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Gene expression analysis (e.g., targeted gene panels, transcriptomics) from whole blood can elucidate mechanisms of immune function and aid in the discovery of biomarkers. Conventional venipuncture offers only a small snapshot of our broad immune landscape as immune responses may occur outside of the time and location parameters available for conventional venipuncture. A self-operated method that enables flexible sampling of liquid whole blood coupled with immediate stabilization of cellular RNA is instrumental in facilitating capture and preservation of acute or transient immune fluxes. To this end, we developed homeRNA: a kit for self-collection of peripheral blood (∼0.5 mL) and immediate stabilization of cellular RNA, using the Tasso- SST™ blood collection device with a specially designed stabilizer tube containing RNAlater™. To assess the feasibility of homeRNA for self-collection and stabilization of whole blood RNA, we conducted a pilot study (n = 47 participants) where we sent homeRNA to participants aged 21-69, located across 10 US states (94% successful blood collections, n = 61/65). Among participants who successfully collected blood, 93% reported no or minimal pain/discomfort using the kit (n = 39/42), and 79% reported very easy/somewhat easy stabilization protocol (n = 33/42). Total RNA yield from the stabilized samples ranged between 0.20 µg and 5.99 µg (mean = 1.51 µg), and all but one RNA Integrity Number (RIN) values were above 7.0 (mean = 8.1), indicating limited RNA degradation. Results from this study demonstrate the self-collection and RNA stabilization of whole blood with homeRNA by participants themselves, in their own home.

Background To test the advantages of positron emission tomography and computed tomography (PET/CT) for diagnosing lymph nodes and staging nasopharyngeal carcinoma and to investigate its benefits for survival and treatment decisions. Methods The performance of PET/CT and magnetic resonance imaging (MRI) in diagnosis was compared based on 460 biopsied lymph nodes. Using the propensity matching method, survival differences of T3N1M0 patients with (n = 1093) and without (n = 1377) PET/CT were compared in diverse manners. A radiologic score model was developed and tested in a subset of T3N1M0 patients. Results PET/CT performed better than MRI with higher sensitivity, accuracy, and area under the receiver operating characteristic curve (96.7% vs. 88.5%, p p p p p = 0.006) for the high-risk patients selected by the model but not for those without risk stratification (p = 0.78). Conclusion PET/CT showed advantages in staging nasopharyngeal carcinoma due to a more accurate diagnosis of lymph nodes and this contributed to a survival benefit. PET/CT combined with MRI provided prognostic factors that could identify high-risk patients and guide individualized treatment.

Objectives This study aimed to retrospectively assess whether community pharmacy customers accepted the pharmacist’s recommendations for the selection of an antihistamine based on medicine optimization guidelines. Methods A retrospective study was conducted on the implementation of an antihistamine use optimization guide for patients who were seeking first-generation antihistamines between July and December 2019 across forty-five community pharmacies in Singapore. The primary outcome measure was the acceptance rate of ceasing or substituting first-generation antihistamine with a second-generation antihistamine. Secondary measures included the reduction in types of first-generation antihistamines used, adverse drug-related events reported, intended use of antihistamines and the types of recommendations. Key findings During the study period, 2328 patients fulfilled the inclusion criteria, out of which 523 patients agreed to optimize their use of sedating first-generation antihistamines. Chlorpheniramine (95.2%) was the most widely accepted first-generation antihistamine for optimization, with 59.6% of the users experiencing adverse events, the most common being drowsiness (53.2%). The main indication of use was allergic conditions (allergic rhinitis or atopic dermatitis) (70.3%). After implementation of the guide, most interventions were direct substitution (72.8%) with a less-sedating antihistamine, followed by gradual tapering (22.6%). Loratadine, a second-generation antihistamine, was most frequently (51.4%) used to substitute first-generation antihistamines. The optimization guide can potentially reduce adverse effects in 59.6% (297 patients) of chlorpheniramine users, which were mainly drowsiness (265 patients; 53.2%) and dry mouth (14 patients; 2.8%). Conclusions This study highlighted the importance of assessing and reducing potentially inappropriate first-generation antihistamine self-use and that a guided approach and substitution with less-sedating antihistamines can be employed in the community pharmacy setting.

Botanic bioactive substances have issues with their solubility, stability, and oral bioavailability in the application, which could be improved by nanotechnologies. In another hands, green synthesis of nanoparticles (NPs) with plant extract is also a promising technology for preparation of NPs due to its safety advantage, yet the bioactive botanic substances that could be more than the assistant of the green synthesis of NPs. Based on the above concerns, this review summarized the preparation of botanic NPs with various plant extract, their solubility, stability, and oral bioavailability; specific attention has been paid to the botanic Ag/Au NPs, their capacity of antioxidant, bioavailability, antimicrobial, anti-inflammatory, and anticancer.

It has been identified that malnutrition can influence the immune system and time of engraftment, and it's also associated with increased incidence of complications, prolonged length of hospital stays, and transplant mortality and morbidity in patients undergoing hematopoietic stem cell transplantation (HSCT), so dynamic nutrition care is highly important. The aim of this study was to better understand the differences between clinical nutrition practices and international recommendations as well as possible barriers to the use of nutrition support in HSCT patients. An evidence-based nutrition support pathway was constructed through a systematic literature review to identify evidence and recommendations relating to the relevant issues. Then, a questionnaire consisting of 28 questions that focused on the 4 topics, namely, assessment and screening for malnutrition, nutrition support interventions, nutrition support in gastrointestinal graft-versus-host disease (GVHD) and neutropenic diet was developed by the study authors and used for data collection. Responses of 18 HSCT centers from 17 provinces were received. General assessment for malnutrition was performed at 72% (13/18) centers. Parenteral nutrition (PN) was given as the first option to HSCT patients in the majority of centers, despite the fact that current guidelines recommend enteral nutrition (EN) over PN. As many as 72% (13/18) of the centers considered a neutropenic diet in the management of HSCT patients, but only one center had a formal neutropenic diet protocol in place for transplant recipients. Criteria for initiating nutrition support in patients with gastrointestinal GVHD were heterogeneous among the centers, and PN was the most widely used technique. The survey results revealed significant heterogeneity with regard to nutrition support practices among the centers, as well as between the practices and the guidelines. Standard nutrition support guidelines or protocols for nutrition support practices were absent in most of the centers.

Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.

Ascorbate (vitamin C) is an essential micronutrient in humans. The chronic severe deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. Here, from a micronutrient screen, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique, as other antioxidants failed to promote plasma cell differentiation. Ascorbate is critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. Consistent with its role as a cofactor for epigenetic enzymes, ascorbate potentiates plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translocation), the enzymes responsible for DNA demethylation by oxidizing 5-methylcytosines into 5-hydroxymethylcytosine (5hmC). Genome-wide 5hmC profiling identified ascorbate responsive elements (EAR) at the Prdm1 locus, including a distal element with a STAT3 motif overlapped with a CpG that was methylated and modified by TET in the presence of ascorbate. The results suggest that an adequate level of VC is required for antibody response and highlight how micronutrients regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions.

Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Autophagy is an important mechanism for cellular self-digestion and basal homeostasis. This gene- and modulator-regulated pathway is conserved in cells. Recently, several studies have shown that autophagic dysfunction is associated with pulmonary hypertension (PH). However, the relationship between autophagy and PH remains controversial. In this review, we mainly introduce the effects of autophagy-related genes and some regulatory molecules on PH and the relationship between autophagy and PH under the conditions of hypoxia, monocrotaline injection, thromboembolic stress, oxidative stress, and other drugs and toxins. The effects of other autophagy-related drugs, such as chloroquine, 3-methyladenine, rapamycin, and other potential therapeutic drugs and targets, in PH are also described.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Background: First degree family history of cancer is associated with developing esophageal cancer and sparse data is about the impact on poor survival among established esophageal squamous cell cancer (ESCC) patients. In this study, we investigated the prognoses of patients with ESCC with a family history. Methods: A total of 479 ESCC patients were retrospectively enrolled from a Southern Chinese institution. A positive family history was defined as having malignant cancer among parents and siblings. Kaplan-Meier plots and Cox proportional hazards regressions were applied for overall survival (OS) and progression-free survival (PFS). Results: Among 479 patients, 119 (24.8%) and 68 (14.2%) reported a first-degree family history of cancer and digestive tract cancer, respectively. Compared with patients without a family history of cancer, the adjusted hazard ratios (HR) among those with it were 1.40 (95% CI, 1.08-1.82, p=0.011) for death, 1.36 (95% CI, 1.05-1.76, p=0.018) for progression. Similar results were observed in those with a family history of digestive tract cancer (HR=1.69, 95%CI, 1.24-1.98, p=0.001 for death and HR=1.77, 95%CI, 1.30-2.37, p

Background The implication of circular RNAs (circRNAs) in human cancers has aroused much concern. In this study, we investigated the function of circ_0000745 and its potential functional mechanisms in oral squamous cell carcinoma (OSCC) to further understand OSCC pathogenesis. Methods The expression of circ_0000745, miR-488 and cyclin D1 (CCND1) mRNA was measured by quantitative real-time polymerase chain reaction (qPCR). Cell proliferation capacity was assessed by cell counting kit-8 (CCK-8) assay and colony formation assay. Cell cycle progression and cell apoptosis were determined by flow cytometry assay. The protein levels of CCND1, PCNA, Cleaved-caspase 3 and HuR were detected by western blot. Animal study was conducted to identify the role of circ_0000745 in vivo. The targeted relationship was verified by dual-luciferase reporter assay, pull-down assay or RNA immunoprecipitation (RIP) assay. Results The expression of circ_0000745 was increased in OSCC tissues and cells. Circ_0000745 downregulation inhibited OSCC cell proliferation and induced cell cycle arrest and apoptosis in vitro, as well as blocked tumor growth in vivo. MiR-488 was a target of circ_0000745, and circ_0000745 downregulation suppressed OSCC development by enriching miR-488. Besides, circ_0000745 regulated CCND1 expression by targeting miR-488. In addition, circ_0000745 regulated CCND1 expression by interacting with HuR protein. CCND1 knockdown also inhibited OSCC cell proliferation and induced cell cycle arrest and apoptosis in vitro, and CCND1 overexpression recovered the inhibitory effects on OSCC cell malignant behaviors caused by circ_0000745 downregulation. Conclusions Circ_0000745 regulated the expression of CCND1 partly by acting as miR-488 sponge and interacting with HuR protein, thus promoting the progression of OSCC.

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

Stevia leaves have been claimed to possess the highest antioxidant capacity among botanic foods, yet the antioxidant activity has been attributed to the polyphenols from Stevia leaves (PPS). However, most studies about the PPS were based on Stevia extracts that contain abundant polyphenols and flavonoids. The PPS excluded flavonoids were found to possess antioxidant activity similar to that of epigallocatechin gallate, demonstrating stronger hydrophilic antioxidant activity and stability than that of ascorbic acid (VC), vitamin E, or chlorogenic acid under the assayed circumstances. Both of the PPS and their antioxidant activity are very stable in various physical environments, but less stable in the presence of potassium sorbate or sucrose. Moreover the combination of PPS and VC could increase the antioxidant stability of either VC or PPS. Therefore, the PPS have the potential to be a natural, inexpensive, and abundant antioxidant that can be utilized in the pharmaceutical and cosmetics. PRACTICAL APPLICATIONS: The PPS excluded flavonoids were found to possess antioxidant activity similar to that of epigallocatechin gallate, demonstrating stronger hydrophilic antioxidant activity and stability than that of ascorbic acid (VC), vitamin E, or chlorogenic acid under the assayed circumstances. Both of the PPS and their antioxidant activity are very stable in various physical environments, but less stable in the presence of potassium sorbate or sucrose. Moreover the combination of PPS and VC could increase the antioxidant stability of either VC or PPS. Therefore, the PPS have the potential to be a new natural, inexpensive, and abundant antioxidant that can be utilized in the pharmaceutical and cosmetics.

BACKGROUND This study aimed to summarize the association between diabetes mellitus (DM) and the incidence of lung cancer using a meta-analysis of cohort studies. MATERIALS AND METHODS We systematically searched PubMed, Embase and the Cochrane Library to identify potential cohort studies. Relative risk (RR) was used to calculate the association between DM and the risk of lung cancer. Subgroup analysis, sensitivity analysis and test for publication bias were performed. Twenty cohort studies were selected. RESULTS The participants with DM showed little or no significant effect on the risk of lung cancer (RR: 1.10; 95% CI: 0.99-1.23; P = .087). DM was not associated with the risk of lung cancer in men (RR: 1.11; 95%CI: 0.92-1.35; P = .270), but a significant association was observed in women (RR: 1.18; 95%CI: 1.10-1.28; P

Zhen Su,1,* Guo-rong Zou,1,* Jie Tang,1 Xiu Yue Li,1 Fang-Yun Xie2 1Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang-Yun XieDepartment of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of ChinaTel +86 20 87343484Email xiefy0758@sina.comBackground: The aim of this study was to evaluate the efficacy of induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) patients with moderate-risk treated with intensity-modulated radiotherapy (IMRT).Methods: We retrospectively assessed 506 patients with T1-2N1M0 or T3-4N0-1M0 NPC (according to the 2010 UICC/AJCC staging system) who received concurrent chemoradiotherapy (CCRT) with or without IC at a single center in China between 2005 and 2010. Survival outcomes were compared between the IC + CCRT and CCRT groups using the Kaplan–Meier method, Log-rank test and a Cox regression model.Results: Among the 506 patients, CCRT alone resulted in equivalent overall survival (86.8% vs 88.5%, p=0.661), progression-free survival (79.6% vs 79.6%, p=0.756), locoregional relapse-free survival (90.2% vs 87.0%, p=0.364) and distant metastasis-free survival (88.0% vs 89.8%, p= 0.407) to IC plus CCRT. In multivariate analysis, IC did not lower the risk of death (HR 0.76, 95% CI 0.46– 1.25, p= 0.278), progression (HR 0.78, 95% CI 0.51– 1.19, p= 0.244), locoregional relapse (HR 1.06, 95% CI 0.81– 1.42, p= 0.651) or distant metastasis (HR 0.66, 95% CI 0.38– 1.15, p= 0.140) in the entire cohort; similar results were obtained in stratified analysis based on N category (N0 vs N1) and EBV DNA (< vs ≥ 4000 copies/mL).Conclusion: Addition of IC to CCRT does not improve survival outcomes in moderate-risk NPC; the use of IC should be carefully considered in these patients, though additional prospective trials are warranted to confirm the conclusions of this study.Keywords: nasopharyngeal carcinoma, induction chemotherapy, prognosis, survival

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

Fungal spores contain secondary metabolites that can protect them from a multitude of abiotic and biotic stresses. Conidia (asexual spores) of the human pathogen Aspergillus fumigatus synthesize several metabolites, including melanin, which has been reported to be important for virulence in this species and to be protective against UV radiation in other fungi. Here, we investigate the role of melanin in diverse isolates of A. fumigatus and find variability in its ability to protect spores from UV-C radiation or impact virulence in a zebrafish model of invasive aspergillosis in two clinical strains and one ISS strain. Further, we assess the role of other spore metabolites in a clinical strain of A. fumigatus and identify fumiquinazoline as an additional UV-C-protective molecule but not a virulence determinant. The results show differential roles of secondary metabolites in spore protection dependent on the environmental stress and strain of A. fumigatus. As protection from elevated levels of radiation is of paramount importance for future human outer space explorations, the discovery of small molecules with radiation-protective potential may result in developing novel safety measures for astronauts., Fungi are versatile organisms which thrive in hostile environments, including the International Space Station (ISS). Several isolates of the human pathogen Aspergillus fumigatus have been found contaminating the ISS, an environment with increased exposure to UV radiation. Secondary metabolites (SMs) in spores, such as melanins, have been shown to protect spores from UV radiation in other fungi. To test the hypothesis that melanin and other known spore SMs provide UV protection to A. fumigatus isolates, we subjected SM spore mutants to UV-C radiation. We found that 1,8-dihydroxynaphthalene (DHN)-melanin mutants of two clinical A. fumigatus strains (Af293 and CEA17) but not an ISS-isolated strain (IF1SW-F4) were more sensitive to UV-C than their respective wild-type (WT) strains. Because DHN-melanin has been shown to shield A. fumigatus from the host immune system, we examined all DHN mutants for virulence in the zebrafish model of invasive aspergillosis. Following recent studies highlighting the pathogenic variability of different A. fumigatus isolates, we found DHN-melanin to be a virulence factor in CEA17 and IF1SW-F4 but not Af293. Three additional spore metabolites were examined in Af293, where fumiquinazoline also showed UV-C-protective properties, but two other spore metabolites, monomethylsulochrin and fumigaclavine, provided no UV-C-protective properties. Virulence tests of these three SM spore mutants indicated a slight increase in virulence of the monomethylsulochrin deletion strain. Taken together, this work suggests differential roles of specific spore metabolites across Aspergillus isolates and by types of environmental stress.

Background The tumor–node–metastasis (TNM) staging system does not perform well for guiding individualized induction or adjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We attempted to externally validate the Pan’s nomogram, developed based on the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system, for patients with locoregionally advanced disease. In addition, we investigated the reliability of Pan’s nomogram for selection of participants in future clinical trials. Methods This study included 535 patients with locoregionally advanced NPC who were treated between March 2007 and January 2012. The 5-year overall survival (OS) rates were calculated using the Kaplan–Meier method and compared with predicted outcomes. The calibration was tested using calibration plots and the Hosmer–Lemeshow test. Discrimination ability, which was assessed using the concordance index, as compared with other predictors. Results Pan’s nomogram was observed to underestimate the 5-year OS of the entire cohort by 8.65% [95% confidence interval (CI) − 9.70 to − 7.60%, P

Mallotus oblongifolius (MO), an edible medicinal plant from Hainan in China, shows a wide range of bioactivities. The daily consumption of MO or its extracts has been observed to ameliorate ischemic nerve injury. However the mechanisms remain unclear. In this study, the effects of MO both in vitro and in vivo were investigated. The results indicated that MO improved the motor ability, neurosensory ability, balance and grasping ability of mice with ischemic injuries, induced by bilateral common carotid artery ligation (BCCAL). In addition, MO improved the morphology of neurons, resisted the loss of neurons, and enhanced the content of the nestin protein in the cerebral cortex and subgranular zone (SGZ) area. Furthermore, in the oxygen-glucose deprivation and reperfusion (OGD/R) treated cell model, MO could effectively activate the Wnt/β-catenin signaling pathway and promote the proliferation of neural stem cells (NSCs) and increase the protein expression levels of β-catenin and CyclinD1. Our results suggest that Mallotus oblongifolius may be used as nutraceuticals or functional foods to alleviate ischemic nerve damage and promote recovery from ischemic stroke.

Background Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. Results Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. Conclusion This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population. Electronic supplementary material The online version of this article (10.1186/s12979-018-0120-0) contains supplementary material, which is available to authorized users.

Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most common acute optic neuropathies that affect the over 55-year-old population. NAION causes the loss of visual function, and it has no safe and effective therapy. Bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate, CDDO-Me, RTA 402) is a semisynthetic triterpenoid with effects against antioxidative stress and inflammation in neurodegeneration and kidney disease that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402 is an FDA-approved compound for the treatment of solid tumors, lymphoid malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also under clinical investigation for Friedreich ataxia (FA). In this study, a rodent anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on retinal ganglion cell (RGC) survival and visual function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the retina and optic nerve. However, these effects were not observed after RTA 408 treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2 and NFκB signaling pathways to protect RGCs from apoptosis and maintain the visual function in an rAION model. These findings indicate that RTA 402 may a potential therapeutic agent for ischemic optic neuropathy.

Objectives We aimed to validate and compare the 7th and 8th edition of AJCC staging systems for non-metastatic nasopharyngeal carcinoma, and proposed staging systems from Hong Kong, Guangzhou, and Guangxi. Materials and methods We retrospectively included 899 patients treated between November 5, 2002 and May 27, 2010. Separation and discrimination of each staging system in overall survival were primarily compared. Results Compared with the 7th AJCC, the 8th AJCC and all proposed staging systems well separated across T-classification. T-classification from Guangzhou seemed to perform best in discrimination (C-index 0.6454), followed by the 8th AJCC (0.6451), the 7th AJCC (0.6386), Hong Kong (0.6376) and Guangxi (0.5889). For N-classification, no staging systems improved the weakness of the 7th AJCC in separating N2 and N1, except that suggestion from Guangzhou showed higher potential ( P = 0.096). Besides, N-classification from Guangzhou had a C-index of 0.6444, larger than that of the 8th AJCC (0.6235), the 7th AJCC (0.6179), Hong Kong (0.6175) and Guangxi (0.6175). Accordingly, stage group of staging system from Guangzhou showed higher discrimination (C-index 0.6839), compared with the 8th AJCC (0.6791), the 7th AJCC (0.6766), Hong Kong (0.6765) and Guangxi (0.6688), despite that stage I and II remained inseparable ( P = 0.322). Conclusions The 8th AJCC staging system appeared to be better than the 7th AJCC. But the proposed staging system from Guangzhou was more likely to improve the separation and discrimination abilities.

Background It was recently reported Lipoxins (LXs) had protective effects on fibrous diseases, and renin-angiotensin-aldosterone system (RAAS) had played vital and bidirectional roles in hepatic fibrosis. In this paper, a hepatic fibrosis model, induced by carbon tetrachloride (CCL4) in rats, was used to observe the relations between RAAS and LXs, as well as to further explore the alternative anti-fibrosis mechanisms of LXs. Methods The model was evaluated by morphological observations and biochemical assays. The activities and contents of angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2) were examined through assay kits and ELISA. The expression levels of angiotensinII (AngII), Angiotensin II type 1 receptor (AT1R), angiotensin-(1-7) (Ang-1-7), and Mas were all measured using real time PCR, ELISA, and Western blot. Results The model was established successfully and BML-111 significantly ameliorated CCL4-induced hepatic fibrosis, including reduction inflammation injury, decrease extracellular matrix deposition, and improvement hepatic functions. Furthermore, BML-111 could obviously decrease not only the activities of ACE but also the expression levels of ACE, AngII,and AT1R, which were induced by CCL4. On the other hand, BML-111 could markedly increase the activities of ACE2, besides the expression levels of ACE2, Ang-(1-7) and Mas. More importantly, BOC-2, a lipoxin A4 receptor blocker, could reverse all these phenomena. Conclusions Equilibrating ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis mediated the protective effect of BML-111 on hepatic fibrosis in rats.

This study investigated roles of serum ST2, IL‐33 and BNP in predicting major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Blood samples were collected from the included AMI patients (n = 180) who underwent PCI. All patients were divided into the MACEs and MACEs‐free groups. Enzyme‐linked immunosorbent assay was performed to measure serum levels of ST2, IL‐33 and BNP. Severity of coronary artery lesion was evaluated by Gensini score. Pearson correlation analysis was used. A receiver operating characteristics curve was drawn to evaluate the potential roles of ST2, IL‐33 and BNP in predicting MACEs, and Kaplan–Meier curve to analyse the 1‐year overall survival rate. Logistic regression analysis was conducted to analyse the independent risk factors for MACEs. Compared with the MACEs‐free group, the serum levels of ST2, IL‐33 and BNP were significantly higher in the MACEs group. Serum levels of ST2, IL‐33 and BNP were positively correlated with each other and positively correlated with Gensini score. The area under curves of ST2, IL‐33 and BNP, respectively, were 0.872, 0.675 and 0.902. The relative sensitivity and specificity were, respectively, 76.27% and 85.92%, 69.49% and 58.68%, as well as, 96.61% and 77.69%. Serum levels of ST2, IL‐33 and BNP were independent risk factors for MACEs. The 1‐year overall survival rate was higher in AMI patients with lower serum levels of ST2, IL‐33 and BNP. In conclusion, serum levels of ST2, IL‐33 and BNP have potential value in predicting MACEs in AMI patients undergoing PCI.

Objectives We have attempted to validate two published nomograms in nasopharyngeal carcinoma (NPC) and individualize induction chemotherapy (IC) accordingly. Materials and methods From 2007 to 2011, 920 patients were included in the study. The validity of the nomograms was assessed by Harrell’s concordance index (C-index), areas under the curve (AUC), and calibration curves. Disease-free survival (DFS) and overall survival (OS) by IC were evaluated in and out of risk stratified patients with and without propensity score matching analysis. Results Compared with the 7th edition of the Union for International Cancer Control (UICC) staging system, Tang’s nomogram better discriminated DFS (C-index 0.629 versus 0.569, P = 0.002; AUC 0.635 versus 0.576, P = 0.018), whereas Yang’s nomogram had no advantage in predicting OS (C-index 0.648 versus 0.606, P = 0.184; AUC 0.643 versus 0.604, P = 0.157). Calibration curves indicated good agreement between predicted and observed DFS or OS probability. Without risk stratification, patients achieved no benefit from IC in DFS ( P ⩾ 0.101) or OS ( P ⩾ 0.370). However, among 580 high-risk patients stratified by Tang’s nomogram, IC improved five-year DFS from 68.8 to 74.8% ( P = 0.072), and OS from 82.6 to 87.9% ( P = 0.065), and the improvement of DFS and OS increased to 9.3% ( P = 0.019) and 7.3% ( P = 0.036), respectively, in 426 propensity-matched patients. Conclusions Tang’s nomogram helps to stratify stage III-IVa-b NPC, and IC is beneficial to high-risk patients in clinical practice.

Aim of the study Previous results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC). Methods Patients with stage III–IVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m2 weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m2 and fluorouracil 800 mg/m2/d for 120 h every 4 weeks for three cycles. The primary end-point was failure-free survival. Results Two hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64–1.22; p = 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3–4 toxicities (p = 0.14). Conclusion Adjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the long-term follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities. Registration number NCT00677118 .

Aims Palmitate, a common saturated free fatty acid, induces endothelial apoptosis in vitro in culture endothelial cells and in vivo in type 2 diabetes mellitus (T2DM) patients. The present study aimed to investigate whether Kv1.5 regulates palmitate-induced endothelial apoptosis and endothelial dysfunction in T2DM. Main methods In vitro experiments were carried out in primary human HUVECs. Apoptosis was analyzed by flow cytometry. Cell viability was determined by Cell Counting Assay Kit-8. The siRNA transfection was employed to knockdown Kv1.5 protein expression. Intracellular and mitochondrial ROS, and mitochondrial membrane potential were detected using fluorescent probes. Male C57BL/6 mice fed with high-sucrose/fat diet were injected with streptozotocin (35 mg/kg body weight) to establish T2DM animal model. Key findings We found that palmitate-induced endothelial apoptosis was parallel to a significant increase in endogenous Kv1.5 protein expression in endothelial cells. Silencing of Kv1.5 with siRNA reduced palmitate-induced endothelial apoptosis, intracellular ROS generation, mitochondrial ROS generation and membrane potential (Δψ m ) alteration and cleaved caspase-3 protein expression; while increased cell viability and ratio of Bcl-2/Bax. Furthermore, we observed that Kv1.5 protein expression increased in endothelial cells of thoracic aorta of T2DM mice. Silencing of Kv1.5 significantly improved the endothelium-dependent vasodilation in thoracic aortic rings of T2DM mice. Significance These results demonstrate that suppression of Kv1.5 protects endothelial cells against palmitate-induced apoptosis via inhibiting mitochondria-mediated excessive ROS generation and apoptotic signaling pathway, suggesting that Kv1.5 may serve as a therapeutic target of treatment for endothelial dysfunction induced by palmitate and lipid metabolism in T2DM patients.

Background: Literature pertaining to prophylactic inguinal nodal treatment for anal adenocarcinoma in China is scarce. Methods: In this retrospective study, we analyzed 126 patients from 1965 to 2015. Among these, 67 patients received surgery only, 18 patients received chemoradiotherapy only, 27 patients received a combination of both, and the remaining 14 patients received palliative treatment. Results: The median follow up period was 30 months. The 1-year, 3-year, and 5-year overall survival rates were 85.8%, 62.5%, and 43.4%, respectively. The 5-year overall survival was 46.9% for patients with negative inguinal lymph nodes and 19.1% for patients with positive inguinal lymph nodes (p=0.007). The overall 5-year inguinal node relapse-free survival was 83.0%. The 5-year inguinal node relapse-free survival was 87.5% for stage I, 86.9% for stage II, and 76.5% for stage III cancers. Among those with negative inguinal nodes, the 5-year inguinal node relapse-free survival was 85.7% for negative regional lymph nodes and 75.4% for positive regional lymph nodes (p=0.089). Conclusion: Inguinal lymph node is a high-risk subclinical area. Prophylactic inguinal nodal treatment is necessary for patients with anal adenocarcinoma irrespective of positive or negative inguinal lymph nodes.

The gene encoding a β- galactosidase was cloned from Lactobacillus plantarum FMNP01 and expressed in Escherichia coli BL21(DE3). The characteristics of this purified recombinant enzyme, L.pFMNP01Gal, were determined, and its transgalactosylation reaction conditions for the production of lactulose were optimized. Using ONPG as substrate, the L.pFMNP01Gal showed specific activity of 980 U/g with a Km of 6.86 mM and a Kcat of 22.47/s. This enzyme was most stable at 40–50 °C, and exhibited optimum catalytic activity at 40 °C and pH 7.0. The activity of L.pFMNP01Gal was greatly inhibited by Cu2+, while other tested metal ions had little influence on it. For the optimization of transgalactosylation reaction, high lactulose production was achieved when 60% (W/V) sugars were used as substrates with a lactose/fructose mass ratio of 2:1, and 2 U/mL of L.pFMNP01Gal as catalyst. Under these optimum conditions, 18.38 ± 2.17 g/L of lactulose was synthesized in 6 h at 50 °C. This study provides an alternative method for enzymatic synthesis of lactulose.

6003 Background: Patients suffering from locoregionally advanced nasopharyngeal carcinoma (NPC) commonly develop disease recurrence, despite a high rate of complete clinical remission after standard of care (concurrent cisplatin-radiotherapy, with or without induction chemotherapy). The benefit of additional adjuvant chemotherapy remains unclear. Methods: Patients with high-risk locoregionally advanced NPC (stage III to IVA, excluding T3-4N0 and T3N1), and with no locoregional disease or distant metastasis after definitive chemoradiotherapy, were eligible. They were randomly assigned (1:1) within 12 to 16 weeks after the last radiation dose to receive either capecitabine at a dose of 650 mg/m2 twice daily for 1 year (metronomic capecitabine group) or observation (standard-therapy group). The primary end point was recurrence-free survival (RFS). The calculated sample size was 201 per group, with an 80% power (two-sided α 0.05) to detect a target hazard ratio (HR) of 0.52. Results: A total of 406 patients underwent randomization, comprising 204 in the metronomic capecitabine group and 202 in the standard-therapy group. After a median follow-up of 36 months (corresponding to 43 months when calculated from the start of standard therapy), the estimated 3-year RFS was 85.9% in the metronomic capecitabine group, as compared with 76.5% in the standard-therapy group (intention-to-treat population; HR 0.51, 95% confidence interval 0.32–0.81; P = 0.003). The incidence of grade 3 adverse events was 17.4% in the metronomic capecitabine group and 5.5% in the standard-therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (9.0%). One grade 4 neutropenia occurred in the metronomic capecitabine group. Neither group sufferd from treatment-related deaths. During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of metronomic adjuvant capecitabine. Conclusions: The addition of metronomic capecitabine as adjuvant therapy to chemoradiotherapy significantly improved RFS in locoregionally advanced NPC, with a manageable safety profile and no compromise to quality of life. Clinical trial information: NCT02958111. [Table: see text]

BACKGROUND: Head and neck mucosal melanoma (HNMM) is defined as a rare malignant tumor derived from melanocytes. There is no consensus regarding the treatment protocol for HNMM in elderly patients. METHODS: The National Cancer Institute’s Surveillance, Epidemiology, and End Results database was used to identify elderly patients diagnosed with HNMM from 1975 to 2016. The chi-squared test was used to compare patient characteristics. The reverse Kaplan-Meier method was used to estimate the median follow-up time. The Kaplan-Meier method and log-rank test were used to estimate and compare the overall survival (OS) and disease-specific survival (DSS) of the groups. Cox regression analysis was used to evaluate the risk factors for OS and DSS of HNMM. RESULTS: Our retrospective study included 828 elderly patients with HNMM, and the 5-year OS and DSS rates were 22.4% and 27.4%, respectively. After adjusting for other variables in multivariate analysis, patients undergoing radiotherapy alone had worse OS [hazard ratio (HR) =1.449, 95% confidence interval (CI): 1.010–1.742, P=0.006] and DSS (HR =1.656, 95% CI: 1.257–2.181, P

Summary Background The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. Methods We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III–IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18–59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m 2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m 2 on day 1), intravenous cisplatin (60 mg/m 2 on day 1), and continuous intravenous fluorouracil (600 mg/m 2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. Findings Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38–49), 3-year failure-free survival was 80% (95% CI 75–85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66–78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48–0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). Interpretation Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. Funding Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

// Pu-Yun OuYang 1, * , Dingbo Shi 2, * , Rui Sun 3, * , Yu-Jia Zhu 1, * , Yao Xiao 1 , Lu-Ning Zhang 1 , Xu-Hui Zhang 1 , Ze-Ying Chen 1 , Xiao-Wen Lan 1 , Jie Tang 1 , Yuan-Hong Gao 1 , Jun Ma 1 , Wuguo Deng 2, ** , Fang-Yun Xie 1, ** 1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China 2 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China 3 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China * Co-first authors ** Co-senior authors Correspondence to: Fang-Yun Xie, e-mail: xiefy@sysucc.org.cn Keywords: intensity-modulated radiotherapy, nasopharyngeal carcinoma, propensity score matching, two-dimensional conventional radiotherapy Received: February 12, 2016 Accepted: March 27, 2016 Published: April 4, 2016 ABSTRACT Background: Albeit intensity-modulated radiotherapy (IMRT) is currently the recommended radiation technique in treating nasopharyngeal carcinoma, the effect of IMRT versus two-dimensional conventional radiotherapy (2DCRT) alone is still contradictory. Results: In the original unmatched cohort of 1198 patients, IMRT obtained comparable 5-year overall survival (OS) (91.3% vs 87.1%, P = 0.120), locoregional relapse-free survival (LRFS) (92.3% vs 90.4%, P = 0.221) and distant metastasis-free survival (DMFS) (92.9% vs 92.1%, P = 0.901) to 2DCRT. In the propensity-matched cohort of 604 patients, no significant survival differences were observed between the two arms (5-year OS 90.9% vs 90.5%, P = 0.655; LRFS 92.5% vs 92.4%, P = 0.866; DMFS 92.5% vs 92.9%, P = 0.384). In multivariate analysis, IMRT did not significantly lower the risk of death, locoregional relapse or distant metastasis, irrespective of tumor stage. Methods: Overall, 1198 patients who underwent IMRT (316 patients) or 2DCRT (882 patients) without any chemotherapy was retrospectively analyzed. Patients in both arms were matched at equal ratio using propensity-score matching method. OS, LRFS and DMFS were assessed with Kaplan-Meier method, log-rank test and Cox regression. Conclusions: In this propensity-matched study, IMRT showed no survival advantage over 2DCRT alone in nasopharyngeal carcinoma.