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1.
Cancer Med ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505641

RESUMO

INTRODUCTION: The immune system and hypoxia are major factors influencing radiosensitivity in patients with different cancer types. This study aimed at developing a model to predict radiotherapy response in patients with head and neck squamous cell carcinoma (HNSCC) based on the tumor immune microenvironment and hypoxia signature. MATERIALS AND METHODS: We first evaluated the hypoxia status and tumor immune microenvironment in the Cancer Genome Atlas (TCGA) cohort by using transcriptomic data. Differentially expressed genes (DEGs) were identified between the "high immunity and low hypoxia" and "low immunity and high hypoxia" groups and those DEGs significantly associated with disease-specific survival in the univariate Cox regression analysis were selected as the prognostic DEGs. We selected the immune hypoxia-related genes (IHRGs) by intersecting prognostic DEGs with immune and hypoxia gene sets. We used the IHRGs to train a multivariate Cox regression model in the TCGA cohort, based on which we calculated the IHRG prognostic index (IHRGPI) for each patient and validated its efficacy in predicting radiotherapy response in the Gene Expression Omnibus cohorts. Furthermore, we explored potential mechanisms and effective combinational treatment strategies for different IHRGPI groups. RESULTS: Five IHRGs were used to construct the IHRGPI, which was used to dichotomize the cohorts. The patients with lower IHRGPI showed a better radiotherapy response across different cohorts and endpoints, including overall survival, progression-free survival, and recurrence-free survival (p < 0.05). Patients with higher IHRGPI showed greater hypoxia and lesser immune cell infiltration. A lower IHRGPI indicated a better immunotherapy response, while a higher IHRGPI indicated a better chemotherapy response. CONCLUSIONS: IHRGPI is promising for predicting radiotherapy response and guiding combinational treatment strategies in patients with HNSCC.

2.
J Oncol ; 2022: 3647462, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251172

RESUMO

PURPOSE: To quantify the long-term evaluation of optic chiasma (OC) and/or optic nerve(s) (ONs) and to develop predictive models for radiation-induced optic neuropathy (RION) in nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 3,662 patients' OC/ONs with full visual acuity and dosimetry data between 2010 and 2015 were identified. Critical dosimetry predictors of RION were chosen by machine learning and penalized regression for survival. A nomogram containing dosimetry and clinical variables was generated for predicting RION-free survival. RESULTS: The median follow-up was 71.79 (2.63-120.9) months. Sixty-six eyes in 51 patients (1.39%) developed RION. Two patients were visual field deficient, and 49 patients had visual acuity of less than 0.1 (20/200). The median latency time was 36 (3-90) months. The 3-, 5-, and 8-year cumulative incidence of RION was 0.78%, 1.19%, and 1.97%, respectively. Dmax was the most critical dosimetry variable for RION (AUC: 0.9434, the optimal cutoff: 64.48 Gy). Patients with a Dmax ≥64.48 Gy had a significantly higher risk of RION (HR = 102.25; 95%CI, 24.86-420.59; P < 0.001). Age (>44 years) (HR = 2.234, 95% CI = 1.233-4.051, p = 0.008), advanced T stage (T3 vs. T1-2: HR = 7.516, 95% CI = 1.725-32.767, p=0.007; T4 vs. T1-2: HR = 37.189, 95% CI = 8.796-157.266, P < 0.001), and tumor infiltration/compression of the OC/ONs (HR = 4.572, 95% CI = 1.316-15.874, p=0.017) were significant clinical risk factors of RION. A nomogram comprising age, T stage, tumor infiltration/compression of the OC/ON, and Dmax significantly outperformed the model, with only Dmax predicting RION (C-index: 0.916 vs. 0.880, P < 0.001 in the training set; 0.899 vs. 0.874, P=0.038 in the test set). The nomogram-defined high-risk group had a worse 8-year RION-free survival. CONCLUSIONS: In the IMRT era, Dmax <60 Gy is safe and represents an acceptable dose constraint for most NPC patients receiving IMRT. A reasonable trade-off for selected patients with unsatisfactory tumor coverage due to proximity to the optic apparatus would be Dmax <65 Gy. Caution should be exercised when treating elderly and advanced T-stage patients or those with tumor infiltration/compression of the OC/ON. Our nomogram shows strong efficacy in predicting RION.

3.
Cancer Med ; 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35355438

RESUMO

BACKGROUND: Studies are trying to add immunotherapy to gemcitabine and cisplatin (GP) induction chemotherapy, the standard therapy, in nasopharyngeal carcinoma (NPC) patients with locoregionally advanced disease. However, how the immune system responds to GP remains unknown. METHOD: We examined the dynamic changes of circulating immune cells and plasma cytokines in NPC patients administered with GP. RESULT: After GP administration, immunosuppressive myeloid cells, including CD11b+CD14+ monocytes, CD33+ myeloid cells, CD33+CD11+ myeloid cells, total MDSCs (CD33+CD11+HLA-DR-/low), monocytic MDSCs, and granulocytic MDSCs decreased significantly. The regulatory T cells and B cells, two important suppressive lymphocyte subpopulations, also decreased. On the other hand, the levels of CD3+ T cells, total B cells, central memory CD4+ T cells, and pro-inflammatory cytokines (including Interleukin [IL]-1ß, IL-6, IL-2, IL-5, and IL-8) increased significantly after GP administration. Besides, GP chemotherapy did not weaken the cytotoxic activity and proliferative capacity of T cells. CONCLUSION: Our results showed the immune modulation effect of GP induction chemotherapy in locoregionally advanced NPC, providing a solid basis for its combination with immunotherapy.

4.
Radiat Oncol ; 17(1): 36, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35183221

RESUMO

BACKGROUND: The impact of radiotherapy interruption due to the Spring Festival holidays in China on the survival of patients with nasopharyngeal carcinoma (NPC) is unclear. METHODS: Nontrial patients with locoregionally advanced NPC receiving radiotherapy plus induction chemotherapy (IC) and/or concurrent chemotherapy (CC) were included (N = 5035) and divided into two groups based on the Spring Festival-induced radiotherapy interruption. Kaplan-Meier curves for overall survival (OS) and failure-free survival (FFS) were compared between rival groups. Impact of the timing of radiotherapy interruption (during or outside the Spring Festival) on survival was investigated in a propensity score-matched dataset. We adopted ordination correspondence analysis to determine the cut-off of radiotherapy prolongation for prognostic prediction, and accordingly performed subgroup analysis based on delayed days and chemotherapy details. Individual patient data of three phase III NPC trials (NCT00677118, NCT01245959, NCT01872962) were used for validation (N = 1465). RESULTS: Radiotherapy interruption was most frequently observed between December to January of the following year. Significantly lower OS and FFS were associated with the Spring Festival-induced interruption of radiotherapy (P = 0.009 and 0.033, respectively), but not that interruption of IC. In two matched comparison groups, the timing of radiotherapy interruption during the Spring Festival was more likely to lead to a decrease in FFS than outside the Spring Festival (P = 0.046), which was not observed in the validation using clinical trial data or in the subgroup analysis based on the 5-day delayed time. The absence of CC and the accumulated dose of cisplatin < 200 mg were related to the negative influences of the Spring Festival-induced radiotherapy interruption on FFS (P = 0.002) and OS (P = 0.010), respectively. CONCLUSIONS: The poor survival of patients with NPC is associated with the Spring Festival-induced interruption of radiotherapy. We recommend that these patients receive adequate doses of cisplatin concurrently with radiotherapy.


Assuntos
Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/radioterapia , Adulto , China , Ensaios Clínicos como Assunto , Feminino , Férias e Feriados , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
5.
Oral Oncol ; 125: 105718, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35063882

RESUMO

OBJECTIVE: Induction chemotherapy followed by concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, survival benefits from additional induction chemotherapy varied significantly among patients. This study aimed to determine the predictive value of body mass index (BMI) in induction chemotherapy in NPC. MATERIALS AND METHODS: This post-hoc analysis included patients from two multicenter, randomized, phase 3 trials (NCT01245959 and NCT01872962), in which patients were randomized to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. RESULTS: Among 960 patients participated, 957 were included in this analysis. 82 (8.6%) patients had baseline BMI < 18.5 kg/m2 (underweight) and 875 (91.4%) had BMI ≥ 18.5 kg/m2 (normal /overweight). Higher proportion of normal/overweight patients completed ≥2 cycles of induction chemotherapy than underweight patients (96.5% vs. 88.4%, p = 0.042). A strong trend for interaction was observed between BMI and induction chemotherapy regarding failure-free survival (FFS) and overall survival (OS, both pinteraction < 0.001). Normal/overweight patients benefited from induction chemotherapy regarding FFS (83.8% vs. 72.9%, p < 0.001) or OS (93.1% vs. 86.9%, p < 0.001), while underweight patients did not (p = 0.24 and p = 0.65, respectively). These results were confirmed in multivariate analysis and multiple sensitivity analyses. CONCLUSION: Using pooled data from two landmark phase III trials, we found that underweight patients might not benefit from additional induction chemotherapy in locoregionally advanced NPC. If confirmed in prospective studies, this could help guide individual treatment in the clinic.


Assuntos
Quimioterapia de Indução , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Humanos , Quimioterapia de Indução/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Sobrepeso , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Magreza/tratamento farmacológico , Magreza/etiologia
6.
Radiother Oncol ; 167: 179-186, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34971660

RESUMO

BACKGROUND AND PURPOSE: This study aims to identify the optimal high-risk candidates for clinical trials in locoregionally advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Non-metastatic NPC patients (n = 9,468) were included. Recursive partitioning analyses (RPA) were performed to generate risk stratification. Receiver operating characteristics curve was used to determine the cut-off value of pre-treatment Epstein-Barr virus (EBV) DNA for progression-free survival (PFS). Individual-level data from two clinical trials were used for validation. RESULTS: Anatomic stratification based on T and N category (eighth edition TNM, TNM-8) classified the N2-3 or T4 as an anatomic high-risk group with 5-year PFS of 69% (95% confidence interval: 68-71%). Prognostic stratification identified patients with pre-treatment EBV DNA ≥4000 copies/mL as a prognostic high-risk group with 5-year PFS of 69% (67-70%). The c-index was significantly higher for anatomic stratification (0.621, p < 0.001) and prognostic stratification (0.585, p < 0.001) compared with existing TNM-8 stage groups (0.562). The validation cohorts based on clinical trials data showed greater PFS benefit than the results of the original trials [Hazard ratio: NCT01245959, 0.64 vs. 0.67; NCT01872962, 0.42 vs. 0.52]. Moreover, detectable post-treatment EBV DNA indicated a high risk of progression with 5-year PFS of 38.7% and was the most adverse independent factor for all endpoints. CONCLUSIONS: N2-3 or T4 NPC patients were ideal candidates for multicenter clinical trials in locoregionally advanced NPC. Patients with detectable post-treatment EBV DNA are suitable candidates for adjuvant trials.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , DNA Viral , Herpesvirus Humano 4/genética , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico
7.
Clin Transl Radiat Oncol ; 32: 59-68, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34935776

RESUMO

PURPOSE: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC. METHODS: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified. RESULTS: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect. CONCLUSION: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

8.
BMC Cancer ; 22(1): 353, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361153

RESUMO

BACKGROUND: Depression has been reported to be associated with some types of cancer in observational studies. However, the direction and magnitude of the causal relationships between depression and different types of cancer remain unclear. METHODS: We performed the two-sample bi-directional mendelian randomization with the publicly available GWAS summary statistics to investigate the causal relationship between the genetically predicted depression and the risk of multiple types of cancers, including ovarian cancer, breast cancer, lung cancer, glioma, pancreatic cancer, lymphoma, colorectal cancer, thyroid cancer, bladder cancer, and kidney cancer. The total sample size varies from 504,034 to 729,150. Causal estimate was calculated by inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the causal relationship. RESULTS: After correction for heterogeneity and horizontal pleiotropy, we only detected suggestive evidence for the causality of genetically predicted depression on breast cancer (OR = 1.09, 95% CI: 1.03-1.15, P = 0.0022). The causal effect of depression on breast cancer was consistent in direction and magnitude in the sensitivity analysis. No evidence of causal effects of depression on other types of cancer and reverse causality was detected. CONCLUSIONS: The result of this study suggests a causative effect of genetically predicted depression on specific type of cancer. Our findings emphasize the importance of depression in the prevention and treatment of breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Causalidade , Depressão/genética , Feminino , Humanos , Análise da Randomização Mendeliana/métodos
9.
Laryngoscope Investig Otolaryngol ; 6(5): 1049-1061, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34667849

RESUMO

PURPOSE: To explore the peripheral blood cells (neutrophil/monocyte/lymphocyte/platelet) to apolipoprotein AI or high-density lipoprotein-cholesterol ratio (NAR, MAR, LAR, PAR, NHR, MHR, LHR, and PHR) as independent prognostic indicators for stage III nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Between 2009 and 2014, 562 patients diagnosed with stage III NPC who were treated with a concomitant chemotherapy and intensity-modulated radiotherapy with cumulative cisplatin dose ≥200 mg/m2 were included in this retrospective study. Routine blood and biochemical variables and baseline clinical characteristics (T and N stage, age, sex, and induction chemotherapy) were collected. After inserting 19 hematological parameters into a set, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and restricted cubic splines regression to select valuable parameters for predicting 5-year overall survival (OS). Subsequently, univariate and multivariate survival analyses were used to assess independent indicators of 5-year OS, distant metastasis survival, regional recurrence-free survival (RRFS), and disease-free survival. RESULTS: NAR, MAR, serum lactated dehydrogenase (LDH), and Epstein-Barr virus (EBV)-DNA were selected using LASSO regression, and the optimal cut-off values for NAR, MAR, EBV-DNA, and, LDH were 4.39, 0.3, 1590 copies/mL, and 218.4 IU/L, respectively. In multivariate survival analysis, higher NAR was associated with both poor 5-year OS and RRFS (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.09-3.25, P = .024; HR, 3.13; 95% CI, 1.42-6.91, P = .005, respectively). CONCLUSION: NAR could be an attractive indicator for evaluating the 5-year OS in patients with stage III NPC, which is closely related to inflammation and circulating lipid metabolism.Level of Evidence: 4.

10.
Oral Oncol ; 122: 105576, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34689010

RESUMO

The metastatic rate of nasopharyngeal carcinoma (NPC) is the highest among head and neck tumours. Additionally, distant metastasis is the main cause of therapy failure and mortality in NPC. Thus, novel biomarkers are needed for designing new therapeutic strategies to improve the prognosis of this disease. In this study, qRT-PCR and western blotting revealed that the expression of the WD repeat domain phosphoinositide interacting 1 (WIPI-1) was markedly decreased in NPC cells and tissues. Furthermore, low WIPI-1 expression closely correlated with poor prognosis in NPC patients. In vitro functional experiments revealed that overexpression or knockdown of WIPI-1 repressed or facilitated the migration, colony formation, and proliferation of NPC cells. Consistent with the in vitro studies, WIPI-1 significantly inhibited tumour growth, invasion and metastasis in popliteal lymph node metastasis, lung metastasis, and xenograft mouse models in vivo. Mechanistically, WIPI-1 directly interacted with tripartite motif containing 21 (TRIM21) and enhanced starvation-induced autophagy by interacting with TRIM21 in NPC cells. Moreover, MYC gene expression was markedly increased in the WIPI-1 knockdown group, as demonstrated by RNA-seq analysis and qRT-PCR validation. Altogether, WIPI-1 acts as a tumour suppressor gene in NPC that inhibits tumour growth and metastasis. Targeting WIPI-1 may be a novel treatment approach for NPC.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Proteínas de Membrana/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-myc/genética , Ribonucleoproteínas/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica
11.
Cell Death Discov ; 7(1): 129, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075026

RESUMO

Colorectal cancer (CRC) is the most common form of gastrointestinal malignancies. A growing number of reports focusing on oxaliplatin (OXA) resistance in CRC treatment have revealed that drug resistance is an urgent issue in clinical applications, especially for finding effective therapeutic targets. Recently, microRNAs (miRNAs) are reported to play a critical role in tumor progressions and multi-drug resistance. The main aim of this study is to establish whether miR-5000-3p is an oncogene that is resistant to OXA and further confirm its underlying regulatory role in CRC. The OXA-associated gene expression dataset in CRC cells was downloaded from Gene Expression Omnibus (GEO) database. Statistical software R was used for significance analysis of differentially expressed genes (DEGs) between OXA-resistant (OR)-CRC cells and CRC cells, and results indicated ubiquitin-specific peptidase 49 (USP49) was upregulated in OR-CRC cells. Luciferase reporter assay showed that USP49 was verified to act as a downstream target gene of miR-5000-3p. From the results of TCGA database, miR-5000-3p expression was upregulated and USP49 was downregulated in patients with CRC. The function of miR-5000-3p was detected using MTT assay, wound healing, Transwell, and flow cytometry assays. Moreover, through in vitro and in vivo experiments, miR-5000-3p expression was confirmed to be upregulated in CRC cells or OR-CRC cells comparing to normal cell lines. Molecular mechanism assays revealed that USP49 binds to the miR-5000-3p promoter to increase the expression of miR-5000-3p, resulting in cancer cells sensitized to OXA. To sum up, these results suggest that miR-5000-3p may be a novel biomarker involved in drug-resistance progression of CRC. Moreover, the drug-resistance mechanism of miR-5000-3p/USP49 axis provides new treatment strategies for CRC in clinical trials.

12.
Lancet ; 398(10297): 303-313, 2021 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-34111416

RESUMO

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Capecitabina/administração & dosagem , Quimioterapia Adjuvante/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Administração Metronômica , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
JAMA Netw Open ; 4(5): e2110438, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34028549

RESUMO

Importance: Unreported clinical trial results represent a violation of human rights. Oncology trials account for nearly 30% of interventional biopharmaceutical clinical studies registered on ClinicalTrials.gov and are the most numerous among all disciplines. Objective: To analyze the reporting of results among all interventional oncology trials registered on ClinicalTrials.gov from 2007 through 2017. Design, Setting, and Participants: This cohort study analyzed all clinical studies registered between June 1, 2007, and May 8, 2017, on ClinicalTrials.gov, the largest public clinical trial registry in the world. Trials with a recruitment status of completed or terminated and a primary completion date of on or before September 30, 2017, were selected. Data were analyzed between February 20, 2021, and February 26, 2021. Main Outcomes and Measures: The main outcome was the percentage of trials that reported results either on ClinicalTrials.gov or in journal publications within 24 months of the primary completion date. Journal publication was ascertained by searching ClinicalTrials.gov for a link to the publication, PubMed using national clinical trial number, and Embase using national clinical trial number and filters. Results: Of the 12 240 clinical trials registered in ClinicalTrials.gov, 7425 trials (60.7%; 95% CI, 60.0%-61.5%) reported results, with a 34.0% (95% CI, 30.3%-37.7%) increase in 24-month reporting rate from 2007 to 2017. Multivariable analyses confirmed that more recent trials (adjusted hazard ratio [HR], 1.11 per year increase; 95% CI, 1.10-1.13) and trials with larger sample sizes (51-100 patients: adjusted HR, 1.17 [95% CI, 1.09-1.24]; >100 patients: adjusted HR, 1.43 [95% CI, 1.33-1.54]) were more likely to report results. Terminated trials were less likely to report results compared with completed trials (adjusted HR, 0.88; 95% CI, 0.83-0.93). Compared with trials funded by industry, those funded by the National Institutes of Health were more likely to report results (adjusted HR, 1.39; 95% CI, 1.29-1.49), whereas those funded by other academic or nonprofit organizations were less likely to report results (adjusted HR, 0.66; 95% CI, 0.62-0.70). Among all 7425 trials, the results of 2807 trials (37.8%; 95% CI, 36.7%-38.9%) were posted only on ClinicalTrials.gov. These trials tended to be terminated early and to have small sample sizes (≤50 patients) compared with trials that published results in journals. Conclusions and Relevance: This study found a gradual improvement in results reporting among oncology trials over a 10-year period. Trial registries could serve as a results reporting platform for unpublished trials and as a data source of trial outcomes for future studies.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Oncologia/estatística & dados numéricos , Oncologia/tendências , Relatório de Pesquisa/tendências , Estudos de Coortes , Previsões , Humanos , Estados Unidos
14.
Mol Cancer ; 20(1): 14, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430876

RESUMO

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.


Assuntos
Heterogeneidade Genética , Imunoterapia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/terapia , Microambiente Tumoral , Estudos de Coortes , Genoma Humano , Humanos , Carcinoma Nasofaríngeo/genética , Prognóstico , Reprodutibilidade dos Testes , Microambiente Tumoral/genética
15.
Radiother Oncol ; 155: 56-64, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33039423

RESUMO

BACKGROUND AND PURPOSE: In the intensity-modulated radiotherapy (IMRT) era, the role of concurrent chemoradiotherapy (CCRT) after induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is undetermined, while concerns exist about CCRT-associated excessive toxicity. We aimed to combine tumor response and risk assessment to guide decisions about concurrent chemotherapy. MATERIALS AND METHODS: From April 2009 to December 2015, 744 LANPC patients treated with CCRT/IMRT after IC were included. Matching techniques were performed for treatment effect evaluation. Tumor response to IC was used for patient stratification. A nomogram was built based on multivariable Cox regression analysis to predict overall survival (OS). RESULTS: After IC, 508 patients (68.3%) had favorable tumor response (complete or partial response), among whom IC + CCRT achieved significantly superior 5-year disease-free survival and OS than IC + IMRT (82.2% vs. 72.5%, P = 0.025; 89.2% vs. 79.9%, P = 0.025). However, no significant difference was found in patients with unfavorable response (both P > 0.05). For favorable responders, a nomogram was built integrating age, smoking, T category, N category, pretreatment Epstein-Barr virus DNA and treatment modality. The concordance index was 0.713 and calibration was good. The nomogram determined three risk groups with distinct OS. High-risk patients benefited from CCRT after IC regarding disease-free survival, OS and distant metastasis-free survival, whereas low- and intermediate-risk patients did not. CONCLUSIONS: For LANPC patients with unfavorable response to IC, subsequent CCRT seems inadequate, rendering intensification necessary. For favorable responders with low risk, IC + IMRT represents a reasonable de-intensification approach, although confirmation by prospective data is needed.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Quimiorradioterapia/efeitos adversos , Herpesvirus Humano 4 , Humanos , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos
16.
Clin Rheumatol ; 40(1): 167-179, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32557257

RESUMO

OBJECTIVES: To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. METHODS: All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case-control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. RESULTS: rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. CONCLUSIONS: FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients. Key Points • FKBP5 gene polymorphisms were associated with depression of SLE patients. • FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients. • FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients. • FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.


Assuntos
Lúpus Eritematoso Sistêmico , Qualidade de Vida , Proteínas de Ligação a Tacrolimo , Ansiedade/genética , Estudos de Casos e Controles , China , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/genética , Masculino
17.
J Natl Cancer Inst ; 113(4): 471-480, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33094348

RESUMO

BACKGROUND: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma. However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene-expression signature that can identify beneficiaries of IC. METHODS: We screened chemosensitivity-related genes by comparing gene-expression profiles of patients with short-term tumor response or nonresponse to IC (n = 95) using microarray analysis. Chemosensitivity-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Tests of statistical significance are 2-sided. RESULTS: We identified 43 chemosensitivity-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] = 0.87, sensitivity = 87.5%, specificity = 75.6%). We further found that IC conferred failure-free survival benefits only in patients in the benefit group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.34 to 0.87; P = .01) and not on those in the no-benefit group (HR = 1.25, 95% CI = 0.62 to 2.51; P = .53). In the clinical trial cohort, the 6-gene signature was also highly accurate at predicting the tumor response (AUC = 0.82, sensitivity = 87.5%, specificity = 71.8%) and indicated failure-free survival benefits. In the external independent cohort, similar results were observed. CONCLUSIONS: The 6-gene signature can help select beneficiaries of IC and lay a foundation for a more individualized therapeutic strategy for locoregionally advanced nasopharyngeal carcinoma patients.


Assuntos
Expressão Gênica , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Sensibilidade e Especificidade , Resultado do Tratamento
18.
Cancer Res Treat ; 53(2): 339-354, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33171025

RESUMO

PURPOSE: The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear. MATERIALS AND METHODS: Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software. RESULTS: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 weeks vs. 8.4 weeks, p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 weeks vs. 6.0 weeks, p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 weeks vs. 40.6 weeks, p=0.002) and NIV+IPI treatment (3.1 weeks vs. 5.9 weeks, p=0.031). CONCLUSION: This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pan-cancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Estudos Prospectivos
19.
Radiother Oncol ; 151: 306-313, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32866562

RESUMO

BACKGROUND: Prognosis often differs between trial participants and nontrial (pragmatic) patients in similar clinical scenarios, raising a concern that results of trials may not represent those in real-world practice. METHODS AND MATERIALS: Individual patient data were extracted from three phase III randomized controlled trials and a big-data real-world database (n = 10,126). Patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy (CCRT [control]: 2438 vs. 519) or induction chemotherapy plus CCRT (experimental) were included. Propensity score matching and correspondence analysis were used for data mining. RESULTS: Compared with the real-world CCRT cohort, clinical trials preferred to include cases with T4 (25.3-43.3% vs. 18.8%) and N2 (44.4-60.7% vs. 38.9%) categories. Real-world patients were more likely to undergo shorter irradiation time (44 vs. 46-49 days), inadequate chemotherapy cycles (70.6% vs. 25.2-43.9%), other chemotherapy (36.4% vs. 0.0%), and flexible regimens (≥3 vs. 1). Although real-world patients had better survival than trial participants, the survival disparities disappeared in the matched cohorts, except for in one trial with the lowest pragmatism assessment caused by stringent eligibility criteria and low flexibility of delivery. Stage specification, year of treatment, and Epstein-Barr virus DNA were related to survival disparities (all P ≤ 0.034). The influence of pragmatic features on survival mainly affected the control (all P ≤ 0.043) rather than the experimental group. CONCLUSION: Special attention should be paid to the control group when interpreting trial results. Assessing whether the pragmatic features of studies deviate from routine practice will lead to better conversion of trial findings into clinical guidelines.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia , Estudos de Coortes , Herpesvirus Humano 4 , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudos Retrospectivos
20.
Chin Med J (Engl) ; 133(17): 2044-2053, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32810045

RESUMO

BACKGROUND: The classification criteria and staging groups for nasopharyngeal carcinoma described in the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system have been revised over time. This study assessed the proportion of patients whose staging and treatment strategy have changed due to revisions of the UICC/AJCC staging system over the past 10 years (ie, from the sixth edition to the eighth edition), to provide information for further refinement. METHODS: We retrospectively reviewed 1901 patients with non-metastatic nasopharyngeal carcinoma treated in our cancer center between November 2009 and June 2012. The Akaike information criterion and Harrell concordance index were applied to evaluate the performance of the staging system. RESULTS: In total, 25 (1.3%) of the 1901 patients who were staged as T2a according to the sixth edition system were downgraded to T1 in the eighth edition; 430 (22.6%) staged as N0 in the sixth edition were upgraded to N1 in the eighth edition; 106 (5.6%) staged as N1/2 in the sixth edition were upgraded to N3 in the eighth edition. In addition, 51 (2.7%) and 25 (1.3%) of the study population were upstaged from stage I to stage II and stage II to stage IVa, respectively; 10 (0.5%) was downgraded from stage II to stage I. The survival curves of adjacent N categories and staging groups defined by eighth classification system were well-separated. However, there was no significant difference in the locoregional failure-free survival (P = 0.730) and disease-free survival (P = 0.690) rates between the T2 and T3 categories in the eighth edition classification system. CONCLUSIONS: Modifications to the tumor-node-metastasis staging system over the past 10 years have resulted in N classification changes in numerous cases. Although the eighth edition tumor-node-metastasis staging system better predicts survival outcomes, the T classification could be simplified in future revisions.


Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
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