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

We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6658 human samples were analyzed. The tumor melatonergic system was characterized by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism Index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1]). Samples of each cancer type were classified into two subgroups (high vs low) based on median values. Clinical outcomes, mutational burden, and neoepitope abundance were analyzed and compared. We found that the ability of the tumor microenvironment to synthesize and accumulate melatonin varied across cancer types and negatively correlated with tumor burden. Kaplan-Meier survival analyses and multivariable modeling showed that the three indexes played different roles across different cancers and harbored prognostic values in breast cancer (adjusted hazard ratio [AHR]Index-II = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHRIndex-I = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHRIndex-III = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHRIndex-I = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHRIndex-III = 0.68 [0.41-0.94]; P = 0.02). We further investigated its clinical relevance with tumor immunogenic features (mutational burden and neoantigen abundance), which may predict immunotherapy benefits. We observed significant negative correlations with mutational burden in the majority of tumors (P

Objective To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer. Design Systematic review and network meta-analysis. Data sources Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018. Review methods Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group. Results 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer. Conclusions Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events. Systematic review registration PROSPERO CRD42017082553.

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

Denitrification is the stepwise microbial reduction of nitrate or nitrite (NO2−) to nitrogen gas via the obligate intermediates nitric oxide (NO) and nitrous oxide (N2O). Substantial N2O accumulation has been reported in denitrifying enhanced biological phosphorus removal (EBPR) bioreactors enriched in denitrifying polyphosphate accumulating organisms (DPAOs), but little is known about underlying mechanisms for N2O generation, prevalence of complete versus truncated denitrification pathways, or the impact of NO2− feed on DPAO-enriched consortia. To address this knowledge gap, we employed genome-resolved metagenomics to investigate nitrogen transformation potential in a NO2− fed denitrifying EBPR bioreactor enriched in Candidatus Accumulibacter and prone to N2O accumulation. Our analysis yielded 41 near-complete metagenome-assembled genomes (MAGs), including two co-occurring Accumulibacter strains affiliated with clades IA and IC (the first published genome from this clade) and 39 non-PAO flanking bacterial genomes. The dominant Accumulibacter clade IA encoded genes for complete denitrification, while the lower abundance Accumulibacter clade IC harbored all denitrification genes except for a canonical respiratory NO reductase. Analysis of the 39 non-PAO MAGs revealed a high prevalence of taxa harboring an incomplete denitrification pathway. Of the 27 MAGs harboring capacity for at least one step in the denitrification pathway, 10 were putative N2O producers lacking N2O reductase, 16 were putative N2O reducers that lacked at least one upstream denitrification gene, and only one harbored a complete denitrification pathway. We also documented increasing abundance over the course of reactor operation of putative N2O producers. Our results suggest that the unusually high levels of N2O production observed in this Accumulibacter-enriched consortium are linked in part to the selection for non-PAO flanking microorganisms with truncated denitrification pathways.

The recent discovery of key methane-metabolizing genes in the genomes from the archaeal phyla Bathyarchaeota and Verstraetearchaeota has expanded our understanding of the distribution of methane metabolism outside of the phylum Euryarchaeota. Here, we recovered two near-complete crenarchaeotal metagenome-assembled genomes (MAGs) from circumneutral hot springs that contain genes for methanogenesis, including the genes that encode for the key methyl-coenzyme M reductase (MCR) complex. These newly recovered archaea phylogenetically cluster with Geoarchaeota (deep lineage of archaeal order Thermoproteales), and the MCR-encoding genes clustered with the recently reported methanogens within the Verstraetearchaeota. In addition, genes encoding hydroxybutyryl-CoA dehydratase were identified in the newly recovered methanogens, indicating they might carry out the β-oxidation process. Together, our findings further expanded the methane metabolism outside the phylum Euryarchaeota.

The prognosis of patients who have Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without EBV-related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV-related NPC by incorporating the measurement of plasma EBV DNA.In total, 979 patients with NPC who received intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT.The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression-free survival and overall survival in univariate analysis (all P.001) and multivariate analysis (all P.05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2-T3N0 or T1-T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2-T3N0 or T1-T3N1, EBV DNA2000 copies/mL; T1-T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1-T3N2, EBV DNA2000 copies/mL; T4N0-N2), and stage RIVA (any T and N3). In the validation cohort, the 5-year progression-free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P.001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance.The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV-related NPC.

Little is known about the value of the nutritional risk screening 2002 (NRS2002) scale in nasopharyngeal carcinoma (NPC). We conducted a large-scale study to address this issue. We employed a big-data intelligence database platform at our center and identified 3232 eligible patients treated between 2009 and 2013. Of the 3232 (12.9% of 24 986) eligible patients, 469 (14.5%), 13 (0.4%), 953 (29.5%), 1762 (54.5%) and 35 (1.1%) had NRS2002 scores of 1, 2, 3, 4 and 5, respectively. Survival outcomes were comparable between patients with NRS20023 and ≥3 (original scale). However, patients with NRS2002 ≤3 vs3 (regrouping scale) had significantly different 5-year disease-free survival (DFS; 82.7% vs 75.0%, P .001), overall survival (OS; 88.8% vs 84.1%, P = .001), distant metastasis-free survival (DMFS; 90.2% vs 85.9%, P = .001) and locoregional relapse-free survival (LRRFS; 91.6% vs 87.2%, P = .001). Therefore, we proposed a revised NRS2002 scale, and found that it provides a better risk stratification than the original or regrouping scales for predicting DFS (area under the curve [AUC] = 0.530 vs 0.554 vs 0.577; P .05), OS (AUC = 0.534 vs 0.563 vs 0.582; P .05), DMFS (AUC = 0.531 vs 0.567 vs 0.590; P .05) and LRRFS (AUC = 0.529 vs 0.542 vs 0.564; P .05 except scale A vs B). Our proposed NRS2002 scale represents a simple, clinically useful tool for nutritional risk screening in NPC.

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

Little is known about the efficacy and toxicity of anti-epidermal growth factor receptor therapy concurrently with induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The present study aimed to address this question. We identified 2848 patients with newly diagnosed LA-NPC receiving IC between January 2012 and May 2015. The propensity score matching (PSM) method was used to balance various factors and to match patients. Survival outcomes and toxicities between different groups were compared. In total, 596 patients were selected at a 1:3 ratio, with 149 in the IC + CTX/NTZ group and 447 in the IC alone group. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for IC + CTX/NTZ vs IC alone were 84.3% vs 75.2% (P = .059), 94.0% vs 87.9% (P = .053), 88.0% vs 84.9% (P = .412) and 93.3% vs 88.2% (P = .242). Multivariate analysis established a treatment group (IC vs IC + CTX/NTZ) as a prognostic predictor for DFS (hazard ratio [HR], 1.497; 95% confidence interval [CI], 1.016-2.206; P = .041) and OS (HR, 1.984; 95%, CI, 1.023-3.848; P = .043). Grade 3-4 skin reaction (15.4% vs 0.4%, P < .001) and mucositis (10.1% vs 2.7%, P < .001) were more common in the IC + CTX/NTZ group than that in the IC alone group. Our findings suggested that CTX/NTZ in combination with IC may be a more effective and promising strategy for patients with LA-NPC treated with intensity-modulated radiotherapy.

Objectives This study aimed at identifying the optimal induction chemotherapy regimen for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy. Materials and methods We identified eligible patients with newly-diagnosed stage III-IVA NPC (excluding T3N0) between September 2009 and May 2015. Survival outcomes and grade 3–4 toxicities were compared between different IC regimen groups. Results In total, 3738 patients were eligible for this study, with 1572 (42.1%), 1085 (29.0%) and 1081 (28.9%) receiving TPF, PF and TP, respectively. In the whole population, multivariate analysis found that TPF seems to be better than PF and TP. Howerver, subgroup analysis revealed TPF and TP had same effectiveness in patients receiving a cumulative cisplatin dose (CCD) ≥ 200 mg/m2 in concurrent chemotherapy, while TPF shows relatively better survival benefit in patients receiving CCD Conclusions Our study concluded that induction TP regimen may be enough for patients receiving a CCD ≥ 200 mg/m2, while TPF may be superior to TP and PF for patients receiving a CCD

This study aimed to evaluate the efficacy of concurrent chemoradiotherapy (CCRT) for stage II nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT). A total of 249 patients were retrospectively reviewed. All patients were treated with IMRT. One hundred forty-three patients treated with CCRT and 106 patients treated with IMRT alone. With a median follow-up of 59.4 months, adding concurrent chemotherapy did not statistically significantly improve the 5-year overall survival (OS) (89.7 % vs 99.0 %, p = 0.278), locoregional relapse-free survival (LRFS) (94.8 % vs 89.3 %, p = 0.167), and distant metastases-free survival (DMFS) (93.4 % vs 97.5 %, p = 0.349). The patients with CCRT significantly experienced more acute toxic effects. The main grades 3-4 toxicity reactions were mucositis (26.6 % vs 15.1 %, p = 0.03) and leukopenia/neutropenia (9.1 % vs 0.9 %, p = 0.005). In subgroup analysis of patients with concurrent platinum single-agent chemotherapy the 5-year OS (98.4 % vs 81.9 %, p = 0.013) and DMFS (96.9 % vs 84.4 %, p = 0.043) of patients with platinum every 3 weeks (Q3W) were significantly higher than those with platinum weekly (QW) and no significant difference for LRFS (96.8 % vs 90.4 %, p = 0.150). CCRT did not improve the survival of patients with stage II NPC but increased the acute toxicity reactions. Patients with platinum Q3W improved the 5-year OS and DMFS, compared with those with platinum QW.

// Yu-Pei Chen 1, * , Wen-Na Zhang 1, * , Lei Chen 1, * , Ling-Long Tang 1 , Yan-Ping Mao 1 , Wen-Fei Li 1 , Xu Liu 1 , Guan-Qun Zhou 1 , Ying Sun 1 , Tie-Bang Kang 1 , Mu-Sheng Zeng 1 , Na Liu 1 , Jun Ma 1 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Na Liu, e-mail: liun1@sysucc.org.cn Jun Ma, e-mail: majun2@mail.sysu.edu.cn Keywords: LMP1, EBV, cancer, survival, meta-analysis Received: May 20, 2015 Accepted: August 07, 2015 Published: August 18, 2015 ABSTRACT Latent membrane protein 1 (LMP1) is identified as the main transforming oncoprotein of Epstein-Barr virus (EBV). LMP1 is frequently expressed in a variety of EBV-associated cancers, including nasopharyngeal carcinoma (NPC), non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), and gastric cancer (GC). However, due to conflicting results, the prognostic value of LMP1 expression on clinical outcomes in EBV-associated cancers remains unclear. We performed a meta-analysis on 32 studies with a total of 3752 patients to explore the association between LMP1 expression and overall survival (OS) in EBV-associated cancers. Overall, LMP1 expression was significantly associated with poorer OS (hazard ratio, HR = 1.51, 95% confidence interval, CI, 1.13–2.03), irrespective of cancer type. Further analyses showed that LMP1 expression correlated with poorer OS in NPC (HR = 2.48, 95% CI, 1.77–3.47) and NHL patients (HR = 1.83, 95% CI, 1.07–3.15), but not in HD patients (HR = 0.98, 95% CI, 0.60–1.62) or GC patients (HR = 0.70, 95% CI, 0.44–1.12). Subgroup analyses indicated that the age and geographical factors seemed to have an effect on the clinical outcomes of HD patients with positive LMP1 expression. In conclusion, LMP1 expression can be used as a prognostic biomarker in NPC, NHL, and certain HD patients. This data suggests that novel therapies targeting LMP1 may improve clinical outcomes for EBV-associated cancer patients.

Background and purpose We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). Methods and materials We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination ( R 2 ), and the surrogate threshold effect (STE) to assess the trial-level correlation. Results Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS ( R 2 =0.88, STE=0.84), as was PFS ( R 2 =0.90, STE=0.88). Moreover, FFS and PFS at 3years were still strongly correlated with 5-year OS ( R 2 =0.80, STE=0.83; R 2 =0.85, STE=0.84). Conclusions Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS.

This study investigated the contribution of intensity-modulated radiotherapy (IMRT) to improved treatment outcome in patients with nasopharyngeal carcinoma (NPC) and parapharyngeal space (PPS) extension.A total of 1052 cases with PPS extension were retrospectively reviewed, including 512 (48.7%) patients treated with two-dimensional conventional radiotherapy (2D-CRT) and 540 (51.3%) patients treated with IMRT.Significant differences in local relapse-free survival (LRFS) and overall survival (OS) (P0.001, P0.001, respectively), but not distant metastasis-free survival (DMFS; P=0.383), were observed between the 2D-CRT and IMRT groups in univariate analysis. The radiotherapy technique was found to be an independent prognostic factor for death (HR=0.674, 95% CI: 0.537-0.846, P=0.001) and local recurrence (HR=0.486, 95% CI: 0.324-0.727, P0.001), but not for DMFS. IMRT improved local control in patients with carotid space (CS) involvement compared to 2D-CRT (P0.001). LRFS was significantly different between patients with and without CS extension in the 2D-CRT group (P0.001), but not in the IMRT group (P=0.215).Compared to 2D-CRT, IMRT improved LRFS in patients with PPS extension, especially patients with CS extension, but did not improve DMFS. CS extension was not statistically prognostic for local control in NPC patients with PPS extension.

Purpose: To investigate prognostic impact of chemoradiotherapy-induced hemoglobin (Hb) decrease on treatment outcomes of endemic nasopharyngeal carcinoma (NPC). Materials and Methods: Eight hundred and fifteen non-metastatic NPC, receiving neoadjuvant chemotherapy followed by radiotherapy (NACT+RT group) or concomitant chemoradiotherapy (CCRT group), were enrolled in this study, who were regrouped according to pre-radiotherapy Hb (pre-RT Hb), post-radiotherapy Hb (post-RT Hb) and individual Hb decrease through radiotherapy or CCRT (△Hb), respectively. Survival curves were estimated using Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed using the COX proportional hazard model and binary logistic regression model. Results: A poorer 5-year disease-free survival (DFS) was observed when pre-RT Hb

The impact of comorbidity on prognosis in nasopharyngeal carcinoma (NPC) is poorly characterized.Using the Adult Comorbidity Evaluation-27 (ACE-27) system, we assessed the prognostic value of comorbidity and developed, validated and confirmed a predictive score model in a training set (n=658), internal validation set (n=658) and independent set (n=652) using area under the receiver operating curve analysis.Comorbidity was present in 40.4% of 1968 patients (mild, 30.1%; moderate, 9.1%; severe, 1.2%). Compared to an ACE-27 score ⩽1, patients with an ACE-27 score1 in the training set had shorter overall survival (OS) and disease-free survival (DFS) (both P0.001), similar results were obtained in the other sets (P0.05). In multivariate analysis, ACE-27 score was a significant independent prognostic factor for OS and DFS. The combined risk score model including ACE-27 had superior prognostic value to TNM stage alone in the internal validation set (0.70 vs. 0.66; P=0.02), independent set (0.73 vs. 0.67; P=0.002) and all patients (0.71 vs. 0.67; P0.001).Comorbidity significantly affects prognosis, especially in stages II and III, and should be incorporated into the TNM staging system for NPC. Assessment of comorbidity may improve outcome prediction and help tailor individualized treatment.

Background: Due to the lack of studies, it remains unclear whether the additional neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC). The main objective of this Bayesian network meta-analysis was to determine the efficacy of NACT+CCRT as compared with CCRT alone. Methods: We comprehensively searched databases and extracted data from randomized controlled trials involving NPC patients who received NACT+CCRT, CCRT, NACT+radiotherapy (RT), or RT. Overall survival (OS) with hazard ratio (HR), and locoregional recurrence rate (LRR) and distant metastasis rate (DMR) with relative risks (RRs), were concerned. Results: Nine trials involving 1988 patients were analyzed. In the network meta-analysis, there was significant benefit of NACT+CCRT over CCRT for DMR (RR=0.54, 95% credible interval [CrI]=0.27-0.94). However, NACT+CCRT had a tendency to worsen locoregional control significantly as compared with CCRT (RR =1.71, 95%CrI =0.94-2.84), and no significant improvement in OS was found (HR =0.73, 95%CrI=0.40-1.23). Conclusions: NACT+CCRT is associated with reduced distant failure as compared with CCRT alone, and whether the additional NACT can improve survival for locoregionally advanced NPC should be further explored. Optimizing regimens and identifying patients at high risk of metastasis may enhance the efficacy of NACT+CCRT.

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.

Objectives The objective of this network meta-analysis is to optimize the prophylactic treatment for radiotherapy-induced oral mucositis in patients with head and neck cancer (HNSCC) receiving postoperative or definitive radiotherapy with or without chemotherapy. Materials and methods We searched electronic databases to identify all eligible randomized clinical trials on oral mucositis. The endpoint was grade 0–2 oral mucositis. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were extracted. Network meta-analysis was performed using the frequentist approach to conduct multiple treatment comparisons. Results In total, 57 trials with 5261 patients were eligible for this study. Both direct and network meta-analysis revealed that low-level laser additional to standard oral care (SOC) was better than most of the other treatments and achieved the highest effect on grade 0–2 oral mucositis, with a surface under the cumulative ranking curve (SUCRA) of 95.8%; however, SOC with or without placebo had worse effect than most of the other treatments and was ranked worst (SUCRA = 0.4%). Moreover, sensitivity analysis performed after we had combined the SOC and placebo groups (non-medication treatment, NMT) yielded similar results, with SUCRA of 91.3% and 3.5% for low-level laser and NMT, respectively. Conclusions Low-level laser additional to SOC may be a more effective prophylactic treatment for reducing severe radiotherapy-induced oral mucositis; SOC alone is insufficient for patients with HNSCC receiving postoperative or definitive radiotherapy with or without chemotherapy.

Chemotherapy, target therapy, and immunotherapy are increasingly being used in the systematic treatment of nasopharyngeal carcinoma (NPC), during which the occurrence of hepatitis B virus (HBV) reactivation might increase. However, data regarding HBV screening and reactivation and the clinical management of NPC patients with HBV infections are lacking. This study was aimed at clarifying the risk of reactivation for NPC patients on different regimens while providing evidence concerning HBV screening and management in an endemic area.With the NPC database from an established big-data intelligence platform at Sun Yat-Sen University Cancer Center in China, NPC patients who were diagnosed between 2008 and 2016 and underwent HBV screening and regular monitoring of liver enzymes and HBV deoxyribonucleic acid (DNA) were analyzed.Among the 46,919 patients identified, the HBV screening rate was 24.8% (11,616 of 46,919). Among the screened patients with an HBV infection, regular monitoring of liver enzymes and HBV DNA occurred for 563 patients. The incidence of HBV reactivation and HBV-related hepatitis was 9.1% (51 of 563) and 2.5% (14 of 563), respectively. The reactivation risk varied for different treatments and regimens and ranged from 0.0% to 21.4%. Detectable baseline HBV DNA (odds ratio [OR], 2.93; P.01), the presence of liver metastasis at diagnosis (OR, 7.19; P.01), and antiviral prophylaxis (OR, 0.29; P.01) were significantly associated with reactivation.In NPC patients with chronic HBV infections on high-risk regimens, the reactivation risk is similar to or exceeds the risk associated with other immunosuppressive therapies for which screening and prophylaxis are recommended. Our findings, therefore, support HBV screening and prophylaxis for these patients, whereas regular monitoring might be appropriate for patients with resolved HBV infections or those receiving low-risk regimens. Cancer 2017;123:3540-9. © 2017 American Cancer Society.

Background In the era of intensity-modulated radiotherapy (IMRT), the role of neoadjuvant chemotherapy (NACT) in treating ascending-type nasopharyngeal carcinoma (NPC) is under-evaluated. This study was to compare the efficacy of NACT followed by IMRT (NACT + RT) with the efficacy of concurrent chemoradiotherapy (CCRT) on ascending-type NPC. Methods Clinical data of 214 patients with ascending-type NPC treated with NACT + RT or CCRT between December 2009 and July 2011 were analyzed. Of the 214 patients, 98 were treated with NACT followed by IMRT, and 116 were treated with CCRT. The survival rates were assessed using Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Results The 4-year overall survival, locoregional failure-free survival, distant failure-free survival, and failure-free survival rates were not significantly different between the two groups (all P > 0.05). However, patients in the CCRT group exhibited more severe acute adverse events than did patients in the NACT + RT group during radiotherapy, including leukopenia (30.2% vs. 15.3%, P = 0.016), neutropenia (25.9% vs. 11.2%, P = 0.011), and mucositis (57.8% vs. 40.8%, P = 0.028). After radiotherapy, patients in the CCRT group exhibited significantly higher rates of xerostomia (21.6% vs. 10.2%, P = 0.041) and hearing loss (17.2% vs. 6.1%, P = 0.023). Conclusions The treatment outcomes of the NACT + RT and CCRT groups were similar; however, CCRT led to higher rates of acute and late toxicities. NACT + RT may therefore be a better treatment strategy for ascending-type NPC.

To investigate the pattern of lymph node metastasis and treatment outcome after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC), and assess the possibility of replacing Ho's supraclavicular fossa (SCF) with the lower level (LL; cervical extension below caudal edge of cricoid cartilage) based on magnetic resonance imaging (MRI) as a criterion for N3 disease.We retrospectively reviewed 749 patients with biopsy-proven non-metastatic NPC treated with IMRT. Lymph node metastasis was mapped using the 2013 International Consensus Guidelines.Cervical lymph node (CLN) laterality, CLN greatest dimension (60 vs. ⩽60 mm) and Ho's SCF were independent prognostic factors for disease-free survival (DFS) and distant metastasis-free survival (DMFS; P0.01) in multivariate analysis. Replacing Ho's SCF with the LL was also predictive for DFS and DMFS (P0.01). Compared to the 7th UICC/AJCC, N-categories based on the LL provided more satisfactory distinction between hazard ratios for distant and disease failure for each N-category. N3a and N3b as defined by the 7th UICC/AJCC had similar DMFS (P=0.31) and DFS (P=0.21).Replacing Ho's SCF with the LL is simple and practical. The N-category staging system could be further simplified by merging N3 subcategories.

We report the first integrated metatranscriptomic and metagenomic analysis of enhanced biological phosphorus removal (EBPR) sludge. A draft genome of Candidatus Accumulibacter spp. strain HKU-1, a member of Clade IB, was retrieved. It was estimated to be ∼90% complete and shared average nucleotide identities of 83% and 88% with the finished genome CAP IIA UW-1 and the draft genome CAP IA UW-2, respectively. Different from CAP IIA UW-1, the phosphotransferase (pap) in polyphosphate metabolism and V-ATPase in orthophosphate transport were absent from CAP IB HKU-1. Additionally, unlike CAP IA UW-2, CAP IB HKU-1 carried the genes for carbon fixation and nitrogen fixation. Despite these differences, the key genes required for acetate uptake, glycolysis and polyhydroxyalkanoate (PHA) synthesis were conserved in all these Accumulibacter genomes. The preliminary metatranscriptomic results revealed that the most significantly up-regulated genes of CAP IB HKU-1 from the anaerobic to the aerobic phase were responsible for assimilatory sulfate reduction, genetic information processing and phosphorus absorption, while the down-regulated genes were related to N2O reduction, PHA synthesis and acetyl-CoA formation. This study yielded another important Accumulibacter genome, revealed the functional difference within the Accumulibacter Type I, and uncovered the genetic responses to EBPR stimuli at a higher resolution.

This study aimed to investigate the expression pattern and prognostic value of friend leukemia virus integration 1 (FLI-1) in nasopharyngeal carcinoma (NPC). Immunohistochemistry (IHC) staining of FLI-1 was performed in specimens from 198 untreated NPC patients. Ninety-nine patients were randomly assigned to the training set to analyze the prognostic value of FLI-1 and other clinicopathological characteristics, while the others were assigned to the testing set for validation. Clinicopathological data were compared using the Pearson chi-square test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to test independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI). Cytoplasmic FLI-1 expression positively correlated with N stage, distant metastasis and death (P

Background: To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT). Methods: We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN. Results: White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077). Conclusions: The IMRT-induced TLN was less extensive and milder than 2D-RT-induced TLN, but both had similar clinical features.

The development of improved diagnostic and therapeutic techniques has revolutionized the management of nasopharyngeal carcinoma (NPC). The purpose of this study is to revaluate the prognostic value of parapharyngeal extension in NPC in the IMRT era.We retrospectively reviewed data from 749 biopsy-proven non-metastatic NPC patients. All patients were examined with magnetic resonance imaging (MRI) and received intensity-modulated radiotherapy (IMRT) as the primary treatment.The incidence of parapharyngeal extension was 72.1%. A significant difference was observed in the disease-free survival (DFS; 70.3% vs. 89.1%, P0.001), distant metastasis-free survival (DMFS; 79.3% vs. 92.0%, P0.001), and local relapse-free survival (LRFS; 92.8% vs. 99.0%, P=0.002) of patients with and without parapharyngeal extension. Parapharyngeal extension was an independent prognostic factor for DFS and DMFS in multivariate analysis (P=0.001 and P=0.015, respectively), but not LRFS. The difference between DMFS in patients with or without parapharyngeal space extension was statistically significant in patients with cervical lymph node metastasis (P0.001).In the IMRT era, parapharyngeal extension remains a poor prognosticator for DMFS in NPC, especially in patients with positive lymph node metastasis. Additional therapeutic improvements are required to achieve a favorable distant control in NPC with parapharyngeal extension.

Background: We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown. Methods: We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy. Results: Cranial nerve invasion was observed in 299 (39.9%) patients with T3–4 disease. In T3–4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively). Conclusions: Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

Background: In this study, we evaluated the 8th edition of the Union for International Cancer Control (UICC)/AJCC staging system for nasopharyngeal carcinoma (NPC) in an endemic area, with the aim of validating its applicability and providing further information for future refinements. Methods: A total of 1,790 patients with newly diagnosed, non-distant metastatic, histologically proven NPC treated with intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. The performance of various staging systems was compared using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: For N (node) category, the survival curves of different groups according to the 8th edition were well-separated, and the prognostic model predicted outcomes fairly well. The 8th edition had higher AIC and c-index values for all end points than the 7th edition. However, probably due to the improved locoregional control provided by IMRT, the survival curves for T2 and T3 almost overlapped, without significant differences in locoregional failure-free survival (P=.606) and disease-free survival (P=.735). Due to the difficultly of differentiating T2 and T3, the AIC and c-index values were similar for the T categories of the 7th and 8th editions. Similarly, the overall survival and disease-free survival curves for stage II and III disease were not clearly separated for either the 8th or 7th editions. Conclusions: The 8th edition of the UICC/AJCC staging system for NPC enables more accurate prediction of treatment outcomes. However, several limitations need to be addressed in future editions, and it would be reasonable to further optimize the T category classification.

Background The prognostic values of staging parameters require continual re-assessment amid changes in diagnostic and therapeutic methods. This study aimed to identify the prognostic factors and failure patterns of non-metastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. Methods We reviewed the data from 749 patients with newly diagnosed, biopsy-proven, non-metastatic NPC in our cancer center (South China, an NPC endemic area) between January 2003 and December 2007. All patients underwent magnetic resonance imaging (MRI) before receiving IMRT. The actuarial survival rates were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insignificant explanatory variables. Results The 5-year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5-year survival rates were as follows: local relapse-free survival, 94.6%; nodal relapse-free survival, 97.0%; distant metastasis-free survival, 82.6%; disease-free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only significant prognostic factor for local failure (P = 0.011). Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho’s location of the cervical lymph nodes were significant prognostic factors for both distant failure and disease failure (all P

Bromate is a weakly carcinogenic disinfection by-product generated from naturally existing bromide during ozonation. In order to uncover the phylogenetic diversity of bromate-reducing aquatic bacteria, the microbial mixed cultures were enriched anaerobically from various activated sludge samples with a high concentration of 3.6 mmol/L bromate which served as the electron acceptor in batch-fed reactors. Then the phylogenetic diversity was characterized by employing 16S rRNA gene-based clone libraries and high-throughput sequencing. Results showed that as highest as 48.65 mg/L [BrO3−-Br] (0.61 mmol/L) could be reduced to Br− within an operational cycle of 48 h, indicating the presence of bromate-reducing bacteria. The microbial analysis based on 16S rRNA gene clone libraries indicated that the dominant bacteria in the enriched consortium were affiliated to the genera of Aeromonas, which had been reported and implied its functional application to reduce bromate. In addition, some other subdivisions of bromate-reducing bacteria were enriched at different operational cycles. The abundance of the genus Rivibacter belonging to Comamonadaceae were increased after 10 cycles enrichment, which might represent another type of novel bromate bio-reducers. The study provided new insights for the phylogenetic diversity of the bromate-reducing microorganisms while further researches are required to verify the bromate bio-reduction mechanism.

This study investigated a new method of multiple-cycle operation of a sulphur-cycle-enhanced biological phosphorus (P) removal system to maintain good phosphorus removal performance at a high temperature (30 °C). The findings demonstrate that P removal was low and unstable under a normal cycle (77 ± 18%), but multiple cycles resulted in a high and quite stable level of P removal (88 ± 9%). Moreover, in the normal mode, the polyhydroxyalkanoate levels increased significantly from 2 to 15 mg C/g of VSS, the glycogen level doubled from 5 to 10 mg C/g of VSS and the polyhydroxyalkanoate and glycogen levels were maintained at considerably low levels after multiple cycles (only 5 C/g of VSS). The 16S rRNA high-throughput sequencing analysis revealed that the genera Thioalbus and Psychrobacter in the gamma-Proteobacteria class were the key functional communities. These findings suggest a high level of P removal with multiple cycles of sulphur-cycle enhanced biological phosphorus removal.

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

Background: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC. Methods: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database. Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer. Results: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival. Conclusions: Many NPC trials excluded patients with prior cancer, which impacts trial accrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials. Citation Format: Ya-Qin Wang, Jia-Wei Lv, Ling-Long Tang, Xiao-Jing Du, Lei Chen, Wen-Fei Li, Xu Liu, Ying Guo, Ai-Hua Lin, Yan-Ping Mao, Ying Sun, Yu-Pei Chen, Jun Ma. Effect of Prior Cancer on Trial Eligibility and Treatment Outcomes in Nasopharyngeal Carcinoma: Implications for Clinical Trial Accrual [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4006.

Recent findings have reported that human serum microRNAs (miRNAs) can be used as prognostic biomarkers in various cancers. We aimed to explore the prognostic value of serum miRNAs in nasopharyngeal carcinoma (NPC) patients. The level of serum miRNA was retrospectively analyzed in 512 NPC patients recruited between January 2001 and December 2006. In the discovery stage, a microarray followed by reverse transcription-quantitative polymerase chain reaction was used to identify differentially altered miRNAs in eight patients with shorter survival and eight patients with longer survival who were well matched by age, sex and clinical stage. The identified serum miRNAs were then validated in all 512 samples, which were randomly divided into a training set and a validation set. Four serum miRNAs (miR-22, miR-572, miR-638 and miR-1234) were found to be differentially altered and were used to construct a miRNA signature. Risk scores were calculated to classify the patients into high- or low-risk groups. Patients with high-risk scores had poorer overall survival [hazard ratio (HR), 2.54; 95% confidence interval (CI), 1.57-4.12; p < 0.001] and distant metastasis-free survival (HR, 3.28; 95% CI, 1.82-5.94; p < 0.001) than those with low-risk scores in the training set; these results were confirmed in the validation and combined sets. The miRNA signature and TNM stage were independent prognostic factors. The combination of the miRNA signature and TNM stage had a better prognostic value than the TNM stage or miRNA signature alone. The four-serum miRNA signature may add prognostic value to the TNM staging system and provide information for personalized therapy in NPC.

BACKGROUND The current study investigated the prevalence and prognostic value of chronic hepatitis B virus (HBV) infection in patients with nasopharyngeal carcinoma (NPC) from an area in southern China in which HBV and NPC are endemic. METHODS A total of 1301 patients with nonmetastatic, histologically proven NPC who were treated with radiotherapy or chemoradiotherapy were retrospectively reviewed. RESULTS In this series, 142 of the 1301 patients (10.9%) had chronic HBV infection (hepatitis B surface antigen [HBsAg] seropositive). The percentages of non–cancer-related deaths (15.0% vs 12.1%; P = .618) and severe hepatic adverse events (3.5% vs 0.9%; P = .145) were similar among patients with NPC with and without HBV infection. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRFS) rates for patients with NPC with or without HBV infection were 70.9% and 80.8% (P = .003), 63.7% and 73.0% (P = .016), and 81.7% and 88.2% (P = .035), respectively. Multivariate analysis identified chronic HBV infection in patients with NPC as an independent unfavorable prognostic factor for OS (hazards ratio [HR], 1.684; P = .003), PFS (HR, 1.451; P = .015), and LRFS (HR, 1.573; P = .048). Further analysis revealed that chronic HBV infection was an unfavorable, independent prognostic factor in patients with locoregionally advanced NPC, but not those with early-stage disease. In patients with stage III/IV NPC, HBsAg-positive patients had poorer OS (64.0% vs 77.2%; P = .003), PFS (56.2% vs 70.6%; P = .004), and LRFS (76.2% vs 88.3%; P = .002) compared with HBsAg-negative patients. On multivariate analysis, chronic HBV infection was found to be an independent adverse prognostic predictor for OS (HR, 1.734; P = .004), PFS (HR, 1.644; P = .003), and LRFS (HR, 2.108; P = .003) in patients with stage III/IV NPC. CONCLUSIONS Chronic HBV infection is an independent adverse prognostic factor in patients with locoregionally advanced NPC. Cancer 2014;120:68–76. © 2013 American Cancer Society.

The prognostic value of T category for locoregional control in patients with nasopharyngeal carcinoma (NPC) has decreased with the extensive use of intensity-modulated radiotherapy (IMRT). We aimed to develop a prognostic scoring system (PSS) that incorporated tumor extension and clinical characteristics for locoregional control in NPC patients treated with IMRT. The magnetic resonance imaging scans and medical records of 717 patients with nonmetastatic NPC treated with IMRT at Sun Yat-sen University Cancer Center between January 2003 and January 2008 were reviewed. Age, pathologic classification, primary tumor extension, primary gross tumor volume (GTV-p), T and N categories, and baseline lactate dehydrogenase (LDH) level were analyzed. Hierarchical cluster analysis as well as univariate and multivariate analyses were used to develop the PSS. Independent prognostic factors for locoregional relapse included N2–3 stage, GTV-p ≥26.8 mL, and involvement of one or more structures within cluster 3. We calculated a risk score derived from the regression coefficient of each factor and classified patients into four groups: low risk (score 0), intermediate risk (score >0 and ≤1), high risk (score >1 and ≤2), and extremely high risk (score >2). The 5-year locoregional control rates for these groups were 97.4%, 93.6%, 85.2%, and 78.6%, respectively (P < 0.001). We have developed a PSS that can help identify NPC patients who are at high risk for locoregional relapse and can guide individualized treatments for NPC patients.

Background: Family history of cancer is associated with developing nasopharyngeal carcinoma (NPC); however, the impact of it on survival among established NPC patients remains unknown. Methods: We retrospectively analysed 1773 southern Chinese patients. Associations between a first-degree family history of NPC and overall survival (OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) were estimated by Cox regression. Results: Among 1773 patients, 207 (11.7%) reported a first-degree family history of NPC. Compared with patients without a family history, the adjusted hazard ratios among those with it were 0.60 (95% confidence interval (CI), 0.37–0.98; P=0.040) for OS, 0.52 (95% CI, 0.24–1.12; P=0.096) for LRFS and 0.51 (95% CI, 0.27–0.97; P=0.040) for DMFS. There were trends for improving OS, LRFS and DMFS with increasing number of affected relatives (Ptrend: 0.050, 0.114 and 0.044, respectively). But no significant benefits of family history in second- or third-degree relatives were observed. In subgroup analysis, we observed the effects of family history with restriction to male patients and those of advanced stage and treated with conventional radiotherapy and addition of chemotherapy. Conclusion: A first-degree family history of NPC is associated with improved survival of patients.

Background The purpose of this study was to summarize the treatment outcomes and evaluate the feasibility of partial neck irradiation in patients with nasopharyngeal carcinoma (NPC) with only retropharyngeal lymph nodes (RLNs) metastasis. Methods Between January 2003 and December 2007, 54 patients with NPC who received partial neck irradiation to levels II, III, and VA and 100 patients who received whole neck irradiation were reviewed. Results The 5-year disease free survival (DFS), disease metastasis-free survival, (DMFS) local relapse-free survival (LRFS), and regional relapse-free survival (RRFS) rates were 81.8%, 87.7%, 94.8%, and 98.1%, respectively. The 5-year RRFS and DFS rates for the partial neck irradiation group and whole neck irradiation group were 98.1% versus 98.0% (p = .882), 87.0% vs 77.0% (p = .117), respectively. Partial neck irradiation was not considered a significant prognostic factor for any endpoint in univariate and multivariate analyses. Conclusion Partial irradiation of neck levels II, III, and VA might be acceptable for patients with NPC with only RLN metastasis. © 2013 Wiley Periodicals, Inc. Head Neck 36: 468–473, 2014

To propose a lymph node (N) staging system for nasopharyngeal carcinoma (NPC) based on the International Consensus Guidelines for lymph node (LN) levels and MRI-determined nodal variables.The MRI scans and medical records of 749 NPC patients receiving intensity modulated radiation therapy with or without chemotherapy were retrospectively reviewed. The prognostic significance of nodal level, laterality, maximal axial diameter, extracapsular spread, necrosis, and Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) size criteria were analyzed.Nodal level and laterality were the only independent prognostic factors for distant failure and disease failure in multivariate analysis. Compared with unilateral levels Ib, II, III, and/or Va involvement (hazard ratio [HR] 1), retropharyngeal lymph node involvement alone had a similar prognostic value (HR 0.71; 95% confidence interval [CI] 0.43-1.17; P=.17), whereas bilateral levels Ib, II, III, and/or Va involvement (HR 1.65; 95% CI 1.06-2.58; P=.03) and levels IV, Vb, and/or supraclavicular fossa involvement (HR 3.47; 95% CI 1.92-6.29; P.01) both significantly increased the HR for distant failure. Thus we propose that the N category criteria could be revised as follows: N0, no regional LN metastasis; N1, retropharyngeal lymph node involvement, and/or unilateral levels Ib, II, III, and/or Va involvement; N2, bilateral levels Ib, II, III, and/or Va involvement; N3, levels IV, Vb, and/or supraclavicular fossa involvement. Compared with the 7th edition of the UICC/AJCC criteria, the proposed N staging system provides a more satisfactory distinction between the HRs for regional failure, distant failure, and disease failure in each N category.The proposed N staging system defined by the International Consensus Guidelines and laterality is predictive and practical. However, because of no measurements of the maximal nodal diameter on MRI slices, the prognostic significance of LN size needs further evaluation.

The present study, for the first time, reported a Thauera-dominated hydrogen-oxidizing autotrophic denitrifying microbial community enriched from different seed sludges including activated sludge and anaerobic digestion sludge. After 244 days enrichment, nitrogen removal rates reached up to 0.2 mg N/mg VSS/ d which were comparable to that of the model organism Paracoccus denitrificans under the same conditions. Furthermore, high-throughput sequencing was applied to characterize and compare the seed sludges and enriched cultures. Operational taxonomic units (OTU)-based analysis (97% similarity cutoff) of total 280,000 16S rRNA gene V6 region sequences from 7 sludge samples (40,000 sequences per sample) revealed that the microbial diversity decreased after the enrichment, indicated by OTU numbers drop of 55–60%. Thauera species in the class of b-Proteobacteria were enriched into the dominant populations with relative abundances of 47–62%, regardless of seed sludge sources.

PURPOSE Conditional survival (CS) provides important information on survival for a period of time after diagnosis. Currently, information on CS patterns of patients with nasopharyngeal carcinoma (NPC) is lacking. We aimed to analyze survival rate over time and estimate CS for NPC patients using a national population-based registry. MATERIALS AND METHODS Patients diagnosed with NPC between 1973 and 2007 with at least 5-year follow-up were identified from the Surveillance Epidemiology End Results registry. Traditional survival rates and crude CS estimateswere calculated using Kaplan-Meier analysis. Risk-adjusted survival curves were plotted from the proportional hazards model using the correct group prognosis method. RESULTS registry. Traditional survival rates and crude CS estimateswere calculated using Kaplan-Meier analysis. Risk-adjusted survival curves were plotted from the proportional hazards model using the correct group prognosis method. RESULTS For 7,713 patients analyzed, adjusted baseline 5-year overall survival improved significantly from 36.0% in patients diagnosed in 1973-1979, 41.7% in 1980-1989, 46.6% in 1990-1999, to 54.7% in 2000-2007 (p < 0.01). CS analysis demonstrated that for every additional year survived, adjusted probability of surviving the next 5 years increased from 66.7% (localized), 54.0% (regional), and 35.3% (distant) at the time of diagnosis, to 83.7% (localized), 75.0% (regional), and 62.2% (distant) for patients who had survived 5 years. Adjusted 5-year CS differed among age, sex, tumor histology, ethnicity, and stage subgroups initially, but converged with time. CONCLUSION Treatment outcomes of NPC patients have greatly improved over the decades. Increases in CS become more prominent in patients with distant disease than in those with localized or regional disease as patients survive longer. CS provides more dynamic prognostic information for patients who have survived a period of time after diagnosis.

Tumor response to neoadjuvant chemotherapy using the regimen of cisplatin and 5-fluorouracil could define high-risk patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, the regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) appears to be more effective than the regimen of cisplatin and 5-fluorouracil. Therefore, one needs to redefine the high-risk subpopulation of patients receiving neoadjuvant chemotherapy with TPF.A total of 231 patients from a randomized phase 3 trial with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC (except T3-T4N0 disease) who were receiving treatment with the TPF regimen were enrolled. Patient survival rates between different groups were compared.Of the 231 patients, the overall response to neoadjuvant chemotherapy was a complete response (CR) for 26 (11.3%), a partial response (PR) for 184 patients (79.6%), and stable disease (SD) for 21 patients (9.1%). Univariate analysis revealed the 3-year failure-free survival (FFS) rates in the CR (88.5% vs 61.9%; P =.017) and PR (81.2% vs 61.9%; P = .01) groups, and the 3-year overall survival rates for the CR (96.2% vs 76.2%; P =.048) and PR (93.4% vs 76.2%; P =.025) groups were obviously higher compared with that of the SD group. In multivariate analysis, CR was established as a favorable prognostic factor for FFS (hazard ratio [HR], 0.210; 95% confidence interval [95% CI], 0.057-0.779 [P =.02]), and PR for FFS (HR, 0.447; 95% CI, 0.213-0.936 [P =.033]) and OS (HR, 0.361; 95% CI, 0.132-0.986 [P =.047]) when compared with SD. No survival difference was observed between the CR and PR groups.Tumor response to TPF may be a properly powerful prognosis predictor and help to develop individualized treatment strategies for patients with locoregionally advanced NPC. Cancer 2017;123:1643-1652. © 2017 American Cancer Society.

Purpose : To evaluate the prognostic value of magnetic resonance imaging (MRI)-detected tumor residue after intensity-modulated radiation therapy (IMRT) and its association with post-treatment plasma Epstein-Barr virus deoxyribonucleic acid (EBV DNA) in nasopharyngeal carcinoma (NPC). Methods and materials : A prospective database of patients with histologically-proven NPC was used to retrospectively analyze 664 cases. Pre- and post-treatment MRI scans were independently reviewed by two senior radiologists who were blinded to clinical findings. Factors significantly associated with MRI-detected tumor residue were identified and included in the following multivariate logistic regression model. Residual risk model were established. Receiver operating characteristic (ROC) identify the optimal cut-off risk score for tumor residue. Results : MRI-detected residual tumor at three months after IMRT was associated with poor prognosis. The 5-year survival rates for the non-residual and residual groups were: OS (93.8% vs. 76.6%, P

A sequencing batch reactor fed mainly by acetate was operated to perform enhanced biological phosphorus removal (EBPR). A short-term pH shock from 7.0 to 6.0 led to a complete loss of phosphate-removing capability and a drastic change of microbial communities. 16S rRNA gene pyrosequencing showed that large proportions of glycogen accumulating organisms (GAOs) (accounted for 16% of bacteria) bloomed, including Candidatus Competibacter phosphatis and Defluviicoccus-related tetrad-forming organism, causing deteriorated EBPR performance. The EBPR performance recovered with time and the dominant Candidatus Accumulibacter (Accumulibacter) clades shifted from Clade IIC to IIA while GAOs populations shrank significantly. The Accumulibacter population variation provided a good opportunity for genome binning using a bi-dimensional coverage method, and a genome of Accumulibacter Clade IIC was well retrieved with over 90% completeness. Comparative genomic analysis demonstrated that Accumulibacter clades had different abilities in nitrogen metabolism and carbon fixation, which shed light on enriching different Accumulibacter populations selectively.

We designed novel quantitative real-time polymerase chain reaction (qPCR) primers for the polyphosphate kinase 1 (ppk1) gene, targeting eight individual “Candidatus Accumulibacter” (referred to as Accumulibacter) clades. An evaluation of primer sets was conducted regarding the coverage, specificity, and PCR efficiency. (i) All primer sets were designed to cover all available sequences of the target clade. (ii) The phylogenetic analysis of the sequences retrieved from the qPCR products by each primer set demonstrated a high level of specificity. (iii) All calibration curves presented high PCR efficiencies in the range of 85–112% (R2 = 0.962–0.998). In addition, the possible interference of non-target amplicons was individually examined using the qPCR assay for 13 Accumulibacter clades, which were either undetected or showed negligible detection. With the primers designed by other research groups, a highly selective and sensitive qPCR-based method was developed to quantify all Accumulibacter clades, with the exception of Clade IE, in one assay, which enables more comprehensive insights into the community dynamics. The applicability to environmental samples was demonstrated by profiling the Accumulibacter clades in activated sludge samples of nine full-scale wastewater treatment plants.

The prognostic value of the tumour response to induction chemotherapy (IC) for long-term survival outcomes after intensity-modulated radiation therapy in nasopharyngeal carcinoma (NPC) remains unknown. We retrospectively reviewed 1811 consecutive patients with newly diagnosed NPC treated using IMRT, and 399 eligible patients with pre- and post-induction chemotherapy magnetic resonance images were recruited. The clinicopathological features of patients with different tumour responses were compared using the Chi-square test or Fisher’s exact test. Prognostic value was assessed using a multivariate Cox proportional hazards model. After IC, 101/399 (25.3%) patients had a complete tumour response overall (CR), 262 (65.7%) had a partial response (PR) and 36 (9.0%) had stable disease (SD). The 4-year disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) rates for CR vs. PR vs. SD were 90.0% vs. 79.0% vs. 58.2% (CR vs. PR: P1 = 0.007; CR vs. SD: P2 P3 = 0.004), 95.7% vs. 88.7% vs. 70.2% (P1 = 0.017, P2 P3 = 0.005), 92.0% vs. 87.4% vs. 74.3% (P1 = 0.162, P2 = 0.005, P3 = 0.029) and 95.9% vs. 88.8% vs. 81.8% (P1 = 0.024, P2 = 0.006, P3 = 0.268), respectively. Multivariate analysis identified that the tumour response to IC was an independent prognostic factor for DFS, OS and LRRFS.

The prognostic value of dynamic serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) hasn’t been explored. We retrospectively analyzed 1,428 cases of NPC treated with IMRT with or without chemotherapy. Elevated pre- and/or post-treatment LDH levels were found to be associated with unfavorable overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS), but not with local relapse-free survival (LRFS). The dynamic variations in LDH levels were prognostic factors for OS, DFS and DMFS, but not for LRFS. Multivariate analysis revealed that the N category, T category, post-treatment serum LDH level and age were independent prognostic factors for OS. Our results demonstrated that dynamic variations in LDH levels were associated with risk of distant failure and death, which may shed light on the dynamics of the disease and the response to therapy. We consider that LDH measurements will be of great clinical importance in the management of NPC, especially, when considering “decision points” in treatment algorithms. Therefore, we strongly recommend that LDH levels should be determined before and after treatment in NPC patients and the results integrated into decisions regarding treatment strategies.