RESUMO
Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.
RESUMO
BACKGOUND: Neurosurgical resection is a standard local treatment for lung cancer brain metastases (BMs). This study aims to investigate whether neurosurgical resection provides survival benefit in lung cancer BMs with poor KPS. MATERIALS AND METHODS: This multicenter retrospective study included 386 lung cancer BMs with pretreatment KPS ≤ 70 among a total of 1177 lung cancer BMs treated at three centers from August 2010 to July 2021. Data analysis was performed from July to September 2022. Inverse probability of treatment weighting (IPTW) and propensity scores matching (PSM) based on propensity scoring were used to minimize bias. The main outcome was overall survival (OS) after diagnosis of BMs. Risk factors of OS were estimated using Cox proportional hazards regression models. All Characteristics were included in the multivariate Cox regression. RESULTS: 386 patients with pretreatment KPS ≤ 70 were included (age mean [SD], 57.85 [10.36] years; KPS mean [SD], 60.91 [10.11]). Among them, 111 patients received neurosurgical resection, while 275 patients did not. Baseline characteristics were balanced between groups after IPTW or PSM. Neurosurgical resection was associated with significantly better prognosis in unadjusted multivariate COX analysis (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.51-0.91, P = 0.01), and PSM-adjusted multivariate COX analysis (HR: 0.61, 95%CI: 0.39-0.94, P = 0.03), IPTW-adjusted multivariate COX analysis (HR: 0.58, 95%CI: 0.40-0.84, P = 0.004). OS was significantly longer in neurosurgical resection group compared with non-surgical resection group according to unadjusted data (Median OS, surgery vs non-surgery, 14.7 vs 12.5 months, P = 0.01), PSM-adjusted data (median OS, 17.7 vs 12.3 months, P < 0.01) and IPTW-adjusted data (median OS, 17.7 vs 12.5 months, P < 0.01). CONCLUSIONS: Neurosurgical resection was associated with improved survival in patients with lung cancer BMs with poor KPS, suggesting that poor KPS is not a contraindication for neurosurgical resection in these patients.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Criança , Estudos Retrospectivos , Avaliação de Estado de Karnofsky , Estudos de Coortes , Pontuação de Propensão , Neoplasias Pulmonares/patologia , Neoplasias Encefálicas/terapia , ContraindicaçõesRESUMO
BACKGROUND: Lung cancer is the most common cause of cancer-related death globally. There are several reasons for this high mortality rate, including metastasis to multiple organs, especially the brain. Exosomes play a pivotal role in tumor metastasis by remodeling the microenvironment of remote target organs and promoting the pre-metastatic niche's formation. Since astrocytes are indispensable for maintaining the homeostasis of brain microenvironment, it's of great interest to explore the influence of lung cancer cell-derived exosomes on astrocytes to further understand the mechanism of lung cancer brain metastasis. RESULTS: Twenty four h after co-culture of H1299 cell-derived exosomes and SVG P12 cells, the viability of astrocytes decreased and the apoptosis increased. The levels of cytokines in the supernatant including GROα/CXCL1, IFN-γ, IL-3, IL-5, IL-15, LIF, M-CSF, NGF, PDGF, and VEGF were significantly enhanced, while IL-7 secretion was significantly reduced. Meanwhile, apoptosis-related proteins MAP2K1, TUBA1C, RELA, and CASP6 were up-regulated. And the differentially expressed proteins were involved in regulating metabolic pathways. CONCLUSION: Exosomes of H1299 could induce apoptosis of astrocytes as well as promote their secretion of cytokines that were conducive to the formation of the inflammatory microenvironment and immunosuppressive microenvironment, and affect their metabolic pathways, thus facilitating the formation of pre-metastatic niche in lung cancer brain metastases.
RESUMO
BACKGROUND: Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with poor prognosis factors. METHODS: We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model. RESULTS: Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS. CONCLUSIONS: Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Idoso , Estudos Retrospectivos , Neoplasias Pulmonares/patologia , Neoplasias Encefálicas/secundário , Receptores ErbB , PrognósticoRESUMO
Objective To explore the dosimetric effects of a self-developed planning mode of boundary range scattering dose(BRSD)on Cyberknife treatment of lung cancer brain metastases.Methods The positioning images of 15 patients with lung cancer brain metastases treated in the radiotherapy department of some institution from January 1,2021 to December 31,2021 were selected and introduced into Cyberknife Multiplan 4.0.3 treatment planning system.A fractionated stereotactic radiotherapy(FSRT)plan(as the FSRT planning group)and a BRSD plan(as the BRSD planning group)were developed for each patient.The FSRT planning group developed a plan for the planning target volume(PTV)in the conventional way,so that V100 covered more than 95％of the PTV;the BRSD planning group prepared a plan for the gross tumor volume(GTV)with the same parameter conditions as the FSRT planning group and the prescription dose was normalized to the PTV so that V100 covered more than 95％of the PTV.The dosimetric parameters of the target area and normal tissue of the 2 groups were compared by dose-volume histograms and isodose curves.Statistical analysis was performed using SPSS 24.0 software.Results The D98,Dmax and Dmean in the target area of the BRSD planning group were significantly higher than those of the FSRT planning group,and the differences were statistically significant(P<0.05);the differences in the conformity index,dose gradient index,and Dmean,V30,V24 and D3cc in normal tissue of the 2 groups were not statistically significant(P>0.05);the BRSD planning group gained a denser dose distribution when compared with the FSRT planning group.Conclusion The BRSD planning mode gains significant dosimetric advantage by enhancing the absorbed dose to the target area without increasing or decreasing the dose to normal tissue.
RESUMO
Stereotactic radiosurgery (SRS) is a costly procedure used to irradiate disease tissue while sparing healthy tissue, ideally limiting the side effects of treatment. SRS is frequently used in the setting of lung cancer, which is associated with greater rates of BM, though its cost may lead to potentially inequitable use across patient populations. This study investigates potential disparities in the use of SRS to treat Medicare patients. Surveillance, Epidemiology, and End-Results cancer registry data for patients diagnosed between the years 2010 and 2012 were examined to identify lung cancer patients diagnosed with BM at the same time as their primary cancer (SBM). Medicare claims for SRS were identified; the odds of having SRS claims and hazards of mortality associated with those odds were examined with respect to various clinical and demographic characteristics. Of 74,142 Medicare-enrolled patients diagnosed with lung cancer, 9192 were diagnosed with SBM and 3259 of those patients received SRS. Adjusting for clinical and demographic characteristics, males with SBM had 0.85 times the odds of SRS compared to females with SBM. Black patients and those of other race had significantly lower odds of evidence of SRS compared to WNH patients. SRS may not be delivered equitably among Medicare patients. Males and minority patients may have decreased odds of SRS and worse survival compared to female and WNH patients, respectively.
Assuntos
Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Neoplasias Pulmonares/radioterapia , Radiocirurgia/estatística & dados numéricos , Carcinoma de Pequenas Células do Pulmão/radioterapia , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/economia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Seguimentos , Disparidades em Assistência à Saúde/economia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Medicare/economia , Medicare/estatística & dados numéricos , Grupos Minoritários/estatística & dados numéricos , Radiocirurgia/economia , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Carcinoma de Pequenas Células do Pulmão/economia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/secundário , Estados Unidos/epidemiologiaRESUMO
El cáncer de pulmón es uno de los tumores que tienen la capacidad de metastatizarse en el cerebro y tienen la capacidad de penetrar la barrera hematoencefálica, la clínica es variada dependiendo del sitio afectado, así como los riesgos asociados de convulsión. Por lo tanto, la elección del tratamiento es compleja, considerando el primario, el número de metástasis y los sitios afectados. La radioterapia ha sido durante mucho tiempo la elección de los pacientes que no son candidatos a la cirugía, La presencia de mutaciones han permitido brindar terapias dirigidas como los inhibidores tirosin kinasas que penetran la barrera hematoencefálica y han sido clave para el manejo terapéutico.
Lung cancer is one of the tumors that have the ability to metastasize in the brain and have the ability to penetrate the blood-brain barrier, the clinic is varied depending on the affected site, as well as the associated risks of seizure. Therefore, the choice of treatment is complex, considering the primary, the number of metastases and the affected sites. Radiotherapy has long been the choice of patients who are not candidates for surgery. The presence of mutations have allowed targeted therapies such as tyrosine kinase inhibitors that penetrate the blood-brain barrier and have been key to therapeutic management.