Publications by authors named "Yu-Pei Chen"

90 Publications

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

Lancet 2021 Jun 4. Epub 2021 Jun 4.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

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/m 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 (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.

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.
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http://dx.doi.org/10.1016/S0140-6736(21)01123-5DOI Listing
June 2021

Agricultural management practices influence the soil enzyme activity and bacterial community structure in tea plantations.

Bot Stud 2021 May 18;62(1). Epub 2021 May 18.

Department of Soil and Environmental Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.

Background: The soil quality and health of the tea plantations are dependent on agriculture management practices, and long-term chemical fertilizer use is implicated in soil decline. Hence, several sustainable practices are used to improve and maintain the soil quality. Here, in this study, changes in soil properties, enzymatic activity, and dysbiosis in bacterial community composition were compared using three agricultural management practices, namely conventional (CA), sustainable (SA), and transformational agriculture (TA) in the tea plantation during 2016 and 2017 period. Soil samples at two-months intervals were collected and analyzed.

Results: The results of the enzyme activities revealed that acid phosphatase, arylsulfatase, β-glucosidase, and urease activities differed considerably among the soils representing the three management practices. Combining the redundancy and multiple regression analysis, the change in the arylsulfatase activity was explained by soil pH as a significant predictor in the SA soils. The soil bacterial community was predominated by the phyla Proteobacteria, Acidobacteria, Actinobacteria, Chloroflexi, and Bacteroidetes in the soil throughout the sampling period. Higher Alpha diversity scores indicated increased bacterial abundance and diversity in the SA soils. A significant relationship between bacterial richness indices (SOBS, Chao and ACE) and soil pH, K and, P was observed in the SA soils. The diversity indices namely Shannon and Simpson also showed variations, suggesting the shift in the diversity of less abundant and more common species. Furthermore, the agricultural management practices, soil pH fluctuation, and the extractable elements had a greater influence on bacterial structure than that of temporal change.

Conclusions: Based on the cross-over analysis of the bacterial composition, enzymatic activity, and soil properties, the relationship between bacterial composition and biologically-driven ecological processes can be identified as indicators of sustainability for the tea plantation.
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http://dx.doi.org/10.1186/s40529-021-00314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131499PMC
May 2021

Editorial: Advances in the Pathogenesis and Therapeutic Strategies for Nasopharyngeal Carcinoma.

Front Oncol 2021 9;11:647809. Epub 2021 Mar 9.

State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

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http://dx.doi.org/10.3389/fonc.2021.647809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985254PMC
March 2021

Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades.

Mol Cancer 2021 02 4;20(1):27. Epub 2021 Feb 4.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

The development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.
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http://dx.doi.org/10.1186/s12943-021-01317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863268PMC
February 2021

Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

Mol Cancer 2021 01 11;20(1):14. Epub 2021 Jan 11.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China.

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
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http://dx.doi.org/10.1186/s12943-020-01292-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798236PMC
January 2021

Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline.

J Clin Oncol 2021 Mar 6;39(7):840-859. Epub 2021 Jan 6.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, and Chinese Society of Clinical Oncology, Beijing, People's Republic of China.

Purpose: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC).

Methods: The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations.

Results: The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options.

Recommendations: Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.Additional information is available at www.asco.org/head-neck-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03237DOI Listing
March 2021

A Gene-Expression Predictor for Efficacy of Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma.

J Natl Cancer Inst 2021 Apr;113(4):471-480

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

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.
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http://dx.doi.org/10.1093/jnci/djaa100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023816PMC
April 2021

ZNF582 hypermethylation promotes metastasis of nasopharyngeal carcinoma by regulating the transcription of adhesion molecules Nectin-3 and NRXN3.

Cancer Commun (Lond) 2020 12 10;40(12):721-737. Epub 2020 Oct 10.

Experimental Research Department, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, 510060, P. R. China.

Background: Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC). However, the epigenetic mechanisms underlying NPC metastasis remains poorly understood. We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment.

Methods: Bisulfite pyrosequencing was used to analyze zinc finger protein 582 (ZNF582) methylation in NPC tissues and cell lines. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting were used to determine the expression of ZNF582. In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC. ZNF582-targeting genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) and were confirmed by ChIP-qPCR and luciferase assay.

Results: ZNF582 promoter was hypermethylated in NPC, and both the mRNA and protein levels of ZNF582 were down-regulated in NPC tissues and cell lines. The restoration of ZNF582 inhibited NPC migration, invasion, and metastasis, while the knockdown of ZNF582 promoted NPC migration, invasion, and metastasis in vitro and in vivo. ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin-3 and NRXN3. Both Nectin-3 and NRXN3 were identified as functional targets of ZNF582, and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis.

Conclusions: ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin-3 and NRXN3, which may provide novel therapeutic targets for NPC treatment.
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http://dx.doi.org/10.1002/cac2.12104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743023PMC
December 2020

Clinical Characteristics and Prognostic Factors of Early and Late Recurrence After Definitive Radiotherapy for Nasopharyngeal Carcinoma.

Front Oncol 2020 25;10:1469. Epub 2020 Aug 25.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.

We investigated the clinical characteristics, prognostic factors, and post-recurrence prognostic factors of early- and late-recurrence patients for nasopharyngeal carcinoma (NPC) after definitive intensity-modulated radiation therapy (IMRT). This was a single-center retrospective analysis of patients in China from January 2010 to December 2015. The prognostic factors for overall survival (OS) and post-recurrence OS of early- and late-recurrence patients were identified using univariate and multivariate Cox regression analyses. Of the 9,468 patients included, 409 (4.3%), 325 (3.4%), and 182(1.9%) developed purely local recurrence, purely regional recurrence, and locoregional recurrence during follow-up, respectively. In the purely local recurrence group, 192 patients (46.9%) developed early local recurrence (ETR), and 217 patients (53.1%) developed late local recurrence (LTR). Of the 192 ETR patients, multivariate Cox regression analysis revealed that age and gender were independent risk factors of OS, and post-recurrence best supportive treatment (PRBST) was associated with poorer post-recurrence OS. Of the 217 LTR patients, the results revealed that baseline value of EBV-DNA was an independent risk factor for OS, while PRBST was associated with poorer post-recurrence OS. In the purely regional recurrence group, 183 patients (56.3%) developed early regional recurrence (ENR), and 142 patients (43.7%) developed late regional recurrence (LNR). Of the 183 ENR patients, multivariate Cox regression analysis revealed that alcohol abuse and TNM stage were independent risk factors of OS, while alcohol drinkers and PRBST were associated with poorer post-recurrence OS. Of the 142 LNR patients, PRBST was associated with poorer post-recurrence OS. In the locoregional recurrence group, 87 patients (47.8%) developed early locoregional recurrence (ELR), and 95 patients (52.2%) developed late locoregional recurrence (LLR). Of the 87 ELR patients, multivariate Cox regression analysis revealed that N stage and TNM stage were independent risk factors of OS, and N2/3 stage and PRBST were associated with poorer post-recurrence OS. Of the 95 LLR patients, the results revealed that T stage was an independent risk factor for OS, while T3/4 stage and PRBST were associated with poorer post-recurrence OS. Patients with LTR/LNR/LLR demonstrate significantly better OS compared with patients with ETR/ENR/ELR, Nevertheless, post-recurrence OS between patients with ETR/ENR/ELR and LTR/LNR/LLR was not significantly different.
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http://dx.doi.org/10.3389/fonc.2020.01469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479816PMC
August 2020

Prognostic value of immune score in nasopharyngeal carcinoma using digital pathology.

J Immunother Cancer 2020 07;8(2)

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis andTherapy, Sun Yat-sen University Cancer Center, GuangZhou, China

Background: Tumor-infiltrating lymphocytes have been reported as prognostic markers in tumors. We aimed to assess the prognostic value of total T cell (CD3) density, cytotoxic T cell (CD8) density and memory T cell (CD45RO) density in patients with nasopharyngeal carcinoma (NPC).

Methods: The expression of CD3, CD8 and CD45RO was detected by immunohistochemistry in the training (n=221) and validation cohorts (n=115). The densities of these three markers were quantified by digital pathology both in the tumor and stroma. Then, we developed the immune score based on the density of these three markers and further analyzed its prognostic value.

Results: The high density of CD3, CD8 and CD45RO T cells both in the tumor and/or stroma were significantly associated with the decrease in mortality in the training cohort, respectively. High immune score predicted a prolonged overall survival (OS) (HR 0.34, 95% CI 0.18 to 0.64, p=0.001, disease-free survival (DFS) (HR 0.44, 95% CI 0.25 to 0.78, p=0.005) and distant metastasis-free survival (DMFS) (HR 0.43, 95% CI 0.21 to 0.87, p=0.018) in NPC patients. The findings were confirmed in the validation cohort. Multivariate analysis revealed that immune score remained an independent prognostic indicator for OS, DFS and DMFS. In addition, we established a nomogram with the integration of all independent variables to predict individual risk of death.

Conclusions: We established an immune score model, which provides a reliable estimate of the risk of death, disease progress and distant metastasis in NPC patients.
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http://dx.doi.org/10.1136/jitc-2019-000334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371227PMC
July 2020

Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma.

Cell Res 2020 11 20;30(11):1024-1042. Epub 2020 Jul 20.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.
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http://dx.doi.org/10.1038/s41422-020-0374-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784929PMC
November 2020

Recent Advances in the Development of Biomarkers and Chemoradiotherapeutic Approaches for Nasopharyngeal Carcinoma.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-11

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China.

Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) is endemic in Southern China, and the prognosis of this cancer has improved in part due to advances in radiotherapy (RT) techniques, broadened therapeutic options, and more precise prognostic stratification of patients. RT is the primary curative treatment of NPC, and the incorporation of chemotherapy (induction, concurrent, adjuvant) to RT has contributed to improved survival in patients with locoregionally advanced NPC. Concurrent chemoradiotherapy (CCRT) in combination with adjuvant or induction chemotherapy is now the standard treatment of locoregionally advanced NPC, but the ideal CCRT therapeutic strategy for NPC remains controversial. Plasma EBV DNA is the archetypal tumor-derived DNA in NPC, and three generations of studies have gradually expanded its clinical applications. Recently, the advent of whole exome/genome sequencing of NPC and the promising clinical activity of immune checkpoint inhibitors have also spurred interest in the development of newer biomarkers. This review will focus on two clinical advances in NPC research that have made substantial impact on the contemporary management of NPC: (1) The integration of plasma EBV DNA in an expanding spectrum of clinical indications, and the development of promising immune-related biomarkers; (2) the current development of CCRT with special emphasis on the use of induction and adjuvant chemotherapy, as well as the potential applications of metronomic chemotherapy and immune checkpoint inhibitors in the treatment of locoregionally advanced NPC.
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http://dx.doi.org/10.1200/EDBK_280747DOI Listing
March 2020

Identification of cross-talk between mA and 5mC regulators associated with onco-immunogenic features and prognosis across 33 cancer types.

J Hematol Oncol 2020 03 18;13(1):22. Epub 2020 Mar 18.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (mA) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between mA and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between mA and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between mA and 5mC methylation at the multiomic level. Then, we further established mA/5mC epigenetic module eigengenes by combining hub mA/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.
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http://dx.doi.org/10.1186/s13045-020-00854-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081591PMC
March 2020

Effects of Chinese and Western Medicine on Patients with Dengue Fever.

Am J Chin Med 2020 5;48(2):329-340. Epub 2020 Mar 5.

Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Dengue fever is an important epidemic disease with a high prevalence in tropical and subtropical countries. We aimed to investigate the effects of a treatment integrating traditional Chinese (TCM) and Western medicines on dengue inpatients with warning signs (i.e., group B) according to the World Health Organization dengue classification in this retrospective cohort study of medical records. Inpatients who were treated with conventional Western therapies in the absence or presence of TCM were assigned to the control and treatment groups, respectively. Data were compared using an analysis of variance, general linear analysis, and chi-square test. The most common clinical symptoms and signs of dengue fever were fever and muscle ache. The treatment group patients were significantly more likely to present general weakness and poor appetite than the control group patients. Patients in the treatment group were more likely to experience stomachache than those in the control group. Moreover, comparisons of the changes in hemoglobin and alanine aminotransferase levels over time revealed significant differences between the patient groups. Zhu Ye Shi Gao Tang, Gui Pi Tang, , and were the most commonly administered TCM formula and single herbs in this study. Patients in the treatment group experienced a resolution of symptoms, signs, and laboratory data and were discharged smoothly, without deterioration to death or critical care. Our findings suggest that the integration of TCM and Western medicine may yield an appropriate treatment for dengue fever.
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http://dx.doi.org/10.1142/S0192415X20500160DOI Listing
August 2020

Development and validation of an immune checkpoint-based signature to predict prognosis in nasopharyngeal carcinoma using computational pathology analysis.

J Immunother Cancer 2019 11 13;7(1):298. Epub 2019 Nov 13.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Background: Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC).

Methods: The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients.

Results: High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P < 0.001), disease-free (P = 0.002), and distant metastasis-free survival (P = 0.004), which were confirmed in the validation cohort. Multivariate analysis revealed that the ICS classifier was an independent prognostic factor. A combination of the ICS classifier and TNM stage had better prognostic value than the TNM stage alone. In addition, the ICS classifier was significantly associated with survivals in patients with high EBV-DNA load.

Conclusions: We determined the expression status of nine immune checkpoints consistent with 13 features in NPC and further constructed an ICS prognostic model, which might add prognostic value to the TNM staging system.
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http://dx.doi.org/10.1186/s40425-019-0752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854706PMC
November 2019

Development of a multiplex and sensitive lateral flow immunoassay for the diagnosis of periprosthetic joint infection.

Sci Rep 2019 10 30;9(1):15679. Epub 2019 Oct 30.

Institute of Applied Mechanics, National Taiwan University, Taipei, 106, Taiwan.

The diagnosis of periprosthetic joint infection (PJI) remains a challenge. However, recent studies showed that synovial fluid biomarkers have demonstrated greater diagnostic accuracy than the currently used PJI diagnostic tests. In many diagnostic tests, combining several biomarkers into panels is critical for improving diagnostic efficiency, enhancing the diagnostic precision for specific diseases, and reducing cost. In this study, we prove that combining alpha-defensin and C-reactive protein (CRP) as biomarkers possesses the potential to provide accurate PJI diagnosis. To further verify the result, we developed a multi-target lateral flow immunoassay strip (msLFIA) with staking pad design to obtain on-site rapid response for clinical diagnosis of PJI. A total of 10 synovial fluid samples were tested using the msLFIA, and the results showed that the combined measurements of synovial fluid alpha-defensin and CRP levels were consistent with those obtained from a commercial enzyme-linked immunosorbent assay kit. In addition, we developed a multi-target lateral flow immunoassay strip (msLFIA) with staking pad design to obtain on-site rapid response for clinical diagnosis of PJI, which the multi-target design is used to increase specificity and the stacking pad design is to enhance detection sensitivity. As a result, the turnaround time of the highly sensitive test can be limited from several hours to 20 min. We expect that the developed msLFIA possesses the potential for routine monitoring of PJI as a convenient, low-cost, rapid and easy to use detection device for PJI.
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http://dx.doi.org/10.1038/s41598-019-52051-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821814PMC
October 2019

An integrated model of the gross tumor volume of cervical lymph nodes and pretreatment plasma Epstein-Barr virus DNA predicts survival of nasopharyngeal carcinoma in the intensity-modulated radiotherapy era: a big-data intelligence platform-based analysis.

Ther Adv Med Oncol 2019 25;11:1758835919877729. Epub 2019 Sep 25.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People's Republic of China.

Background: Few studies have evaluated the prognostic value of the integrated model consisting of gross tumor volume of lymph nodes (GTVnd) and pretreatment plasma Epstein-Barr virus DNA (pre-EBV DNA) in nasopharyngeal carcinoma (NPC) patients.

Methods: A well-established big-data intelligence platform with 10,126 NPC patients was used for a retrospective review. A total of 1500 cases with cervical nodal metastases but without distant metastases were randomly assigned to a training ( = 503) or test condition ( = 997) for analyses. The cut-off point for the GTVnd derived from the receiver operating characteristic (ROC) curve was combined with the published cut-off point for pre-EBV DNA to develop an integrated model by which patients were classified into four groups.

Results: Both GTVnd and pre-EBV DNA were independent prognostic factors. Regardless of whether patients received induction chemotherapy (IC), the 5-year distant metastasis-free survival (DMFS) (69.5%) and overall survival (OS) (68.4%) were significantly worse in those with both a GTVnd >20 ml and pre-EBV DNA >2000 copies/ml (all values < 0.001). In patients with IC, all others had better 5-year DMFS and OS; in patients without IC, those with either a GTVnd >20 ml or pre-EBV DNA >2000 copies/ml had the medium 5-year DMFS and OS, while patients with neither of them had the best.

Conclusions: The integrated GTVnd and pre-EBV DNA model not only predicted DMFS and OS in NPC patients effectively, but was an indicator of timely adjustment of therapeutic strategies for NPC patients, especially those completing IC.
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http://dx.doi.org/10.1177/1758835919877729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763945PMC
September 2019

Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.

J Immunother Cancer 2019 06 25;7(1):159. Epub 2019 Jun 25.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
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http://dx.doi.org/10.1186/s40425-019-0636-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593483PMC
June 2019

Nasopharyngeal carcinoma.

Lancet 2019 Jul 6;394(10192):64-80. Epub 2019 Jun 6.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China. Electronic address:

Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.
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http://dx.doi.org/10.1016/S0140-6736(19)30956-0DOI Listing
July 2019

[Effect of electroacupuncture at "Weizhong" (BL40) on expression of collagen I and matrix meta-lloproteinases 2 in rats with lumbar multifidus muscle injury].

Zhen Ci Yan Jiu 2019 May;44(5):341-6

Department of Chinese Medicine, The Third Hospital of Peking University, Beijing 100191.

Objective: To observe the effect of electroacupuncture (EA) at "Weizhong" (BL40) on histopathological changes and expression of extracellular matrix (ECM) component Collagen Ⅰ, matrix metalloproteinases 2 (MMP2), MyoD and Pax7 proteins of lumbar muscle tissues in rats with lumbar multifidus muscle injury (LMMI), so as to explore its underlying mechanisms in improving muscular injury.

Methods: A total of 24 male SD rats were equally randomized into blank control, model and EA groups. The LMMI model was established by injection of 0.5% Bupivacaine (100 µL/ point) into bilateral multifidus muscles of lumbar 4 and 5 (4 points). EA (2 Hz/100 Hz in frequency, 1-2 mA) was applied to BL40 for 20 min, once a day for 3 days. The morphological changes of the left lumbar multifidus muscle were observed under microscope after H.E. and Masson staining, and the expression of Collagen Ⅰ, MMP2, MyoD and Pax7 of the right lumbar multifidus muscle was determined by Western blot.

Results: H.E. staining showed large areas of degeneration and necrosis of muscle fibers, and vacuolar structure formed by degradation of muscle fibers in the model group, and newborn juvenile muscle fibers with different diameters in the EA group. Masson staining showed a large number of morphologically damaged muscle fibers and blue stained collagen fibers in the model group, and significantly reduced collagen fibers as well as new muscle fibers with uneven diameters in the EA group. The expression levels of Collagen Ⅰ, MMP2 and MyoD proteins were significantly up-regulated (<0.01, <0.05), and that of Pax7 was considerably down-regulated in the model group relative to the control group (<0.01). After EA intervention, the expression levels of Collagen Ⅰ was significantly down-regulated (<0.01), and those of MMP2, MyoD and Pax7 proteins were obviously or further obviously up-regulated in the EA group compared with the model group (<0.01, <0.05).

Conclusion: EA at BL40 can reduce the degree of skeletal muscle fibrosis to promote the regeneration of the injured multifidus at the early phase, which may be related to its effect in regulating the expression of Collagen Ⅰ and MMP2 proteins.
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http://dx.doi.org/10.13702/j.1000-0607.180593DOI Listing
May 2019

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

N Engl J Med 2019 09 31;381(12):1124-1135. Epub 2019 May 31.

From the Departments of Radiation Oncology (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), Medical Oncology (Y.-H.L.), and Nasopharyngeal Carcinoma (H.-Y.M.) and the Clinical Trials Center (Y.G.), Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), and the Department of Radiation Oncology, First Affiliated Hospital of Guangdong Pharmaceutical University (X.-C.W., Q.-F.S.), Guangzhou, the Cancer Center, Tongji Hospital Affiliated to Tongji Medical College (G.-Q.H., G.-X.L.), and the Cancer Center, Union Hospital, Tongji Medical College (K.-Y.Y., J.H.), Huazhong University of Science and Technology, Wuhan, the Department of Radiation Oncology, First People's Hospital of Foshan, Foshan (N.Z., S.-Q.L.), the Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning (X.-D.Z., L.L.), the Department of Head and Neck Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang (F.J., J.-H.L.), the Department of Radiation Oncology, XiJing Hospital of Fourth Military Medical University, Xi'an (M.S., J.Z.), the Cancer Center (Z.-B.C.), and the Department of Head and Neck Oncology (S.-Y.W., Q.-D.L.), Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, the Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou (Y.T., L.Z.), the Department of Radiation Oncology, Peking University Cancer Hospital, Beijing (Yan Sun, B.-M.Z.), and the Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang (J.-G.L., Y.X.) - all in China; and the Divisions of Radiation Oncology and Medical Sciences, National Cancer Center Singapore, and the Oncology Academic Program, Duke-National University of Singapore Medical School - both in Singapore (M.L.K.C.).

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).
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http://dx.doi.org/10.1056/NEJMoa1905287DOI Listing
September 2019

The next decade of clinical trials in locoregionally advanced nasopharyngeal carcinoma.

Br J Radiol 2019 Oct 24;92(1102):20181031. Epub 2019 May 24.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

Clinical trials are powerful weapons in the battle against nasopharyngeal carcinoma (NPC). Based on clinical trials conducted in the past two decades, concurrent chemoradiotherapy combined with adjuvant chemotherapy or induction chemotherapy has been recommended as the standard treatment for locoregionally advanced NPC in various guidelines. However, there remain shortcomings concerning current treatment modalities that should be refined in future research. In this article, we review the achievements of published clinical trials for locoregionally advanced NPC and propose future directions for subsequent clinical trials. We believe that refinement of current regimens of chemotherapy, de-intensification of treatment for specific groups of patients, developing personalized treatment based on predictors ( applying plasma Epstein-Barr virus DNA) and investigating novel therapies, such as targeted therapy and immunotherapy, should be applied with the highest priority when designing clinical trials for locoregionally advanced NPC in the next decade.
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http://dx.doi.org/10.1259/bjr.20181031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774586PMC
October 2019

Anticandidal Potential of Stem Bark Extract from and the Identification of Its Major Anticandidal Compound.

Molecules 2019 Apr 22;24(8). Epub 2019 Apr 22.

Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.

Plant-derived extracts are a promising source of new drugs. is traditionally used in China for heat clearing, detoxification, and treatment of furuncles. In this study, the anticandidal properties and mechanism of action of (SSE) were explored using a stem bark extract. SSE possessed high polyphenol and saponin contents of 256.6 ± 5.1 and 357.8 ± 31.5 µg/mg, respectively. A clear inhibition zone was observed for growth through the disc diffusion method and the 50% inhibition of by SSE was 415.2 µg/mL. Transcriptomic analysis in treated with different doses of SSE was conducted through RNA-seq. Average values of 6068 genes and 20,842,500 clean reads were identified from each sample. Among these samples, 1680 and 1956 genes were differentially expressed genes (DEGs) from the SSE treatments of 0.2 and 0.4 mg/mL, respectively. growth was inhibited by the changes in gene expression associated with the cell wall and membrane composition including the regulation of chitin degradation and ergosterol biosynthesis. This result could be reflected in the irregularly wrinkled morphology of the ruptured cell as revealed through SEM analysis. ESI-MS and NMR analyses revealed that the major compound purified from SSE was sasanquasaponin III and the 50% inhibition of was 93.1 µg/mL. In summary, the traditional Chinese medicine can be applied as an anticandidal agent in complementary and alternative medicine.
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http://dx.doi.org/10.3390/molecules24081587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515076PMC
April 2019

Evaluation of synthetic gene encoding α-galactosidase through metagenomic sequencing of paddy soil.

J Biosci Bioeng 2019 Sep 5;128(3):274-282. Epub 2019 Apr 5.

Department of Soil and Environmental Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Innovation and Development Center of Sustainable Agriculture, National Chung Hsing University, Taichung 40227, Taiwan. Electronic address:

Many genes of industrial relevance can be found in soil. In this study, metagenome sequencing of paddy soil was performed with 55.68 Gb sequences and 1,787,113 putative open reading frames (ORFs). The functional profiles and metabolic pathway of soil metagenomes were examined using Gene Ontology, Metagenomics RAST, and Kyoto Encyclopedia of Genes and Genomes. To verify the protein function and assembly of ORFs, a putative gene encoding α-galactosidase, namely GalR, which shares 65% identity with an unpublished glycoside hydrolase (GH) 27 family protein, was synthesized using its optimal codon for overexpression in Escherichia coli. GalR was successfully obtained and characterized. The optimal temperature and pH for GalR activity were 30°C and pH 9, respectively. Enzymatic activity indicated that GalR was alkaliphilic and different from acidophilic α-galactosidase in the GH 27 family. Furthermore, 50% of the relative activity of GalR can be attained for 1.7 and 0.7 h preincubation at 40°C and 50°C, respectively. Significant inhibition of GalR was observed in the presence of ethylenediaminetetraacetic acid (EDTA), MgCl, sodium dodecyl sulfate (SDS), and HO; however, it was resistant to 0.1% methanol and ethanol and was slightly activated with NaCl and KCl. The specific activity of GalR was achieved at 11.6 and 0.59 μmol/min/mg of protein using p-nitrophenyl-α-d-galactopyranoside and raffinose as substrates, respectively. Consequently, the metagenomic sequencing-based strategy can provide information for mining novel genes.
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http://dx.doi.org/10.1016/j.jbiosc.2019.03.006DOI Listing
September 2019

Effect of prior cancer on trial eligibility and treatment outcomes in nasopharyngeal carcinoma: Implications for clinical trial accrual.

Oral Oncol 2019 03 1;90:23-29. Epub 2019 Feb 1.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060, People's Republic of China. Electronic address:

Objective: 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, whichimpacts trialaccrual 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.
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http://dx.doi.org/10.1016/j.oraloncology.2019.01.023DOI Listing
March 2019

Optimizing the cumulative cisplatin dose during radiotherapy in nasopharyngeal carcinoma: Dose-effect analysis for a large cohort.

Oral Oncol 2019 02 31;89:102-106. Epub 2018 Dec 31.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China. Electronic address:

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/m (range, 0-300 mg/m). As the CCD increased, the risk of death remained steady until 180 mg/m, then decreased sharply until 250 mg/m, and then increased until 300 mg/m. The optimal CCD of 230-270 mg/m 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/m (240 mg/m 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.
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http://dx.doi.org/10.1016/j.oraloncology.2018.12.028DOI Listing
February 2019

The prolonged interval between induction chemotherapy and radiotherapy is associated with poor prognosis in patients with nasopharyngeal carcinoma.

Radiat Oncol 2019 Jan 17;14(1). Epub 2019 Jan 17.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Objectives: Induction chemotherapy (IC) now is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). The current study was conducted to examine the association between prognosis and the interval between IC and radiotherapy (RT) in NPC patients.

Methods: Patients with newly diagnosed, non-metastatic NPC who were treated with IC followed by RT from 2009 to 2012 were identified from an inpatient database. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS) were compared between those with interval ≤ 30 and >  30 days by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis.

Results: A total of 668 patients met inclusion criteria with median follow-up of 64.4 months. Patients were categorized by interval: 608 patients with interval ≤ 30 days, and 60 with interval >  30 days. The 5-year OS, DFS, DMFS and LRFS rates were 86.6, 78.2, 88.0 and 89.8% for patients with interval ≤ 30 days, respectively, and 69.2, 64.5, 71.2 and 85.1% for patients with interval >  30 days, respectively. The prolonged interval was a risk factor for OS, DFS and DMFS with adjusted hazard ratios (95% confidence intervals) were 2.44 (1.48-4.01), 1.99 (1.27-3.11) and 2.62 (1.54-4.47), respectively.

Conclusions: Prolonged interval >  30 days was associated with a significantly higher risk of distant metastasis and death in NPC patients. Efforts should be made to avoid prolonged interval between IC and RT to minimize the risk of treatment failure.
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http://dx.doi.org/10.1186/s13014-019-1213-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335732PMC
January 2019

Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types.

J Pineal Res 2019 Apr 14;66(3):e12557. Epub 2019 Feb 14.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

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]  = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHR  = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHR  = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHR  = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHR  = 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 < 0.05), except cervical cancer, pancreatic adenocarcinoma, and thyroid carcinoma. Our study provides a systematic overview of the oncostatic values of the melatonergic system and highlights the utilization of this simple and promising gene signature as a prognosticator and potential predictor of response to immunotherapy.
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http://dx.doi.org/10.1111/jpi.12557DOI Listing
April 2019

The Efficacy and Safety of Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Nasopharyngeal Carcinoma: Literature-based Meta-analyses.

J Cancer 2018 31;9(23):4510-4520. Epub 2018 Oct 31.

Department of Radiation Oncology, Sun Yat-sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Centre of Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), such as cetuximab and nimotuzumab have been used in the treatment of nasopharyngeal carcinoma (NPC), yet their efficacy and safety are undetermined. : We performed two meta-analyses based on systematic searches of PubMed, EMBASE, the Cochrane Library and SinoMed: comparison 1 (standard therapy plus mAbs vs. standard therapy) and comparison 2 (radiotherapy plus concurrent mAbs vs. concurrent chemoradiotherapy) to explore the treatment value of anti-EGFR mAbs in NPC. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcomes, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and grade 3 and above acute adverse events. : Four randomized controlled trials and thirteen observational studies were eligible. Comparison 1 (twelve studies): adding mAbs to standard therapy (radiotherapy or chemoradiotherapy) significantly improved OS (HR, 0.51; 95% CI, 0.39-0.66) and DFS (HR, 0.68; 95% CI, 0.54-0.86), but increased the frequency of skin rashes and mucositis. Comparison 2 (six studies): OS (HR, 1.17; 95% CI, 0.81-1.70) and DFS (HR, 1.16; 95% CI, 0.86-1.57) were not significantly different when mAbs replaced conventional cytotoxic chemotherapy concurrently with radiotherapy, with fewer hematological, gastrointestinal and renal toxicities and more skin rashes in the mAb group. : We recommend anti-EGFR mAbs enhance-but should not replace-current treatment paradigms for locoregionally advanced NPC. Further evidence from phase III clinical trials is required.
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http://dx.doi.org/10.7150/jca.27611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277641PMC
October 2018

Reduced Risks of Both Ischemic and Hemorrhagic Strokes in Nurses: A Population-Based Cohort Study in Taiwan.

Int J Environ Res Public Health 2018 11 22;15(12). Epub 2018 Nov 22.

Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung 40447, Taiwan.

Background: Nurses are typically required to address patient emergencies, and they experience high stress levels in their work, which may expose them to a higher risk of stroke. This cohort study compared the risk of stroke between nurses and the general population.

Methods: We used the Taiwan National Health Insurance database to conduct our retrospective cohort study, and we identified 83,641 individuals in the nurse group and 334,564 individuals in the control group. For the nurse group and the control group, we used the chi-square test in addition to applying Student's -test, in order to compare the distribution differences for the continuous variables. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for ischemic stroke and hemorrhagic stroke through univariate and multivariate Cox proportional-hazards regression models, with stratification according to age, sex, and comorbidity.

Results: The nurse group had a lower risk of ischemic stroke and hemorrhagic stroke in the crude model (HR = 0.66, 95% CI = 0.58⁻0.75; HR = 0.58, 95% CI = 0.47⁻0.72). After adjusting the prevalent variables, the nurse group still had a lower risk of stroke (HR = 0.68, 95% CI = 0.60⁻0.77; HR = 0.59, 95% CI = 0.48⁻0.73).

Conclusion: The risks of both stroke types were lower in the nurse group than in the control. For stroke prevention, more frequent physical examinations are needed in order to enhance the health and well-being of people, including the nurses.
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http://dx.doi.org/10.3390/ijerph15122615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313420PMC
November 2018