Anxiety and depression in nasopharyngeal carcinoma patients and network analysis to identify central symptoms: A cross-sectional study from a high-incidence area.

PURPOSE: To determine the prevalence of anxiety and depression in patients with nasopharyngeal carcinoma (NPC) and to identify central symptoms and bridge symptoms among psychiatric disorders. METHODS: This cross-sectional study recruited patients with NPC in Guangzhou, China from May 2022, to October 2022. The General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used for screening anxiety and depression, respectively. Network analysis was conducted to evaluate the centrality and connectivity of the symptoms of anxiety, depression, quality of life (QoL) and insomnia. RESULTS: A total of 2806 respondents with complete GAD-7 and PHQ-9 scores out of 3828 were enrolled. The incidence of anxiety in the whole population was 26.5% (depression, 28.5%; either anxiety or depression, 34.8%). Anxiety was highest at caner diagnosis (34.2%), while depression reached a peak at late-stage radiotherapy (48.5%). Both moderate and severe anxiety and depression were exacerbated during radiotherapy. Coexisting anxiety and depression occurred in 58.3% of those with either anxiety or depression. The generated network showed that anxiety and depression symptoms were closely connected; insomnia was strongly connected with QoL. "Sad mood", "Lack of energy", and "Trouble relaxing" were the most important items in the network. Insomnia was the most significant bridge item that connected symptom groups. CONCLUSION: Patients with NPC are facing alarming disturbances of psychiatric disorders; tailored strategies should be implemented for high-risk patients. Besides, central symptoms (sad mood, lack of energy, and trouble relaxing) and bridge symptoms (insomnia) may be potential interventional targets in future clinical practice.

Impact of magnetic resonance imaging-derived skeletal muscle index in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: To evaluate the clinical implication of magnetic resonance imaging (MRI)-derived skeletal muscle index (SMI) in locoregionally advanced nasopharyngeal carcinoma (LANPC) patients undergoing induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) and further to develop a nomogram for predicting survival prognosis. METHODS: SMI was determined through baseline MRI at the third cervical level. The nomogram was based on a training cohort involving 409 LANPC patients. We validated the prognostic accuracy of this prognostic model in an internal validation cohort (n = 204) and an external independent cohort (n = 272). RESULTS: SMI was an independent risk factor for OS. A prognostic model comprising age, TNM stage and SMI for individual survival prediction was developed and graphically represented as a nomogram. The model showed favorable discrimination (C-index: 0.686), predictive accuracy [time dependent area under the curve (tAUC) at 5 years: 0.70], and calibration, and was further validated in the internal and external validation datasets. A risk stratification derived from the model stratified these patients into three prognostic subgroups with significantly different survival. CONCLUSIONS: Low SMI accessed by MRI was significantly associated with poor overall survival in LANPC patients undergoing IC + CCRT. Moreover, we established and validated a novel nomogram involving age, TNM stage and SMI that could provide accurate prognostic stratification among this population.

A deep learning-based semiautomated workflow for triaging follow-up MR scans in treated nasopharyngeal carcinoma.

It is imperative to optimally utilize virtues and obviate defects of fully automated analysis and expert knowledge in new paradigms of healthcare. We present a deep learning-based semiautomated workflow (RAINMAN) with 12,809 follow-up scans among 2,172 patients with treated nasopharyngeal carcinoma from three centers (ChiCTR.org.cn, Chi-CTR2200056595). A boost of diagnostic performance and reduced workload was observed in RAINMAN compared with the original manual interpretations (internal vs. external: sensitivity, 2.5% [p = 0.500] vs. 3.2% [p = 0.031]; specificity, 2.9% [p < 0.001] vs. 0.3% [p = 0.302]; workload reduction, 79.3% vs. 76.2%). The workflow also yielded a triaging performance of 83.6%, with increases of 1.5% in sensitivity (p = 1.000) and 0.6%-1.3% (all p < 0.05) in specificity compared to three radiologists in the reader study. The semiautomated workflow shows its unique superiority in reducing radiologist's workload by eliminating negative scans while retaining the diagnostic performance of radiologists.

Deep learning-based recurrence detector on magnetic resonance scans in nasopharyngeal carcinoma: A multicenter study.

OBJECTIVES: Accuracy in the detection of recurrent nasopharyngeal carcinoma (NPC) on follow-up magnetic resonance (MR) scans needs to be improved. MATERIAL AND METHODS: A total of 5 035 follow-up MR scans from 5 035 survivors with treated NPC between April 2007 and July 2020 were retrospectively collected from three cancer centers for developing and evaluating the deep learning (DL) model MODERN (MR-based Deep learning model for dEtecting Recurrent Nasopharyngeal carcinoma). In a reader study with 220 scans, the accuracy of two radiologists in detecting recurrence on scans with vs without MODERN was evaluated. The performance was measured using the area under the receiver operating characteristic curve (ROC-AUC) and accuracy with a 95% confidence interval (CI). RESULTS: MODERN exhibited sound performance in the validation cohort (internal: ROC-AUC, 0.88, 95% CI, 0.86-0.90; external 1: ROC-AUC, 0.88, 95% CI, 0.86-0.90; external 2: ROC-AUC, 0.85, 95% CI, 0.82-0.88). In a reader study, MODERN alone achieved reliable accuracy compared to that of radiologists (MODERN: 84.1%, 95% CI, 79.3%-88.9%; competent: 80.9%, 95% CI, 75.7%-86.1%, P < 0.001; expert: 85.9%, 95% CI, 81.3%-90.5%, P < 0.001). The accuracy of radiologists was boosted by the MODERN score (competent with MODERN score: 84.6%, 95% CI, 79.8%-89.3%, P < 0.001; expert with MODERN score: 87.7%, 95% CI, 83.4%-92.1%, P < 0.001). CONCLUSION: We developed a DL model for recurrence detection with reliable performance. Computer-human collaboration has the potential to refine the workflow in interpreting surveillant MR scans among patients with treated NPC.

Integrated strategies for chemotherapy cycles in nasopharyngeal carcinoma patients: Real-world data from two epidemic centers guiding decision-making.

Objective: Two cycles of induction chemotherapy (IC) followed by 2 cycles of platinum-based concurrent chemoradiotherapy (CCRT) (2IC+2CCRT) for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is widely adopted but not evidence-confirmed. This study aimed to determine the clinical value of 2IC+2CCRT regarding efficacy, toxicity and cost-effectiveness. Methods: This real-world study from two epidemic centers used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses. The enrolled patients were divided into three groups based on treatment modality: Group A (2IC+2CCRT), Group B (3IC+2CCRT or 2IC+3CCRT) and Group C (3IC+3CCRT). Long-term survival, acute toxicities and cost-effectiveness were compared among the groups. We developed a prognostic model dividing the population into high- and low-risk cohorts, and survivals including overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were compared among the three groups according to certain risk stratifications. Results: Of 4,042 patients, 1,175 were enrolled, with 660, 419, and 96 included in Groups A, B and C, respectively. Five-year survivals were similar among the three groups after PSM and confirmed by IPTW. Grade 3-4 neutropenia and leukocytopenia were significantly higher in Groups C and B than in Group A (52.1% vs. 41.5% vs. 25.2%; 41.7% vs. 32.7% vs. 25.0%) as were grade 3-4 nausea/vomiting and oral mucositis (29.2% vs. 15.0% vs. 6.1%; 32.3% vs. 25.3% vs. 18.0%). Cost-effective analysis suggested that 2IC+2CCRT was the least expensive, while the health benefits were similar to those of the other groups. Further exploration showed that 2IC+2CCRT tended to be associated with a shorter PFS in high-risk patients, while 3IC+3CCRT potentially contributed to poor PFS in low-risk individuals, mainly reflected by LRRFS. Conclusions: In LA-NPC patients, 2IC+2CCRT was the optimal choice regarding efficacy, toxicity and cost-effectiveness; however, 2IC+2CCRT and 3IC+3CCRT probably shortened LRRFS in high- and low-risk populations, respectively.

Upregulated Long Non-coding RNA Lnc-MRPL39-2:1 Induces the Growth and Invasion of Nasopharyngeal Carcinoma by Binding to HuR and Stabilizing ß-Catenin mRNA.

Long non-coding RNAs (lncRNAs) have been to regulate tumor progression and therapy resistance through various molecular mechanisms. In this study, we investigated the role of lncRNAs in nasopharyngeal carcinoma (NPC) and the underlying mechanism. Using lncRNA arrays to analyze the lncRNA profiles of the NPC and para-tumor tissues, we detected the novel lnc-MRPL39-2:1, which was validated by in situ hybridization and by the 5' and 3' rapid amplification of the cDNA ends. Further, its role in NPC cell growth and metastasis was verified in vitro and in vivo. The researchers conducted the RNA pull-down assays, mass spectrometry (MS), dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and the MS2-RIP assays were then used to identify the lnc-MRPL39-2:1-interacting proteins and miRNAs. We found that lnc-MRPL39-2:1, which was highly expressed in in NPC tissues, was related to a poor prognosis in NPC patients. Furthermore, lnc-MRPL39-2:1 was shown to induce the growth and invasion of NPC by interacting directly with the Hu-antigen R (HuR) to upregulate ß-catenin expression both in vivo and in vitro. Lnc-MRPL39-2:1 expression was also suppressed by microRNA (miR)-329. Thus, these findings indicate that lnc-MRPL39-2:1 is essential in NPC tumorigenesis and metastasis and highlight its potential as a prognostic marker and therapeutic target for NPC.

PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis.

Background: Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC. Materials and methods: PubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis. Results: In total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively. Conclusions: PD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.

Prognostic significance of cervical radiologic carotid artery invasion by lymph node on magnetic resonance imaging in nasopharyngeal carcinoma.

PURPOSE: Carotid artery invasion (CAI) has been demonstrated to be an important prognosticator in some head and neck cancers. This study aimed to examine the prognostic value of radiologic CAI (rCAI) by cervical lymphadenopathy in nasopharyngeal carcinoma (NPC). METHODS: NPC patients treated between January 2013 and December 2016 were included. Pre-treatment MRIs were reviewed for cervical rCAI according to the radiologic criteria. Univariate and multivariate models were constructed to assess the association between cervical rCAI and clinical outcomes. A new N classification system was proposed and compared to the 8th AJCC system. RESULTS: The percentage of patients with MRI-positive lymph nodes was 84.7% (494/583), of whom cervical rCAI cases accounted for 42.3% (209/494). Cervical rCAI was associated with significantly poorer OS, DFS, DFFS and RFFS compared to non-rCAI (P < 0.05). Multivariate analyses confirmed that cervical rCAI was an independent prognosticator for DFS and DFFS, surpassing other nodal features, such as laterality, size, cervical node necrosis (CNN) and radiologic extranodal extension (rENE), while location of positive LNs remained independently associated with OS, DFS and DFFS. We propose a refined N classification: New_N1: upper neck LNs only without cervical rCAI; New_N2: upper neck LNs only with cervical rCAI; New_N3: upper and lower LNs. The proposed classification broadened the differences in OS, DFS and DFFS between N1 and N2 disease, and achieved a higher c-index for DFS and DFFS. CONCLUSIONS: Cervical rCAI was an independent unfavorable indicator of NPC. Compared to the AJCC system, the proposed N category showed satisfactory stratification between N1 and N2 disease, and better prediction of distant metastasis and disease failure.

Concurrent chemoradiotherapy combined with nimotuzumab in stage III-IVa nasopharyngeal carcinoma: a retrospective analysis.

PURPOSE: The efficacy and safety of nimotuzumab (NTZ) added to concurrent chemoradiotherapy (CCRT) were investigated in patients with stage III-IVa nasopharyngeal carcinoma (NPC). METHODS: Patients with stage III-IVa NPC treated with CCRT, with or without NTZ, were screened between January 2015 and December 2017. We compared patients' overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) between different therapeutic regimens. Propensity score matching (PSM) was applied to reduce the selection bias. Nomogram models were developed to predict the survival of CCRT with or without NTZ. RESULTS: Four hundred and twenty-six patients were included after PSM, with 213 patients in each regimen. Compared with NPC patients receiving CCRT alone, patients who received NTZ plus CCRT treatment had significantly better OS (5 year OS, 76.1 vs. 72.3%, P = 0.004), PFS (5 year PFS, 73.2 vs. 69.0%, P = 0.002), and LRFS (5 year LRFS, 73.2 vs. 69.0%, P = 0.028). A multivariate Cox regression analysis demonstrated that, compared with receiving CCRT alone, NTZ plus CCRT was an independently positive factor for OS, PFS, and LRFS. No significant difference was observed in the major toxicities between the two treatments (all P > 0.05). In addition, the nomogram presented good accuracy for predicting the prognosis of NPC patients. CONCLUSION: CCRT combined with NTZ presented favorable clinical outcomes for stage III-IVa NPC patients with good tolerance and similar toxicity compared to CCRT alone. A prospective, randomized clinical trial is essential to validate the current findings.

Reaction Analysis and Process Optimization with Online Infrared Data Based on Kinetic Modeling and Partial Least Squares Quantitation.

In-situ Fourier transform infrared (FT-IR) spectroscopy has been recognized as an important technology for online monitoring of chemical reactions. However, analysis of the real-time IR data for identification and quantification of uncertain reactants or intermediates is often ambiguous and difficult. Here, we propose an analysis algorithm based on reaction kinetic modeling and the chemometric method of partial least squares (PLS) to comprehensively and quantitatively study reaction processes. Concentration profiles and apparent kinetic parameters can be simultaneously calculated from the spectral data, without the demand of complicated analysis on characteristic absorbance peaks or tedious sampling efforts for multivariate modeling. Paal-Knorr reactions and glyoxylic acid synthesis reactions were selected as typical reactions to validate the algorithm. A lack of fit of the Paal-Knorr reaction spectra was less than 2.5% at various conditions, and the absolute errors between the predicted values and HPLC measurement of glyoxylic acid synthesis were less than 6% during the reaction process. Moreover, the reaction kinetic models extracted from FT-IR data were used to simulate reaction processes and optimize the conditions in order to maximize product yields, which proved that this analysis method could be used for process optimization.

Prognostic impact of pretreatment serum superoxide dismutase activity in patients with locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: To evaluate the prognostic effect of pretreatment serum superoxide dismutase (SOD) activity in locoregionally advanced nasopharyngeal carcinoma. METHODS: A total of 498 patients diagnosed with stage III-IVA nasopharyngeal carcinoma between January 2013 and December 2016 were involved in this study. The X-tile program was used to determine the cut-off value of pretreatment serum SOD activity based on disease-free survival. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the impact of serum SOD levels on survival outcomes. The receiver operating characteristic (ROC) curve analysis was used to compare the prognostic value of clinical stage, pretreatment serum SOD level, and the combination of them regarding disease-free survival. RESULTS: Based on the X-tile plot, the optimal cutoff value of pretreatment serum SOD activity for disease-free survival was 146.0U/mL. As a dichotomous variable, SOD was significantly higher in non-keratinizing differentiated disease (P = 0.027) and early T stage (P = 0.011). Compared with the lower subset, higher SOD activity predicted an inferior 3-year rates of overall survival (84.6 vs. 94.7%, P < 0.001), distant metastasis-free survival (78.3 vs. 92.8%, P < 0.001) and disease-free survival (78.2 vs. 92.8%, P < 0.001). Multivariate analysis verified that the SOD activity was an independent prognostic indicator to predict distant metastasis, disease progression, and death. The area under the ROC curve (AUC) of the combination was superior to that of clinical stage or SOD alone for disease-free survival (both P < 0.01). CONCLUSION: Serological SOD activity before treatment is an important prognostic indicator for patients with stage III-IV non-metastatic nasopharyngeal carcinoma undergoing chemoradiation therapy.

Docetaxel and cisplatin induction chemotherapy with or without fluorouracil in locoregionally advanced nasopharyngeal carcinoma: A retrospective propensity score matching analysis.

PURPOSE: To investigate whether the addition of fluorouracil to docetaxel and cisplatin induction chemotherapy (IC) can truly improve the prognosis of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 801 patients newly diagnosed with non-metastatic locoregionally advanced NPC were included as the subjects. In this study, propensity score matching (PSM) was used for analysis of overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional relapse-free survival (LRRFS), and the chi-squared test or Fisher's exact test was used to investigate toxic reactions. RESULTS: Patients received treatment with docetaxel and cisplatin (TP) or docetaxel, cisplatin and fluorouracil (TPF). With a median follow-up time of 60 months (range: 5-124 months), the TPF group had better 5-year OS (84.7% vs 79.0%; P = 0.037), PFS (84.6% vs 76.8%; P = 0.008) and DMFS (89.5% vs 82.3%; P = 0.004) than the TP group. After PSM, 258 patients were matched in each cohort. The Kaplan-Meier analysis showed that the 5-year OS, PFS and DMFS were 85.5%, 84.2% and 89.2%, respectively, in the TPF group, higher than the 80.8%, 75.0% and 81.4%, respectively, in the TP group (P = 0.048, 0.009 and 0.006, respectively). Moreover, the multivariate analysis revealed that different IC regimens were independent prognostic factors for PFS and DMFS (P = 0.014 and 0.010, respectively). CONCLUSION: This study found that compared with the TP regimen, TPF induction chemotherapy is associated with improved survival in patients with locoregionally advanced NPC. TPF can produce more mucosal and nausea/vomiting adverse reactions than TP.

Mechanism and kinetic study of Paal-Knorr reaction based on in-situ MIR monitoring.

An in-depth understanding of reaction processes is beneficial to the development and quality control of chemical products. In this work, the mechanism and kinetics of the Paal-Knorr reaction for pyrrole derivatives are thoroughly studied using in-situ Fourier transform infrared (FTIR) spectroscopy. The hemiacetal amine intermediate, reactants, and products were identified and quantified by the treatment of real-time infrared spectra via chemometrics method and two-dimensional correlation spectroscopy (2DCOS) technique. Based on the IR quantitative models, influences of operating conditions on reaction processes were investigated, and the reaction kinetic model was built with kinetic parameters of two rate-limiting reaction steps calculated. This approach of analysis on the in-situ FTIR data demonstrated the ability to extract useful information on reaction components, especially the intermediate spectrum, from the confounding real-time IR data. The in-situ FTIR monitoring combined with the IR analysis methods is proved as a powerful tool for revealing the reaction mechanism and kinetics.

Pyroptosis relates to tumor microenvironment remodeling and prognosis: A pan-cancer perspective.

Background and aim: Pyroptosis is an inflammatory form of programmed cell death implicated in inflammation and disease. Moreover, inducing pyroptosis has been appreciated as anti-cancer therapy for its ability to unleash anti-cancer immune responses. Methods: Utilizing the data available in The Cancer Genome Atlas (TCGA), pyroptosis-related genes' (PRGs) expression, genomic aberrations, and clinical significance were systematically analyzed in pan-cancer. A GSVA score was obtained to rate pyroptosis level and divide the cancers into pyroptosis-low and pyroptosis-high groups. Immunohistochemistry (IHC) was used to evaluate the differential expression of major PRGs (GSDMC, GSDMD, GSDME, NLRP3, NLRC4, IL1B) in selected tumor types (COAD, HNSC, KIRC, LIHC, LUAD, LUSC). Selection of tumors for immunohistochemistry (IHC) was based on their expression pattern in TCGA cancers, clinical relevance, tumor epidemiology, and sample availability. Results: Differential expression of PRGs was evident in various cancers and associated with prognosis which was driven by genomic variations and epigenetic abnormalities, such as single nucleotide variations (SNVs), copy number variation (CNV) and DNA methylation level. For example, methylation of PRGs in lower grade glioma (LGG), uveal melanoma (UVM) and kidney renal clear cell carcinoma (KIRC) were predictive of improved survival as upregulation of PRGs was risky in these cancers. Pyroptosis level significantly differentiated tumor from normal samples in 15 types of cancers, exhibited a progressive trend with cancer stage, observed variation among cancer subtypes, and showed a significant association with cancer prognosis. Higher pyroptosis level was associated with worst prognosis in majority of the cancers in terms of OS (KIRC, LGG, and UVM), PFS (GBM, KIRC, LGG, PRAD, THCA, and THYM) and DSS (KIRC and LGG) as estimated by Kaplan-Meier survival curves. Moreover, Pyroptosis level was strongly indicative of a hot tumor immune microenvironment with high presence of CD8+ T cell and other T cell subtypes. Several oncogenic pathways, such as P53 pathway, DNA repair, KRAS signaling, epithelial-mesenchymal transition (EMT), IL6 JAK STAT3 signaling, IL2 STAT5 signaling, PI3K AKT MTOR signaling and angiogenesis, were enriched in pyroptosis-hi subgroups across cancers. Conclusions: Genetic alterations in PRGs greatly influence the pyroptosis level and cancer prognosis. A relatively hot tumor immune microenvironment was associated with pyroptosis irrespective of the cancer prognosis. Overall, our study reveals the critical role of pyroptosis in cancer and highlights pyroptosis-based therapeutic vulnerabilities.

Retrospective Analysis of Induction Chemotherapy plus Concurrent Chemoradiotherapy under Intensity-Modulated Radiotherapy Mode for Locally Advanced Nasopharyngeal Carcinoma.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) originates from the mucous epithelium of the nasopharynx. Although induction chemotherapy plus concurrent chemoradiotherapy is the major therapeutic protocol used for locally advanced NPC without metastasis, more research studies are needed to evaluate the curative effects. We aim to identify the therapeutic effects and prognosis after induction chemotherapy plus concurrent chemoradiotherapy in the treatment of locally advanced NPC under the intensity-modulated radiotherapy mode. METHODS: The patients (N = 544) with locally advanced NPC (III and Iva, UICC 8th) after intensity-modulated radiotherapy with induction chemotherapy and concurrent chemoradiotherapy were included in this study. We analyzed the characteristics of patients including gender, age, smoking status, tumor node staging system, clinical stage, pathological type, the therapy protocol of induction chemotherapy and concurrent chemoradiotherapy, and chemotherapy prescription. RESULTS: We have found the 5-year survival rates of overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 85.21%, 78.51%, 90.71%, and 85.21% in follow-up, and these data indicated that our therapeutic procedure provided beneficial effects on survival rates. Subsequently, the chemotherapy drug based on docetaxel (DOC) provided a more beneficial effect on survival rate compared with taxol (TXT) (all estimated HR >1; p = 0.005, 0.004, and <0.001 of OS, PFS, and DMFS), but there was no significant difference between chemotherapy drugs based on cisplatin (DDP) and nedaplatin (NDP) in treating NPC patients (p = 0.390, 0.549, 0.364, and 0.645 of OS, PFS, LRRFS, and DMFS). The therapeutic effects of induction chemotherapy revealed no difference between TPF and TP (T: DOC or TXT, P: DDP or NDP, and F: 5-fluorouracil) (p = 0.541, 0.897, 0.498, and 0.765 of OS, PFS, LRRFS, and DMFS). In addition, there was also no significant change between concurrent chemotherapy with TP dual drugs or a single platinum drug (being excluded in the multivariate model using forward [Wald] procedure). Moreover, the survival rate showed no difference between platinum accumulation dose of more or less than 150 mg/m2 for concurrent chemotherapy (being excluded in the multivariate model using forward [Wald] procedure). CONCLUSION: Our results indicate that induction chemotherapy plus concurrent chemoradiotherapy under intensity-modulated radiotherapy which is the standard therapeutic method for locally advanced NPC provides beneficial therapeutic effects, and it is worthy of further study.

The Optimal Second-Line Systemic Treatment Model for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: A Bayesian Network Meta-Analysis.

Background: The optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity. Methods: By searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity. Results: In total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE. Conclusion: For R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.

A Randomized Controlled Trial Comparing Two Different Schedules for Cisplatin Treatment in Patients with Locoregionally Advanced Nasopharyngeal Cancer.

PURPOSE: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. PATIENTS AND METHODS: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. RESULTS: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of -0.2% (95% confidence interval, -6.3 to 5.9; P noninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3-4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). CONCLUSIONS: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Clinical value of docetaxel plus cisplatin (TP) induction chemotherapy followed by TP concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma.

Objective: To investigate the clinical value of induction chemotherapy (IC) with docetaxel plus cisplatin (TP) followed by concurrent chemoradiotherapy (CCRT) with TP in locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 544 patients with locoregionally advanced NPC that was newly diagnosed from January 2009 to December 2015 were included in this study. Among these patients, 251 were treated with TP induction chemotherapy followed by CCRT with cisplatin (DDP) alone (TP + DDP group), 167 were treated with TP followed by CCRT with TP (TP + TP group), and 126 were treated with docetaxel, DDP and fluorouracil (TPF) followed by CCRT with DDP alone (TPF + DDP group). Overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional relapse-free survival (LRRFS) were analyzed using the Kaplan-Meier method and a Cox proportional hazards model. Results: Survival analysis showed that the 5-year OS, PFS and DMFS rates in the TP + DDP group were significantly lower than those in the TP + TP group after propensity score matching (PSM). Multivariate analysis revealed that CCRT with TP was an independent prognostic factor for OS, PFS and DMFS. During CCRT, the incidence rates of grade 3/4 nausea/vomiting, oral mucositis, leukocytopenia and neutropenia were significantly increased in the TP + TP group compared with the TP + DDP group (all P < 0.05). To further explore the value of TP + TP, we performed PSM again with the TPF + DDP group. After PSM, there were 100 patients in each group. Survival analysis showed no significant differences in the 5-year OS, PFS, DMFS and LRRFS rates between the two groups. During IC and CCRT, the rate of grade 3/4 nausea/vomiting in the TPF + DDP group was higher than that in the TP+TP group (9.0% vs. 2.0%, P = 0.030; 18.0% vs. 8.0%, P = 0.036, respectively). No significant difference in the incidence of grade 3/4 hematologic toxicity was found between the two groups (all P > 0.05). Conclusion: TP + TP can reduce the distant metastasis of locoregionally advanced NPC and improve OS compared with TP + DDP; TP + TP has the same effect as TPF + DDP and is clinically feasible.

Engineered Coatings via the Assembly of Amino-Quinone Networks.

Engineering coatings with precise physicochemical properties allows for control over the interface of a material and its interactions with the surrounding environment. However, assembling coatings with well-defined properties on different material classes remains a challenge. Herein, we report a co-assembly strategy to precisely control the structure and properties (e.g., thickness, adhesion, wettability, and zeta potential) of coatings on various materials (27 substrates examined) using quinone and polyamine building blocks. By increasing the length of the amine building blocks from small molecule diamines to branched amine polymers, we tune the properties of the films, including the thickness (from ca. 5 to ca. 50 nm), interfacial adhesion (0.05 to 5.54 nN), water contact angle (130 to 40°), and zeta potential (-42 to 28 mV). The films can be post-functionalized through the in situ formation of diverse nanostructures, including nanoparticles, nanorods, and nanocrystals. Our approach provides a platform for the rational design of engineered, substrate-independent coatings for various applications.