Efficacy and Safety of Immune Checkpoint Inhibitors Combined With Chemotherapy as First-line Treatment for Recurrent or Metastatic Nasopharyngeal Carcinoma: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Different clinical trials for recurrent or metastatic nasopharyngeal carcinoma have studied different combinations of immuno-oncology in first-line treatment, but the optimal choice has not been determined. OBJECTIVE: To systematically examine and compare the efficacy and safety of different immune checkpoint inhibitors (ICIs) combined with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. METHODS: Several electronic databases were systematically searched up to February 2023. Articles meeting the inclusion criteria were included. RESULTS: Three RCTs were eligible in the study. Compared with placebo plus gemcitabine-cisplatin (GP), toripalimab plus GP (HR = 0.59, 95% CI: 0.37-0.95) was significantly associated with a better OS. Tislelizumab plus GP generated best progression-free survival (PFS) benefit (HR = 0.50, 95% CI: 0.37-0.67), greatest improvement in 1-year PFS rate (RR = 3.00, 95% CI: 1.84-5.22), and objective response rate (ORR) (RR = 1.26, 95% CI: 1.04-1.53) over the placebo plus GP. Furthermore, tislelizumab plus GP appeared to be safer than toripalimab plus GP and camrelizumab plus GP in terms of adverse events (AEs)-grade ≥3, treatment-related AEs (TRAEs)-grade ≥3, serious AEs (SAEs), treatment-related SAEs (TRSAEs), and AEs leading to discontinuation of treatment. CONCLUSION AND RELEVANCE: In recurrent or metastatic nasopharyngeal carcinoma, programmed death 1 (PD-1) inhibitors plus GP as first-line treatment have better survival outcomes than placebo plus GP with comparable toxicity. Toripalimab plus GP shows the best OS benefit over placebo plus GP, while tislelizumab plus GP generates the best PFS, 1-year PFS rate, ORR, and safety. Tislelizumab plus GP could be the best choice among the ICIs combined with chemotherapy regimens as first-line treatment in recurrent or metastatic nasopharyngeal carcinoma.

Cost-effectiveness of camrelizumab combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma in China.

OBJECTIVE: This study aimed to investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody camrelizumab to first-line platinum-doublet chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (L/M NPC) from the perspective of Chinese healthcare system. DESIGN: A Markov model consisting of four health states, progression-free survival, first progression survival, second progression survival and death, was built to simulate 3-week patient transitions over a 20-year horizon. A direct comparison between first-line camrelizumab in combination with gemcitabine plus cisplatin and gemcitabine plus cisplatin was performed by calculating transition probabilities from the CAPTAIN-1st trial. Costs and utilities were collected from the local public database and literature. One-way and probabilistic sensitivity analyses were employed to evaluate the robustness of the model. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: A hypothetical cohort of Chinese patients with pathologically diagnosed L/M NPC who had an Eastern Cooperative Oncology Group performance status of 0 or 1. INTERVENTIONS: First-line camrelizumab in combination with camrelizumab and gemcitabine plus cisplatin (CGP) versus gemcitabine plus cisplatin (GP). PRIMARY OUTCOME MEASURE: Cost, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER). RESULTS: The baseline analysis demonstrated that, compared with first-line GP, first-line CGP yields an effectiveness increase of 0.26 QALY, accompanied by an increment of US$6137.59 in healthcare cost. This results in an ICER of US$23 482.32/QALY. With the willingness-to-pay (WTP) threshold for a QALY set at US$37 654.50, first-line CGP proves to be cost-effective in 97.20% of the iterations. Deterministic sensitivity analyses indicated that the uncertainty in model parameters had no substantial effect on our results. Probability sensitivity analysis indicated that CGP was cost-effective at the assumed WTP threshold. CONCLUSION: For Chinese patients with L/M NPC, adding Chinese-developed anti-PD-1 antibody camrelizumab to the first-line GP chemotherapy may be cost-effective.

Exclusive waterpipe smoking and the risk of nasopharynx cancer in Vietnamese men, a prospective cohort study.

Tobacco smoking is carcinogenic to humans. Besides cigarettes, the most common form of tobacco smoking, there was sparse evidence of waterpipe's carcinogenicity-induced nasopharyngeal cancer (NPC). This study investigated the association between waterpipe smoking and NPC mortality. Our study followed up with 20,144 eligible man participants from nine northern Vietnam communes between 2007 and 2019. Face-to-face interviews were conducted to gather data on exclusive waterpipe and cigarette smoking and dietary intake using structured semi-quantitative food frequency and lifestyle questionnaires. Nasopharyngeal cancer was determined by accessing the medical records at the state health facilities. We estimated the Cox proportional hazard ratio and 95% confidence intervals, HR (95% CI). The proportion of never smokers, exclusive waterpipe, exclusive cigarette, and dual waterpipe and cigarette smokers was 55.8%, 14.5%, 16.6%, and 13.1%, respectively. Exclusively waterpipe smokers increased the risk of NPC death compared to exclusively cigarette smokers, HR (95% CI): 4.51 (1.25, 16.31), p = 0.022. A dose-dependent positive relationship between NPC and exclusive waterpipe smoking was significantly seen for higher intensity HR (95% CI): 1.35 (1.07, 1.71), earlier age of smoking initiation HR (95% CI): 1.26 (1.06, 1.50), longer duration HR (95% CI): 1.31 (1.04, 1.66), and the cumulative number of a smoke lifetime HR (95% CI): 1.37 (1.08, 1.74). We observed a significant positive association between exclusive waterpipe smoking and NPC in men. The findings suggested that waterpipe smoking is likely more harmful than cigarettes in developing this cancer. A firm tobacco control against waterpipe smoking is highly recommended.

The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment.

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples (n = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL-ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment (n = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management.

Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Early Stage and Locally Advanced Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Going?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is a rare malignancy, endemic in China, that is commonly diagnosed in locally advanced scenarios. Its pathogenesis is strongly associated with Epstein-Barr virus (EBV), an infection for which measuring EBV plasma DNA levels has helped as a prognostic factor guiding treatment options, including a stronger treatment in those with high titers. Additionally, tobacco and alcohol are often implicated in EBV-negative patients. The local disease is treated with radiotherapy alone, preferentially intensity modulated radiotherapy. For locally advanced disease, the backbone treatment is concurrent chemoradiotherapy with the ongoing research dilemma being adding adjuvant chemotherapy or induction chemotherapy. The ongoing research is focused not only on identifying patients that will benefit from adjuvant or induction chemotherapy, but also on identifying the best chemotherapeutic regimen, regimen alternatives to diminish toxicity, the role that immune checkpoint inhibitors play, and the use of molecularly guided treatment targeting patients with NPC whether driven by EBV or tobacco and alcohol. Knowing the precise oncogenesis of NPC not only offers a better understanding of the role that EBV plays in this tumor but also helps create targeted therapies that could potentially block important pathways such as the NF-κB pathway. Much is yet to be done, but the prognosis and management of NPC patients have changed drastically, offering precise treatment methods and excellent control of the disease, even in locally advanced scenarios.

Risk Factors Associated with Nasopharyngeal Cancer Incidences in Indonesia: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the risk factors associated the incidence of NPC, particularly in Indonesia. METHODS: This systematic review and meta-analysis was conducted according to PRISMA statement. Database including PubMed, Scopus, Science Direct, Web of Science, and GARUDA were retrieved. Newcastle-Ottawa scale was used to assess the quality of published study and analyse the risk of bias of included study. Random-effect model and reported pooled Odds Ratio (OR) with 95%CI was carried out in our meta-analysis. RESULTS: A pooled of 7 studies were included in our study which included 764 participants. We found that female gender was not associated with the incidences of NPC (OR 1.45, 95% CI: 0.61-3.45, p=0.40), and smoking was highly increased the incidence of NPC (OR 4.39 95% CI (0.79-24.40), but not statistically significant (p=0.09). Furthermore, salted fish consumption and some HLA alleles were associated with increased risk. CONCLUSION: The incidence of NPC is not associated with female gender nor smoking habits. However, the risk of NPC is higher for those who consume salted fish and have some susceptible HLA alleles. Further investigations in larger studies are needed to confirm these findings.

Optimal plan target in cases with locally advanced nasopharyngeal cancer: Comparison of VMAT, IMRT, hybrid, and tomotherapy results.

PURPOSE: In locally advanced nasopharyngeal cancer (NC), the spread of the disease, proximity to critical structures, and high dose requirement for tumor control may complicate the treatment plan. In this study, VMAT/IMRT/hybrid/tomotherapy plans were made to reach the safest and most effective dose distribution for each of the patients and the results were compared. METHODS: Double volumetric-modulated arc therapy (VMAT) and 7- and 9-field intensity-modulated radiation therapy (IMRT) plans were made to 21 locally advanced NCs with Varian Trilogy System. It was observed that appropriate dose distributions could not be achieved with IMRT or VMAT, and hybrid IMRT-VMAT plans were made. All cases were also planned with Tomotherapy Precision System, and the data of four different techniques were compared retrospectively. RESULTS: For normal tissue tolerances in 73 structures could not be obtained with VMAT and 38 structures with IMRT whereas the desired tolerance was provided with the hybrid plan. Hybrid plans were made with an average of 14 VMATs and 20 IMRTs. The maximum brainstem and spinal cord doses were found significantly lower in hybrid and tomotherapy techniques. Homogeneity index (HI) and conformity index (CI) values were the best in hybrid plans. No statistically significant difference between the hybrid plan and tomotherapy in terms of normal tissue tolerance doses and HI whereas a significant difference was found in the hybrid plan for CI. CONCLUSION: It was observed that the most ideal plans for the locally advanced NC could be obtained with tomotherapy and hybrid plan techniques that the better protection in critical structures and desired dose distribution at target volumes.

Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022. Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]). Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms). Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation. Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02633202.

A novel causal model for nasopharyngeal carcinoma.

The development of nasopharyngeal carcinoma (NPC) and its unique geographic distribution have long been attributed to a combination of dietary intake of salt-preserved fish, inherited susceptibility, and early-life infection with the Epstein-Barr virus (EBV). New findings from our large, rigorously designed, population-based case-control study of NPC in southern China have enabled substantial revision of this causal model. Here, we briefly summarize these results and provide an updated model of the etiology of NPC. Our new research identifies two EBV genetic variants that may be causally involved in the majority of NPC in southern China, and suggests the rise of modern environmental co-factors accompanying cultural and economic transformation in NPC-endemic regions. These discoveries can be translated directly into clinical and public health advances, including improvement of indoor air quality and oral health, development of an EBV vaccine, enhanced screening strategies, and improved risk prediction. Greater understanding of the roles of environmental, genetic, and viral risk factors can reveal the extent to which these agents act independently or jointly on NPC development. The history of NPC research demonstrates how epidemiology can shed light on the interplay of genes, environment, and infections in carcinogenesis, and how this knowledge can be harnessed for cancer prevention and control.

Dosimetric Comparison between Volumetric Modulated Arc Therapy (VMAT) and Intensity-Modulated Radiotherapy (IMRT) for Dental Structures of Head and Neck Cancer Patients.

Background: This retrospective study aimed to evaluate the radiation dose delivered to dental structures in intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) without dental dose constraints, compare the dosimetry differences of dental structures between the two radiation techniques, and determine whether dental structures should be one of the organs at risk for IMRT and VMAT plans according to the dosimetric analysis. Materials and Methods: A total of 138 head and neck cancer patients (nasopharyngeal, oral cavity, pharyngeal, hypopharynx, and larynx), who underwent IMRT (69 patients) or VMAT (69 patients) from March 2016 to March 2021 in our hospital, were included to assess the dosimetry difference between two radiotherapy techniques for dental structures. Results: The radiation dose delivered by IMRT and the mean maximum doses delivered by VMAT to the maxillary teeth of nasopharyngeal cancer patients were significantly higher than the dose received by the mandibular teeth. In contrast, the mandibular teeth of oral cavity cancer, oropharynx cancer, and laryngeal cancer received higher radiation doses than maxillary teeth. Except for mandibular teeth of oral cancer patients, the molars received significantly high-dose radiation than premolars and/or incisors in both radiotherapy techniques. No significant difference was observed between IMRT and VMAT in the dosimetric comparison of dental structures, except that oral cavity cancer patients treated with VMAT received a significantly higher mean average dose than those treated with IMRT. When PTV included level Ib, the radiation doses of the mandibular teeth delivered by both radiotherapy techniques were significantly higher than that in PTV when level Ib was excluded. Conclusion: Without dental dose constraints, no major difference was observed between IMRT and VMAT plans in tooth dose distribution. We suggest that dental structures should be delineated as part of the organ at risk (OAR) when IMRT and VMAT are planned. Meanwhile, attention should be paid to dental structures that might have a high-dose area according to the specific tumor location.

Salted fish and processed foods intake and nasopharyngeal carcinoma risk: a dose-response meta-analysis of observational studies.

PURPOSE: This study aims to analyze whether the consumption of salted fish and processed foods increases the risk of nasopharyngeal carcinoma by analyzing the relevant case-control or cohort design. METHODS: Major databases such as PubMed, ScienceDirect, Embase and Cochrane Library were searched to conduct related studies. In addition, Newcastle-Ottawa scale was employed for assessing the quality of articles. Random-effect model was utilized for meta-analysis. Total relative risk (RR) and 95% confidence interval (95% CI) were calculated. RESULTS: Dose response showed a consistent linear relationship between the intake of salted fish and processed foods and the risk of nasopharyngeal carcinoma. In salted fish, the summary RR was 1.23 (1.04-1.47) for low intake and 1.45 (1.19-1.76) for high intake. For processed meat, low intake was 1.33 (1.09-1.62) and high intake was 1.65 (1.35-2.02). Low intake of processed vegetables was 1.28 (1.05-1.55) and high intake was 1.45 (1.17 -1.79) for high intake. Significant heterogeneity existed in all data but decreased in some subgroups after subgroup analysis. CONCLUSION: Salted fish and processed foods are risk factors for increasing nasopharyngeal carcinoma, but they have different risk characteristics due to different intakes, different stages, and different types.

Gemcitabine-Related Atrial Fibrillation: A Case Report and Review of the Literature.

INTRODUCTION: Gemcitabine is a commonly used antimetabolite that has been effective in a broad spec- trum of tumors so far. The main grade three and four known toxicity of this drug is myelosuppres- sion. Cardiac adverse events have been rarely reported and gemcitabine-induced Atrial-Fibrillation (AF) has been described in only five previous cases so far. Here we report the 6th case of gemc- itabine-related AF. CASE PRESENTATION: A 68-year-old man diagnosed with metastatic nasopharyngeal cancer was referred to our oncology department. He started first-line chemotherapy with gemcitabine and cisplatin. He presented poorly tolerated atrial fibrillation related to gemcitabine infusion that lasted for six days. The treatment was then withdrawn, and the patient received the best supportive care. CONCLUSION: We conclude that medical oncologists and cardiologists should be aware of such toxicities of gemc- itabine, especially in the elderly who seem to be at a higher risk of such adverse events and which may dictate discontinuation of the drug.

A comprehensive model based on temporal dynamics of peripheral T cell repertoire for predicting post-treatment distant metastasis of nasopharyngeal carcinoma.

Many nasopharyngeal carcinoma (NPC) patients develop distant metastases after treatment, leading to poor outcomes. To date, there are no peripheral biomarkers suitable for all NPC patients to predict distant metastasis. Hence, we purposed to develop a noninvasive comprehensive model for predicting post-treatment distant metastasis of all NPC. Since T-cell receptor ß chain (TCRB) repertoire has achieved prognostic prediction in many cancers, the clinical characteristics and parameters of TCRB repertoire of 71 cases of peripheral blood samples (pairwise pre-treatment and post-treatment samples from 40 NPC patients who without (nM, n = 21) or with (M, n = 19) post-treatment distant metastasis) were collected. The least absolute shrinkage and selection operator algorithm was used to construct a distant metastasis prediction model. In terms of TCRB repertoire parameters, the diversity of TCRB repertoire was significantly decreased in M group after treatment but not in nM group. Ascending TCRB diversity and higher similarity between pre- and post-treatment samples showed better distant metastasis-free survival (DMFS). The similarity still had robust DMFS prediction in patients with reduced TCRB diversity. More importantly, the 5-factor comprehensive model consisting of basic clinical characteristics and TCRB repertoire indices showed a higher prognostic accuracy than any one individual factor in DMFS predicting. In conclusion, treatment had different effects on the composition of TCRB repertoire in patients without and with post-treatment distant metastasis. The dynamics of TCRB diversity, the similarity of TCRB repertoires, and combinations of these factors with basic clinical characteristics could serve as noninvasive DMFS predictors for all NPC patients.

Forkhead Box Protein M1 Promotes Nasopharyngeal Carcinoma Cell Tumorigenesis Possibly via the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND Forkhead box protein M1 (FoxM1) is an important transcription factor involved in the development and progression of various malignancies. However, its role in nasopharyngeal carcinoma (NPC) remains largely unknown. This study aimed to assess the effect of FoxM1 on NPC cell tumorigenesis as well as the underlying mechanism. MATERIAL AND METHODS NPC cell lines CNE-1 and CNE-2 were treated with vehicle and FoxM1 inhibitor thiostrepton or transfected with small interfering RNA. CCK-8 assay, flow cytometric assay, and Hoechst 33258 staining were performed to assess the viability, apoptosis and nuclear morphological impairment, and cell cycle, respectively. The expression of apoptosis-related caspase-3 and caspase-9 was detected by western blot analysis The tumor growth in the mouse xenograft model of NPC treated with thiostrepton or control was assessed. The expression of Wnt/ß-catenin signaling proteins p27, FoxM1, S phase kinase-associated protein 2 (SKP2), and Cyclin D1 were determined both in cells and xenograft tissues by western blot analysis. RESULTS Inhibition of FoxM1 by thiostrepton significantly suppressed NPC cell viability, induced apoptosis, increased cell cycle arrest, impaired nuclear morphology, and reduced NPC cell-derived tumor xenograft growth. Mechanistically, inhibition or knockdown of FoxM1 inactivated the Wnt/ß-catenin signaling pathway, as demonstrated by altered expression of Wnt/ß-catenin signaling-related genes, including p27, SKP2, and cyclin D1, in both NPC cells and xenograft tissues. CONCLUSIONS We identified FoxM1 as a novel regulator of NPC cell tumorigenesis in vitro and in vivo. Targeting FoxM1 could be a promising therapeutic strategy against NPC.

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.

Low vitamin D exposure and risk of nasopharyngeal carcinoma: Observational and genetic evidence from a multicenter case-control study.

BACKGROUND & AIMS: Little is known about the risk of nasopharyngeal carcinoma (NPC) in relation to vitamin D exposure. The aim of this study was to examine the associations of NPC risk with serum level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD, and potential effect modification by several putative risk factors of NPC. METHODS: Our multicenter case-control study in Hong Kong recruited 815 NPC cases and 1502 frequency-matched (by sex and age) hospital controls from five major regional hospitals, and recruited 299 healthy subjects from blood donation centers (2014-2017). Circulating level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD (rs12785878, rs11234027, rs12794714, rs4588 and rs6013897) were measured by validated enzyme immunoassay and the iPLEX assay on the MassARRAY System, respectively. Data were also collected on demographics, lifestyle factors, ultraviolet radiation exposure, and potential confounders using a computer-assisted, self-administered questionnaire with satisfactory test-retest reliability. Unconditional logistic regression models were used to estimate ORs and 95% CIs. RESULTS: Despite no significant association of NPC risk with circulating 25OHD and genetic predicted 25OHD, there was evidence for an inverse association in participants with normal body mass index (between 18.5 and 27.5) across categories of 25OHD (Ptrend = 0.003), and a positive association in those with low socioeconomic status across categories based on the genetic score (Ptrend = 0.005). In addition, risk of NPC diagnosed at an early stage was higher for genetically lower 25OHD level (adjusted OR = 3.09, 95% CI = 1.04-9.21, Ptrend = 0.022). CONCLUSIONS: Findings of this first comprehensive study to investigate the positive association of NPC risk with vitamin D deficiency need to be confirmed and be best interpreted with results of further similar studies. Our findings may inform possible etiological mechanisms of the associations with several putative risk/protective factors of NPC.

Necrosis Factor-α (TNF-α) and the Presence of Macrophage M2 and T Regulatory Cells in Nasopharyngeal Carcinoma.

OBJECTIVE: To investigate the correlation between TLR3 and pro-inflammatory cytokines (TNFα, IL6) expression with the distribution of macrophage M2 and Treg on Epstein Barr virus-encoded RNAs (EBER+) nasopharyngeal carcinoma (NPC) tissues. METHODS: A total of 23 FFPE NPC tissue samples were obtained from patients in Dr. Sardjito General Hospital, Yogyakarta, Indonesia in 2008-2010, which expressed EBER was collected. The expressions of TLR3, TNFα, and IL6 were examined using immunofluorescence assay. The distribution of macrophage M2 and Treg were examined by immunohistochemistry with anti-CD163 and -FOXP3 antibodies, respectively. The quantification of fluorescence intensity was analyzed by the RGB space method using ImageJ software. The M2 interpretation was done by the eyeballing method and the M2 scores were divided into 0 (negative), 1 (scant), 2 (focal), 3 (abundant). The average number of Treg FOXP3+ cells in five high power fields was counted. The relationship between variables were tested by the Spearman correlation test, and the coefficient correlation was used to see the correlation between variables. RESULTS: All EBER+ NPC specimens showed TLR3 expression intracellularly. The expression of TNFα could be observed in the cell membranes and secreted extracellularly, while IL6 was secreted to the extracellular area. The expression of TNFα was two times higher than IL6. Most specimens showed low M2 score (56.52%) and high Treg (52.17%). A positive correlation was found between TLR3 and IL6 (12.9%). TNFα was positively correlated with the M2 distribution of 13.7% and Treg distribution of 12.9%, while the rest were explained by other factors. CONCLUSION: TNFα has a positive correlation with M2 and Treg distribution,but mostly through a different mechanism other than EBER-TLR3 interaction. Possibly, other pro-inflammatory and anti-inflammatory cytokines are involved in the formation of the NPC microenvironment, especially related to the presence of M2 and Treg, which provide immunosuppressive effects in NPC tumors. 
.

Dietary patterns and risk of nasopharyngeal carcinoma: a population-based case-control study in southern China.

BACKGROUND: Dietary factors, such as consumption of preserved foods, fresh vegetables, and fruits, have been linked to the risk of nasopharyngeal carcinoma (NPC). However, little is known about associations between dietary patterns and the risk of NPC in NPC-endemic areas. OBJECTIVES: We aimed to evaluate whether dietary patterns are associated with NPC risk. METHODS: We studied 2554 newly diagnosed NPC patients aged 20-74 y living in 3 endemic regions of southern China, and 2648 population-based controls frequency-matched to case patients by age, sex, and region, between 2010 and 2014. Dietary components were derived from food frequency data in adulthood and adolescence using principal component analysis. Four dietary components were identified and highly similar in adulthood and adolescence. We used multivariable unconditional logistic regression to calculate ORs with 95% CIs for the association between dietary patterns and NPC risk. RESULTS: Compared with the lowest quartile, individuals in the highest quartile of the "plant-based factor" in adulthood had a 52% (OR: 0.48; 95% CI: 0.38, 0.59) decreased risk of NPC, and those in the highest quartile of the "animal-based factor" had a >2-fold (OR: 2.26; 95% CI: 1.85, 2.77) increased risk, with a monotonic dose-response trend (P-trend < 0.0001). Similar but weaker associations were found in adolescence. High intakes of the "preserved-food factor" were associated with increased NPC risk in both periods, although stronger associations were found in adolescence. Results from joint analysis and sensitivity analyses indicated that dietary factors in adulthood might be more stable and robust predictors of NPC risk than those in adolescence. CONCLUSIONS: Our results deliver compelling evidence that plant- and animal-based dietary factors are associated with NPC risk, and provide more insights on the associations of diets and cancer risk that may assist healthy diet recommendations.