ADAR1-regulated miR-142-3p/RIG-I axis suppresses antitumor immunity in nasopharyngeal carcinoma.

Following the initial treatment of nasopharyngeal carcinoma (NPC), tumor progression often portends an adverse prognosis for these patients. MicroRNAs (miRNAs) have emerged as critical regulators of tumor immunity, yet their intricate mechanisms in NPC remain elusive. Through comprehensive miRNA sequencing, tumor tissue microarrays and tissue samples analysis, we identified miR-142-3p as a significantly upregulated miRNA that is strongly associated with poor prognosis in recurrent NPC patients. To elucidate the underlying molecular mechanism, we employed RNA sequencing, coupled with cellular and tissue assays, to identify the downstream targets and associated signaling pathways of miR-142-3p. Our findings revealed two potential targets, CFL2 and WASL, which are directly targeted by miR-142-3p. Functionally, overexpressing CFL2 or WASL significantly reversed the malignant phenotypes induced by miR-142-3p both in vitro and in vivo. Furthermore, signaling pathway analysis revealed that miR-142-3p repressed the RIG-I-mediated immune defense response in NPC by inhibiting the nuclear translocation of IRF3, IRF7 and p65. Moreover, we discovered that ADAR1 physically interacted with Dicer and promoted the formation of mature miR-142-3p in a dose-dependent manner. Collectively, ADAR1-mediated miR-142-3p processing promotes tumor progression and suppresses antitumor immunity, indicating that miR-142-3p may serve as a promising prognostic biomarker and therapeutic target for NPC patients.

Comparative evaluation of machine learning models in predicting overall survival for nasopharyngeal carcinoma using 18F-FDG PET-CT parameters.

PURPOSE: The objective of this study is to assess the prognostic efficacy of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET-CT) parameters in nasopharyngeal carcinoma (NPC) and identify the best machine learning (ML) prognostic model for NPC patients based on these 18F-FDG PET/CT parameters and clinical variables. METHOD: A cohort of 678 patients diagnosed with NPC between 2016 and 2020 was analyzed in this study. The model was constructed using four advanced ML algorithms, namely Random Forest (RF), Extreme Gradient Boosting (XGBoost), Least Absolute Shrinkage and Selection Operator (LASSO), and multifactor COX step-up regression. Statistical significance of the models was assessed using Kaplan-Meier (K-M) curves, with a significance level established at P < 0.05. The prognostic efficacy of the models was evaluated through the analysis of receiver operating characteristic (ROC) curves, with the area under the ROC curve (AUC) serving as a criterion for model selection. The decision curve analysis (DCA) and concordance index (C-index) were employed to assess the precision of the optimal model. RESULTS: Multivariate analysis revealed age, T stage, and metabolic tumor volume (MTV) for the primary nasopharyngeal tumor (MTVT) as significant independent prognostic factors for overall survival (OS) in NPC patients. Additionally, the LASSO model identified six key variables, including peak standardized uptake value (SUV-peak) for the primary nasopharyngeal tumor (SUV-peak(T)), MTVT, heterogeneity index for neck lymph nodes (HIN), age, pathological type, and T stage. Remarkably, the LASSO model demonstrated superior performance with a 5-year AUC of 0.849 compared to other models. Further assessment using the C-index and DCA confirmed the accuracy of the LASSO model. Subgroup analysis revealed notable risk factors, such as a high heterogeneity index (HI) for the primary nasopharyngeal tumor (HIT), MTV values for neck lymph nodes (MTVN), and HIN. CONCLUSIONS: We developed a novel prognostic machine learning model that integrates 18F-FDG PET-CT parameters and clinical characteristics, significantly enhancing prognosis prediction in NPC.

Joint modeling of longitudinal health-related quality of life during concurrent chemoradiotherapy period and long-term survival among patients with advanced nasopharyngeal carcinoma.

BACKGROUND: To investigate the prognosis of longitudinal health-related quality of life (HRQOL) during concurrent chemoradiotherapy (CCRT) on survival outcomes in patients with advanced nasopharyngeal carcinoma (NPC). METHODS: During 2012-2014, 145 adult NPC patients with stage II-IVb NPC were investigated weekly using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORCT QLQ-C30) during their CCRT period. The effects of longitudinal trends of HRQOL on survival outcomes were estimated using joint modeling, and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were reported as a 10-point increase in HRQOL scores. RESULTS: After a median follow-up of 83.4 months, the multivariable models showed significant associations of longitudinal increasing scores in fatigue and appetite loss during the CCRT period with distant metastasis-free survival: 10-point increases in scores of fatigue and appetite loss domains during CCRT period were significantly associated with 75% (HR: 1.75, 95% CI: 1.01, 3.02; p = 0.047) and 59% (HR: 1.59, 95% CI: 1.09, 2.59; p = 0.018) increase in the risk of distant metastasis, respectively. The prognostic effects of the longitudinal HRQOL trend on overall survival and progress-free survival were statistically non-significant. CONCLUSION: Increases in fatigue and appetite loss of HRQOL during the CCRT period are significantly associated with high risks of distant metastasis in advanced NPC patients. Nutritional support and psychological intervention are warranted for NPC patients during the treatment period.

The plasma EBV DNA load with IL-6 and VEGF levels as predictive and prognostic biomarker in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein-Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up.

Comparative effectiveness and cost-effectiveness of endoscopic nasopharyngectomy versus intensity-modulated radiotherapy in the treatment of recurrent nasopharyngeal carcinoma: A microsimulation analysis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a significant health concern in southern China, like Guangdong and Hong Kong. This study aims to predict the effectiveness and cost-effectiveness of two prevalent NPC treatments, intensity-modulated radiotherapy (IMRT) and endoscopic nasopharyngectomy (ENPG). METHODS: A microsimulation model was developed to project the long-term outcomes of IMRT and ENPG, simulating 5000 patients with hypothetical locally recurrent NPC for each treatment option. The tumors of patients confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Analyses were performed from the healthcare system perspectives of Mainland China and the healthcare provider perspective of Hong Kong, with input parameters sourced from the existing literature and databases. The robustness of findings was evaluated through one-way and probabilistic sensitivity analyses. RESULTS: For DFS, ENPG showed a 29% reduction in risk with an HR of 0.71 (95% CI: 0.64-0.77) compared to IMRT. ENPG demonstrated a significant survival benefit in OS with an HR of 0.59 (95% CI: 0.54-0.65), equating to a 41% reduction in mortality risk. In Hong Kong, IMRT and ENPG yielded QALY gains of 4.59 and 6.29, respectively, with ENPG exhibiting an incremental cost-effectiveness ratio (ICUR) of USD 13 057 per QALY. For Mainland China, ENPG denominated the IMRT and the ICUR was USD -1450 QALY. Probabilistic sensitivity analysis showed a 100% probability of ENPG being cost-effective at the willingness-to-pay thresholds of USD 130 490 per QALY in Hong Kong and USD 12 741 per QALY in Mainland China. CONCLUSION: The analysis confirms that ENPG is more effective and cost-effective than IMRT for treating recurrent NPC in both Hong Kong and Mainland China.

B7-H3 promotes nasopharyngeal carcinoma progression by regulating CD8+ T cell exhaustion.

BACKGROUND: B7-H3 protein is an important regulator of the adaptive immune response in human tumorigenesis. 4-1BB is a co-stimulatory receptor expressed on activated CD8+ T cells, and regulates T cell immunity. Here, we investigated the role of B7-H3 in the growth and invasion of nasopharyngeal carcinoma (NPC) and the effect of its interaction with 4-1BB on tumor immunity. METHODS: Short hairpin (sh) RNA was designed to knock down B7-H3 expression in NPC cells. NPC cells with stable knockdown of B7-H3 were established and injected into nude mice. The effects of B7-H3 on cell proliferation, apoptosis, and epithelial-to-mesenchymal transition (EMT) were detected by the CCK8 assay, flow cytometry, TUNEL assay, and western blot analysis. The migration and invasion abilities were determined using the Transwell assay and scratch assay. Co-immunoprecipitation (Co-IP) assays were performed to study the interaction between B7-H3 and 4-1BB. Anti-4-1BB antibody was used in a co-culture system and xenograft mice to study the effect of 4-1BB on NPC development. RESULTS: NPC cells transfected with sh-B7-H3 showed a higher rate of apoptosis, slower growth rate, impaired migration, and less EMT in vitro. Xenograft mice with stable knockout of B7-H3 had lower tumor burdens, and the stripped tumors had lower rates of cell proliferation, higher rates of apoptosis, and less EMT in vivo. Additionally, decreased B7-H3 expression was positively correlated with interferon-γ, tumor necrosis factor-α, and 4-1BB+CD8+ tumor-infiltrating lymphocytes. Co-IP studies showed that B7-H3 interacts with 4-1BB. Also, the inhibitory effects of sh-B7-H3 on NPC tumor growth, invasion, and tumor immunity could be alleviated by the anti-4-1BB antibody both in vivo and in vitro. CONCLUSION: Our findings suggest that B7-H3 may accelerate tumor growth, tumor cell invasion, and EMT, and interact with 4-1BB to produce CD8+ T cell exhaustion that inhibits tumor immunity. B7-H3 might serve as a novel target for treating NPC.

The prognostic implications of radiologic extranodal extension in the lymph nodes of patients with nasopharyngeal cancer.

Objective: This study was developed to explore the prognostic relevance of radiologic extranodal extension (rENE) in lymph node-positive nasopharyngeal carcinoma (NPC) patients. Materials and methods: A retrospective review of data from 249 eligible patients with NPC was performed, with magnetic resonance imaging scans being used for rENE grading. The prognostic value of rENE was assessed through univariate and multivariate analyses. Results: Log-rank tests revealed significant differences between patients with and without rENE in terms of overall survival, progression-free survival (PFS) and distant metastasis-free survival (DMFS). G2 and G3 patients tended to exhibit worse PFS and DMFS relative to G0/G1 patients (p < 0.05). Long-term chemotherapy cycles were associated with significant improvements in the PFS and DMFS of G2 and G3 patients. Conclusion: These results suggest that higher rENE grades (G2/G3) are independently associated with worse survival outcomes among NPC patients, with more aggressive treatment strategies potentially affording greater prognostic benefits to these individuals.

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L48H37, a curcumin analog, suppresses matrix metalloproteinase-9 expression and activity to hamper nasopharyngeal cancer cell migration.

OBJECTIVE: Metastatic disease is a major issue of treatment failure in nasopharyngeal carcinoma (NPC) patients and often linked to high mortality. L48H37, a synthetic analog of curcumin with augmented bioavailability over its parent compound, has demonstrated several oncostatic characteristics. This study was aimed to explore the anti-metastatic effect of L48H37 on NPC cancer cells and its underlying mechanism. METHODS: Cell viability was evaluated using MTT assay. Regulation of signaling pathways was elucidated by immunoblotting, and specific kinase inhibitors. RESULTS: In this study, we showed that L48H37 suppressed TPA-stimulated invasive and migratory capacities of NPC cell lines and gave rise to very little cytotoxic responses. Such anti-cancer effect of L48H37 was accompanied with attenuated expression levels and enzymatic activities of matrix metalloproteinase-9 (MMP-9), a pivotal mediator of metastatic processes. In addition, L48H37 interfered with TPA-induced JNK activation, and the treatment of L48H37 combined with a JNK antagonist demonstrated a synergistic effect on restraining TPA-stimulated MMP-9 activity and migration events in NPC cells. CONCLUSIONS: Our results revealed that L48H37 impeded the invasive potential of NPC cells via impairment of MMP-9 function and abundance, highlighting possible complementary therapies using curcumin or its effective analogs to manage NPC dissemination.

[Dihydroartemisinin enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis by promoting ROS production].

OBJECTIVE: To investigate the effect of dihydroartemisinin (DHA) for enhancing the inhibitory effect of cisplatin (DDP) on DDP-resistant nasopharyngeal carcinoma cell line HNE1/DDP and explore the mechanism. METHODS: CCK-8 method was used to assess the survival rate of HNE1/DDP cells treated with DHA (0, 5, 10, 20, 40, 80, and 160 µmol/L) and DDP (0, 4, 8, 16, 32, 64, 128 µmol/L) for 24 or 48 h, and the combination index of DHA and DDP was calculated using Compusyn software. HNE1/DDP cells treated with DHA, DDP, or their combination for 24 h were examined for cell viability, proliferation and colony formation ability using CCK-8, EdU and colony-forming assays. Flow cytometry was used to detect cell apoptosis and intracellular reactive oxygen species (ROS). The expression levels of apoptosis-related proteins cleaved PARP, cleaved caspase-9 and cleaved caspase-3 were detected by Western blotting. The effects of N-acetyl-cysteine (a ROS inhibitor) on proliferation and apoptosis of HNE1/DDP cells with combined treatment with DHA and DDP were analyzed. RESULTS: Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 µmol/L) combined with DDP (8, 16, 32, 64, 128 µmol/L) were all below 1. Compared with DHA or DDP alone, their combined treatment more potently decreased the cell viability, colony-forming ability and the number of EdU-positive cells, and significantly increased the apoptotic rate, intracellular ROS level, and the expression levels of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 in HNE1/DDP cells. N-acetyl-cysteine pretreatment obviously attenuated the inhibitory effect on proliferation and apoptosis-inducing effect of DHA combined with DDP in HNE1/DDP cells (P<0.01). CONCLUSION: DHA enhances the growth-inhibitory and apoptosis-inducing effect of DDP on HNE1/DDP cells possibly by promoting accumulation of intracellular ROS.

Dual role of targeting NAE1 in nasopharyngeal carcinoma: Antitumor effects yet inducing radiotherapy resistance.

Background and objectives: The inhibitor MLN4924 of Neural Precursor Cell-Expressed Developmentally Down-Regulated 8 (NEDD8) Activating Enzyme 1 (NAE1) has been found to suppress the growth of nasopharyngeal carcinoma (NPC). However, its effect on NPC's radiotherapy sensitivity remains unclear. Methods: By integrating single-cell RNA sequencing and bulk RNA sequencing, we predict the impact of NAE1 on the cell cycle, cell death, and its relationship with radiotherapy sensitivity and prognosis in NPC. The effect of inhibiting NAE1 on NPC cell behavior and radiation sensitivity is explored through MLN4924 intervention in vitro and in vivo. We construct a prognosis prediction model based on NAE1 using machine learning methods and validate the efficacy of NAE1 and the model in clinical cohorts. Results: NPC patients with high NAE1 expression have better prognosis and higher expression in the radiotherapy-sensitive group. Inhibiting NAE1 with MLN4924 causes cell cycle arrest in NPC cells, preventing them from entering the G2/M phase, thereby inhibiting proliferation but not affecting migration and metastasis. However, in vitro and in vivo experiments demonstrate that inhibiting NAE1 with MLN4924 leads to increased resistance of NPC to radiation. Conclusions: Targeting NAE1 for NPC treatment may have dual effects, inhibiting NPC proliferation while also increasing radiation resistance.

Tension pneumocephalus related to nasopharyngeal carcinoma: A case report.

Tension pneumocephalus associated with nasopharyngeal carcinoma is an exceptionally rare but potentially fatal condition. We report a case of tension pneumocephalus associated with nasopharyngeal carcinoma treated by radiochemotherapy. Three-month follow-up computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) showed significant tumor regression but moderate intracranial pneumocephalus. Four days later, the patient was found in a comatose state and emergency brain CT showed extensive pneumocephalus with transtentorial descending and right temporal herniations. The patient died 5 days later. A summary of tension pneumocephalus is presented and the mechanism of fistula formation is discussed. This case enlightens tension pneumocephalus as a possible early complication of nasopharyngeal carcinoma treatment.

Lung immune prognostic index is associated with clinical outcomes in recurrent or metastatic (R/M) nasopharyngeal carcinoma receiving immunotherapy: Results from the multicenter, single-arm, phase 2 study.

BACKGROUND: Immune-related biomarkers are linked to the outcomes of cancer immunotherapy. This study evaluates the baseline and longitudinal association between the lung immune prognostic index (LIPI) and immune checkpoint inhibitor outcomes in previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC) patients. METHODS: Data from 153 R/M NPC patients (median age = 49.00 years old) enrolled in a multicenter, single-arm, phase 2 study (NCT03848286) were analyzed. Pretreatment LIPI was classified into good and intermediate/poor (inter/poor) groups. Longitudinal LIPI variations were categorized into "Stable good", "Trend to increase", "Trend to decrease", and "Stable inter/poor". Primary and secondary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS: Pretreatment LIPI was significantly associated with OS (inter/poor vs. good: HR = 2.54, 95 % CI: 1.60-4.04, P < 0.001), PFS [inter/poor vs. good: hazard ratio (HR) = 2.18, 95 % CI: 1.47-3.23, P < 0.001], and DCR [inter/poor vs. good: odd ratio (OR) = 0.26, 95 % CI: 0.12-0.58, P < 0.001)]. Patients with persistently inter/poor LIPI status showed worse OS (HR = 3.25, 95 % CI: 1.84-5.74, P < 0.001), PFS (HR = 2.96, 95 % CI: 1.85-4.74, P < 0.001), and ORR (OR = 0.21, 95 % CI: 0.08-0.56, P < 0.001) compared to the persistently good subgroup. CONCLUSION: Pretreatment LIPI and its longitudinal variations may serve as potential biomarkers for predicting immune checkpoint inhibitor outcomes in R/M NPC patients.

Demystifying the challenging diagnosis of post-radiation nasopharyngeal necrosis on multimodality imaging.

Post-radiation nasopharyngeal necrosis (PRNN) is a rare but life-threatening condition that often poses a diagnostic challenge in imaging studies owing to its overlapping features with recurrent nasopharyngeal tumours. We herein describe the characteristic imaging appearance of PRNN on post-contrast T1-weighted magnetic resonance imaging, diffusion-weighted imaging (DWI) and fluorodeoxyglucose (FDG)-PET/CT which may provide insights into its pathological findings.

Evaluating the reduction of elective radiotherapy fields for de novo metastatic nasopharyngeal carcinoma in the immunotherapy era.

BACKGROUND: This study evaluates the outcomes of omitting the high- and low-risk clinical tumor volume (CTV1 and CTV2) radiation in de novo metastatic nasopharyngeal carcinoma (dnm-NPC) patients in the immunotherapy era. METHODS: We retrospectively analyzed 45 consecutive dnm-NPC patients receiving chemotherapy and immunotherapy combined with radiotherapy (CIR) from October 9, 2018 to June 1, 2022. Irradiation was only delivered to the primary tumor and retropharyngeal nodes (GTVnx+rn) and gross cervical lymph nodes (GTVnd). RESULTS: The median follow-up was 45 (range, 15-67) months. There was no recurrence in the omitted elective regions. The 36-month LRRFS, PFS, and OS were 95.4%, 44.6%, and 90.8%, respectively. The main grade 3/4 hematologic toxicities were neutropenia (42.2%), anemia (20.0%), and thrombocytopenia (13.3%). The incidence of acute grade 3/4 dermatitis, mucositis, and xerostomia were 4.4%, 8.9%, and 4.4%, respectively. CONCLUSIONS: Omitting CTV1 and CTV2 was well-tolerated and provided favorable clinical outcomes in the era of immunotherapy.

Head-to-Head Comparison of [18F]FDG PET Imaging and MRI for the Detection of Recurrence or Residual Tumor in Patients with Nasopharyngeal Carcinoma: A Meta-Analysis.

BACKGROUND: This meta-analysis compared the diagnostic performance of [18F] fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) or PET versus Magnetic resonance imaging (MRI) in detecting recurrence or residual tumors at the primary site in patients with nasopharyngeal carcinoma (NPC). METHODS: A comprehensive literature search was conducted in the PubMed/MEDLINE and CENTRAL databases to find studies with at least 20 patients with NPC undergoing both [18F]FDG PET/CT (or [18F]FDG PET) and MRI for detecting recurrence or assessing residual disease at the primary site. The pooled sensitivity and specificity of PET/CT and MRI were calculated with 95% confidence intervals (CIs) and compared. RESULTS: Five studies, including 1908 patients (six patient groups), were included. PET imaging had higher sensitivity [93.3% (95% CI: 91.3-94.9%); I2 = 52.6%] compared to MRI [80.1% (95% CI: 77.2-82.8%); I2 = 68.3%], but the specificity of the two modalities was similar: 93.8% (95% CI: 92.2-95.2%; I2 = 0%) for PET/CT and 91.8% (95% CI: 90.1-93.4%; I2 = 94.3%) for MRI. The areas under the curve (AUCs) for PET/CT and MRI were 0.978 and 0.924, respectively, without significant difference (p = 0.23). CONCLUSIONS: This meta-analysis suggests that [18F]FDG PET imaging and MRI do not significantly differ in diagnostic performance. Nevertheless, [18F]FDG PET imaging shows higher sensitivity than MRI.

Early recurrence as a pivotal event in nasopharyngeal carcinoma: identifying predictors and key molecular signals for survivors.

PURPOSE: The duration of response to treatment is a significant prognostic indicator, with early recurrence (ER) often predicting poorer survival outcomes in nasopharyngeal carcinoma (NPC) survivors. This study seeks to elucidate the factors contributing to the onset of ER following radiotherapy in NPC survivors. METHODS: This investigation encompassed 2,789 newly diagnosed NPC patients who underwent radical intensity-modulated radiotherapy. Ordinal logistic regression analysis was employed to evaluate the independent predictors of earlier recurrence. A machine learning-based prediction model of NPC recurrence patterns was developed. Tumorous RNA-sequencing (in-house cohort: N = 192) and biological tipping point analysis were utilized to infer potential molecular mechanisms associated with ER. RESULTS: Our results demonstrated that ER within 24 months post-initial treatment was the optimal time frame for identifying early malignant progression in NPC survivors. The ER cohort (150 of 2,789, 5.38%) exhibited a notably short median overall survival of 48.6 months. Multivariate analyses revealed that male gender, T4 stage, local or regional residual disease, detectable pre- and post-radiotherapy EBV DNA, and the absence of induction chemotherapy were significant predictors of earlier recurrence. The machine learning-based predictive model further underscored the importance of tumor-related factors in NPC recurrence. Moreover, ER emerged as a pivotal stage in NPC progression, with 15 critical transition signals identified potentially associated with the negative modulation of the immune response. CONCLUSIONS: Our comprehensive analysis of NPC recurrence patterns has unveiled insights into the key factors driving ER and provided novel insights into potential early warning biomarkers and the mechanisms underlying NPC progression.

Circulating mRNA Expression of VEGF, PTEN, and SOCS1 as Potential Prognostic Predictor for Nasopharyngeal Carcinoma Progression.

BACKGROUND: The molecular mechanisms underlying nasopharyngeal carcinoma (NPC) progression remain poorly understood. In particular, the roles of circulating mRNAs encoding key regulatory proteins have yet to be explored. This study aimed to identify NPC-associated expression signatures of circulating VEGF, PTEN, and SOCS1 mRNAs and their potential as biomarkers. METHODS: A case-control study was conducted comprising 160 nasopharyngeal carcinoma (NPC) patients and 80 controls, from whom peripheral blood samples. Total RNA was extracted and the levels of VEGF, PTEN, and SOCS1 mRNAs were quantified using reverse transcription quantitative PCR (RT-qPCR). Relative expression was calculated using the 2-ΔΔCt method. Bioinformatic analyses, including GeneMANIA, Gene Ontology (GO), and KEGG pathway analysis, were performed to predict the functional roles and interactions of these mRNAs. RESULTS: We identified significantly increased circulating VEGF mRNA in lymph node metastases (1.66-fold, p<0.05) and elevated SOCS1 mRNA in late-stage NPC (20-fold, p<0.05). PTEN mRNA was reduced 4.26-fold in NPC patients. These data suggest that circulating VEGF, PTEN, and SOCS1 mRNAs represent signatures of NPC progression and can potentially be biomarkers. Network analyses implicate these mRNAs in mechanisms enabling NPC pathogenesis. CONCLUSIONS: Our study reveals NPC-associated expression changes of circulating VEGF, PTEN, and SOCS1 mRNAs. These molecular signatures may serve as biomarkers during NPC progression and provide insights into underlying mechanisms. Further validation of their utility as prognostic indicators of NPC is warranted.

Multi-Omics Exploration of the Mechanism of Curcumol to Reduce Invasion and Metastasis of Nasopharyngeal Carcinoma by Inhibiting NCL/EBNA1-Mediated UBE2C Upregulation.

Nasopharyngeal carcinoma (NPC) is closely linked to Epstein-Barr virus (EBV) infection. Curcumae Rhizoma, a traditional Chinese herb, has shown antitumor effects, primarily through its component curcumol (Cur), which has been shown to reduce NPC cell invasion and migration by targeting nucleolin (NCL) and Epstein-Barr Virus Nuclear Antigen 1 (EBNA1). We constructed an EBV-positive NPC cell model using C666-1 cells and performed transcriptomics studies after treatment with curcumol, which revealed a significant enrichment of ubiquitin-mediated proteolysis, the PI3K-AKT and mTOR signaling pathways, cell cycle and apoptosis involved in tumor invasion and migration. To investigate the importance of NCL and EBNA1 in curcumol-resistant EBV-positive NPC, we performed a multi-omics study using short hairpin NCL (shNCL) and shEBNA1 EBV-positive NPC cells, and the proteomics results showed enrichment in complement and coagulation cascades and ubiquitin-mediated proteolysis signaling pathways. Here, we focused on ubiquitin-conjugating enzyme E2C (UBE2C), which plays an important role in the ubiquitin-mediated proteolysis signaling pathway. In addition, metabolomics revealed that UBE2C is highly associated with 4-Aminobutanoic acid (GABA). In vitro studies further validated the function of the key targets, suggesting that UBE2C plays an important role in NCL and EBNA1-mediated curcumol resistance to nasopharyngeal carcinoma invasion and metastasis.

The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.

Recent data have shown a continued rise in the worldwide annual incidence and mortality rates of head and neck cancers. The present standard for diagnosis and monitoring for disease recurrence or progression involves clinical examination, imaging, and invasive biopsy techniques of lesions suspected of being malignant. In addition to limitations relating to cost, time, and patient discomfort, these methodologies have inherent inaccuracies for detecting recurrence. In view of these limitations, the analysis of patient bodily fluid samples via liquid biopsy proposes a cost-effective and convenient alternative, which provides insight on the biogenetic and biomolecular underpinnings of oncologic disease processes. The monitoring of biomarkers for head and neck cancer via liquid biopsy, including circulating tumor DNA, circulating tumor cells, and circulating cell-free RNA, has shown clinical utility in the screening, diagnosis, prognostication, and monitoring of patients with various forms of head and neck cancer. The present review will provide an update on the current literature examining the use of liquid biopsy in head and neck cancer care and the clinical applicability of potential biomarkers, with a focus on viral and non-viral circulating tumor DNA. Possible future avenues for research to address specific shortcomings of liquid biopsy will be discussed.

Optimizing Hearing Outcomes in Nasopharyngeal Cancer Survivors in the Era of Modern Radiotherapy and Systemic Therapy.

Intensity-modulated radiation therapy (IMRT) improves disease control and reduces treatment-related toxicity in patients with localized nasopharyngeal carcinoma (NPC). However, due to the proximity of the auditory apparatus to the treatment volume and the frequent incorporation of cisplatin-based chemotherapy, treatment-related sensorineural hearing loss (SNHL) remains a common debilitating complication among NPC survivors. The reported crude incidence of SNHL following IMRT for NPC varies widely at 1-46% due to differences in auditory assessment methods and thresholds, follow-up durations, chemotherapy usage, and patient compositions. International guidelines and radiation dosimetric studies have recommended constraining the cochlear mean dose to less than 44-50 Gy, but the risk of SNHL remains high despite adherence to these constraints. Potential strategies to improve hearing outcomes in NPC survivors include cautious de-escalation of radiotherapy dose and volume, individualization of cochlear constraints, optimization of radiotherapy planning techniques, and the use of substitutes or alternative schedules for cisplatin-based chemotherapy. The addition of immune checkpoint inhibitors to chemoradiotherapy did not impact ototoxicity. Prospective studies that employ both objective and patient-reported auditory outcomes are warranted to test the long-term benefits of various approaches. This article aims to provide a comprehensive review of the incidence and radiation dose-toxicity relationship of SNHL in NPC survivors and to summarize potential strategies to optimize hearing outcomes in relation to nuances in radiotherapy planning and the selection of systemic therapy.