Survival Of Nasopharyngeal Carcinoma Patients Research Articles

A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma

Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate PLD1's oncogenic role, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA (p65), which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression significantly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, significantly inhibits NPC tumorigenesis in a patient-derived xenograft model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

Novel prognostic biomarkers in nasopharyngeal carcinoma unveiled by mega-data bioinformatics analysis

Nasopharyngeal carcinoma (NPC) is commonly diagnosed at an advanced stage with a high incidence rate in Southeast Asia and Southeast China. However, the limited availability of NPC patient survival data in public databases has resulted in less rigorous studies examining the prediction of NPC survival through construction of Kaplan-Meier curves. These studies have primarily relied on small samples of NPC patients with progression-free survival (PFS) information or data from head and neck squamous cell carcinoma (HNSCC) studies almost without NPC patients. Thus, we coanalyzed RNA expression profiles in eleven datasets (46 normal (control) vs 160 tumor (NPC)) downloaded from the Gene Expression Omnibus (GEO) database and survival data provided by Jun Ma from Sun Yat-sen University. Then, differential analysis, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and network analysis were performed using STRING database. After that, 2142 upregulated differentially expressed genes (DEGs) and 3857 downregulated DEGs were screened. Twenty-five of them were identified as hub genes, which were enriched in several pathways (cilium movement, extracellular matrix structural constituent, homologous recombination and cell cycle). Utilizing the comprehensive dataset we amassed from GEO database, we conducted a survival analysis of DEGs and subsequently constructed survival models. Seven DEGs (RASGRP2, MOCOS, TTC9, ARHGAP4, DPM3, CD37, and CD72) were identified and closely related to the survival prognosis of NPC. Finally, qRT-PCR, WB and IHC were performed to confirm the elevated expression of RASGRP2 and the decreased expression of TTC9, CD37, DPM3 and ARHGAP4, consistent with the DEG analysis. Conclusively, our findings provide insights into the novel prognostic biomarkers of NPC by mega-data bioinformatics analysis, which suggests that they may serve special targets in the treatment of NPC.

Predicting the overall survival and progression-free survival of nasopharyngeal carcinoma patients based on hemoglobin, albumin, and globulin ratio and classical clinicopathological parameters.

Serum biomarkers have a significant impact on the prediction of treatment outcomes in patients diagnosed with nasopharyngeal carcinoma (NPC). The primary aim of this study was to develop and validate a nomogram that incorporates hemoglobin, albumin, and globulin ratio (HAGR) and clinical data to accurately forecast treatment outcomes in patients with NPC. A total of 796 patients diagnosed with NPC were included in the study. The results of the multivariate Cox analysis revealed that TNM stage and HAGR were found to be significant independent prognostic factors for OS and PFS. Furthermore, the utilization of the nomogram demonstrated a significant improvement in the evaluation of OS, PFS compared with the eighth TNM staging system. Additionally, the implementation of Kaplan-Meier curves and decision curve analysis curves further confirmed the discriminability and clinical effectiveness of the nomogram. The HAGR, an innovative prognostic factor grounded in the realm of immunonutrition, has emerged as a promising prognostic marker for both OS and PFS in individuals afflicted with NPC.

M6A-mediated molecular patterns and tumor microenvironment infiltration characterization in nasopharyngeal carcinoma

ABSTRACT N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in the regulation of tumor microenvironment (TME) cell infiltration in several tumors. Nevertheless, the potential role and mechanism of m6A modification in nasopharyngeal carcinoma (NPC) remains unknown. mRNA expression data and clinical information from GSE102349, and GSE53819 datasets obtained from Gene Expression Omnibus (GEO) was used for differential gene expression and subsequent analysis. Consensus clustering was used to identify m6A-related molecular patterns of 88 NPC samples based on prognostic m6A regulators using Univariate Cox analysis. The TME cell-infiltrating characteristics of each m6A-related subclass were explored using single-sample gene set enrichment (ssGSEA) algorithm and CIBERSORT algotithm. DEGs between two m6A-related subclasses were screened using edgeR package. The prognostic signature and predicated nomogram were constructed based on the m6A-related DEGs. The cell infiltration and expression of prognostic signature in NPC was determined using immunohistochemistry (IHC) analysis. Chi-square test was used to analysis the significance of difference of the categorical variables. And survival analysis was performed using Kaplan–Meier plots and log-rank tests. The NPC samples were divided into two m6A-related subclasses. The TME cell-infiltrating characteristics analyses indicated that cluster 1 is characterized by immune-related and metabolism pathways activation, better response to anit-PD1 and anti-CTLA4 treatment and chemotherapy. And cluster 2 is characterized by stromal activation, low expression of HLA family and immune checkpoints, and a worse response to anti-PD1 and anti-CTLA4 treatment and chemotherapy. Furthermore, we identified 1558 DEGs between two m6A-related subclasses and constructed prognostic signatures to predicate the progression-free survival (PFS) for NPC patients. Compared to non-tumor samples, REEP2, TMSB15A, DSEL, and ID4 were upregulated in NPC samples. High expression of REEP2 and TMSB15A showed poor survival in NPC patients. The interaction between REEP2, TMSB15A, DSEL, ID4, and m6A regulators was detected. Our finding indicated that m6A modification plays an important role in the regulation of TME heterogeneity and complexity.

Abstract 3272: PJA1 inhibits docetaxel-induced pyroptosis and results in chemoresistance in nasopharyngeal carcinoma

Abstract Background: Nasopharyngeal carcinoma (NPC) is highly prevalent in South China. More than 70% of patients are diagnosed with locoregionally advanced NPC (LA-NPC) at initial presentation, and the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy is recommended for these patients. However, chemoresistance is a main reason for treatment failure in NPC patients, and the exact regulatory mechanism underlying chemoresistance in NPC remains to be elucidated. Methods: A gene expression dataset and STRING database were used to identify core module and gene that are related to the efficacy of docetaxel-cisplatin-5-fluorouracil (TPF) IC in NPC patients. In vitro and in vivo functional experiments were used to test the effects of PJA1 on docetaxel chemoresistance of NPC cells. The flow cytometric analysis, western blot, and lactate dehydrogenase (LDH) release assays were performed to determine the effects of PJA1 on GSDME-mediated cell pyroptosis. Co-immunoprecipitation, mass spectrometry, immunofluorescence staining, and ubiquitination assays were performed to explore the regulatory manners between PJA1 and PGAM5-DRP1 axis. Finally, multiplex immunofluorescence and immunohistochemical staining were used to evaluate the clinical significance of PJA1 -PGAM5-DRP1 axis in patients with NPC. Results: PJA1 was identified as a key E3 ligase of the top-ranked module ubiquitin-proteasome system dysregulation that involved in NPC chemoresistance, which was highly expressed in NPC patients with nonresponse to the TPF IC. PJA1 facilitated the docetaxel resistance of NPC cells through inhibiting the GSDME-mediated pyroptosis. Mechanistically, PJA1 promoted the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, further increasing the phosphorylation of DRP1 at S637 and reducing the mitochondrial reactive oxygen species (ROS) production, in turn resulting in a suppressive of GSDME-mediated pyroptosis. PGAM5 knockdown fully restored the docetaxel sensitization effect of PJA1 knockdown. Moreover, RTA402, a pharmacological inhibitor of PJA1, enhanced the docetaxel sensitivity of NPC cells. Clinically, high PJA1 expression indicated resistance to TPF IC an inferior survival in NPC patients. Conclusions: Our study emphasizes the essential role of E3 ligase PJA1 in regulating chemoresistance in NPC and provides new therapeutic strategies for NPC patients based on targeting the ubiquitin-proteasome system. Citation Format: Na Liu, Ying-Qing Li, Sheng-Yan Huang. PJA1 inhibits docetaxel-induced pyroptosis and results in chemoresistance in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3272.

MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma.

Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR-2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR-2110 can be regulated by cinobufotalin (CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT-PCR, and in situ hybridization were used to observe the expression of miR-2110 in NPC tissues and cells. Scratch, Boyden, and tail vein metastasis model of nude mouse were used to detect the effect of miR-2110 on NPC metastasis. Western blot, Co-IP, luciferase activity, colocalization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR-2110 affecting NPC metastasis. Finally, miR-2110 induced by CB participates in CB-stimulated inhibition of NPC metastasis was explored. The data showed that increased miR-2110 significantly suppresses NPC cell migration, invasion, and metastasis. Suppressing miR-2110 markedly restored NPC cell migration and invasion. Mechanistically, miR-2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4-induced phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT-stimulated epithelial-mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, CB, a potential new inhibitory drug for NPC metastasis, significantly induced miR-2110 expression by suppressing PI3K/AKT/c-Jun-mediated transcription inhibition. Suppression of miR-2110 significantly restored cell migration and invasion in CB-treated NPC cells. Finally, a clinical sample assay indicated that reduced miR-2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival prognosis. In summary, miR-2110 is a metastatic suppressor involving in CB-induced suppression of NPC metastasis.

Serum ferritin predicted prognosis in patients with nasopharyngeal carcinoma

Elevated serum ferritin (SF) levels have been associated with poor prognosis in various cancer types, but its impact on nasopharyngeal carcinoma (NPC) remains unclear. This retrospective study analyzed clinical data from 252 non-metastatic NPC patients admitted to Hainan General Hospital between January 2014 and May 2016. SF levels were measured using the chemiluminescence method. Patients were categorized into low, medium, and high-level SF groups based on tertile median SF levels. Survival outcomes were assessed using Kaplan–Meier analysis and Cox regression models. The overall survival rates of the entire patient cohort at 1, 3, 5, and 8 years were 95.2%, 85.7%, 76.2%, and 68.9% respectively. The high-level SF group (SF > 164.00 ng/mL) had significantly worse overall survival (83.1 vs 96.3 months, P = 0.023) and progression-free survival (77.8 vs 93.3 months, P = 0.019) compared to the low-level SF group. Univariate and multivariate analyses confirmed that high SF levels, along with T3/T4 staging and N3 staging, were independent risk factors for poor prognosis. In conclusion, high SF levels are associated with shorter overall survival and progression-free survival in NPC patients.

Soluble CD27 as a predictive biomarker for intra-tumoral CD70/CD27 interaction in nasopharyngeal carcinoma.

In CD70-expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27-positive lymphocytes infiltrate around tumor cells. NPC patients with CD27-positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27-positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70-positive NPC with CD27-positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27-targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC.

Association between time from diagnosis to treatment and survival of patients with nasopharyngeal carcinoma: A population-based cohort study

BackgroundTreatment delays have frequently been observed in cancer patients. Whether the treatment delays would impair the survival of patients with nasopharyngeal carcinoma (NPC) is still unclear. MethodsThe data were derived from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Patients were divided into groups of timely treatment (<1 month), intermediate delay (1 and 2 months), and long delay (3–6 months). The influence of different treatment delay intervals on long-term survival was evaluated by multivariate Cox regression analysis. ResultsIn total, 2,048 patients with NPC were included in our study. There were 551 patients in the early stage (I, II stage: 26.9 %) and 1,497 patients in the advanced stage (III, IV stage: 73.1 %). No significant difference in overall survival (OS) or cancer-specific survival (CSS) was observed among the groups with various treatment delay intervals (p = 0.48 in OS and p = 0.43 in CSS, respectively). However, upon adjusting for covariates, a significantly improved OS probability emerged in patients with intermediate treatment delays compared to those who received timely interventions in both the entire study population (adjustedHazard Ratio (aHR)=0.86, 95 % CI: 0.74–0.99, p = 0.043) and the subgroup with advanced stage (aHR=0.85, 95 % CI: 0.72–1.00, p = 0.049). Regarding the CSS probability, similar associations were also observed in the entire study population (aHR=0.84, 95 % CI: 0.71–0.98, p = 0.030) as well as the advanced-stage patients (aHR=0.83, 95 % CI: 0.70–0.99, p = 0.038). ConclusionsOur results revealed that treatment delays are not associated with worse survival of NPC patients. Tumor-specific characteristics and subsequent treatment modalities play more pivotal roles in the prognosis of NPC.

Use of survival support vector machine combined with random survival forest to predict the survival of nasopharyngeal carcinoma patients.

The Cox regression model is not sufficiently accurate to predict the survival prognosis of nasopharyngeal carcinoma (NPC) patients. It is impossible to calculate and rank the importance of impact factors due to the low predictive accuracy of the Cox regression model. So, we developed a system. Using the SEER (The Surveillance, Epidemiology, and End Results) database data on NPC patients, we proposed the use of random survival forest (RSF) and survival-support vector machine (SVM) from the machine learning methods to develop a survival prediction system specifically for NPC patients. This approach aimed to make up for the insufficiency of the Cox regression model. We also used the Cox regression model to validate the development of the nomogram and compared it with machine learning methods. A total of 1,683 NPC patients were extracted from the SEER database from January 2010 to December 2015. We used R language for modeling work, established the nomogram of survival prognosis of NPC patients by Cox regression model, ranked the correlation of influencing factors by RSF model VIMP (variable important) method, developed a survival prognosis system for NPC patients based on survival-SVM, and used C-index for model evaluation and performance comparison. Although the Cox regression models can be developed to predict the prognosis of NPC patients, their accuracy was lower than that of machine learning methods. When we substituted the data for the Cox model, the C-index for the training set was only 0.740, and the C-index for the test set was 0.721. In contrast, the C index of the survival-SVM model was 0.785. The C-index of the RSF model was 0.729. The importance ranking of each variable could be obtained according to the VIMP method. The prediction results from the Cox model are not as good as those of the RSF method and survival-SVM based on the machine learning method. For the survival prognosis of NPC patients, the machine learning method can be considered for clinical application.

Targeting Glutamine Metabolism through Glutaminase Inhibition Suppresses Cell Proliferation and Progression in Nasopharyngeal Carcinoma.

Glutaminase (GLS), the key enzyme involved in glutamine metabolism, has been identified as a critical player in tumor growth and progression. The GLS inhibitor CB-839 has entered several clinical trials against a variety of tumors. Our study aimed to investigate the role and underlying mechanism of GLS and its inhibitor CB-839 in nasopharyngeal carcinoma (NPC). The expression, downstream genes, and signaling pathways of GLS in NPC were determined by real-time polymerase chain reaction (RT-PCR), PCR array, western blotting (WB), and immunohistochemical staining (IHC), and the phenotype of GLS was confirmed by in vivo experiments of subcutaneous tumor formation in mice and in vitro experiments of functional biology, including Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, transwell migration, and Boyden invasion assay. Finally, it was also verified whether the treatment of NPC cells by GLS inhibitor CB-839 can change various biological functions and protein expression to achieve the purpose of blocking tumor progression. GLS was remarkably overexpressed in NPC cells and tissues, predicting a poor overall survival of NPC patients. GLS promoted cell cycle, proliferation, colony formation, migratory, and invasive capacities by regulating Cyclin D2 (CCND2) via PI3K/AKT/mTOR pathway in NPC in vitro and in vivo. Notably, CB-839 showed an effective anti-NPC tumor effect by blocking the biological functions of the tumor. The first innovative proof is that GLS promotes cell proliferation by regulating CCND2 via PI3K/AKT/mTOR pathway in NPC, and GLS inhibitor CB-839 may serve as a new potential therapeutic target for NPC treatment.

M6A Reader YTHDC1 Inhibits Ferroptosis and Radiosensitivity by Promoting SREBF1 mRNA Nuclear Export in Nasopharyngeal Carcinoma

Radioresistance is the main reason for nasopharyngeal carcinoma (NPC) recurrence leading to treatment failure, and inducing ferroptosis has gradually been a new way to enhance radiosensitivity. N6-methyladenosine (m6A) is involved in regulation of numerous biological processes. However, whether m6A affects ferroptosis in NPC is still unclear. In this study, we conducted a siRNA library screening to identify m6A reader YTHDC1 as an essential oncogene that suppressed ferroptosis and radiosensitivity by promoting SREBF1 mRNA nuclear export in nasopharyngeal carcinoma. The expression and function of YTHDC1 were assessed via CCK8 cell viability assay, immunostaining, real-time PCR, western blot, radiation clonogenic assay and fluorescence in situ hybridization assay. Ferroptosis was determined by detecting cell viability, lipid peroxidation, abnormal mitochondrial and cell death rate. The in vivo effects of YTHDC1 were examined with RSL3 treatment or lentivirus modification of YTHDC1 expression in radiated mouse models. Based on RSL3-induced ferroptotic cell death model and a siRNA library about m6A modification associated gene screening, we identified m6A reader YTHDC1 could inhibit ferroptosis as well as radiosensitivity of NPC, both in vivo and in vitro. Mechanistically, YTHDC1 protein could recognize m6A sites in the CDS region and 3' untranslated region (3'UTR) of SREBF1 mRNA and promote SREBF1 mRNA nuclear export, which finally resulted in transcriptional upregulation of genes key to ferroptosis such as SCD and FASN. Furthermore, the high expression of YTHDC1 was negatively regulated by ZNF598 via ubiquitination and associated with unfavorable survival in NPC patients due to radioresistance. Our findings reveal the critical role of YTHDC1 specifically in inhibiting ferroptosis and radiosensitivity via m6A-dependent mechanism and provide an exploitable target and therapeutic strategy for overcoming radioresistance in NPC.

An analysis of long-term survival trends for nasopharyngeal carcinoma in Qidong, Jiangsu

Objective: To analyze the survival of nasopharyngeal carcinoma patients in Qidong from 1972 to 2016, and provide a basis for the prognosis evaluation and prevention for nasopharyngeal carcinoma patients. Methods: A total of 1 060 registered nasopharyngeal carcinoma patients were followed up for survival outcomes until December 31, 2021. Observed survival rate (OSR) and relative survival rate (RSR) was calculated by Hakulinen method in SURV3.01 software, and Hakulinen's likelihood ratio test was used for statistical difference comparison. Age-standardized relative survival rate (ARSR) was calculated according to the International Cancer Survival Standard (ICSS). Joinpoint 4.7.0.0 software was used to conduct the annual average percentage change (AAPC) in nasopharyngeal carcinoma survival rate. The period from 1972 to 2016 is divided into 9 periods for grouping processing according to 5 years. Results: The OSR of nasopharyngeal carcinoma at 1, 5, 10 years were 63.02%, 34.70% and 24.72%, the RSR at 1, 5, 10 years were 64.44%, 38.98% and 31.64%, respectively. The uptrends of RSR in the nine periods were statistically significant (χ(2)=112.16, P<0.001). The 1, 5, 10 years RSR for males were 62.66%, 35.89% and 27.94%, while the 1, 5, 10 years RSR for females were 68.30%, 45.67% and 39.68%, respectively. There was no statistically significant difference in RSR between males and females (χ(2)=14.16, P=0.656). The 5-year RSR for the age groups of 25-34, 35-44, 45-54, 55-64, 65-74, and over 75 years old were 52.83%, 40.92%, 42.64%, 38.65%, 27.23% and 28.88%, respectively. There was a statistically significant difference in RSR among different age groups (χ(2)=42.33, P=0.003). Moreover, the ARSR of nasopharyngeal carcinoma at 1, 5, 10 years were 63.64%, 37.33% and 27.10%, for males were 61.82%, 35.60% and 25.20%, for females were 68.36%, 43.12% and 32.93%. Period trend showed that the AAPC of 5-ARSR was 2.71% (t=7.47, P<0.001) from 1972 to 2016 in Qidong. The AAPC of 5-ARSR in males and females were 2.63% (t=4.98, P=0.002) and 2.71% (t=6.08, P=0.001). There was statistically significant increase in 5-year ARSR among both genders. Furthermore, the AAPC of 5-year RSR among 25-34, 35-44, 45-54, 55-64, 65-74 and 75+ years old were 2.16% (t=4.28, P=0.004), 3.38% (t=5.06, P=0.001), 1.99% (t=2.82, P=0.026), 2.82% (t=3.39, P=0.012), 2.20% (t=2.82, P=0.026) and -0.91% (t=-0.42, P=0.689), respectively. Except for the 75+ years old age group, the other age groups were significantly upward trend. Conclusions: The overall survival rate of nasopharyngeal carcinoma in Qidong from 1972 to 2016 has shown an upward trend. It is necessary to introduce standardized multi-disciplinary treatment mode to improve treatment effect and survival rate.

Contribution of age at diagnosis to cancer-specific survival of nasopharyngeal carcinoma patients receiving radiotherapy.

To assess age as a continuous variable for the prognosis of patients with nasopharyngeal carcinoma (NPC) receiving radiotherapy. Patients diagnosed with NPC between 2004 and 2016 were extracted from the Surveillance, Epidemiology, and End Results database. The X-tile was used to calculate the optimal cutoff values for age at diagnosis. Age at diagnosis was divided into subgroups based on the cutoff values. Cancer-specific survival (CSS) between age subgroups was assessed using the Kaplan-Meier method. The age cutoff values for CSS were 42 and 70 years. The 5-year CSS was 85.8%, 73.8%, and 67.1% for the ≤42, 43 to 70, and >70 subgroups. Multivariate regression analysis revealed that race, pathology, T stage, N stage, and age were independent prognostic factors. A nomogram based on the prognostic factors showed that the area under the receiver operating characteristic curve was 0.723 (95% confidence interval, 0.697-0.749). The calibration plots showed good agreement for the 5-year CSS between the predicted and actual observations. All patients were divided into 3 groups according to risk score stratification. Kaplan-Meier survival analyses showed that patients in the low-risk cohort had a greater 5-year CSS than those in the medium- and high-risk cohorts (P < .05). Age subgroups of ≤42, 43 to 70, and >70 years may be useful for determining the prognosis of patients with NPC.

Prognostic significance of the novel nutrition-inflammation marker of lymphocyte-C-reactive protein ratio in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy.

Recent studies indicate that the novel lymphocyte-C-reactive protein ratio (LCR) is strongly associated with the survival of various tumors, but its prognostic value in nasopharyngeal carcinoma (NPC) is understudied. This study aimed to explore the relationship between LCR and overall survival (OS) in NPC and develop a predictive model. A total of 841 NPC patients who received concurrent chemoradiotherapy (CCRT) between January 2010 and December 2014 were retrospectively enrolled and randomly divided into a training cohort (n = 589) and a validation cohort (n = 252), and 122 patients between January 2015 and March 2015 were included as an additional validation cohort. Univariate and multivariate Cox analyses were performed to identify variables associated with OS and construct a predictive nomogram. The predictive accuracy of the nomogram was evaluated and independently validated. The LCR score differentiated NPC patients into two groups with distinct prognoses (HR = 0.53; 95% CI: 0.32-0.89, P = 0.014). Multivariate analysis showed that age, T stage, N stage, EBV-DNA status, and LCR score were independently associated with OS, and a predictive nomogram was developed. The nomogram had a good performance for the prediction of OS [C-index = 0.770 (95% CI: 0.675-0.864)]. and outperformed the traditional staging system [C-index = 0.589 (95% CI: 0.385-0.792)]. The results were internally and additionally validated using independent cohorts. The pretreatment LCR could independently predict the overall survival in NPC patients. A novel LCR-based prognostic model of an easy-to-use nomogram was established, and it outperformed the conventional staging system in terms of predictive power. Further external verification remains necessary.

Prognosis-related molecular subtyping of nasopharyngeal carcinoma.

e18047 Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a mRNA -based prognostic model for prediction of treatment efficacy. Methods: We retrospectively collected a total of 193 NPC tissue samples from 2016 to 2018 for mRNA sequencing. Consensus clustering was performed to identify new molecular subgroups based on the ssgsea algorithm. Then, weighted gene co-expression network analysis (WGCNA) was used to recognize molecular subtype-associated hub genes. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of recurrence and metastasis. Results: Three NPC subtypes (immune, proliferation and metabolism) were identified that are molecularly distinct and clinically relevant, of which proliferation subtype is associated with poor prognosis. Immune subtype characterized by higher expression of immune checkpoint, immune cells infiltration and immunesore. Interestingly, compared with other cells, tumor cells in TME exhibited the most active metabolism pathway in single-cell sequencing analyses. The Cox regression model built on hub genes showed a close correlation with outcome (AUC = 0.81). We further validated the results using the GEO database. Conclusions: Based on biological characteristics, NPC can be novelly stratified into three subtypes. Our study identified and validated a promising prognostic model associated with molecular subtype, which may accurately anticipate the survival of NPC patients.

Chemotherapy combined with anlotinib, toripalimab and stereotactic radiotherapy in oligo-metastatic nasopharyngeal carcinoma: A prospective, multicenter phase II clinical study.

e18011 Background: Distant metastasis is the main cause of nasopharyngeal carcinoma (NPC) related death while there are few treatment options for it. How to further improve the survival of NPC patients with distant metastases is an urgent problem to be solved in clinical practice. This study investigated the efficacy and safety of chemotherapy in combination with anlotinib (a multi-target tyrosine kinase inhibitor), toripalimab, and stereotactic radiotherapy(SBRT) in treatment of metastatic NPC. Methods: This is a prospective, multi-centered, single-arm, phase II trial (ChiECRCT20210147). Patients with histologically confirmed non-keratinous carcinoma and post-treatment metastatic NPC (stage IVb, AJCC 8th) who had no local recurrence and received no systemic antitumor therapy for metastatic lesions previously were enrolled. No more than 5 metastatic lesions (metastatic sites include lung, liver, bone, etc.), and with at least one measurable target lesion according to RECIST1.1. Other inclusion criteria included 18-65 years old and ECOG 0-1. All patients received gemcitabine (1000 mg/m2, ivgtt, d1/8), cisplatin (80 mg/m2, ivgtt, d1), toripalimab (240mg, ivgtt, d1) and anlotinib (12mg, oral, qd, d1-14) every 3 weeks for 6 cycles, then followed by toripalimab (240mg, ivgtt, d1) and anlotinib (12mg, oral, qd, d1-14) every 3 weeks for 11 cycles. The SBRT was initiated after 2 cycles of chemotherapy (bone GTV 30-45Gy/3-5f, liver and lung GTV 45-60Gy/4-6f). The primary endpoint was objective response rate (ORR). Here we report the results of a preliminary analysis. Results: Between January 2022 and January 2023, a total of 19 patients were enrolled (13 males and 6 females), the median age was 46 years old. At the data cutoff date on January 31, 2023, 15 patients were eligible for the evaluation of tumor response with metastatic lesions. 100% of the patients (15 of 15) had a response and the confirmed ORR was 100% (complete response, n = 4; partial response, n = 11) for metastatic lesions. The most common treatment-related adverse events (TRAE) of any grade were leukopenia (15 of 15,100%), anaemia(13 of 15, 93.3%), decreased appetite (10 of 15, 66.7%), hypothyroidism (6 of 15, 40.0%), rash(5 of 15, 33.3%) and pneumonitis (5 of 15, 33.3%). Grade 3-4 TRAE included leukopenia (3 of 15, 20.0%) and no fatal adverse events occurred. Conclusions: This preliminary analysis indicated that chemotherapy combined with anlotinib, toripalimab, and stereotactic radiotherapy had promising efficacy and favorable tolerance as treatment of oligo-metastatic NPC. Clinical trial information: ChiECRCT20210147 .

Long-Term Outcomes of Nasopharyngeal Carcinoma by Epstein-Barr Virus Status in the Chinese Population: A Multicenter Investigation.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein-Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013-2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan-Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions.

Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation.

Senescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircWDR37 deficiency limits cisplatin or gemcitabine-induced senescent NPC cells from proliferation, migration, and invasion. Mechanistically, circWDR37 binds to and dimerizes double-stranded RNA-activated protein kinase R (PKR) to initiate PKR autophosphorylation and activation. Independent of its kinase activity, phosphorylated PKR induces I-kappaB kinase beta (IKKβ) phosphorylation, binds to and releases RELA from NF-κB inhibitor alpha (IκBα) to trigger nuclear factor kappa B (NF-κB) activation, thereby stimulating cyclin D1 (CCND1)and senescence-associated secretory phenotype component gene transcription in a circWDR37-dependent manner. Low circWDR37 levels correlate with chemotherapy response and favorable survival in NPC patients treated with gemcitabine or cisplatin induction chemotherapy. This study uncovers a new mechanism of circWDR37 activated PKR in senescence-driven metastasis and provides appealing therapeutic targets in NPC.

Systemic immune-inflammation index during treatment predicts prognosis and guides clinical treatment in patients with nasopharyngeal carcinoma

PurposeSystemic immune-inflammation index (SII) has been demonstrated to be closely associated with the poor prognosis of nasopharyngeal carcinoma (NPC). However, the role of SII during treatment of NPC has not been reported. This study aimed to determine the prognostic value of SII during treatment for NPC patients.MethodsA total of 759 patients diagnosed with NPC were included in this retrospective study (393 in training cohort and 366 in validation cohort). The correlation between variables was analyzed by the chi-squared test, the Fisher’s exact test or the likelihood test. Kaplan–Meier method and log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). The independent prognostic factors were determined by multivariate analysis of Cox proportional hazards regression model. The uncontrolled risk was analyzed by Logistic regression. Receiver operating characteristic (ROC) curves were used to assess prognostic value.ResultsThe optimal cut-off point for the SII during treatment was 937.32. High SII during treatment group had higher uncontrolled risk than low SII during treatment group (p = 0.008). In multivariate Cox proportional hazard models analysis, SII during treatment was an independent prognostic factor for 5-year PFS (p < 0.001) and 5-year OS (p < 0.001). All results were found in the training cohort and confirmed in the validation cohort.ConclusionsThe SII during treatment is a promising indicator of predicting the survival in NPC patients, especially the risk of uncontrolled occurrence. By monitoring the SII during treatment, it is possible to better evaluate the treatment effect and formulate personalized treatment.