epidemiología , Humanos , Neoplasias Pulmonares/cirugía , Pandemias , Alta del Paciente , Calidad de Vida/psicologíaRESUMEN
BACKGROUND: Older adults undergoing cancer surgery are at greater risk for poor postoperative outcomes. Caregivers also endure significant burden. Participation in perioperative physical activity may improve physical functioning and enhance overall well-being for both patients and caregivers. In this study, we assessed the feasibility of a personalized telehealth intervention to enhance physical activity for older (≥ 65 years) gastrointestinal (GI) and lung cancer surgery patients/caregivers. METHODS: Participants completed four telehealth sessions with physical therapy/occupational therapy (PT/OT) before surgery and up to 2 weeks post-discharge. Outcomes included preop geriatric assessment, functional measures, and validated measures for symptoms and psychological distress. Pre/post-intervention trends/trajectories for outcomes were explored. RESULTS: Thirty-four patient/caregiver dyads (16, GI; 18, lung) were included. Accrual rate was 76% over 8 months; retention rate was 88% over 2 months. Median for postop of a 6-min walk test, timed up and go, and short physical performance battery test scores improved from baseline to postop. Participant satisfaction scores were high. CONCLUSION: Our conceptually based, personalized, multimodal, telehealth perioperative physical activity intervention for older patient/caregiver dyads is feasible and acceptable. It offers an opportunity to improve postoperative outcomes by promoting functional recovery through telehealth, behavior change, and self-monitoring approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03267524.
Asunto(s)
Cuidadores/psicología , Neoplasias/enfermería , Neoplasias/psicología , Periodo Posoperatorio , Calidad de Vida/psicología , Telemedicina/métodos , Anciano , Femenino , Humanos , Masculino , Proyectos PilotoRESUMEN
Flap endonuclease 1 (FEN1) plays a crucial role in both DNA replication and damage repair. In this study, FEN1 expression and its clinical-pathologic significance in non-small-cell lung cancer (NSCLC) was investigated. Quantitative RT-PCR and immunohistochemistry analysis identified that both FEN1 mRNA and protein were highly overexpressed in about 36% of 136 cancer tissues compared to adjacent tissues, in which FEN1 was generally undetectable. Notably, patients with FEN1-overexpressed cancers were prone to have poor differentiation and poor prognosis. A strong positive correlation between the levels of FEN1 and Ki-67 staining was identified in these NSCLC tissues (r = 0.485), suggesting overexpressed FEN1 conferred a proliferative advantage to NSCLC. Furthermore, knockdown of FEN1 resulted in G1/S or G2/M phase cell cycle arrest and suppressed in vitro cellular proliferation in NSCLC cancer cells. Consistently, a selective FEN1 inhibitor was shown to effectively inhibit cellular proliferation of NSCLC cells in a dose-dependent manner. Additionally, knockdown of FEN1 significantly attenuated homologous DNA repair efficiency and enhanced cytotoxic effects of cisplatin in NSCLC cells. Taken together, these findings have indicated that overexpressed FEN1 represents a prognostic biomarker and potential therapeutic target for NSCLC treatment, which warrants further study.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular/genética , Endonucleasas de ADN Solapado/metabolismo , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Endonucleasas de ADN Solapado/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Regulación hacia ArribaRESUMEN
BACKGROUND: Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor differentiation, cancer stemness, and enhanced malignancy of non-small cell lung cancer (NSCLC). Herein, we investigated the biological significance and therapeutic implications of ubiquitin-specific protease 22 (USP22), an H2Bub1 deubiquitinase, in non-small cell lung cancer (NSCLC). METHODS: USP22 expression and its clinical relevance were assessed in NSCLC patients. The effects of USP22 knockout on sensitivity to cisplatin and irradiation, and growth, metastasis of NSCLC xenografts, and survival of cancer-bearing mice were investigated. The underlying mechanisms of targeting USP22 were explored. RESULTS: Overexpression of USP22 was observed in 49.0% (99/202) of NSCLC tissues; higher USP22 immunostaining was found to be associated with enhanced angiogenesis and recurrence of NSCLC. Notably, USP22 knockout dramatically suppressed in vitro proliferation, colony formation; and angiogenesis, growth, metastasis of A549 and H1299 in mouse xenograft model, and significantly prolonged survival of metastatic cancer-bearing mice. Furthermore, USP22 knockout significantly impaired non-homologous DNA damage repair capacity, enhanced cisplatin and irradiation-induced apoptosis in these cells. In terms of underlying mechanisms, RNA sequencing and gene ontology enrichment analysis demonstrated that USP22 knockout significantly suppressed angiogenesis, proliferation, EMT, RAS, c-Myc pathways, concurrently enhanced oxidative phosphorylation and tight junction pathways in A549 and H1299 NSCLC cells. Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells. CONCLUSIONS: Our findings suggest USP22 plays critical roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which induces broad anti-cancer activities, as a novel therapeutic strategy for NSCLC patient.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neovascularización Patológica/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Reparación del ADN , ADN de Neoplasias/análisis , Modelos Animales de Enfermedad , Femenino , Humanos , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/secundario , Neoplasias Pulmonares/terapia , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Persona de Mediana Edad , Metástasis de la Neoplasia , Neovascularización Patológica/patología , Neovascularización Patológica/terapia , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/deficienciaRESUMEN
BACKGROUND: Dysregulated histone methyltransferase G9a may represent a potential cancer therapeutic target. The roles of G9a in tumorigenesis and therapeutics are not well understood in non-small cell lung cancer (NSCLC). Here we investigated the impact of G9a on tumor growth and signaling pathways in NSCLC. METHODS: Immunohistochemistry analyzed G9a expression in NSCLC tissues. Both siRNA and selective inhibitor were used to target G9a. The impact of targeting G9a on key genes, signaling pathways and growth were investigated in NSCLC cells by RNA sequencing analysis, rescue experiments, and xenograft models. RESULTS: Overexpression of G9a (≥ 5% of cancer cells showing positive staining) was found in 43.2% of 213 NSCLC tissues. Multiple tumor-associated genes including HP1α, APC2 are differentially expressed; and signaling pathways involved in cellular growth, adhesion, angiogenesis, hypoxia, apoptosis, and canonical Wnt signaling pathways are significantly altered in A549, H1299, and H1975 cells upon G9a knockdown. Additionally, targeting G9a by siRNA-mediated knockdown or by a selective G9a inhibitor UNC0638 significantly inhibited tumor growth, and dramatically suppressed Wnt signaling pathway in vitro and in vivo. Furthermore, we showed that treatment with UNC0638 restores the expression of APC2 expression in these cells through promoter demethylation. Restoring HP1α and silencing APC2 respectively attenuated the inhibitory effects on cell proliferation and Wnt signaling pathway in cancer cells in which G9a was silenced or suppressed. CONCLUSIONS: These findings demonstrate that overexpressed G9a represents a promising therapeutic target, and targeting G9a potentially suppresses growth and Wnt signaling pathway partially through down-regulating HP1α and epigenetically restoring these tumor suppressors such as APC2 that are silenced in NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas del Citoesqueleto/genética , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad/genética , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Vía de Señalización Wnt , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Homólogo de la Proteína Chromobox 5 , Metilación de ADN , Modelos Animales de Enfermedad , Epigénesis Genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Neoplasias Pulmonares/patología , Ratones , Quinazolinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The surgical treatment of lung malignancies often results in persistent symptoms, psychosocial distress, and decrements in quality of life (QOL) for cancer patients and their family caregivers (FCGs). The potential benefits of providing patients and FCGs with preparatory education that begins in the preoperative setting have been explored in multiple medical conditions, with positive impact observed on postoperative recovery, psychological distress, and QOL. However, few studies have explored the benefits of preparatory educational interventions to promote self-management in cancer surgery, including lung surgery. This paper describes the systematic approach used in the development of a multimedia self-management intervention to prepare cancer patients and their FCGs for lung surgery. Intervention development was informed by (1) contemporary published evidence on the impact of lung surgery on patients and FCG, (2) our previous research that explored QOL, symptoms, and caregiver burden after lung surgery, (3) the use of the chronic care self-management model (CCM) to guide intervention design, and (4) written comments and feedback from patients and FCGs that informed intervention development and refinement. Pilot-testing of the intervention is in process, and a future randomized trial will determine the efficacy of the intervention to improve patient, FCG, and system outcomes.
Asunto(s)
Cuidadores/educación , Neoplasias Pulmonares/cirugía , Multimedia , Educación del Paciente como Asunto/métodos , Automanejo/educación , Adaptación Psicológica , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Periodo Posoperatorio , Desarrollo de Programa , Calidad de Vida/psicología , Estrés Psicológico/epidemiologíaRESUMEN
Deregulated monoubiquitination of histone H2B (H2Bub1), mainly catalyzed by E3 ubiquitin-protein ligase RNF20/RNF40 complex, may play an important role in cancer. Here we investigate potential roles of H2Bub1 and the underlying mechanisms through which it contributes to cancer development and progression in lung adenocarcinoma. We show that downregulation of H2Bub1 through RNF20 knockdown dramatically decreases H3K79 and H3K4 trimethylation in both normal and malignant lung epithelial cell lines. Concurrently, global transcriptional profiling analysis reveals that multiple tumor-associated genes such as CCND3, E2F1/2, HOXA1, Bcl2 modifying factor (BMF), Met, and Myc; and signaling pathways of cellular dedifferentiation, proliferation, adhesion, survival including p53, cadherin, Myc, and anti-apoptotic pathways are differentially expressed or significantly altered in these lung epithelial cells upon downregulation of H2Bub1. Moreover, RNF20 knockdown dramatically suppresses terminal squamous differentiation of cultured bronchial epithelial cells, and significantly enhances proliferation, migration, invasion, and cisplatin resistance of lung cancer cells. Furthermore, immunohistochemistry analysis shows that H2Bub1 is extremely low or undetectable in >70% of 170 lung adenocarcinoma samples. Notably, statistical analysis demonstrates that loss of H2Bub1 is significantly correlated with poor differentiation in lung adenocarcinoma (p = 0.0134). In addition, patients with H2Bub1-negative cancers had a trend towards shorter survival compared with patients with H2Bub1-positive cancers. Taken together, our findings suggest that loss of H2Bub1 may enhance malignancy and promote disease progression in lung adenocarcinoma probably through modulating multiple cancer signaling pathways.
Asunto(s)
Adenocarcinoma/patología , Perfilación de la Expresión Génica/métodos , Histonas/metabolismo , Neoplasias Pulmonares/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Apoptosis , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transducción de Señal , Análisis de Supervivencia , UbiquitinaciónRESUMEN
BACKGROUND: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer. METHODS: Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed. RESULTS: Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors. CONCLUSIONS: These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrenos/uso terapéutico , Vía de Señalización Wnt/efectos de los fármacos , Células A549 , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diterpenos/efectos adversos , Diterpenos/uso terapéutico , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/uso terapéutico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Invasividad Neoplásica , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversos , Proteínas Represoras/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lung cancer is the leading cause of cancer mortality in the United States and worldwide. Since lung cancer outcomes are dependent on stage at diagnosis with early disease resulting in longer survival, the goal of screening is to capture lung cancer in its early stages when it can be treated and cured. Multiple studies have evaluated the use of chest X-ray (CXR) with or without sputum cytologic examination for lung cancer screening, but none has demonstrated a mortality benefit. In contrast, the multicenter National Lung Screening Trial (NLST) from the United States found a 20 % reduction in lung cancer mortality following three consecutive screenings with low-dose computed tomography (LDCT) in high-risk current and former smokers. Data from European trials are not yet available. In addition to a mortality benefit, lung cancer screening with LDCT also offers a unique opportunity to promote smoking cessation and abstinence and may lead to the diagnoses of treatable chronic diseases, thus decreasing the overall disease burden. The risks of lung cancer screening include overdiagnosis, radiation exposure, and false-positive results leading to unnecessary testing and possible patient anxiety and distress. However, the reduction in lung cancer mortality is a benefit that outweighs the risks and major health organizations currently recommend lung cancer screening using age, smoking history, and quit time criteria derived from the NLST. Although more research is needed to clearly define and understand the application and utility of lung cancer screening in the general population, current data support that lung cancer screening is effective and should be offered to eligible beneficiaries.
Asunto(s)
Detección Precoz del Cáncer/métodos , Neoplasias Pulmonares/diagnóstico por imagen , HumanosRESUMEN
We report results of a study utilizing a novel tissue classification method, based on label-free spectral techniques, for the classification of lung cancer histopathological samples on a tissue microarray. The spectral diagnostic method allows reproducible and objective classification of unstained tissue sections. This is accomplished by acquiring infrared data sets containing thousands of spectra, each collected from tissue pixels â¼6 µm on edge; these pixel spectra contain an encoded snapshot of the entire biochemical composition of the pixel area. The hyperspectral data sets are subsequently decoded by methods of multivariate analysis that reveal changes in the biochemical composition between tissue types, and between various stages and states of disease. In this study, a detailed comparison between classical and spectral histopathology is presented, suggesting that spectral histopathology can achieve levels of diagnostic accuracy that is comparable to that of multipanel immunohistochemistry.
Asunto(s)
Técnicas Histológicas/métodos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/patología , Espectrofotometría Infrarroja/métodos , Análisis de Matrices Tisulares/métodos , Humanos , Análisis MultivarianteRESUMEN
BACKGROUND: Esophageal sarcoma (ES) is a rare malignancy. The literature is limited to small case series and reports. This study used a population data set to study the characteristics, treatments, surgical outcomes, and prognostic factors for survival among ES patients. METHODS: The study identified 178 ES cases (0.3 %) and 63,548 esophageal carcinoma (EC) cases (99.7 %) including adenocarcinoma and squamous cell carcinoma using the Surveillance, Epidemiology, and End Results (SEER) Registry (1973-2011). Characteristics and therapeutics were compared between ES and EC. Survival data were analyzed using Kaplan-Meier estimation. Uni- and multivariate Cox proportional hazard models determined predictors of 5-year overall survival (OS). RESULTS: Compared with the EC patients, the ES patients were more likely to be women, to have localized tumors, and to undergo surgery but less likely to receive radiation (p < 0.001). The most common histologies were carcinosarcoma, leiomyosarcoma, and gastrointestinal stromal tumor (GIST). The 5-year OS for the ES patients was 38 % compared with 17 % for the EC patients (p < 0.001). The median survival period for the ES and EC surgical patients with locoregional disease was respectively 50 and 24 months. The ES patients with nonmetastatic disease who received surgery had better OS than those who did not (37 vs. 14 %; p < 0.0001). In the multivariate analysis, age and advanced stage conferred worse OS, whereas GIST histology and surgery were favorable predictors for OS. CONCLUSION: The ES patients were more likely to have localized disease, to be treated with surgery, and to have better OS than the EC patients. The survival benefit of surgery suggests that surgery should be the primary treatment for ES patients with resectable disease, particularly those with GIST.
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Adenocarcinoma/mortalidad , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/mortalidad , Esofagectomía/mortalidad , Adenocarcinoma/epidemiología , Adenocarcinoma/cirugía , Anciano , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/cirugía , Estudios de Cohortes , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Programa de VERF , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS: A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS: Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION: Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING: UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/mortalidad , Reacción en Cadena de la Polimerasa , Adulto , Anciano , California/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Cooperación Internacional , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Medición de RiesgoRESUMEN
Liquid biopsy (LB) is clinically utilized to detect minute amounts of genetic material or protein shed by cancer cells, most commonly cell free DNA (cfDNA), as a noninvasive precision oncology tool to assess genomic alterations to guide cancer therapy or to detect the persistence of tumor cells after therapy. LB is also being developed as a multi-cancer screening assay. The use of LB holds great promise as a tool to detect lung cancer early. Although lung cancer screening (LCS) with low-dose computed tomography (LDCT) substantially reduces lung cancer mortality in high-risk individuals, the ability of current LCS guidelines to reduce the public health burden of advanced lung cancer through early detection has been limited. LB may be an important tool to improve early lung cancer detection among all populations at risk for lung cancer. In this systematic review, we summarize the test characteristics, including sensitivity and specificity of individual tests, as they pertain to the detection of lung cancer. We also address critical questions in the use of liquid biopsy for early detection of lung cancer including: 1. How might liquid biopsy be used to detect lung cancer early; 2. How accurate is liquid biopsy in detecting lung cancer early; and 3. Does liquid biopsy perform as well in never and light-smokers compared with current and former smokers.
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Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Detección Precoz del Cáncer/métodos , Medicina de Precisión/métodos , Biopsia Líquida/métodos , Ácidos Nucleicos Libres de Células/genéticaRESUMEN
INTRODUCTION: With a median age at diagnosis of 70, lung cancer represents an enormous public health problem among older Americans. An estimated 19,000 people age 65 and older undergo lung cancer surgery annually in the US. Older adults undergoing lung cancer surgery are often frail with limited physiologic reserves, multi-morbidities, and functional impairments. Physical function, dyspnea, and quality of life return to baseline slower in older adults compared with younger adults after lung surgery. AREAS COVERED: In this review, we summarize available data about perioperative physical activity interventions that may improve outcomes for older adults undergoing lung cancer surgery. We also review the limitations of existing studies and discuss emerging data on the roles of telehealth and family caregiver inclusion in peri-operative physical activity interventions. EXPERT OPINION: We propose that future perioperative physical activity interventions in older adults undergoing lung cancer surgery should include a comprehensive geriatric assessment to guide personalized interventions. Interventions should be conceptually based, with a focus on enhancing self-efficacy, motivation, and adherence through classic behavior change strategies that are proven to impact outcomes. Finally, interventions should be designed with attention to feasibility and scalability. Exercise programs delivered via telehealth (telephone or tele-video) may improve access and convenience for patients.
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Neoplasias Pulmonares , Telemedicina , Humanos , Anciano , Neoplasias Pulmonares/cirugía , Calidad de Vida , Ejercicio Físico , DisneaRESUMEN
The goal of oncology is to provide the longest possible survival outcomes with the therapeutics that are currently available without sacrificing patients' quality of life. In lung cancer, several data points over a patient's diagnostic and treatment course are relevant to optimizing outcomes in the form of precision medicine, and artificial intelligence (AI) provides the opportunity to use available data from molecular information to radiomics, in combination with patient and tumor characteristics, to help clinicians provide individualized care. In doing so, AI can help create models to identify cancer early in diagnosis and deliver tailored therapy on the basis of available information, both at the time of diagnosis and in real time as they are undergoing treatment. The purpose of this review is to summarize the current literature in AI specific to lung cancer and how it applies to the multidisciplinary team taking care of these complex patients.
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Inteligencia Artificial , Neoplasias Pulmonares , Humanos , Calidad de Vida , Medicina de PrecisiónRESUMEN
OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.