RESUMEN
Brain metastasis is a significant clinical challenge for patients with advanced lung cancer, occurring in about 20-40% of cases. Brain metastasis causes severe neurological symptoms, leading to a poor prognosis and contributing significantly to lung cancer-related mortality. However, the underlying molecular mechanism behind brain metastasis remains largely unknown. MicroRNAs (miRNAs) are small, non-coding RNAs linked to several aspects of cancer progression, including metastasis. In the context of lung cancer, significant research has shown the involvement of miRNAs in regulating critical pathways related to metastatic spread to the brain. This review summarizes the scientific evidence regarding the regulatory roles of intra- and extracellular miRNAs, which specifically drive the spread of lung cancer cells to the brain. It also revises the known molecular mechanisms of brain metastasis, focusing on those from lung cancer as the primary tumor to better understand the complex mechanisms underlying this regulation. Understanding these complex regulatory mechanisms holds promise for developing novel diagnostic biomarkers and potential therapeutic strategies in brain metastasis.
Asunto(s)
Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , AnimalesRESUMEN
BACKGROUND: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet. METHODS: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts. RESULTS: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Camptotecina , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacologíaRESUMEN
BACKGROUND: Breast cancer is a leading cause of cancer-related deaths in females, and the hormone receptor-positive subtype is the most frequent. Breast cancer is a common source of brain metastases; therefore, we aimed to generate a brain metastases prediction model in females with hormone receptor-positive breast cancer. METHODS: The primary cohort included 3,682 females with hormone receptor-positive breast cancer treated at a single center from May 2009 to May 2020. Patients were randomly divided into a training dataset (n = 2,455) and a validation dataset (n = 1,227). In the training dataset, simple logistic regression analyses were used to measure associations between variables and the diagnosis of brain metastases and to build multivariable models. The model with better calibration and discrimination capacity was tested in the validation dataset to measure its predictive performance. RESULTS: The variables incorporated in the model included age, tumor size, axillary lymph node status, clinical stage at diagnosis, HER2 expression, Ki-67 proliferation index, and the modified Scarff-Bloom-Richardson grade. The area under the curve was 0.81 (95 % CI 0.75-0.86), p < 0.001 in the validation dataset. The study presents a guide for the clinical use of the model. CONCLUSION: A brain metastases prediction model in females with hormone receptor-positive breast cancer helps assess the individual risk of brain metastases.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias Encefálicas/secundario , Persona de Mediana Edad , Medición de Riesgo , Anciano , Receptor ErbB-2/metabolismo , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Receptores de Progesterona/metabolismoRESUMEN
Akinetopsia is a rare neurological syndrome characterized by an impaired perception of movement, often resulting from brain damage due to ischemia, epilepsy, or medication. It is also known as visual motion blindness, and patients with this condition are unable to perceive motion normally even with perfect visual acuity. This report aims to present a case of a patient in their late 40 s who developed akinetopsia and also an impairment in movement perception of objects without emitting sounds, after experiencing a late relapse of breast cancer with the occurrence of multiple brain metastases. The patient also experienced visual hallucinations, night terrors, and difficulty forming anterograde memory. Neuroimaging with MRI revealed severe brain damage, especially in the middle temporal area of the visual cortex. Akinetopsia is a rare phenomenon, and this is the first known case of its association with brain metastases.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/complicaciones , Neoplasias de la Mama/patología , Neoplasias de la Mama/complicaciones , Imagen por Resonancia Magnética , Percepción de Movimiento/fisiologíaAsunto(s)
Neoplasias Encefálicas , Neoplasias Renales , Imagen por Resonancia Magnética , Vasculitis del Sistema Nervioso Central , Humanos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/diagnóstico por imagen , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/diagnóstico por imagen , Diagnóstico Diferencial , Neoplasias Renales/patología , Neoplasias Renales/diagnóstico por imagen , Vasculitis del Sistema Nervioso Central/diagnóstico por imagen , Vasculitis del Sistema Nervioso Central/patologíaRESUMEN
Breast cancer is the most frequent neoplasia in developed countries and the leading cause of death in women worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process through which epithelial cells decrease or lose their epithelial characteristics and gain mesenchymal properties. EMT mediates tumor progression, because tumor cells acquire the capacity to execute the multiple steps of invasion and metastasis. Benzo[a]pyrene (B[a]P) is an environmental organic pollutant generated during the burning of fossil fuels, wood, and other organic materials. B[a]P exposition increases the incidence of breast cancer, and induces migration and/or invasion in MDA-MB-231 and MCF-7 breast cancer cells. However, the role of B[a]P in the induction of an EMT process and metastasis of mammary carcinoma cells has not been studied in detail. In this study, we demonstrate that B[a]P induces an EMT process in MCF10A mammary non-tumorigenic epithelial cells. In addition, B[a]P promotes the formation of larger tumors in Balb/cJ mice inoculated with 4T1 cells than in untreated mice and treated with dimethyl sulfoxide (DMSO). B[a]P also increases the number of mice with metastasis to brain and the total number of brain metastatic nodules in Balb/cJ mice inoculated with 4T1 cells compared with untreated mice and treated with DMSO. In conclusion, B[a]P induces an EMT process in MCF10A cells and the growth of mammary tumors and metastasis to brain in Balb/cJ mice inoculated with 4T1 cells.
Asunto(s)
Benzo(a)pireno , Neoplasias Encefálicas , Transición Epitelial-Mesenquimal , Ratones Endogámicos BALB C , Animales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Benzo(a)pireno/toxicidad , Humanos , Ratones , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/inducido químicamente , Neoplasias de la Mama/patología , Neoplasias de la Mama/inducido químicamente , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacosRESUMEN
PURPOSE: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM. METHODS: Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes). Expression was confirmed by qPCR in a validation cohort. Statistical analyses including multivariate logistic regression followed by receiver operating characteristic (ROC) analysis were performed. RESULTS: EMILIN3, MTA1, SV2B, TMPRSS6, ACVR1C, NFAT5 and SMC3 were differentially expressed in BRA and HEP/M0 groups. In the validation cohort, differential NFAT5, ACVR1C and SMC3 expressions were confirmed. BRA patients showed highest NFAT5 levels compared to HEP/M0 groups (global p = 0.02). High ACVR1C expression was observed more frequently in the BRA group (42.9%) than in HEP (0%) and M0 (7.1%) groups (global p = 0.01). High SMC3 expressions were only detectable in the BRA group (global p = 0.003). Only patients with BM showed a combined high expression of NFAT5, ACVR1C or SMC3 as well as of all three genes. ROC analysis revealed a good prediction of brain metastasis by the three genes (area under the curve (AUC) = 0.78). CONCLUSIONS: The NFAT5, ACVR1C and SMC3 gene expression signature is associated with colorectal BM. Future studies should further investigate the importance of this biomarker signature.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Encefálicas , Neoplasias Colorrectales , Humanos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano , Transcriptoma , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Pronóstico , Perfilación de la Expresión Génica , Curva ROC , Adulto , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Brain metastasis (BM) is common in lung adenocarcinoma (LUAD) and has a poor prognosis, necessitating predictive biomarkers. MicroRNAs (MiRNAs) promote cancer cell growth, infiltration, and metastasis. However, the relationship between the miRNA expression profiles and BM occurrence in patients with LUAD remains unclear. METHODS: We conducted an analysis to identify miRNAs in tissue samples that exhibited different expression levels between patients with and without BM. Using a machine learning approach, we confirmed whether the miRNA profile could be a predictive tool for BM. We performed pathway analysis of miRNA target genes using a matched mRNA dataset. RESULTS: We selected 25 miRNAs that consistently exhibited differential expression between the two groups of 32 samples. The 25-miRNA profile demonstrated a strong predictive potential for BM in both Group 1 and Group 2 and the entire dataset (area under the curve [AUC] = 0.918, accuracy = 0.875 in Group 1; AUC = 0.867, accuracy = 0.781 in Group 2; and AUC = 0.908, accuracy = 0.875 in the entire group). Patients predicted to have BM, based on the 25-miRNA profile, had lower survival rates. Target gene analysis of miRNAs suggested that BM could be induced through the ErbB signaling pathway, proteoglycans in cancer, and the focal adhesion pathway. Furthermore, patients predicted to have BM based on the 25-miRNA profile exhibited higher expression of the epithelial-mesenchymal transition signature, TWIST, and vimentin than those not predicted to have BM. Specifically, there was a correlation between EGFR mRNA levels and BM. CONCLUSIONS: This 25-miRNA profile may serve as a biomarker for predicting BM in patients with LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Encefálicas , Neoplasias Pulmonares , Aprendizaje Automático , MicroARNs , ARN Mensajero , Humanos , MicroARNs/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , ARN Mensajero/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Transición Epitelial-Mesenquimal/genética , Conjuntos de Datos como Asunto , Vimentina/metabolismo , Vimentina/genéticaRESUMEN
Melanoma, an infrequent yet significant variant of skin cancer, emerges as a primary cause of brain metastasis among various malignancies. Despite recognizing the involvement of inflammatory molecules, particularly chemokines, in shaping the metastatic microenvironment, the intricate cellular signaling mechanisms underlying cerebral metastasis remain elusive. In our pursuit to unravel the role of cytokines in melanoma metastasis, we devised a protocol utilizing mixed cerebral cortical cells and SK-MEL-28 melanoma cell lines. Contrary to expectations, we observed no discernible morphological change in melanoma cells exposed to a cerebral conditioned medium (CM). However, a substantial increase in both migration and proliferation was quantitatively noted. Profiling the chemokine secretion by melanoma in response to the cerebral CM unveiled the pivotal role of interferon gamma-induced protein 10 (CXCL10), inhibiting the secretion of interleukin 8 (CXCL8). Furthermore, through a transwell assay, we demonstrated that knockdown CXCL10 led to a significant decrease in the migration of the SK-MEL-28 cell line. In conclusion, our findings suggest that a cerebral CM induces melanoma cell migration, while modulating the secretion of CXCL10 and CXCL8 in the context of brain metastases. These insights advance our understanding of the underlying mechanisms in melanoma cerebral metastasis, paving the way for further exploration and targeted therapeutic interventions.
Asunto(s)
Movimiento Celular , Quimiocina CXCL10 , Melanoma , Transducción de Señal , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Humanos , Medios de Cultivo Condicionados/farmacología , Melanoma/patología , Melanoma/metabolismo , Línea Celular Tumoral , Interleucina-8/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Invasividad Neoplásica , Proliferación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/patologíaRESUMEN
OBJECTIVE: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. MATERIALS AND METHODS: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. RESULTS: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS. CONCLUSION: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy.
Asunto(s)
Adenocarcinoma del Pulmón , Bevacizumab , Neoplasias Encefálicas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Bevacizumab/uso terapéutico , Masculino , Femenino , Receptores ErbB/genética , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Pronóstico , Anciano , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/radioterapia , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/terapia , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Adenocarcinoma/genética , Adenocarcinoma/radioterapia , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adenocarcinoma/secundario , Irradiación Craneana/métodos , Tasa de Supervivencia , Anciano de 80 o más Años , Estimación de Kaplan-Meier , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estudios de SeguimientoRESUMEN
PURPOSE: A previous real-world study conducted in China confirmed that first-line atezolizumab, in combination with etoposide/platinum (EP), leads to significantly longer progression-free survival (PFS) compared to EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC). The present study aimed to provide updated survival outcome data and evaluate the clinical efficacy of atezolizumab plus chemotherapy in ES-SCLC patients with brain metastasis (BM). METHODS: This retrospective study included 225 patients with ES-SCLC who were treated with EP alone (EP group) or a combination of EP + atezolizumab (atezolizumab group). Survival outcomes for the total study sample and patients in the BM subgroup were estimated using the Kaplan-Meier method. RESULTS: The atezolizumab group continued to demonstrate significantly longer PFS than the EP group (hazard ratio [HR], 0.68). The median overall survival (OS) was 26.2 months in the atezolizumab group vs. 14.8 months in the EP group (HR, 0.63). Additionally, among the BM patients in our study, the median PFS was found to be longer in the atezolizumab group (7.0 months) than in the EP group (4.1 months) (HR, 0.46). The OS of the BM patients did not differ significantly between the two treatment groups. CONCLUSIONS: The addition of atezolizumab to EP as a first-line treatment for ES-SCLC was found to improve survival outcomes. This treatment combination may also prolong PFS in patients with BM, regardless of the administration of cranial irradiation. However, among the BM patients in our study, there was no significant difference in OS between the two treatment groups.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Etopósido , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Anciano , Adulto , Supervivencia sin Progresión , Estimación de Kaplan-Meier , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Tasa de Supervivencia , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Anlotinib, as a salvage treatment for patients after failure of third-line or later-line treatments for small cell lung cancer (SCLC), has shown efficacy in patients with brain metastases (BMs). However, the efficacy and safety of anlotinib alone or in combination with immunotherapy for SCLC with BMs remain unclear. METHOD: Patients treated with anlotinib alone or in combination with an immune checkpoint inhibitor (ICI) at the Zhejiang Cancer Hospital between April 2019 and February 2023 were identified. Kaplan-Meier curves were used to describe the progression-free survival (PFS) and intracranial PFS (iPFS). A waterfall diagram was used to indicate changes in intracranial lesions. RESULTS: A total of 48 patients were included; 29 received anlotinib alone, and 19 were administered anlotinib plus ICI. Combination therapy, compared with anlotinib, was associated with significantly longer PFS and iPFS (PFS: 8.1 months vs. 2.5 months, P < 0.001; iPFS: 8.1 months vs. 2.5 months, P = 0.004). Similar results were observed in patients with multiple BMs (PFS: 8.1 months vs. 1.9 months, P = 0.001; iPFS: 8.1 months vs. 1.9 months, P = 0.002). After third-line or later-line treatments, patients treated with ICI plus anlotinib also achieved significant PFS and iPFS benefits (PFS: 8.4 months vs. 2.1 months, P < 0.001; iPFS: 9.2 months vs. 2.1 months, P = 0.002). No new or severe adverse events were observed with combination therapy. CONCLUSION: The combination of anlotinib and ICI has promising intracranial and extracranial efficacy with tolerable toxicity, and may be a therapeutic option for SCLC patients with BMs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Inhibidores de Puntos de Control Inmunológico , Indoles , Neoplasias Pulmonares , Quinolinas , Carcinoma Pulmonar de Células Pequeñas , Humanos , Indoles/uso terapéutico , Indoles/administración & dosificación , Indoles/efectos adversos , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/administración & dosificación , Masculino , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Progresión , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Estimación de Kaplan-MeierRESUMEN
PURPOSE: This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. METHODS: Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with other mutations. RESULTS: Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33 months for patients with primary T790M mutations as compared to 48 months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17 months vs. 9 months, p = 0.009). CONCLUSION: Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Receptores ErbB/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Pronóstico , Persona de Mediana Edad , Anciano , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/mortalidad , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/uso terapéutico , Tasa de SupervivenciaRESUMEN
The Graded Prognostic Assessment (GPA) score has the best accuracy among prognostic scales for patients with brain metastases (BM). A wide range of GPA-derived scales have been established to different types of primary tumor BM. However, there is a high variability between them, and their characteristics have not been described altogether yet. We aim to summarize the features of the existent GPA-derived scales and to compare their predictor factors and their uses in clinical setting. Medline was searched from inception until January 2023 to identify studies related to the development, update, or validation of GPA. The initial search yielded 1,083 results. 16 original studies and 16 validation studies were included, comprising a total of 33,348 patients. 13 different scales were assessed, including: GPA, Diagnosis-Specific GPA, Extracranial Score, Lung-molGPA, Updated Renal GPA, Updated Gastrointestinal GPA, Modified Breast GPA, Integrated Melanoma GPA, Melanoma Mol GPA, Sarcoma GPA, Hepatocellular Carcinoma GPA, Colorectal Cancer GPA, and Uterine Cancer GPA. The most prevalent prognostic predictors were age, Karnofsky Performance Status, number of BM, and presence or absence of extracranial metastases. Treatment modalities consisted of whole brain radiation therapy, stereotactic radiosurgery, surgery, cranial radiotherapy, gamma knife radiosurgery, and BRAF inhibitor therapy. Median survival rates with no treatment and with a specific treatment ranged from 6.1 weeks to 33 months and from 3.1 to 21 months, respectively. Original GPA and GPA-derived scales are valid prognostic tools, but with heterogeneous survival results when compared to each other. More studies are needed to improve scientific evidence of these scales.
Asunto(s)
Neoplasias Encefálicas , Melanoma , Radiocirugia , Humanos , Pronóstico , Estudios Retrospectivos , Melanoma/patología , Estado de Ejecución de Karnofsky , Terapia Combinada , Neoplasias Encefálicas/secundario , Radiocirugia/métodosRESUMEN
PURPOSE: This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. METHODS: Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. RESULTS: The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). CONCLUSION: Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Anciano , Estados Unidos/epidemiología , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Medicare , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundarioRESUMEN
Purpose. To study the impact on dose coverage and the dose to the healthy tissue applying optimized margins in single isocenter multiple brain metastases radiosurgery (SIMM-SRS) in linac machine based on setup rotations/translations induced errors calculated by a genetic algorithm (GA).Method.The following quality indices of SIMM-SRS were analyzed for 32 plans (256 lesions): Paddick conformity index (PCI), gradient index (GI), maximum (Dmax) and mean (Dmean) doses, local and global V12for the healthy brain. A GA based on Python packages were used to determine the maximum shift produced by induced errors of 0.2°/0.2 mm, and 0.5°/0.5 mm in 6 degrees of freedom.Results.In terms of Dmax, and Dmean, the quality of the optimized-margin plans remains unchanged (p > 0.072) concerning the original plan. However, considering the 0.5°/0.5 mm plans, PCI and GI decreased for ≥10 metastases, and local, and global V12increased considerably in all cases. To consider 0.2°/0.2 mm plans, PCI and GI get worse but local, and global V12improved in all cases.Conclusion.GA facilities to find the individualized margins automatically among the number of possible permutations of the setup order. The user-dependent margins are avoided. This computational approach takes into account more SRS sources of uncertainty, enabling the protection of the healthy brain by 'smartly' reducing the margins, and maintaining clinically acceptable target volumes' coverage in most cases.
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Neoplasias Encefálicas , Planificación de la Radioterapia Asistida por Computador , Humanos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias Encefálicas/secundario , Encéfalo/patología , AlgoritmosRESUMEN
OBJECTIVE: To explore the expression levels and clinical value of FKBP10 in lung adenocarcinoma brain metastases. DESIGN: A retrospective single-institution cohort study. PATIENTS: The perioperative records of 71 patients with lung adenocarcinoma brain metastases who underwent surgical resection at the authors' institution between November 2012 and June 2019 were retrospectively analyzed. METHODS: The authors evaluated FKBP10 expression levels using immunohistochemistry in tissue arrays of these patients. Kaplan-Meier survival curves were constructed, and a Cox proportional hazards regression model was used to identify independent prognostic biomarkers. A public database was used to detect FKBP10 expression and its clinical value in primary lung adenocarcinoma. RESULTS: The authors found that the FKBP10 protein was selectively expressed in lung adenocarcinoma brain metastases. Survival analysis showed that FKBP10 expression (p = 0.02, HR = 2.472, 95% CI [1.156, 5.289]), target therapy (p < 0.01, HR = 0.186, 95% CI [0.073, 0.477]), and radiotherapy (p = 0.006, HR = 0.330, 95% CI [0.149, 0.731]) were independent prognostic factors for survival in lung adenocarcinoma patients with brain metastases. The authors also detected FKBP10 expression in primary lung adenocarcinoma using a public database, found that FKBP10 is also selectively expressed in primary lung adenocarcinoma, and affects the overall survival and disease-free survival of patients. LIMITATIONS: The number of enrolled patients was relatively small and patients' treatment options varied. CONCLUSIONS: A combination of surgical resection, adjuvant radiotherapy, and precise target therapy may benefit the survival of selected patients with lung adenocarcinoma brain metastases. FKBP10 is a novel biomarker for lung adenocarcinoma brain metastases, which is closely associated with survival time and may serve as a potential therapeutic target.
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Adenocarcinoma del Pulmón , Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Estudios de Cohortes , Neoplasias Pulmonares/patología , Pronóstico , Estudios Retrospectivos , Proteínas de Unión a TacrolimusRESUMEN
Melanoma is the most aggressive type of skin cancer. Brain metastasis is the worst scenario in metastatic melanoma and the treatment options for these patients are limited. Temozolomide (TMZ) is a chemotherapy agent used to treat primary central nervous system tumors. Our objective was to develop chitosan-coated nanoemulsion containing temozolomide (CNE-TMZ) for nasal route administration to melanoma brain metastasis treatment. A preclinical model of metastatic brain melanoma was standardized, and the efficiency of the developed formulation was further determined in vitro and in vivo. The nanoemulsion was done by spontaneous emulsification method and the formulation was characterized by size, pH, polydispersity index, and zeta potential. Culture assessments to determine cell viability were done in the A375 human melanoma cell line. To determine the safety of formulation, healthy C57/BL6 mice were treated with a nanoemulsion without TMZ. The model in vivo used B16-F10 cells implanted by stereotaxic surgery in C57/BL6 mice brains. The results demonstrate that the preclinical model used showed to be useful to analyze the efficiency of new candidate drugs to treat melanoma brain metastasis. The chitosan-coated nanoemulsions with TMZ showed the expected physicochemical characteristics and demonstrated safety and efficacy, reducing around 70% the tumor size compared to control mice, and presenting a tendency in mitotic index reduction, becoming an interesting approach to treat melanoma brain metastasis.
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Neoplasias Encefálicas , Quitosano , Melanoma , Humanos , Animales , Ratones , Temozolomida/farmacología , Temozolomida/uso terapéutico , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Línea Celular TumoralRESUMEN
BACKGROUND: Brain metastases are associated with considerable negative effects on patients' outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases. MATERIALS AND METHODS: Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259. RESULTS: Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases. CONCLUSIONS: This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.
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Adenocarcinoma del Pulmón , Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Proteómica , Biomarcadores de Tumor , Neoplasias Encefálicas/secundario , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
BACKGROUND: Osteosarcoma (OS) is the most common primary bone carcinoma. Adulthood most frequent intraocular malignant tumor is choroidal metastasis; however, these are rarely related to sarcomas. There are only two OS-related choroidal metastasis cases reported in the literature, both prior to 1970. CASE PRESENTATION: A 20-year-old man with a history of tibial OS, right leg amputation, and lung and brain metastases, presented with decreased vision in his right eye (OD). Ophthalmic examination revealed a best-corrected visual acuity of hand movements and a large, posterior pole, nodular, subretinal mass, with associated fluid. B-scan revealed a heterogeneous lump, with medium/high reflectivity, and a height-to-base ratio (HBR) of 1-1.2, approximately. Computerized tomography (CT) scan showed a hyperdense and contrast-enhanced mass, while on magnetic resonance imaging (MRI) the lesion appeared T1-isointense and T2-hypointense. CONCLUSION: Choroidal OS metastasis can appear as a pink nodule with high HBR and intralesional hyperreflective deposits. Sudden visual changes in individuals with OS-related systemic metastatic disease should be monitored closely by ophthalmology and oncology jointly.