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Summary: Both concurrent chemoradiotherapy (CCRT) and induction chemotherapy (ICT) followed by CCRT are standard care of advanced nasopharyngeal carcinoma (NPC). However, tailoring personalized treatment is lacking. Herein, we established a radiogenomic clinical decision support system to classify patients into three subgroups according to their predicted disease-free survival (DFS) with CCRT and ICT response. The CCRT-preferred group was suitable for CCRT since they achieved good survival with CCRT, which could not be improved by ICT. The ICT-preferred group was suitable for ICT plus CCRT since they had poor survival with CCRT; additional ICT could afford an improved DFS. The clinical trial–preferred group was suitable for clinical trials since they exhibited poor survival regardless of receiving CCRT or ICT plus CCRT. These findings suggest that our radiogenomic clinical decision support system could identify optimal candidates for CCRT, ICT plus CCRT, and clinical trials, and may thus aid in personalized management of advanced NPC.

Summary: Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for prognosis and treatment decisions. Here, we develop a tumor microenvironment-associated circular RNA (circRNA) signature that can stratify LA-NPC patients with different risks of relapse and vulnerability to induction chemotherapy (IC). Relapsed-related circRNAs are identified by comparing expression profiles between patients with and without relapse, followed by quantitative validation in the training cohort (n = 170). A nine-circRNA signature is constructed to classify patients into high-risk and low-risk groups. Low-risk patients have significantly favorable clinical survivals, which is validated in the internal (n = 170) and external (n = 150) cohorts. They are characterized by an immune-active microenvironment and can derive benefits from IC. Meanwhile, high-risk patients characterized with pro-relapse and DNA repair-associated features, are vulnerable to chemoresistance. Overall, the circRNA-based classifier serves as a reliable prognostic tool and might guide chemotherapy decisions for patients with LA-NPC.

Abstract Objective We analyzed the patterns of lymph node (LN) failure and prognosis in patients with regional recurrent nasopharyngeal carcinoma (rNPC) alone after primary intensity‐modulated radiotherapy (IMRT). Methods A total of 175 patients who were treated with IMRT between 2010 and 2015 and who experienced regional recurrence alone were included. Recurrent LNs were re‐located in the initial pretreatment imaging and IMRT plan and failures were classified as in‐field or out‐field based on target volume delineation. All patients underwent curative salvage treatment. Independent prognostic factors for overall survival (OS) were selected by multivariate Cox analysis. Results Level IIb (49.1%, 86/175) was the most frequent recurrence site, followed by level IIa (36%), level III (18.9%), level IVa (12%), the retropharyngeal region (8%), level Va (6.9%), and the parotid region (6.9%). A total of 264 recurrent LNs were recorded: 149 (56.4%) were classified as in‐field failure with a prescribed dose ≥66 Gy, 60 (22.7%) with 60 to

Abstract 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

Abstract Background: To summarize the impact of radiotherapy (RT) and chemotherapy delays on patients with nasopharyngeal carcinoma (NPC) during the COVID-19 pandemic. Methods: We retrospectively included 233 patients with stage II-IVa NPC treated with RT and chemotherapy between December 11, 2019 and March 11, 2020. The outcomes were elevation in the EBV DNA load between two adjacent cycles of chemotherapy or during RT, and 1-year disease-free survival (DFS). Results: RT delay occurred in 117 (50%) patients, and chemotherapy delay occurred in 220 (94%) patients. RT delay of ≥ 6 days was associated with a higher EBV DNA elevation rate (20.4% vs. 3.6%, odds ratio [OR] = 6.93 [95% CI = 2.49–19.32], P

Abstract 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]‐1β, 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.

Abstract Purpose Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy. Methods and materials 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits. Results The median follow-up was 59.3 (0.39–170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1–2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3–4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184–0.517; P 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy.

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.

Long noncoding RNAs (lncRNAs) can be used for the development of prognostic signatures to predict tumour metastasis. Here the authors identify an immune-associated nine-lncRNA signature for predicting metastasis in a multicentre cohort of locoregionally advanced nasopharyngeal cancer patients.

Abstract 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.

Abstract 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

Abstract 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

Abstract 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.

Abstract 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.

Abstract. 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.

Abstract Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m6A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m6A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m6A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m6A and 5mC methylation at the multiomic level. Then, we further established m6A/5mC epigenetic module eigengenes by combining hub m6A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.

A six-degree-of-freedom gear pair torsional vibration model considering time-varying stiffness, damping, dynamic backlash, bearing radial clearance and comprehensive wear of the tooth surface is established by using the lumped mass method in this paper. According to the comprehensive wear of tooth surface, the wear severity is divided into non-wear, slight wear and severe wear. The triangular function is used to simulate the wear failure of tooth surface. The effects of backlash, bearing clearance and comprehensive wear of tooth surface on the steady-state response of the gear system are analyzed respectively. The results show that the radial clearance of the bearing intensifies the vibration and causes the step phenomenon at high speed. The backlash increases the amplitude of vibration, the meshing force and the impact of back of teeth. Moreover, the side frequency bands generated by amplitude modulation appear on both sides of bearing vibration frequency, and the continuous spectrum line appears near the meshing frequency as well. The increase of wear leads to the increase of transmission error amplitude, tooth back impact and the disappearance of side frequency bands on both sides of bearing vibration frequency. The main frequencies in the spectrum are meshing frequency and its high-order harmonic frequency, and the modulated sideband appears near the meshing frequency and its high-order harmonic.

Abstract Background The role of pretreatment Epstein-Barr virus DNA (pre-DNA) for individualized induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) still remains unknown. We aimed to address this clinical issue. Methods In total, data on 6218 patient with newly diagnosed LA-NPC receiving concurrent chemoradiotherapy (CCRT) with or without IC were retrospectively reviewed. Receiver operating characteristics (ROC) curve was adopted to calculate the cut-off value of pre-DNA based on disease-free survival (DFS). Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes between IC + CCRT and CCRT groups were compared. Results Among the original cohort, no survival difference between IC + CCRT and CCRT groups was found. The cut-off value of pre-DNA was 4650 copies/ml (area under curve [AUC], 0.620; sensitivity, 0.6224; specificity, 0.5673). For patients with Pre-DNA ≤ 4650 copies/ml, the IC + CCRT and CCRT groups also achieved comparable survival outcomes (P > 0.05 for all rates). However, IC + CCRT was associated with significantly improved 3-year DFS (78.6% vs. 74.8%, P = 0.03), overall survival (OS; 91.4% vs. 87.5%, P = 0.002) and distant metastasis-free survival (DMFS; 86.0% vs. 82.2%, P = 0.036) for patient with pre-DNA > 4650 copies/ml. Multivariate analysis also confirm that IC + CCRT was an independent prognostic factor for DFS (HR, 0.817; 95% CI, 0.683–0.977; P = 0.027), OS (HR, 0.675; 95% CI, 0.537–0.848; P = 0.001) and DMFS (HR, 0.782; 95% CI, 0.626–0.976; P = 0.03). Conclusions Pre-DNA may be a feasible and powerful consideration for individualized IC apart from other baseline clinical characteristics in LA-NPC.

Abstract Background Little is known about the prognostic difference of anti-EGFR therapy, cetuximab (CTX) or nimotuzumab (NTZ), concurrently with induction chemotherapy (IC, investigational arm) or RT (control arm) for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We conducted this retrospective study to address this. Methods We identified 296 patients with newly diagnosed LA-NPC at Sun Yat-Sen University Cancer Center between January 2012 and May 2015. Patients were treated by IC with CCRT or RT and CTX/NTZ was delivered during IC or radiotherapy. Survival outcomes and toxicities between different arms were compared. Results In total, there were 149 patients in the investigational arm and 147 in control arm. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for investigational arm vs. control arm were 84.3% vs. 74.3% (P = 0.027), 94.0% vs. 92.1% (P = 0.673), 88.0% vs. 81.8% (P = 0.147) and 93.3% vs. 88.0% (P = 0.093). Multivariate analysis revealed patients in the control arm achieved significantly worse disease-free survival (HR, 1.497; 95% CI, 1.016–2.206; P = 0.026) compared with those in the investigational arm; however, no significant difference was identified for other endpoints. Patients in the investigational arm experienced more grade 3–4 skin reaction (15.4% vs. 2.0%, P

Abstract Background Little is known about the nature of metastasis to small cervical lymph nodes (SCLNs) in the patients with nasopharyngeal carcinoma (NPC) examined by using 18-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The present study aimed to evaluate the diagnostic values of PET/CT in identifying metastasis in SCLNs in NPC patients. Methods Magnetic resonance images (MRI) and PET/CT scans for 470 patients with newly diagnosed, non-distant metastatic NPC were analyzed. Metastatic rates of SCLNs were defined by the positive number of SCLNs on PET/CT scans and total number of SCLNs on MRI scans. Receiver operating characteristic curve was applied to compare PET/CT-determined stage with MRI-determined stage. Results In total, 2082 SCLNs were identified, with 808 (38.8%) ≥ 5 and

Abstract Background The value of Epstein–Barr virus (EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma (NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. In the present study, we aimed to evaluate the prognostic value of plasma EBV DNA assay during posttreatment follow-up in the patients with NPC who have undergone intensity-modulated radiotherapy. Methods The medical records of 385 NPC patients treated with intensity-modulated radiotherapy between November 2009 and February 2012 were reviewed. All patients underwent plasma EBV DNA assays before treatment, within 3 months after treatment, and then every 3–12 months during posttreatment follow-up period. The recurrence rates for patients with different pretreatment and posttreatment follow-up plasma EBV DNA levels were analyzed. Results Of the 385 patients, 267 (69.4%) had detectable pretreatment plasma EBV DNA (> 0 copy/mL) and 93 (24.2%) had detectable posttreatment EBV DNA during a median follow-up of 52.8 months (range 9.3–73.8 months). Detectable EBV DNA during posttreatment follow-up was found in 14.4% (17/118) and 28.5% (76/267) of patients with undetectable and detectable pretreatment EBV DNA, respectively, and was significantly associated with tumor recurrence in both patient groups. EBV DNA was detectable in 12.8% (40/313) of patients who remained disease-free, 56.4% (22/39) of patients with locoregional recurrence alone, and 93.9% (31/33) of patients with distant metastasis as the first recurrence event (P

Abstract Background Nasopharyngeal carcinoma (NPC) shows a high proportion of lymph node metastasis, and treatment guidelines have been developed for positive nodes. However, no irradiation guidelines have been proposed for patients with enlarged neck lymph nodes (ENLNs) that do not meet the radiological criteria of 10 mm in diameter for positive lymph nodes. This study aimed to determine the prognostic value and radiation dose for ENLNs in N0-category NPC patients treated with intensity-modulated radiotherapy (IMRT). Methods We reviewed the medical data of 251 patients with non-metastatic, N0-category NPC treated with IMRT. Receiver operating characteristic curves were used to calculate the cut-off value of the ENLN diameter for the prediction of disease failure. The biological equivalent dose (BED) for ENLNs was calculated. Patient survival was compared between the small and large ENLN groups. Independent prognostic factors were identified using the Cox proportional hazards model. Results The estimated 4-year regional relapse-free survival rate was higher in patients with ENLNs ≥5.5 mm than in those with ENLNs 0.05 for all survival rates). In the subgroup analysis, patients receiving BED ≥72 Gy had a similar prognosis as patients receiving BED

Background and Purpose: Evidence for induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) in nasopharyngeal carcinoma (NPC) was derived from landmark clinical trials excluding the T3N0, T3N1, T4N0 subgroups. This study used Epstein-Barr virus (EBV) DNA to select IC beneficiaries from the three subgroups.Materials and Methods: Significant predictors of overall survival (OS) were identified using multivariate Cox analyses. Risk stratification was generated using recursive partitioning analysis (RPA). IC+CCRT was compared with CCRT in each risk stratification and in different subgroups. Individual-level data from a clinical trial (NCT01245959) was used for validation.Results: Gender and EBV DNA were included in RPA-generated risk stratification, categorizing patients into low-risk (EBV DNA

Abstract The value of adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) for the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. In our recent article entitled “Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial” published in the Lancet Oncology, we reported the results of a phase III, multicenter, randomized controlled trial comparing cisplatin, 5-fluorouracil, and docetaxel (TPF) IC plus CCRT versus CCRT alone in patients with T3-4N1/TxN2-3M0 NPC (ClinicalTrials.gov registration number NCT01245959). The IC-plus-CCRT group showed significantly higher 3-year failure-free survival, overall survival, and distant failure-free survival rates than the CCRT-alone group, with an acceptable toxicity profile. Our study suggests that adding TPF IC to CCRT could increase survival rates and reduce distant failure in patients with locoregionally advanced NPC. However, long-term follow-up is required to assess the eventual efficacy and toxicity of this strategy, and a more accurate method to determine prognosis is needed to enable better tailoring of treatment strategy for individual patients.

Clinical Trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding nasopharyngeal carcinoma (NPC). This study aimed at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database.We used the keyword "nasopharyngeal carcinoma" to search the ClinicalTrials.gov database and assessed the characteristics of these trials.Up to December 30, 2016, 462 eligible trials in total were identified, of which 222 (48.0%) recruited only NPC (NPC trials) and the other 240 (52.0%) recruited both NPC and other cancers (multiple cancer trials). Moreover, 47 (10.2%) were Epstein-Barr virus (EBV)-related trials and 267 (57.8%) focused on metastatic/recurrent disease. Compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%, P < 0.001) studies and more patients with metastatic/recurrent disease (72.5% vs. 41.9%, P < 0.001). Notably, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002) than EBV trials. Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001).The role of plasma EBV DNA in clinical trials is underestimated, and high-level randomized clinical trials should be performed for patients with metastatic/recurrent disease.

The objective of this study is to assess the prognostic value of ABO blood group in nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy (IMRT).We retrospectively reviewed the data on 1397 patients with non-metastatic, newly diagnosed NPC treated using IMRT. Patient survival between different ABO blood groups were compared using log-rank test. Cox hazards model was adopted to establish independent prognostic factors.In our study, the distribution of the A, B, AB and O blood groups was 26.6% (372/1397), 26.2% (366/1397), 5.2% (73/1397) and 42.0% (586/1397), respectively. The cut-off value of pre-treatment Epstein-Barr virus (EBV) DNA based on disease-free survival (DFS) was 1355 copies/ml (area under curve [AUC], 0.649; sensitivity, 0.76; specificity, 0.496) for the whole cohort. Estimated four-year DFS, overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) rates were 81.7%, 89.2%, 89.4% and 92.3% for blood group A; 82.1%, 89.3%, 89.0% and 92.0% for group B; 83.3%, 88.1%, 86.2% and 95.5% for group AB, 80.9%, 90.7%, 88.4% and 90.2% for group O (P > 0.05 for all rates). Multivariate analysis revealed ABO blood group was not an independent prognostic factor for DFS, OS, DMFS or LRRFS (P > 0.05 for all rates) after adjusting for plasma EBV DNA in either the whole cohort or subgroup analysis by gender.The prognostic value of ABO blood group may be limited for patients with NPC in the era of IMRT, and no substantial correlation between ABO blood group and plasma EBV DNA was observed.

Abstract Ginseng, from the roots of Panax ginseng C. A. Meyer, is a widely used herbal medicine in Asian countries, known for its excellent therapeutic properties. The growth of P. ginseng is depend on specific and strict environments, with a preference for wetness but intolerance for flooding. Under excessive soil moisture, some irregular rust-like substances are deposited on the root epidermis, causing ginseng rusty symptoms (GRS). This condition leads to a significant reduce in yield and quality, resulting in substantial economic loses. However, there is less knowledge on the cause of GRS and there are no effective treatments available for its treatment once it occurs. Unsuitable environments lead to the generation of large amounts of reactive oxygen species (ROS). We investigated the key indicators associated with the stress response during different physiological stages of GRS development. We observed a significant change in ROS level, MDA contents, antioxidant enzymes activities, and non-enzymatic antioxidants contents prior to the GRS. Through the analysis of soil features with an abundance of moisture, we further determined the source of ROS. The levels of nitrate reductase (NR) and nitric oxide synthase (NOS) activities in the inter-root soil of ginseng with GRS were significantly elevated compared to those of healthy ginseng. These enzymes boost nitric oxide (NO) levels, which in turn showed a favorable correlation with the GRS. The activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase first rose and then decreased as GRS developed. Excess soil moisture causes a decrease in oxygen levels. This activated NR and NOS in the soil, resulting in a production of excess NO. The NO then diffused into the ginseng root and triggered a burst of ROS through NADPH located on the cell membrane. Additionally, Fe2+ in soil was oxidized to red Fe3+, and finally led to GRS. This conclusion was also verified by the Sodium Nitroprusside (SNP), a precursor compound producing NO. The presence of NO from NR and NOS in water-saturated soil is responsible for the generation of ROS. Among these, NO is the main component that contribute to the occurrence of GRS.

Abstract The ecological significance of secondary metabolites is to improve the adaptive ability of plants. Secondary metabolites, usually medicinal ingredients, are triggered by unsuitable environment, thus the quality of medicinal materials under adversity being better. The quality of the cultivated was heavily declined due to its good conditions. Radix Saposhnikoviae, the dried root of Saposhnikovia divaricata (Turcz.) Schischk., is one of the most common botanicals in Asian countries, now basically comes from cultivation, resulting in the market price being only 1/10 to 1/3 of its wild counterpart, so improving the quality of cultivated Radix Saposhnikoviae is of urgency. Nitric oxide (NO) plays a crucial role in generating reactive oxygen species and modifying the secondary metabolism of plants. This study aims to enhance the quality of cultivated Radix Saposhnikoviae by supplementing exogenous NO. To achieve this, sodium nitroprusside (SNP) was utilized as an NO provider and applied to fresh roots of S. divaricata at concentrations of 0.03, 0.1, 0.5, and 1.0 mmol/L. This study measured parameters including the activities of antioxidant enzymes, secondary metabolite synthesis enzymes such as phenylalanine ammonia-lyase (PAL), 1-aminocyclopropane-1-carboxylic acid (ACC), and chalcone synthase (CHS), as well as the contents of NO, superoxide radicals (O2 ·−), hydrogen peroxide (H2O2), malondialdehyde (MDA), and four secondary metabolites. The quality of Radix Saposhnikoviae was evaluated with antipyretic, analgesic, anti-inflammatory effects, and inflammatory factors. As a result, the NO contents in the fresh roots were significantly increased under SNP, which led to a significant increase of O2 ·− , H2O2, and MDA. The activities of important antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), were found to increase as well, with their peak levels observed on the 2nd and 3rd days. PAL, ACC, and CHS activities were also significantly enhanced, resulting in the increased secondary metabolite contents of Radix saposhnikoviae in all groups, especially the 0.5 mmol/L SNP. The four active ingredients, prim-O-glucosylcimifugin, cimifugin, 4′-O-β-d-glucosyl-5-O-methylvisamminol, and sec-O-glucosylhamaudol, increased by 88.3%,325.0%, 55.4%, and 283.8%, respectively, on the 3rd day. The pharmaceutical effects of Radix Saposhnikoviae under 0.5 mmol/L SNP were significantly enhanced. Exogenous SNP can induce the physiological response of S. divaricata under adverse conditions and significantly improve the quality of Radix Saposhnikoviae.

Hydnum (Hydnaceae, Cantharellales), one of the edible ectomycorrhizal mushrooms, is of considerable ecological and economic importance. Although previous studies have focused on the genus in China, the diversity still remains incompletely understood. In the present study, in addition to the known species from China being reviewed, six phylogenetic species from the country were described/redescribed, which included a new species: H. erectum, and five known taxa: H. cremeoalbum, H. minus, H. orientalbidum, H. tenuistipitum, and H. treui; H. treui is new to China. Detailed descriptions, color photographs of fresh basidiomata, and line drawings of microstructures of them are presented. A key to the accepted species of Hydnum in China is also provided.

Cantharellus, one of the main genera of Hydnaceae (Cantharellales), is both ecologically and economically important. Although many studies have focused on this genus in China, the taxonomy should be further updated. In the present study, Cantharellus subgenera Afrocantharellus and Magni were investigated based on morphology and molecular phylogenetic analyses with new collections from China. Five phylogenetic species were recognized among the studied collections, three of which were described as new: C. bellus, C. cineraceus, and C. laevigatus; one was previously described taxon: C. hygrophoroides; and the remaining species was not defined due to the paucity of the materials. Among the four described species, both C. bellus and C. laevigatus are members of subgen. Magni, whereas C. cineraceus and C. hygrophoroides belong to subgen. Afrocantharellus.

Entomogenous fungi are one of the most diverse fungal groups among ascomycetes. During investigations of macro-fungi biodiversity in Kaihua and Putuo in Zhejiang Province, China, in 2021, several entomopathogenic fungal specimens were collected from subtropical forests. After a careful examination of morphology and multi-gene phylogenetic analyses applying nrSSU, nrLSU, tef1, rpb1 and rpb2, two novel species were discovered, described herein as Blackwellomyces kaihuaensis and Metarhizium putuoense, and further compared with other similar species. Detailed descriptions, color photographs of fresh specimen and figures illustrating microscopic features of the two new species are provided.

Three new phlegmaciod species of Thaxterogaster, T. borealicremeolinus, T. rufopurpureus, and T. sinopurpurascens spp. nov., from subtropical China were described based on their morphological characteristics and molecular data. Thaxterogaster borealicremeolinus belongs to the sect. Cremeolinae and differs from the other species in this section in its larger basidiospores and its habitat in the Northern Hemisphere associated with Quercus sp. trees. Thaxterogaster rufopurpureus and T. sinopurpurascens belong to sect. Purpurascentes, in which T. rufopurpureus is characterized by a pileus with a reddish-brown coloration when mature and a clavate stipe, while T. sinopurpurascens is characterized by a violet basidiomata, except for a greyish orange to brown pileus, the distinctly marginate bulb of its stipe, and its distribution in subtropical China. The phylogenetic analyses were performed based on nrITS, and detailed descriptions of the new species are provided herein.

Species of Cantharellus subgenus Cantharellus are interesting and important for their mycorrhizal properties, medicinal values, and edibility. In China, there are many undescribed species of the subgenus. In this study, four new species of subg. Cantharellus, viz. Cantharellus albopileatus, Cantharellus chuiweifanii, Cantharellus pinetorus, and Cantharellus ravus from Hainan and Hunan Provinces, respectively, were described based on morphological and phylogenetic evidence as a contribution to the knowledge of the species diversity in China. Detailed descriptions, color photographs of fresh basidiomata, and line drawings of microstructures of these four new species are presented as well as comparisons with related species.

The search for extraterrestrial intelligence (SETI) is to search for technosignatures associated with extraterrestrial life, such as engineered radio signals. In this paper, we apply the multibeam coincidence matching (MBCM) strategy, and propose a new search mode based on the MBCM which we call the MBCM blind search mode. In our recent targeted SETI research, 33 exoplanet systems are observed by the Five-hundred-meter Aperture Spherical radio Telescope (FAST). With this blind search mode, we search for narrowband drifting signals across 1.05–1.45 GHz in two orthogonal linear polarization directions separately. There are two special signals, one of which can only be detected by the blind search mode while the other can be found by both blind and targeted search modes. This result reveals huge advantages of the new blind search mode. However, we eliminate the possibility of the special signals being ETI signals based on much evidence, such as the polarization, drift, frequency, and beam coverage characteristics. Our observations achieve an unprecedented sensitivity and our work provides a deeper understanding to the polarization analysis of extraterrestrial signals.

In the standard Friedmann-Lemaître-Robertson-Walker (FLRW) cosmological model, the energy conditions provides model-independent bounds on the behavior of the distance modulus. However, this method can not provide us the detailed information about the violation between the energy conditions and the observation. In this paper, we present an extended analysis of the energy conditions based upon the entropy density of the universe. On the one hand, we find that these conditions imply that entropy density s depends on Hubble parameter H(z). On the other hand, we compare the theoretical entropy density from the conservation law of energy–momentum tensor with that from the energy conditions using the observational Hubble parameter. When we consider a FLRW universe, according to the theoretical prediction, OHD, thermodynamics and several independent cosmological probes, show that the dominant energy condition is fitter than other energy conditions.

Objective To evaluatethe detection rate, typing, and therapeutic effect of second mesiobuccal canals(MB2) of first molars under dental operating microscope.Methods 88 maxillary molars with the presence of MB2 through cone beam computed tomography (CBCT) were collected, in which 68 were received root canal treatment and 20 were received root canal retreatment because of the missing canal of MB2 respectively. The type of mesiobuccal root canal in the former 68 maxillary molars were analyzed under CBCT. The 68 maxillary molars were divided into 2 groups, with 34 in each group. The experienment group received treatment under dental operating microscope, while the control group under naked eyes. MB2 detection rate, treatment and retreatment effect between two groups were compared. The latter 20 maxillary molars were also seperated into 2 groups, in which 10 cases were treated under microscope and 10 cases were treated under naked eye. The effect of retreatment was observed.Results The type of mesiobuccal root canal in 68 maxillary molars under CBCT were mainlytypeⅡand typeⅢ, with the proportion of 77.9% (53 cases) and 22.1% (15 cases) respectively. The detection rate of MB2 in the experimental group was 100%, and 91.2% (30 cases) in the control group, a statistical difference can be found between 2 groups (P < 0.05). 97.5% (33 cases) of the experimental group was successfully treated, and 79.4% (27 cases) for the control group (P < 0.05). The success rate of retreatment under microscope was 60% (6 cases), which was significantly higher than that of the naked eye (P < 0.05). In 3-month and 6-month follow-up, the treatment effect in experimental group was significantly better than the control group (P < 0.05).Conclusion Dental microscope can help to increase MB2 detection rate and improve treatment and retreatment effect.