RESUMO
PURPOSE: To establish and validate a delta-radiomics-based model for predicting progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) following induction chemotherapy (IC). METHODS AND MATERIALS: A total of 250 LA-NPC patients (training cohort: n = 145; validation cohort: n = 105) were enrolled. Radiomic features were extracted from MRI scans taken before and after IC, and changes in these features were calculated. Following feature selection, a delta-radiomics signature was constructed using LASSO-Cox regression analysis. A prognostic nomogram incorporating independent clinical indicators and the delta-radiomics signature was developed and assessed for calibration and discrimination. Risk stratification by the nomogram was evaluated using Kaplan-Meier methods. RESULTS: The delta-radiomics signature, consisting of 12 features, was independently associated with prognosis. The nomogram, integrating the delta-radiomics signature and clinical factors demonstrated excellent calibration and discrimination. The model achieved a Harrell's concordance index (C-index) of 0.848 in the training cohort and 0.820 in the validation cohort. Risk stratification identified two groups with significantly different PFS rates. The three-year PFS for high-risk patients who received concurrent chemoradiotherapy (CCRT) or radiotherapy plus adjuvant chemotherapy (RT+AC) after IC was significantly higher than for those who received RT alone, reaching statistical significance. In contrast, for low-risk patients, the three-year PFS after IC was slightly higher for those who received CCRT or RT+AC compared to those who received RT alone; however, this difference did not reach statistical significance. CONCLUSIONS: Our delta MRI-based radiomics model could be useful for predicting PFS and may guide subsequent treatment decisions after IC in LA-NPC.
Assuntos
Quimioterapia de Indução , Imageamento por Ressonância Magnética , Carcinoma Nasofaríngeo , Nomogramas , Humanos , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidade , Pessoa de Meia-Idade , Quimioterapia de Indução/métodos , Adulto , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Prognóstico , Idoso , Resultado do Tratamento , RadiômicaRESUMO
BACKGROUND: To evaluate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level post-induction chemotherapy (IC) for patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 893 newly diagnosed NPC patients treated with IC were retrospectively reviewed. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off value of post-IC EBV DNA. RESULTS: Post-IC EBV DNA levels and overall stage were independent predictors for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). The RPA model base on post-IC EBV DNA and overall stage categorized the patients into three distinct risk groups: RPA I (low-risk: stage II-III and post-IC EBV DNA < 200 copies/mL), RPA II (median-risk: stage II-III and post-IC EBV DNA ≥ 200 copies/mL, or stage IVA and post-IC EBV DNA < 200 copies/mL), and RPA III (high-risk: stage IVA and post-IC EBV DNA ≥ 200 copies/mL), with 3-year PFS of 91.1%, 82.6%, and 60.2%, respectively (p < 0.001). The DMFS and OS rates in different RPA groups were also distinct. The RPA model showed better risk discrimination than either the overall stage or post-RT EBV DNA alone. CONCLUSIONS: Plasma EBV DNA level post-IC was a robust prognostic biomarker for NPC. We developed an RPA model that provides improved risk discrimination over the 8th edition of the TNM staging system by integrating the post-IC EBV DNA level and the overall stage.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Prognóstico , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Quimioterapia de Indução , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , DNA Viral , Medição de RiscoRESUMO
BACKGROUND: To review our long-term clinical experience, analyze the failure patterns, and give suggestions for target volume delineation of carcinoma showing thymus-like differentiation (CASTLE) treated with intensity-modulated radiotherapy (IMRT). METHODS: From April 2008 to May 2019, 30 patients with CASTLE treated by postoperative or radical IMRT in our center were retrospectively reviewed. A total dose of 56-60 Gy in 28-30 fractions was prescribed to patients without residual disease and 66 Gy in 33 fractions for patients with residual or unresectable disease. Survival rates were calculated using the Kaplan-Meier method. Treatment-related toxicities were graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. RESULTS: Among the 30 patients, 12 (40%) received partial resection or biopsy. Lateral lymph node metastasis was observed in 7 (23.3%) patients. During follow-up, regional lymph node recurrence occurred in 2 patients and distant metastasis in 5 patients. With a median follow-up time of 63.5 months, the 5-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), overall survival (OS) and progression-free survival (PFS) rates were 100, 88.9, 78.9, 93.1 and 78.9%, respectively. For patients with no lateral neck node metastasis, prophylactic radiotherapy for lateral neck nodal regions failed to improve RRFS (p = 0.381) and OS (p = 0.153). CONCLUSION: Distant metastasis was the major failure pattern for CASTLE after surgery and IMRT. For patients with no lateral neck node metastasis, the omission of irradiation for lateral neck nodal regions seems to be safe and feasible.
Assuntos
Carcinoma , Radioterapia de Intensidade Modulada , Humanos , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Carcinoma/patologia , Planejamento da Radioterapia Assistida por Computador/métodos , Metástase Linfática/radioterapiaRESUMO
Nasopharyngeal carcinoma (NPC) has a 10-15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of â¼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8+ T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3+ dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.
Assuntos
Neoplasias Nasofaríngeas , Linfócitos T CD8-Positivos , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Recidiva Local de Neoplasia/genética , Análise de Sequência de RNA , Microambiente Tumoral/genéticaRESUMO
Metastatic liver disease is the most frequent complication of colorectal cancer (CRC), and the development of liver-targeted nanoparticles for drug delivery is a promising therapeutic approach. However, to improve the efficacy of passive drug delivery, its release rate at the sites of liver metastases should be maximized while minimizing drug uptake in nontargeted cells. Herein, we report the development and use of tripolyphosphate (TPP) modified chitosan (CS) nanoparticles loaded with small interfering RNA (siRNA) directed against transforming growth factor ß1 (TGF-ß1), which promotes tumorigenesis in advanced CRC. The nanoparticles efficiently inhibited CRC hepatic metastasis in an animal model. Particles of 300 nm in size and zeta potential at 20 mV showed a more striking liver-targeting effect. A weight ratio of CS/TPP of 8:1 for particles with TGF- ß1 siRNA loaded at a concentration of 20 µM at pH 7.5 showed good pH-responsive drug release when exposed to a CRC homogenate at pH 6.5. In vivo, CS-TPP/TGF- ß1 siRNA nanoparticles significantly reduced the volume and number of CRC metastatic foci. This was accompanied by the downregulation of TGF- ß1 expression in the tumor microenvironment, inhibition of tumor associated macrophage formation, and improvement of the immune microenvironment. These results indicate that it is possible to achieve effective passive liver targeting by optimizing the processing parameters. The design of nanoparticles carrying siRNA against overexpressed oncogenes provides an excellent platform for the development of an efficient liver cancer therapy.
Assuntos
Quitosana/análogos & derivados , Neoplasias Colorretais/patologia , Portadores de Fármacos/química , Neoplasias Hepáticas , Nanopartículas/química , RNA Interferente Pequeno/genética , Fator de Crescimento Transformador beta1/genética , Animais , Quitosana/química , Quitosana/farmacocinética , Quitosana/uso terapêutico , Modelos Animais de Doenças , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/uso terapêutico , Tamanho da Partícula , Interferência de RNA , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The objective of this study was to apply the "on/off" switch consisting of 3' phosphorothioate-modified allele specific primers and exo(+) polymerase in single base discrimination of A1555G and C1494T mutations in the highly conserved sites of the mitochondrial 12S rRNA. The two point mutations are the hotspot mutations associated with either aminoglycoside antibiotics induced deafness or inherited nonsyndromic hearing loss. The PCR products of mitochondrial DNA (mtDNA) 12S rRNA gene were inserted into the pMD19-T vector for transformation into Escherichia coli JM109 competent cells for preparing wild-type pMD19-T/mt vector. Inverse PCR was carried out for mtDNA 12S rRNA gene C1494T and A1555G mutagenesis and DpnI endonuclease degradating methylated pMD19-T/mt vector existing in the inverse PCR products was carried out to construct the mutation-type pMD19-T/mtM vector. These constructed vectors were confirmed by DNA sequencing. Allelic specific primers targeting wild-type and mutation-type templates were designed with 3' terminal phosphorothioate modification. Two-directional primer extension was performed using Pfu polymerases. Amplified by exo(+) polymerase, allelic specific primers perfectly matching wild-type allele were extended while no products were produced from primers targeting point-mutated deafness-related allele. Similarly, allelic specific primers perfectly matching point-mutated deafness-related mutation-type allele were extended and no products were yielded from primers targeting wild-type allele. No specific product was observed in the primer extension reaction mediated by on/off switch in screening the mtDNA 12S rRNA gene harboring either C1494T or A1555G mutation in 40 healthy volunteers tested. These data suggest that the "off switch" mediated by exo(+) polymerase is highly reliable in the diagnosis of monogenic diseases and the novel "on/off" switch has enormous applications in systematic and extended screening of the12S rRNA gene A1555G and C1494T mutations. The established assay can be widely used not only for hearing loss patients but also for normal subjects before the use of aminoglycoside antibiotics.
Assuntos
DNA Mitocondrial/genética , Mutação Puntual/genética , Reação em Cadeia da Polimerase/métodos , RNA Ribossômico/genética , Alelos , Sequência de Bases , DNA Polimerase Dirigida por DNA/química , Surdez/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Escherichia coli/genética , Perda Auditiva/genética , Humanos , Mitocôndrias/genética , Dados de Sequência Molecular , Análise de Sequência de DNA , Transformação GenéticaRESUMO
BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha), a subunit of hypoxia-inducible factor-1 (HIF-1), furnishes tumor cells with the means of adapting to stress parameters, such as tumor hypoxia, and promotes critical steps in tumor progression and aggressiveness by inducing angiogenesis and regulating energy metabolism. In this study, we investigated the relationship between HIF-1alpha and vascular endothelial growth factor (VEGF) and clinicopathologic characteristics, and evaluated the role of HIF-1alpha expression in patients with rectal adenocarcinoma. PATIENTS AND METHODS: The immunohistochemical expression of HIF-1alpha and VEGF was evaluated in 30 formalin-fixed, paraffin-embedded postoperative rectal adenocarcinoma tissue samples. Correlations with clinicopathologic characteristics were determined by cross-tabulations. The impact of the immunoreactivity of HIF-1alpha with regard to the overall survival and local control endpoints was determined by univariate analyses. RESULTS: Increased HIF-1alpha expression was strongly associated with VEGF positivity (P = 0.002), Dukes stage (P = 0.017), and lymph node metastasis (P = 0.001). No correlation was found between the level of HIF-1alpha expression and histologic grade (P = 0.63). The Kaplan-Meier curves showed a significantly shorter overall survival (P = 0.0087) and local control (P = 0.0438) for patients with high HIF-1alpha expression. CONCLUSION: These results show that HIF-1alpha might represent an important biologic marker evaluating the prognosis of patients with rectal adenocarcinoma.