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1.
Cancer Sci ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32232887

RESUMO

Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA-induced 3'UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3'UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3'UTR could escape from miRNA-mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3'UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/ß-catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knock-down in NPC. Altogether, our results suggested that the 3'UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B-MYH9 -Wnt/ß-catenin axis could represent potential targets for individualized treatment in NPC.

2.
Cells ; 9(3)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120844

RESUMO

Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.

3.
Eur Radiol ; 30(2): 816-822, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650266

RESUMO

OBJECTIVES: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. RESULTS: T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). CONCLUSIONS: In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. KEY POINTS: • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.

4.
BMC Med ; 17(1): 190, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31640711

RESUMO

BACKGROUND: In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. METHODS: All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. RESULTS: Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25-0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (pinteraction <  0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06-0.51, p <  0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (pinteraction = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. CONCLUSION: An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.


Assuntos
Quimioterapia de Indução , Imagem por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Estudos de Coortes , Tomada de Decisões , Progressão da Doença , Feminino , Humanos , Quimioterapia de Indução/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/patologia , Valor Preditivo dos Testes , Prognóstico , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
5.
Ther Adv Med Oncol ; 11: 1758835919877729, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598143

RESUMO

Background: Few studies have evaluated the prognostic value of the integrated model consisting of gross tumor volume of lymph nodes (GTVnd) and pretreatment plasma Epstein-Barr virus DNA (pre-EBV DNA) in nasopharyngeal carcinoma (NPC) patients. Methods: A well-established big-data intelligence platform with 10,126 NPC patients was used for a retrospective review. A total of 1500 cases with cervical nodal metastases but without distant metastases were randomly assigned to a training (n = 503) or test condition (n = 997) for analyses. The cut-off point for the GTVnd derived from the receiver operating characteristic (ROC) curve was combined with the published cut-off point for pre-EBV DNA to develop an integrated model by which patients were classified into four groups. Results: Both GTVnd and pre-EBV DNA were independent prognostic factors. Regardless of whether patients received induction chemotherapy (IC), the 5-year distant metastasis-free survival (DMFS) (69.5%) and overall survival (OS) (68.4%) were significantly worse in those with both a GTVnd >20 ml and pre-EBV DNA >2000 copies/ml (all p-values < 0.001). In patients with IC, all others had better 5-year DMFS and OS; in patients without IC, those with either a GTVnd >20 ml or pre-EBV DNA >2000 copies/ml had the medium 5-year DMFS and OS, while patients with neither of them had the best. Conclusions: The integrated GTVnd and pre-EBV DNA model not only predicted DMFS and OS in NPC patients effectively, but was an indicator of timely adjustment of therapeutic strategies for NPC patients, especially those completing IC.

6.
Cancer Med ; 8(16): 6887-6893, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560840

RESUMO

BACKGROUND: To identify thyroid dose-volume thresholds for radiotherapy (RT)-related hypothyroidism (HT) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated RT (IMRT). In this way, we desired to guide the design of treatment plans and, finally, lower HT prevalence. METHODS: In total, 345 NPC patients treated with IMRT were evaluated retrospectively during a median follow-up of 45.2 (range, 11.3-64.9) months. Serum-based assessments of thyroid function before and after IMRT were monitored periodically. Thyroid dose-volume parameters were analyzed for their association with HT risk. RESULTS: In total, 44.1% of patients (152/345) developed primary HT. Analyses of thyroid dose-volume parameters identified a stringent dose-volume histogram (DVH) threshold defined by V25Gy (the percentage thyroid volume that receives >25 Gy, not the absolute volume) ≤60%, V35Gy  ≤ 55%, and V45Gy  ≤ 45%. Patients whose thyroid DVHs satisfied these constraints had a lower prevalence of 2-year HT compared with the overall prevalence (13.2% vs 25.8%, P < .001). Another DVH was defined by V25Gy  > 95%, V35Gy  > 90%, and V45Gy  > 75%, and patients whose thyroid DVHs satisfied with these constraints had a higher prevalence of 2-year HT than the overall incidence (36.0% vs 25.8%, P < .001). CONCLUSION: We recommend V25Gy  ≤ 60%, V35Gy  ≤ 55%, and V45Gy  ≤ 45% as the "stringent" DVH line, and V25Gy  > 95%, V35Gy  > 90%, and V45Gy  > 75% as the "inhibition" DVH line, under the precondition of not compromising the target coverage. These findings could help in the design of individual treatment plans and, eventually, to lowering of HT prevalence.

7.
Br J Radiol ; 92(1102): 20190244, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31298937

RESUMO

The prevalence of nasopharyngeal carcinoma is characterized by an unbalanced distribution: the disease is particularly prevalent in East and Southeast Asia. In this article, we review the evolution of the International Union Against Cancer/American Joint Committee on Cancer staging system for nasopharyngeal carcinoma. With the increasing using of newer imaging methods, more advanced radiotherapy techniques and systemic chemotherapy, we also discuss newer clinical features that might affect staging. Finally, we propose the future direction of staging and potential prognostic factors that have a major influence on the treatment outcomes of this disease.


Assuntos
Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias/tendências , Vértebras Cervicais , Previsões , Herpesvirus Humano 4 , Humanos , Linfonodos/patologia , Metástase Linfática , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/secundário , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/virologia , Invasividade Neoplásica , Estadiamento de Neoplasias/métodos , Neoplasias Parotídeas/patologia , Neoplasias da Coluna Vertebral/patologia
8.
N Engl J Med ; 381(12): 1124-1135, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31150573

RESUMO

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Adolescente , Adulto , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Análise de Sobrevida , Adulto Jovem
9.
Cancer Med ; 8(5): 2213-2222, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30950240

RESUMO

BACKGROUND: Intensity-modulated radiotherapy (IMRT) provides excellent local control in nasopharyngeal carcinoma (NPC). We investigated whether simplifying 8th American Joint Committee on Cancer staging system T categories improves prognostic value. METHODS: We used 2191 NPC patients as a training set and 414 patients separately as an independent, external validation cohort. RESULTS: In the training set, local relapse-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were not significantly different between the 8th edition T2/T3 (P = 0.610, 0.380 and 0.353, respectively). Merging T2 and T3 to proposed T2 (proT2) provided significant differences in LRFS, DFS, and OS between proposed T categories. Proposed T categories had similar c-indices for LRFS, DFS, and OS (vs the 8th edition), which was validated in the external cohorts. Moreover, for DFS, the adjusted HRs of the proT2N0 (3.8), proT1N1 (3.8), and proT2N1 (6.0) subsets were similar; the adjusted HRs of the proT3N0 (7.0), proT3N1 (11.4), proT1N2 (11.0), proT2N2 (11.6), and proT3N2 (13.3) subsets were similar; the adjusted HRs of the proT1N3 (17.8), proT2N3 (15.3), and proT3N3 (26.4) subsets were similar; the results of the adjusted HRs for OS had the same rule. Defining proT1N0 as stage I; proT1N1/proT2N0-1 as stage II; proT3N0-2/proT1-2N2 as stage III; and proT1-3N3 as stage IVa generated orderly, significant differences in DFS and OS between stages in the training set and external validation cohort. CONCLUSIONS: In the IMRT era, three T categories are more reasonable (merging T2/T3 into T2) and proT3N0-2 (the 8th edition T4N0-2) should be down-staged to stage III.

10.
Clin Cancer Res ; 25(14): 4271-4279, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30975664

RESUMO

PURPOSE: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA. RESULTS: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709-0.800] in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC. CONCLUSIONS: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

11.
Oral Oncol ; 91: 7-12, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926066

RESUMO

OBJECTIVES: Epstein-Barr virus (EBV)-positive cervical lymph node (CLN) metastasis of unknown primary origin is classified as nasopharyngeal carcinoma (NPC) T0 by the American Joint Committee on Cancer staging manual (8th edition). We aimed to investigate the possible primary sites and patterns of EBV-positive CLN metastases and to provide implications for the management of NPC T0 classification. MATERIALS AND METHODS: We retrospectively reviewed 269 patients with newly diagnosed EBV-positive CLN metastatic disease who underwent EBV detection via EBV-encoded RNA in situ hybridization. Fifteen patients with unknown primary tumors underwent follow-up after initial treatment. RESULTS: In patients with EBV-positive CLNs, the most common primary sites after the nasopharynx (51.7%) were the salivary gland (24.5%), lung (7.8%), oropharynx (3.3%), nasal cavity/maxillary (3.3%), oral cavity (2.2%), orbit (1.1%), and liver (0.4%). No primary site was found in 15 patients (5.6%). For salivary gland malignancies, level II and I were the most frequently involved regions. Tumors arising from the lung or liver metastasized to the lower neck (level IV, V, and VI) rather than the upper neck. After initial treatment, 2/15 patients with EBV-positive CLNs of unknown primary exhibited primary NPC and oropharyngeal tumor, respectively. Further, even without prophylactic irradiation to the nasopharynx, only one of 13 unknown primary patients developed NPC. CONCLUSIONS: The origins of EBV-positive CLNs may not be restricted to the nasopharynx alone, and are likely to involve the head and neck or non-head and neck regions. NPC T0 classification should be cautiously assigned to such tumors.

12.
Oral Oncol ; 90: 23-29, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30846172

RESUMO

OBJECTIVE: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC. METHODS: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database.Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer. RESULTS: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival. CONCLUSIONS: Many NPC trials excluded patients with prior cancer, whichimpacts trialaccrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials.

13.
Radiology ; 291(3): 677-686, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30912722

RESUMO

Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.


Assuntos
Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico por imagem , Neoplasias Nasofaríngeas/diagnóstico por imagem , Adolescente , Adulto , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nasofaringe/diagnóstico por imagem , Estudos Retrospectivos , Adulto Jovem
14.
Oral Oncol ; 89: 102-106, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30732946

RESUMO

OBJECTIVES: Definitive concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). The cumulative cisplatin dose (CCD) during radiotherapy is an important prognostic factor; however, the optimal CCD is undetermined. MATERIALS AND METHODS: In this retrospective analysis, patients with locoregionally advanced NPC treated with single-agent cisplatin-based CCRT or RT alone from 2009 through 2015 were identified. CCD was entered into a multivariate Cox regression model as a continuous variable using natural cubic splines to allow for a nonlinear relationship between CCD and outcomes. The primary endpoint was overall survival, and the secondary endpoints were locoregional relapse-free survival and distant metastasis-free survival. RESULTS: A total of 2 924 patients were included in our study, with a median CCD of 160 mg/m2 (range, 0-300 mg/m2). As the CCD increased, the risk of death remained steady until 180 mg/m2, then decreased sharply until 250 mg/m2, and then increased until 300 mg/m2. The optimal CCD of 230-270 mg/m2 was associated with the lowest risk of death and disease relapse. However, the CCD had less prognostic value for disease control, especially for distant control among high-risk patients (N2-3 or T4). CONCLUSIONS: A CCD dose of 230-270 mg/m2 (240 mg/m2 is recommended) is optimal for patients with locoregionally advanced NPC, especially for those at low risk (T1-3 and N0-1). For high-risk patients (N2-3 or T4), additional chemotherapy should be administered before or after CCRT.

15.
Radiat Oncol ; 14(1): 9, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654815

RESUMO

OBJECTIVES: Induction chemotherapy (IC) now is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). The current study was conducted to examine the association between prognosis and the interval between IC and radiotherapy (RT) in NPC patients. METHODS: Patients with newly diagnosed, non-metastatic NPC who were treated with IC followed by RT from 2009 to 2012 were identified from an inpatient database. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS) were compared between those with interval ≤ 30 and >  30 days by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. RESULTS: A total of 668 patients met inclusion criteria with median follow-up of 64.4 months. Patients were categorized by interval: 608 patients with interval ≤ 30 days, and 60 with interval >  30 days. The 5-year OS, DFS, DMFS and LRFS rates were 86.6, 78.2, 88.0 and 89.8% for patients with interval ≤ 30 days, respectively, and 69.2, 64.5, 71.2 and 85.1% for patients with interval >  30 days, respectively. The prolonged interval was a risk factor for OS, DFS and DMFS with adjusted hazard ratios (95% confidence intervals) were 2.44 (1.48-4.01), 1.99 (1.27-3.11) and 2.62 (1.54-4.47), respectively. CONCLUSIONS: Prolonged interval >  30 days was associated with a significantly higher risk of distant metastasis and death in NPC patients. Efforts should be made to avoid prolonged interval between IC and RT to minimize the risk of treatment failure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/mortalidade , Quimioterapia de Indução/mortalidade , Neoplasias Nasofaríngeas/terapia , Recidiva Local de Neoplasia/terapia , Tempo para o Tratamento , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
16.
Int J Cancer ; 145(1): 295-305, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30613964

RESUMO

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.


Assuntos
Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Reprodutibilidade dos Testes , Adulto Jovem
17.
J Exp Clin Cancer Res ; 38(1): 11, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621723

RESUMO

BACKGROUND: Increasing evidence support an important role for DNA methylation in nasopharyngeal carcinoma (NPC). Here, we explored the role of circadian clock gene Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL) methylation in NPC. METHODS: We employed bisulfite pyrosequencing to determine the epigenetic change of ARNTL in NPC cell lines and tissues. ARNTL mRNA and protein expression in cell lines and tissues were detected by real-time PCR and western blotting. Then, we constructed cell lines overexpressing ARNTL and knocked down ARNTL to explore its function and effect on chemotherapy sensitivity of NPC cell lines to cisplatin in vitro and vivo. Finally, we investigated the potential molecular mechanism of ARNTL by gene set enrichment analysis (GSEA), dual Luciferase reporter assay and chromatin immunoprecipitation assay. RESULTS: ARNTL was hypermethylated, and its mRNA and protein were significantly down-regulated in NPC cell lines and tissues. When treated by 5-aza-2'-deoxycytidine, mRNA expression was up-regulated. Overexpression of ARNTL could suppress NPC cells proliferation in vitro and vivo while silencing of ARNTL using shRNA achieved opposite results. GSEA assay found that ARNTL was associated with cell cycle and ectopic ARNTL overexpression could induce G2-M phase arrest. Then, we identified and validated cyclin-dependent kinase 5 (CDK5) as the targeting gene of ARNTL by dual Luciferase reporter assay and chromatin immunoprecipitation assay. When transiently infected ARNTL-overexpression cells with PENTER-vector or PENTER-CDK5 plasmids, the later could reverse the suppressive effects of ARNTL on NPC cell proliferation. Moreover, ARNTL significantly enhanced sensitivity to cisplatin in NPC cells. CONCLUSIONS: ARNTL suppresses NPC cell proliferation and enhances sensitivity to cisplatin by targeting CDK5. ARNTL may represent a novel therapeutic target for NPC.


Assuntos
Fatores de Transcrição ARNTL/genética , Cisplatino/farmacologia , Quinase 5 Dependente de Ciclina/genética , Metilação de DNA , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/biossíntese , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Distribuição Aleatória , Transcrição Genética
18.
Int J Radiat Oncol Biol Phys ; 104(2): 355-361, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682489

RESUMO

PURPOSE: To investigate whether plasma Epstein-Barr virus (EBV) DNA load at induction chemotherapy (ICT) completion (postICT-DNA) is a useful outcome predictor in locoregionally advanced nasopharyngeal carcinoma (NPC) and to compare the prognostic value of postICT- DNA and post-chemoradiation therapy (CCRT) DNA (postRT-DNA). METHODS AND MATERIALS: We retrospectively reviewed 278 patients with stage III-IV NPC treated with ICT followed by concurrent CCRT. The EBV DNA load was measured by quantitative polymerase chain reaction pre-ICT (pre-DNA), at ICT completion (postICT-DNA), and 1 week after CCRT completion (postRT-DNA). RESULTS: PostICT-DNA was associated with significantly worse 3-year overall survival (86.4% vs. 93.4%, P = .023), distant metastasis-free survival (69.2% vs. 93.9%, P < .001), and disease-free survival (64.6% vs. 88.7%, P < .001) than was undetectable postICT-DNA. In multivariate analysis, postICT-DNA was an independent predictor of overall survival (hazard ratio [HR], 2.567; 95% confidence interval [CI], 1.104-5.967; P = .029), distant metastasis-free survival (HR, 5.618; 95% CI, 2.781-11.348; P < .001), and disease-free survival (HR, 3.672; 95% CI, 2.064-6.533; P < .001). The postICT-DNA and postRT-DNA areas under the curve were 0.584 and 0.561 (P < .001), respectively, for predicting 3-year death; 0.717 and 0.649 (P < .001), respectively, for predicting 3-year metastasis; and 0.659 and 0.602 (P < .001), respectively, for predicting 3-year disease failure. CONCLUSIONS: Plasma EBV DNA load at ICT completion is a powerful and earlier outcome predictor in locoregionally advanced NPC that would facilitate further risk stratification and early treatment modification.


Assuntos
DNA Viral/sangue , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/terapia , Área Sob a Curva , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
19.
Cancer ; 125(1): 79-89, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351466

RESUMO

BACKGROUND: The prognosis of patients who have Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without EBV-related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV-related NPC by incorporating the measurement of plasma EBV DNA. METHODS: In total, 979 patients with NPC who received intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT. RESULTS: The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression-free survival and overall survival in univariate analysis (all P < .001) and multivariate analysis (all P < .05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2-T3N0 or T1-T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2-T3N0 or T1-T3N1, EBV DNA >2000 copies/mL; T1-T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1-T3N2, EBV DNA >2000 copies/mL; T4N0-N2), and stage RIVA (any T and N3). In the validation cohort, the 5-year progression-free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P < .001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance. CONCLUSIONS: The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV-related NPC.


Assuntos
DNA Viral/sangue , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , DNA Viral/efeitos da radiação , Infecções por Vírus Epstein-Barr/radioterapia , Feminino , Herpesvirus Humano 4/efeitos da radiação , Humanos , Masculino , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/virologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Radioterapia de Intensidade Modulada , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
20.
Oncologist ; 24(4): 498-504, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30459237

RESUMO

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines are among the most widely used guidance in oncology. It is critical to understand the extent to which the recommendations in these guidelines are supported by evidence and to investigate whether these recommendations have been influenced by payments from industry to authors. MATERIALS AND METHODS: We examined the quality and consistency of evidence, as scored by guidelines authors, for systemic treatment incorporated in the NCCN guidelines. Payments data in 2015 were manually abstracted using the Open Payments database, which discloses all payments between the industry and American physicians. Correlations between the percentage of authors who received payments and the proportion of recommendations developed from low-level evidence per guideline were calculated using Spearman rank correlation. RESULTS: In total, 1,782 recommendations were identified in 29 guidelines, of which 1,282 (71.9%) were based on low-quality or low-consistency evidence (low-level evidence), including "case reports or clinical experience only" (18.9%). A substantial proportion (31/143, 21.7%) of category 1 (the highest level) recommendations were based on low-level evidence. The majority of authors (87.1%) received payments from industry. However, no association was found between the prevalence of payments among authors and the percentage of recommendations developed from low-level evidence per guideline. CONCLUSION: The majority of systemic treatment recommendations in the NCCN guidelines are based on low-level evidence, including more than one in five category 1 recommendations. Payments from industry were prevalent among authors. However, industrial payments among authors were not associated with inclusion of regimen/agent for which there is no conclusive evidence in the guidelines. IMPLICATIONS FOR PRACTICE: The authors found that the majority (71.9%) of systemic treatment recommendations issued in the current National Comprehensive Cancer Network guidelines were based on low-level evidence. Physicians should remain cautious when using current guidelines as the sole source guiding patient care decisions.

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