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This article empirically analyses the effect of government subsidies on total factor productivity (TFP) based on the data of listed manufacturing companies in China. The results indicate that government subsidies increase total productivity directly as well as indirectly by increasing R&D investment. The positive effect of government subsidies on TFP is higher in non-state-owned enterprises (non-SOEs) than in state-owned enterprises (SOEs), higher in central SOEs than local SOEs and higher in enterprises with lower rather than higher TFP. Furthermore, the mediating effects of R&D decisions also differ among different enterprises. Therefore, the government should implement differentiated subsidy policies to promote enterprises’ TFP.

The heat shock transcription factors (Hsfs) play critical roles in plant responses to abiotic stresses. However, the mechanism of Hsfs in the regulation of pollen thermotolerance and their specific biological functions and signaling remain unclear. Herein, we demonstrate that HsfA1a played a key role in tomato pollen thermotolerance. Pollen thermotolerance was reduced in

Background and purpose To explore whether a highly refined dose volume histograms (DVH) prediction model can improve the accuracy and reliability of knowledge-based volumetric modulated arc therapy (VMAT) planning for cervical cancer. Methods and materials The proposed model underwent repeated refining through progressive training until the training samples increased from initial 25 prior plans up to 100 cases. The estimated DVHs derived from the prediction models of different runs of training were compared in 35 new cervical cancer patients to analyze the effect of such an interactive plan and model evolution method. The reliability and efficiency of knowledge-based planning (KBP) using this highly refined model in improving the consistency and quality of the VMAT plans were also evaluated. Results The prediction ability was reinforced with the increased number of refinements in terms of normal tissue sparing. With enhanced prediction accuracy, more than 60% of automatic plan-6 (AP-6) plans (22/35) can be directly approved for clinical treatment without any manual revision. The plan quality scores for clinically approved plans (CPs) and manual plans (MPs) were on average 89.02 ± 4.83 and 86.48 ± 3.92 (p mean and V18 Gy for kidney (L/R), the Dmean, V30 Gy, and V40 Gy for bladder, rectum, and femoral head (L/R). Conclusion The proposed model evolution method provides a practical way for the KBP to enhance its prediction ability with minimal human intervene. This highly refined prediction model can better guide KBP in improving the consistency and quality of the VMAT plans.

Aimed to automate the segmentation of organs at risk (OARs) in head and neck (H&N) cancer radiotherapy, we develop a novel Prior Attention enhanced convolutional neural Network (PANet) based Stepwise Refinement Segmentation Framework (SRSF) on full-size computed tomography (CT) images. The SRSF is built with a multiscale segmentation concept, in which OARs are segmented from coarse to fine. PANet is a pyramidal architecture with elements of inception block and prior attention. In this study, the developed PANet based SRSF is applied for OARs segmentation in H&N radiotherapy. 139 CT series and manually delineated contours of twenty-two OARs by experienced oncologists are collected from 139 H&N patients for training and evaluating the proposed PANet based SRSF. The mean testing Dice similarity coefficients (DSC) on 39 CT series range from 76.1± 8.3% (left middle ear) to 91.9± 1.4% (right mandible) for large volume OARs(mean volume >1cc) while the corresponding ranges are 63.4± 12.3%(chiasm) to 81.0± 14.1% (right lens) for small and challenging OARs(mean volume ≤1cc). Furthermore, the proposed method also achieved superior segmentations over reference methods on the MICCAI 2015 H&N dataset with mean DSC of 95.6± 0.7%, 81.3± 4.0%, 77.6± 4.5%, 77.5± 4.6%, and 69.2± 7.6%, on the mandible, left submandibular, left and right optical nerve, and chiasm, respectively. The accurate segmentation of OARs is obtained on both the self-collected testing data and public testing dataset, which implies that the proposed method can be used as a practicable and efficient tool for automated OARs contouring in the H&N cancer radiotherapy.

Backgroud: The optimal treatment strategy for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains unclear. We aimed to develop individualized treatment strategies for such patients according to their pretreatment risk stratification and the degree of comorbidities.Methods: A total of 583 elderly LA-NPC patients diagnosed between January 2011 and January 2018 were retrospectively studied. Based on prognostic factors confirmed by multivariate analysis, we constructed a nomogram for disease-free survival (DFS). The entire cohort was then divided into two groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities was assessed by Charlson Comorbidity Index (CCI). We performed subgroup analysis based on the degree of complications in the low- and high-risk groups to compare the survival outcomes of different treatment regimens using the Kaplan-Meier method and the log-rank test.Results: A nomogram for DFS was constructed with T/N classification, Epstein-Barr virus DNA and albumin. The high-risk group had significantly poorer survival compared with the low-risk group. The 3-year DFS and overall survival (OS) of the low-risk group and the high-risk group were 76.7% vs. 44.6%, 81.5% vs. 51.0% (both P 2) would not have.Conclusion: We constructed a prognostic nomogram for DFS and generated two risk groups. Combining risk stratification and degree of comorbidities can better guide individualized treatment for elderly LA-NPC patients.

Liquid biopsies have the utility for detecting minimal residual disease in several cancer types. Here, we investigate if liquid biopsy tracking on-treatment informs on tumour phenotypes by longitudinally quantifying circulating Epstein-barr virus (EBV) DNA copy number in 673 nasopharyngeal carcinoma patients undergoing radical induction chemotherapy (IC) and chemo-radiotherapy (CRT). We observe significant inter-patient heterogeneity in viral copy number clearance that is classifiable into eight distinct patterns based on clearance kinetics and bounce occurrence, including a substantial proportion of complete responders (≈30%) to only one IC cycle. Using a supervised statistical clustering of disease relapse risks, we further bin these eight subgroups into four prognostic phenotypes (early responders, intermediate responders, late responders, and treatment resistant) that are correlated with efficacy of chemotherapy intensity. Taken together, we show that real-time monitoring of liquid biopsy response adds prognostic information, and has the potential utility for risk-adapted treatment de-intensification/intensification in nasopharyngeal carcinoma., Liquid biopsies are emerging as a useful method for diagnosis and prognosis in cancer. Here, the authors show the prognostic value of monitoring the level of circulating Epstein-barr virus DNA throughout induction chemotherapy and chemo-radiotherapy and its potential utility for risk-adapted individualised therapy in nasopharyngeal carcinomapatients.

Background Oral cavity (OC), oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (LA) squamous cell carcinoma (SCC) have a high incidence of regional lymph node metastasis (LNM). Elective irradiation for clinically node‐negative neck is routinely administered to treat lymph nodes harboring occult metastasis. However, the optimal elective irradiation schemes are still inconclusive. In this study, we aimed to establish individualized elective irradiation schemes for the ipsilateral and contralateral node‐negative neck of these four types of cancer. Methods From July 2005 to December 2018, 793 patients with OC‐SCC, 464 with OP‐SCC, 413 with HP‐SCC, and 645 with LA‐SCC were recruited retrospectively. Based on the actual incidence of LNM and the tumor characteristics, risk factors for contralateral LNM, as well as node level coverage schemes for elective irradiation, were determined using logistic regression analysis. Additionally, we developed a publicly available online tool to facilitate the widespread clinical use of these schemes. Results For the ipsilateral node‐negative neck, elective irradiation at levels I‐III for OC‐SCC and levels II‐IVa for OP‐, HP‐ and LA‐SCC are generally recommended. In addition, level VIIa should be included in patients with OP‐SCC. Multivariate analyses revealed that posterior hypopharyngeal wall and post‐cricoid region involvement were independently associated with level VIIa metastasis in HP‐SCC (all P < 0.05). For the contralateral node‐negative neck, multivariate analyses revealed that ipsilateral N2b2‐N3, tumors with body midline involvement, and degree of tumor invasion were the independent factors for contralateral LNM (all P < 0.05). In patients who require contralateral neck irradiation, levels I‐II are recommended for OC‐SCC, and additional level III is recommended for patients with ipsilateral N3 disease. Levels II‐III are recommended for OP‐, HP‐, and LA‐SCC, and additional level IVa is recommended for patients with advanced T or ipsilateral N classifications. Furthermore, additional level VIIa is recommended only for OP‐SCC with T4 and ipsilateral N3 disease. Conclusion Based on our findings, we suggest that individualized and computer‐aided elective irradiation schemes could reduce irradiation volumes in OC‐, OP‐ and HP‐SCC patients, as compared to current guidelines, and could thus positively impact the patients' quality of life after radiotherapy., Framework of individualized and computer‐aided elective neck irradiation. Firstly, we proposed individual elective neck irradiation schemes for head and neck squamous cell carcinoma. based on the actual incidence of lymph nodes metastasis and the tumor characteristics. Secondly, we developed a publicly available online tool to facilitate the widespread clinical use of these schemes. By inputting the characteristics of the primary tumor and metastatic LNs on this online tool, elective irradiation schemes for the right and left sides of the neck were recommended and delineated based on a set of CT scans.

Background and purposeTo validate the feasibility and efficiency of a fully automatic knowledge-based planning (KBP) method for nasopharyngeal carcinoma (NPC) cases, with special attention to the possible way that the success rate of auto-planning can be improved.Methods and materialsA knowledge-based dose volume histogram (DVH) prediction model was developed based on 99 formerly treated NPC patients, by means of which the optimization objectives and the corresponding priorities for intensity modulation radiation therapy (IMRT) planning were automatically generated for each head and neck organ at risk (OAR). The automatic KBP method was thus evaluated in 17 new NPC cases with comparison to manual plans (MP) and expert plans (EXP) in terms of target dose coverage, conformity index (CI), homogeneity index (HI), and normal tissue protection. To quantify the plan quality, a metric was applied for plan evaluation. The variation in the plan quality and time consumption among planners was also investigated.ResultsWith comparable target dose distributions, the KBP method achieved a significant dose reduction in critical organs such as the optic chiasm (pConclusionThe automatic KBP method using the DVH prediction model provided a possible way to generate clinically acceptable plans in a short time for NPC patients.

In current clinical practice, paired computed tomography (CT) providing electron density information for dose calculation and magnetic resonance imaging (MRI) providing molecular information for GTV delineation are acquired during radiation therapy planning of head cancer. Aimed to reduce repeatedly scanning procedures, we developed a patch-based deep learning approach to generate synthetic CT from paired MRI of the same patient. In this approach, 2D slices of MRI and CT would be divided into several overlap patches and sent to cycle-consistent generative adversarial network (CycleGAN) for training with a combination of multiple loss functions. For comparison, we also applied CycleGAN and pix2pix model using whole 2D slices as input. With IRB approval, a total number of 2542 paired MRI and CT images were collected in the experiment. Mean absolute error (MAE) and peak signal to noise ratio (PSNR) were used as evaluation metrics. The result showed that our proposed model performed best on both whole brain areas. We also provided the difference map between synthetic and real CT to give a visual evaluation of our proposed model.

Background and purpose To investigate the feasibility of synthesizing computed tomography (CT) images from magnetic resonance (MR) images using generative adversarial networks (GANs) for nasopharyngeal carcinoma (NPC) intensity-modulated radiotherapy (IMRT) planning. Materials and methods Conventional T1-weighted MR images and CT images were acquired from 173 NPC patients. The MR and CT images of 28 patients were randomly chosen as the independent tested set. The remaining images were used to build a conditional GAN (cGAN) and a cycle-consistency GAN (cycleGAN). A U-net was used as the generator in cGAN, whereas a residual-Unet was used as the generator in cycleGAN. The cGAN was trained using the deformable registered MR-CT image pairs, whereas the cycleGAN was trained using the unregistered MR and CT images. The generated synthetic CT (SCT) images from cGAN and cycleGAN were compared with the true CT images with respect to their Hounsfield Unit (HU) discrepancy and dosimetric accuracy for NPC IMRT plans. Results The mean absolute errors within the body were 69.67 ± 9.27 HU and 100.62 ± 7.39 HU for the cGAN and cycleGAN, respectively. The 2%/2-mm γ passing rates were (98.68 ± 0.94)% and (98.52 ± 1.13)% for the cGAN and cycleGAN, respectively. Meanwhile, the absolute dose discrepancies within the regions of interest were (0.49 ± 0.24)% and (0.62 ± 0.36)%, respectively. Conclusion Both cGAN and cycleGAN could swiftly generate accurate SCT volume images from MR images, with high dosimetric accuracy for NPC IMRT planning. cGAN was preferable if high-quality MR-CT image pairs were available.

To clarify the optimal cumulative cisplatin dose (CCD) in locoregionally‐advanced nasopharyngel carcinoma (NPC) patients receiving induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). Using the NPC‐specific database from the established big‐data intelligence platform at Sun Yat‐Sen University Cancer Center, 583 non‐disseminated, locoregionally‐advanced NPC patients receiving IC plus CCRT were enrolled. Propensity score matching (PSM) analysis was conducted to control for confounding factors. The median CCD was 160 mg/m2 after IC (range, 40‐300 mg/m2); only 74 patients (12.7%) achieved CCD >200 mg/m2. Patients receiving >200 mg/m2 CCD did not show significantly improved 5‐year overall survival (OS) (HR = 1.19; 95% confidence intervals [CI] 0.69‐2.06, P = .53) and progression‐free survival (PFS) (HR = 1.03; 95% CI: 0.63‐1.68, P = .92) compared with patients receiving 160 mg/m2 and CCD < 160 mg/m2 in both the original and PSM cohorts. In addition, subgroup analysis indicated a favorable PFS, but not OS, with higher cisplatin administration in patients with pretreatment Epstein–Barr virus deoxyribonucleic acid (EBV DNA)

PURPOSE/OBJECTIVE(S) Synthetic CT (sCT) generation with MR image plays an essential role in MR-only radiotherapy, which can be used for electron density estimation and dose calculation in treatment planning. Currently, the reliability of deep learning-based methods for sCT generation depends on two aspects: the MR-CT registration errors, which can eliminate by a cycle-consistent generative adversarial network (CycleGAN) with unpaired training data, and the different anatomy information and contract divergence of various tissue in different sequences MRI which will significantly affect the nonlinear mapping of MR-CT. The purpose of this study is to investigate the effect of different sequence MRI by evaluating the image quality of corresponded sCTs. MATERIALS/METHODS Multi-sequence MR images (T1, T2, T1C) and plan CT images of 151 patients with nasopharyngeal carcinoma were acquired on the same day in the radiation treatment position. 126 cases were randomly selected as the training set with the same preprocessing. Three unsupervised CycleGAN-based models were respectively trained with different sequence MRI with Architecture, which consists of 2 ResUnet-based generators and 2 Patch-GAN-based discriminators. The remaining 25 CT-MR cases with non-rigid registration were selected as the independent paired testing set. The mean error (ME) and mean absolute error (MAE) between plan CT and sCT of each model were used to measure the CT value estimation accuracy, which was calculated within air (Hounsfield Unit, HU 150) and whole body, respectively. Structural similarity index (SSIM) was applied to evaluate the similarity between error (plan CT and sCT. RESULTS The MEs calculated between plan CT and T1, T2, T1C-based sCT images, were (-0.62 ± 3.06) vs. (-1.81 ± 3.13) vs. (0.13 ± 2.56) within air, (154.92 ± 87.93) vs. (173.27 ± 97.62) vs. (262.78 ± 91.74) within soft tissue, (1363.99 ± 294.94) vs. (337.21 ± 50.4) vs. (661.63 ± 168.43) within bone, (22.12 ± 29.47) vs. (17.05 ± 10.51) vs. (35.28 ± 20.75) within the whole body. The MAEs correspondingly were (4.49 ± 3.13) vs. (4.6 ± 3.47) vs. (4.6 ± 3.47) within air, (186.41 ± 61.75) vs. (197.33 ± 58.62) vs. (293.56 ± 72.72) within soft tissue, (186.41 ± 61.75) vs. (197.33 ± 58.62) vs. (293.56 ± 72.72) within bone, (31.28 ± 28.1) vs. (27.64 ± 10.41) vs. (42.6 ± 23.82) within the whole body. The quantitative analysis between T1, T2, T1C-sCTs indicates that the T1C based generated model achieves higher accuracy than the other models in nasopharyngeal carcinoma. CONCLUSION The T1C MRI can provide sufficient anatomy information and tissue contract in synthetic CT prediction of head and neck region, which offers a substantial potential for density estimation and dose calculation in radiotherapy. The generation method and evaluation will investigate synthetic CT prediction with more complex tissue in various body parts.

(1) Purpose: This study aims to explore risk-adapted treatment for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) according to their pretreatment risk stratification and the degree of comorbidity. (2) Methods: A total of 583 elderly LA-NPC patients diagnosed from January 2011 to January 2018 are retrospectively studied. A nomogram for disease-free survival (DFS) is constructed based on multivariate Cox regression analysis. The performance of the model is evaluated by using the area under the curve (AUC) of the receiver operating characteristic curve and Harrell concordance index (C-index). Then, the entire cohort is divided into different risk groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities is assessed by the Charlson Comorbidity Index (CCI). Finally, survival rates are estimated and compared by the Kaplan–Meier method and the log-rank test. (3) Results: A nomogram for DFS is constructed with T/N classification, Epstein-Barr virus DNA and albumin. The nomogram shows well prognostic performance and significantly outperformed the tumor-node-metastasis staging system for estimating DFS (AUC, 0.710 vs. 0.607, C-index, 0.668 vs. 0.585, both p &lt, 0.001). The high-risk group generated by nomogram has significantly poorer survival compared with the low-risk group (3-year DFS, 76.7% vs. 44.6%, p &lt, 0.001). For high-risk patients with fewer comorbidities (CCI = 2), chemotherapy combined with radiotherapy is associated with significantly better survival (p &lt, 0.05) than radiotherapy alone. (4) Conclusion: A prognostic nomogram for DFS is constructed with generating two risk groups. Combining risk stratification and the degree of comorbidities can guide risk-adapted treatment for elderly LA-NPC patients.

This study investigated the combined prognostic value of pretreatment anemia and cervical node necrosis (CNN) in patients with nasopharyngeal carcinoma (NPC). Retrospective review of 1302 patients with newly diagnosed nonmetastatic NPC treated with intensity‐modulated radiotherapy (IMRT) ± chemotherapy. Patients were classified into four groups according to anemia and CNN status. Survival was compared using the log‐rank test. Independent prognostic factors were identified using the Cox proportional hazards model. The primary end‐point was overall survival (OS); secondary end‐points were disease‐free survival (DFS), locoregional relapse‐free survival (LRRFS), and distant metastasis‐free survival (DMFS). Pretreatment anemia was an independent, adverse prognostic factor for DMFS; pretreatment CNN was an independent adverse prognostic factor for all end‐points. Five‐year survival for non‐anemia and non‐CNN, anemia, CNN, and anemia and CNN groups were: OS (93.1%, 87.2%, 82.9%, 76.3%, P

BACKGROUND: The effectiveness of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) over CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and chronic hepatitis B infection in the intensity-modulated radiotherapy (IMRT) era is unknown. PATIENTS AND METHODS: A total of 249 patients with stage T1-2 N2-3 or T3-4 N1-3 NPC and chronic hepatitis B infection treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) was employed to balance covariates; 140 patients were propensity-matched (1:1 basis). Survival outcomes in the IC+CCRT and CCRT groups were compared using the Kaplan–Meier method, log-rank test and Cox proportional hazards model. RESULTS : No significant survival differences were observed between IC+CCRT and CCRT (5-year overall survival, 88.3% vs. 82.2%; P =.484; disease-free survival, 73.9% vs. 75.2%; P =.643; distant metastasis-free survival, 84.1% vs. 85.1%; P =.781; and locoregional failure-free survival, 87.9% vs. 85.1%; P =.834). After adjusting for known prognostic factors in multivariate analysis, IC was not an independent prognostic factor for any outcome (all P >.05); subgroup analysis based on T category (T1-2/T3-4), N category (N0-1/N2-3), and overall stage (III/IV) confirmed these results. The incidence of hepatic function damage in the IC+CCRT and CCRT groups was not significantly different. CONCLUSION : IC+CCRT leads to comparable survival outcomes and hepatic function damage compared to CCRT alone in patients with locoregionally advanced NPC with chronic hepatitis B infection in the IMRT era. Further investigations are warranted.

Background: To analyze the prognostic value of cervical node necrosis (CNN) observed on pretreatment magnetic resonance imaging (MRI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Patients and Methods: The medical records of 1423 NPC patients with cervical node metastasis who underwent IMRT were retrospectively reviewed. Lymph nodes in the axial plane of pretreatment MRI were classified as follows: grade 0 CNN, no hypodense zones; grade 1 CNN, ≤33% areas showing hypodense zones; and grade 2, >33% areas showing hypodense zones. Results: CNN was detectable in 470/1423 (33%) patients. Of these 470 patients, 213 (15%) and 257 (18%) exhibited grade 1 and grade 2 CNN. The grade 0 and grade 1 CNN groups showed significant differences with regard to distant metastasis-free survival (DMFS), but not overall survival (OS), regional relapse-free survival (RRFS), local relapse-free survival (LRFS), and disease-free survival (DFS). Significant differences were observed among the grade 0 and grade 2 CNN groups with regard to OS, RRFS, LRFS, DMFS, and DFS. Moreover, OS, LRFS, RRFS, and DFS were significantly different between the grade 1 and grade 2 CNN groups, whereas DMFS showed no significant differences. Univariate and multivariate analyses revealed CNN on MRI as a significant negative prognostic factor for OS, LRFS, RRFS, DMFS, and DFS in NPC patients. Conclusions: NPC patients with CNN of different grades show various prognosis and failure patterns after IMRT. CNN on MRI can be adopted as a predictive factor for formulating individualized treatment plans for NPC patients.

Purpose To evaluate the evolution of radiation-induced brain stem injury (BSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) and to identify the critical dosimetric predictors of BSI. Methods and Materials A total of 6288 NPC patients treated with IMRT between 2009 and 2015 were retrospectively reviewed. Among these 6288 patients, 24 had radiation-induced BSI, which manifested as edematous lesions and contrast-enhanced lesions (CLs) on magnetic resonance imaging. Latency, symptoms, and evolution of BSI were assessed. Critical dosimetric predictors of BSI were identified using a penalized regression model with performance evaluated by receiver operating characteristic curve analysis. Results Median BSI latency was 14.5 months (range, 7.6-37.5 months), and 9 out of 24 patients (37.5%) were clinically symptomatic. Edematous lesions and CLs were both present in all patients. Necrosis was significantly more common in larger CLs (P = .007). After median follow-up of 12.5 months, 13 out of 24 patients (54.2%) had complete remission, and 5 out of 24 patients (20.8%) had partial remission. Remission was unaffected by whether or not symptomatic treatment was given. Maximum point dose (Dmax) was identified as the critical predictor of BSI (area under the receiver operating curve = 0.898), with the optimal cutoff equivalent dose in 2-Gy fractions (D2) being 67.4 Gy (sensitivity = 0.833, 20 out of 24; specificity = 0.835, 5234 out of 6264). Patients with Dmax ≥67.4 Gy (D2) were significantly more likely to develop BSI (odds ratio = 25.29; 95% CI, 8.63-74.14; P Conclusions In patients with NPC treated with IMRT, BSI generally tends to improve over time. Dmax = 67.4 Gy (D2) appears to be the dose constraint for brain stem, potentially providing clinicians with greater choice and flexibility when balancing the tumor target coverage and brain stem protection. Further studies are needed to validate our findings.

Background: To investigate the survival outcomes and update effective prognostic nomograms of nasopharyngeal carcinoma (NPC) in an endemic area. Methods: A retrospective cohort of 10126 patients who underwent radical intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Center (SYSUCC) from April 2009 to December 2015. We assigned patients into a training cohort (SYSUCC-A; n=6751) and an internal validation cohort (SYSUCC-B; n=3375) based on computer-generated random numbers. Patients collected from Wuzhou Red Cross Hospital (WZRCH) between February 2012 and July 2015 were used as the independent external validation cohort (WZRCH; n=450). Concordance index (C-index) was used to determine predictive accuracy and discriminative ability of the nomogram. Overall survival (OS) was the primary endpoint. Secondary endpoints consisted of local relapse-free survival (LRFS), regional relapse-free survival (RRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS). All statistical tests were two-sided. Findings: The three- and five-year OS, LRFS, RRFS, DMFS, and DFS rates were 92.3% and 86.5%, 95.4% and 93.4%, 96.0% and 94.3%, 89.5% and 87.0%, and 83.4% and 78.4%, respectively. Gender, age, T stage, and N stage were identified independent risk factors that predicted OS, which were all assembled into the nomogram and derived from multivariable analysis of the SYSUCC-A cohort. The nomogram c-index for OS was 0.725 (95% CI, 0.679-0.772). Calibration curve for probability of death revealed the nomogram-based predictions were in good agreement with actual observations. C-index of the nomograms for LRFS, RRFS, DMFS, and DFS were 0.684 (95% CI, 0.611-0.756), 0.650 (95% CI, 0.571-0.728), 0.680 (95% CI, 0.630-0.731), and 0.669 (95% CI, 0.629-0.710), respectively. All results were confirmed in the validation cohorts. Interpretation: Patients with NPC had satisfactory locoregional survival outcomes undergoing IMRT in an endemic area, and distant metastasis predominates as the pattern of disease relapse. These validated nomograms could serve as useful tool for predicting survival outcomes and providing patient counseling. Funding Statement: This work was supported by the Special Support Program of Sun Yat-sen University Cancer Center (16zxtzlc06), the Health & Medical Collaborative Innovation Project of Guangzhou City, China (201604020003), the Natural Science Foundation of Guang Dong Province (No. 2017A030312003), Health & Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), the Innovation Team Development Plan of the Ministry of Education (No. IRT_17R110), the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035) and the National Natural Science Foundation of China (No. 81802707). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All patients provided informed consent, and consent waiver for the rest of the cohort was approved by the respective ethical review boards. Patients’ clinical and demographic information were anonymized before analysis.

The involvement of long non-coding RNAs (lncRNAs) during tumorigenesis is a recent emerging theme. Yet no systematic evaluation of lncRNAs has been previously reported for non-functioning pituitary adenoma (NFPA), a fairly common type of intracranial tumor. Here, we report the first genome-wide expression profile for lncRNAs and mRNAs in NFPA, using formalin-fixed and paraffin-embedded tissue specimens. Using microarray analyses, we identified 113 lncRNAs and 80 mRNAs differentially expressed in NFPA; this list includes lncRNAs previously implicated in a variety of cancers. Using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) we further confirmed differential expression in NFPA for ten of the 113 lncRNAs. Using these ten doubly confirmed lncRNAs, we constructed an lncRNA-mRNA co-expression network comprising of 130 specific lncRNA-mRNA co-expression relationships. In addition, we conducted GO and KEGG analyses for the 80 mRNAs differentially expressed in NFPA. Our microarray and qRT-PCR analyses provided a working list of lncRNAs that may be functionally relevant to NFPA tumorigenesis. Our co-expression network in turn connected these largely uncharacterized lncRNAs to specific mRNAs, whose roles we further elucidated via GO and KEGG analyses, thus providing specific, testable hypotheses for the functions of these lncRNAs. Together, our study laid the foundation for future investigation of the specific function and mechanism by which lncRNAs are involved in NFPA tumorigenesis., Summary statement: We identified long non-coding RNAs and mRNAs differentially expressed in non-functioning pituitary adenomas via microarray analyses, and provided working hypotheses for how these RNAs may function via co-expression network analyses.

PURPOSE To compare clinical features and survival outcomes in patients with ascending type (type A) and descending type (type D) nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. MATERIALS AND METHODS A total of 5194 patients with type A and type D NPC treated at Sun Yat-sen University Cancer Center were randomly selected. Tumors that were mainly advanced local disease (T3-4 stage) with early stage cervical lymph node involvement (N0-1 stage) were determined as type A, while tumors with advanced lymph node disease (N2-3 stage) but early stage local invasion (T1-2 stage) were classified as type D NPC. Kaplan-Meier's analysis was used to evaluate survival rates, and log-rank test survival curves were used for comparison. In the multivariate analysis Cox proportional hazard models were developed. RESULTS There was a larger proportion of type A tumors (82%) than type D tumors (18%). Compared to patients with type A tumors, those with type D tumors had increased likelihood of distant metastasis, regional recurrence, disease recurrence, and death (P

PURPOSE The incidence, risk factors and survival impact of secondary primary malignancies (SPMs) among survivors of nasopharyngeal carcinoma (NPC) treated with definitive intensity-modulated radiation therapy (IMRT) with or without chemotherapy are poorly characterized. METHODS AND MATERIALS Consecutive patients (n=6,377) from the big-data intelligence platform at Sun Yat-sen University Cancer Center, China (in a high-incidence area) with newly diagnosed non-metastatic pathologically proven non-keratinizing undifferentiated NPC treated with IMRT±chemotherapy between January 2003 and June 2013 were retrospectively analyzed. Cumulative incidence of SPMs was calculated using the Kaplan-Meier method. Cox proportional hazards model was used to identify potential risk factors for SPMs and assess whether SPMs affect overall survival. RESULTS Of the 6,377 patients, 189 (3.0%) suffered SPMs (median follow-up, 62 months). One-, 2-, 3-, 4-, and 5-cumulative risks of SPMs were 0.4%, 0.9%, 1.6%, 2.2%, and 2.6%, respectively. Latency from start of IMRT to SPMs diagnosis was 37 months (range, 6 to 102 months). In patients with SPMs, 14.3% suffered SPMs within 1 year post-IMRT: 1-3 years, 38.1%; 3-5 years, 33.9%; and >5 years, 13.7%. Lung cancer was the most common SPM (50/6,377, 0.78%). Multivariate analysis demonstrated sex (male, 64% increase), age (≥50 years, 68% increase), and smoking history (41% increase) were significant risk factors for SPMs, and SPMs were associated with poorer overall survival. CONCLUSION This large cohort study confirms SPMs a dreadful complication for long-term survivors of NPC treated with IMRT. SPMs negatively impact overall survival in NPC. Close follow-up is recommended for older male survivors with a smoking history.

Background To evaluate the incidence of neck muscle spasm in nasopharyngeal carcinoma (NPC) patients that received intensity-modulated radiotherapy (IMRT), and to analyse the patient- and treatment-related risk factors associated with neck muscle spasm. Methods A sample of 152 IMRT-treated, biopsy-proven, nondisseminated NPC patients were retrospectively analysed. All had documented IMRT treatment plans and had returned for follow-up review at 4 years post-radiotherapy. Spasm of the sternocleidomastoid (SCM) muscle was graded from 0 to 3 (absent to severe) and this grade served as the clinical endpoint. Risk factors were identified using logistic regression analysis. Results Within 4 years of radiotherapy, neck muscle spasm developed in 23.68% of the patients; Grades 0, 1, 2 and 3 were respectively assigned to 83.55, 7.57, 6.58 and 2.30% of assessed SCMs. Multivariate analysis indicated that gender, N stage, V60 (percentage of SCM volume that received >60 Gy) were independent prognostic variables, and that the optimal threshold for using V60 to predict neck muscle spasm was 61.92% (sensitivity = 0.900, specificity = 0.953). Conclusions Gender, N stage and V60 were independent predictive factors for post-radiotherapy neck muscle spasm, and a V60 of ≤61.92% in the SCM was relatively safe.

To assess whether consensus guideline-based atlas-based auto-segmentation (ABAS) reduces interobserver variation and improves dosimetric parameter consistency for organs at risk (OARs) in nasopharyngeal carcinoma (NPC).Eight radiation oncologists from 8 institutes contoured 20 OARs on planning CT images of 16 patients via manual contouring and manually-edited ABAS contouring. Interobserver variation [volume coefficient of variation (CV), Dice similarity coefficient (DSC), three-dimensional isocenter difference (3D-ICD)] and dosimetric parameters were compared between the two methods of contouring for each OAR.Interobserver variation was significant for all OARs in manual contouring, resulting in significant dosimetric parameter variation (P0.05). Edited ABAS significantly improved multiple metrics and reduced dosimetric parameter variation for most OARs; brainstem, spinal cord, cochleae, temporomandibular joint (TMJ), larynx and pharyngeal constrictor muscle (PCM) obtained most benefit (range of mean DSC, volume CV and main ICD values was 0.36-0.83, 12.1-84.3%, 2.2-5.0mm for manual contouring and 0.42-0.86, 7.2-70.6%, 1.2-3.5mm for edited ABAS contouring, respectively; range of dose CV reduction: 1.0-3.0%).Substantial objective interobserver differences occur during manual contouring, resulting in significant dosimetric parameter variation. Edited ABAS reduced interobserver variation and improved dosimetric parameter consistency, particularly for brainstem, spinal cord, cochleae, TMJ, larynx and PCM.

Purpose To establish the regional lymph node (LN) distribution probability map and draw the neck clinical target volume specific to nasopharyngeal carcinoma (NPC). Methods and Materials One thousand patients with pathologically proven NPC were enrolled from January 2010 to December 2011. The center point of the LNs with a minimal axial diameter of ≥4 mm was marked on a single treatment planning computed tomography scan. The neck LN levels I to X using the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for clinical target volume boundaries specific to NPC. Results A total of 10,651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, most of the LN levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% of cases (11 of 83) had LNs beyond the posteromedial border. For level VIIa (retropharyngeal LN), 1.5% of cases (12 of 819) had LNs above the cranial boundary, and 5 cases had LNs that emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of levels Ib, II, IVa, and Vc. Accordingly, a new level VIIc was proposed to include the medial group of retropharyngeal LNs, moderately extended boundaries for levels Vb and VIIa were recommended, and reduced boundaries are possibly adaptable for levels Ib, II, IV, and Vc. Conclusions Most LN levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We have proposed a new level VIIc to include a medial group of retropharyngeal LNs, recommended moderate extended boundaries for levels Vb and VIIa, and suggested that the boundaries for levels Ib, II, IV, and Vc might be reduced.

PURPOSE Local relapse-free survival (LRFS) differs widely among patients with T4 category nasopharyngeal carcinoma (NPC). We aimed to build a nomogram incorporating clinicopathological information to predict LRFS in T4 NPC after definitive intensity-modulated radiation therapy (IMRT). Materials and Methods Retrospective study of 415 Chinese patients with non-metastatic T4 NPC treated with definitive IMRT with or without chemotherapy at our cancer center between October 2009 and September 2013. The nomogram for LRFS at 3 and 5 years was generated based on multivariate Cox proportional hazards regression, and validated using bootstrap resampling, assessing discriminative performance using the concordance index (C-index) and determining calibration ability via calibration curves. RESULTS Five-year LRFS was 88.8%. We identified and incorporated four independent prognostic factors for LRFS: ethmoid sinus invasion, primary gross tumor volume, age, and pretreatment body mass index. The C-index of the nomogram for local recurrence was 0.732 (95% confidence interval, 0.726 to 0.738), indicating excellent predictive accuracy. The calibration curve revealed excellent agreement between nomogram-predicted and observed LRFS probabilities. Risk subgroups based on total point score cutoff values enabled effective discrimination of LRFS. CONCLUSION This pretreatment nomogram enables clinicians to accurately predict LRFS in T4 NPC after definitive IMRT, and could help to facilitate personalized patient counselling and treatment strategies.

Purpose To investigate the variability and prognostic value of nodal tumor volume (NTV) in nasopharyngeal carcinoma (NPC). Methods and materials Data on 1230 patients with newly diagnosed stage T1-4N1-3M0 NPC treated with definitive radiation therapy with or without chemotherapy at a single cancer center were reviewed. NTV was determined from dose volume histogram (DVH) data. X-tile analysis was applied to identify the optimal cut-off points for the NTV with respect to regional recurrence-free survival (RRFS). Correlations between the TNM classification system, NTV and RRFS were assessed using a Cox regression model. Cross-validation based on receiver operating characteristic (ROC) curve analysis was applied to compare the prognostic predictive validity of NTV and N categories. Results Within a median follow-up of 49.9 (range, 1.27-76.40) months, 61/1230 (5%) patients developed regional recurrence and 154 (12.5%) developed distant metastasis. NTV values of 7.2 cc and 35.7 cc were identified as the optimal cut-off points. Patients with larger NTV had poorer prognosis. Compared with the N category, NTV was better at determining RRFS for patients with NPC. Hazard ratios increased with NTV, ranging from 1.86 (95% confidence interval [95% CI], 0.92-3.78) for NTV between 7.2 cc to 35.7 cc, and 3.67 (95% CI, 1.58-8.50) for NTV > 35.7 cc. With both NTV and N category in the same Cox regression model, only NTV remained statistically significant in the RRFS of NPC. The validation results with ROC curves also revealed that, NTV was superior to N category for predicting RRFS with significantly larger area under the ROC curve. Conclusions NTV offers important prognostic value for treatment outcomes in NPC, especially regional control. Volumetric analysis of nodal involvement may assist selection of patients with poor prognosis.

Epstein–Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA‐IgA) and viral capsid antigen (VCA‐IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA‐IgA and VCA‐IgA in patients with NPC is less clear. We hypothesize that serum EA‐IgA and VCA‐IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non‐metastatic NPC and undetectable pEBV DNA were included. Serum EA‐IgA and VCA‐IgA were determined by ELISA. After analysis, serum EA‐IgA and VCA‐IgA loads correlated positively with T, N, and overall stage (all P 1:120 had significantly inferior 5‐year progression‐free survival (80.4% vs 89.6%, P = 0.025), distant metastasis‐free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse‐free survival (88.4% vs 95.6%, P = 0.023; log–rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P