RESUMO
BACKGROUND: The CyberKnife Xsight lung-tracking system (XLTS) provides an alternative to fiducial-based target-tracking systems (FTTS) for non-small-cell lung cancer (NSCLC) patients without invasive fiducial insertion procedures. This study provides a method for 3D independent dosimetric verification of the accuracy of the FTTS compared to the XLTS without relying on log-files generated by the CyberKnife system. METHODS: A respiratory motion trace was taken from a 4D-CT of a real lung cancer patient and applied to a modified QUASAR™ respiratory motion phantom. A novel approach to 3D dosimetry was developed using Gafchromic EBT3 film, allowing the 3D dose distribution delivered to the moving phantom to be reconstructed. Treatments were planned using the recommended margins for one and three fiducial markers and XLTS 2-view, 1-view and 0-view target-tracking modalities. The dose delivery accuracy was analysed by comparing the reconstructed dose distributions to the planned dose distributions using gamma index analysis. RESULTS: For the 3%/2 mm gamma criterion, gamma passing rates up to 99.37% were observed for the static deliveries. The 3-fiducial and 1-fiducial-based deliveries exhibited passing rates of 93.74% and 97.82%, respectively, in the absence of target rotation. When target rotation was considered, the passing rate for 1-fiducial tracking degraded to 91.24%. The passing rates observed for XLTS 2-view, 1-view and 0-view target-tracking were 92.78%, 96.22% and 76.08%, respectively. CONCLUSIONS: Except for the XLTS 0-view, the dosimetric accuracy of the XLTS was comparable to the FTTS under equivalent treatment conditions. This study gives us further confidence in the CyberKnife XLTS and FTTS systems.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Marcadores Fiduciais , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Imagens de Fantasmas , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. However, the nature of these interactions and their role in Ras tumor radioresistance remain unclear. Here we use Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discover that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. These findings suggest that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Genes ras , Neoplasias Pulmonares/metabolismo , Tolerância a Radiação , Fatores de Transcrição STAT/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Animais Geneticamente Modificados , Proliferação de Células/efeitos da radiação , Citocinas/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos Nus , Camundongos Transgênicos , Comunicação Parácrina , Tolerância a Radiação/genética , Fatores de Transcrição STAT/genética , Transdução de Sinais , Carga Tumoral/efeitos da radiação , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Genetic instability is one of the hallmarks of cancer cells. As tumors grow, they progressively acquire mutations that ultimately allow them to invade normal tissues and metastasize to distant sites. This increased propensity for mutation also leads to cancers that are resistant to therapeutic intervention. Recent evidence has shown that the tumor microenvironment plays a major role in the etiology of this phenomenon; as tumors are exposed to repeated cycles of hypoxia and reoxygenation, they downregulate a number of DNA repair pathways, thus leading to genetic instability. Understanding the mechanisms involved in this process may provide insights into the development of novel treatment strategies.
Assuntos
Reparo do DNA , DNA de Neoplasias/genética , Hipóxia/genética , Microambiente Tumoral/genética , Animais , Humanos , MutaçãoRESUMO
Dishevelled (Dsh) is a cytoplasmic multidomain protein that is required for all known branches of the Wnt signalling pathway. The Frizzled/planar cell polarity (Fz/PCP) signalling branch requires an asymmetric cortical localization of Dsh, but this process remains poorly understood. Using a genome-wide RNA interference (RNAi) screen in Drosophila melanogaster cells, we show that Dsh membrane localization is dependent on the Na(+)/H(+) exchange activity of the plasma membrane exchanger Nhe2. Manipulating Nhe2 expression levels in the eye causes PCP defects, and Nhe2 interacts genetically with Fz. Our data show that the binding and surface recruitment of Dsh by Fz is pH- and charge-dependent. We identify a polybasic stretch within the Dsh DEP domain that binds to negatively charged phospholipids and appears to be mechanistically important. Dsh recruitment by Fz can be abolished by converting these basic amino-acid residues into acidic ones, as in the mutant, DshKR/E. In vivo, the DshKR/E(2x) mutant with two substituted residues fails to associate with the membrane during active PCP signalling but rescues canonical Wnt signalling defects in a dsh-background. These results suggest that direct interaction between Fz and Dsh is stabilized by a pH and charge-dependent interaction of the DEP domain with phospholipids. This stabilization is particularly important for the PCP signalling branch and, thus, promotes specific pathway selection in Wnt signalling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Membrana Celular/metabolismo , Polaridade Celular , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Células Epiteliais/citologia , Receptores Frizzled/metabolismo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Linhagem Celular , Sinais (Psicologia) , Proteínas Desgrenhadas , Proteínas de Drosophila/metabolismo , Eletroquímica , Células Epiteliais/metabolismo , Olho/citologia , Receptores Frizzled/química , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Fenótipo , Fosfolipídeos , Fosfoproteínas/química , Ligação Proteica , Estrutura Terciária de Proteína , Transdução de SinaisRESUMO
PURPOSE: To analyze the prognosis and outcomes of patients who remain free of biochemical failure during the first 5 years after treatment. METHODS AND MATERIALS: Between 1991 and 2002, 742 patients with prostate cancer were treated with brachytherapy alone (n = 306), brachytherapy and hormonal therapy (n = 212), or combined implantation and external beam radiotherapy (with or without hormonal therapy; n = 224). These patients were free of biochemical failure (American Society for Therapeutic Radiology and Oncology [ASTRO] definition) during the first 5 post-treatment years and had a documented 5-year prostate-specific antigen (PSA) value. The median follow-up was 6.93 years. RESULTS: The actuarial 10-year freedom from PSA failure rate was 97% using the ASTRO definition and 95% using the Phoenix definition. The median 5-year PSA level was 0.03 ng/mL (range, 0-3.6). The 5-year PSA value was
Assuntos
Recidiva Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Terapia Combinada/métodos , Humanos , Masculino , Recidiva Local de Neoplasia/sangue , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Radioterapia/métodos , Dosagem Radioterapêutica , Valores de Referência , Fatores de TempoRESUMO
The related Wnt-Frizzled(Fz)/beta-catenin and Fz/planar cell polarity (PCP) pathways are essential for the regulation of numerous developmental processes and are deregulated in many human diseases. Both pathways require members of the Dishevelled (Dsh or Dvl) family of cytoplasmic factors for signal transduction downstream of the Fz receptors. Dsh family members have been studied extensively, but their activation and regulation remains largely unknown. In particular, very little is known about how Dsh differentially signals to the two pathways. Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKIepsilon) may act as a molecular "switch," promoting Wnt/beta-catenin while inhibiting Fz/PCP signaling. Here, we demonstrate in vivo in Drosophila through a series of loss-of-function and coexpression assays that CKIepsilon acts positively for signaling in both pathways, rather than as a switch. Our data suggest that the kinase activity of CKIepsilon is required for peak levels of Wnt/beta-catenin signaling. In contrast, CKIepsilon is a mandatory signaling factor in the Fz/PCP pathway, possibly through a kinase-independent mechanism. Furthermore, we have identified the primary kinase target residue of CKIepsilon on Dsh. Thus, our data suggest that CKIepsilon modulates Wnt/beta-catenin and Fz/PCP signaling pathways via kinase-dependent and -independent mechanisms.