Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes.

The incidence of nasopharyngeal carcinoma (NPC) exhibits significant variations across different ethnic groups and geographical regions, with Southeast Asia and North Africa being endemic areas. Of note, Epstein-Barr virus (EBV) infection is closely associated with almost all of the undifferentiated NPC cases. Over the past three decades, radiation therapy and chemotherapy have formed the cornerstone of NPC treatment. However, recent advancements in immunotherapy have introduced a range of promising approaches for managing NPC. In light of these developments, it has become evident that a deeper understanding of the tumor microenvironment (TME) is crucial. The TME serves a dual function, acting as a promoter of tumorigenesis while also orchestrating immunosuppression, thereby facilitating cancer progression and enabling immune evasion. Consequently, a comprehensive comprehension of the TME and its intricate involvement in the initiation, progression, and metastasis of NPC is imperative for the development of effective anticancer drugs. Moreover, given the complexity of TME and the inter-patient heterogeneity, personalized treatment should be designed to maximize therapeutic efficacy and circumvent drug resistance. This review aims to provide an in-depth exploration of the TME within the context of EBV-induced NPC, with a particular emphasis on its pivotal role in regulating intercellular communication and shaping treatment responses. Additionally, the review offers a concise summary of drug resistance mechanisms and potential strategies for their reversal, specifically in relation to chemoradiation therapy, targeted therapy, and immunotherapy. Furthermore, recent advances in clinical trials pertaining to NPC are also discussed.

Apigenin Alleviates Allodynia and Hyperalgesia in a Mouse Model of Chemotherapy-Induced Peripheral Neuropathy via Regulating Microglia Activation and Polarization.

BACKGROUND: Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on chemotherapy-induced peripheral neuropathy (CIPN). METHODS: CIPN mouse model was established using Paclitaxel treatment. Hot plate and tail prick latency tests were performed to examine the allodynia and hyperalgesia behaviors. Anti-inflammatory and anti-oxidative effects of Apigenin on CIPN were determined by enzyme-linked immunosorbent (ELISA) assay, Western blot, and qRT-PCR. Nuclear recruitment of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed to evaluate the underlying mechanisms of the protective effects of Apigenin. RESULTS: Apigenin significantly alleviated CIPN-induced nociceptive behaviors of CIPN mice. It also decreased the TNF-α and IL-1ß levels, suppressed oxidative stress and inflammation in the surgical spinal cord tissues. Mechanistically, Apigenin altered the pro-inflammatory and anti-inflammatory phenotypes ratio of microglia through promoting the nuclear recruitment of NRF2 and activating the NRF2/Antioxidant Response Element (ARE) signaling pathway. CONCLUSIONS: In summary, Apigenin relieves CIPN by regulating microglia activation and polarization, which provides a potential therapeutic strategy for CIPN treatment.

Energy intake restriction significantly improves POCD after internal fixation of tibial fractures in mice.

OBJECTIVE: To investigate the effect of energy intake restriction on postoperative cognitive dysfunction (POCD) after internal fixation of tibial fractures in mice. METHODS: Thirty mice were divided into model groups of internal fixation of tibial fractures with 0%, 20%, 30% and 40% energy intake restriction and sham operation group (n = 6). Novel object recognition task and elevated plus maze test were used to assess the ability of recognition memory and anxiety-related behavior before and one week after surgery. The blood samples were collected from mice on days 1, 3 and 7 after surgery, and the mice were euthanized on the 8th day after surgery. RT-PCR and Western blot were employed to detect the expression of AMPK-SIRT1 pathway-related genes and proteins in the hippocampus. ELISA was used to detect the levels of inflammatory factors in the peripheral blood of mice. Hematoxylin-eosin (H&E) staining and immunofluorescence (IF) staining were used to detect the proliferation, differentiation and injury of hippocampal cells. RESULTS: The results showed that 20% and 30% energy intake restriction significantly improved the POCD after internal fixation of tibial fractures in mice. Significantly, 30% energy intake restriction reduced the expression of AP-1, NF-κB, CD45, IBA-1, and inflammatory factors IL-1ß, IL-6, IL-8 and TNF-α, and increased the expression of AMPK and SIRT1 after the operation. H&E and IF staining showed that 30% energy intake restriction reduced postoperative hippocampal neuronal damage. CONCLUSION: Energy intake restriction can significantly improve POCD after internal fixation of tibial fractures in mice and may provide a new treatment paradigm for POCD patients.

A Nomogram for the Determination of the Necessity of Concurrent Chemotherapy in Patients With Stage II-IVa Nasopharyngeal Carcinoma.

BACKGROUND: The efficiency of concurrent chemotherapy (CC) remains controversial for stage II-IVa nasopharyngeal carcinoma (NPC) patients treated with induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT). Therefore, we aimed to propose a nomogram to identify patients who would benefit from CC. METHODS: A total of 434 NPC patients (stage II-IVa) treated with IC followed by IMRT between January 2010 and December 2015 were included. There were 808 dosimetric parameters extracted by the in-house script for each patient. A dosimetric signature was developed with the least absolute shrinkage and selection operator algorithm. A nomogram was built by incorporating clinical factors and dosimetric signature using Cox regression to predict recurrence-free survival (RFS). The C-index was used to evaluate the performance of the nomogram. The patients were stratified into low- and high-risk recurrence according to the optimal cutoff of risk score. RESULTS: The nomogram incorporating age, TNM stage, and dosimetric signature yielded a C-index of 0.719 (95% confidence interval, 0.658-0.78). In the low-risk group, CC was associated with a 9.4% increase of 5-year locoregional RFS and an 8.8% increase of 5-year overall survival (OS), whereas it was not significantly associated with an improvement of locoregional RFS (LRFS) and OS in the high-risk group. However, in the high-risk group, patients could benefit from adjuvant chemotherapy (AC) by improving 33.6% of the 5-year LRFS. CONCLUSIONS: The nomogram performed an individualized risk quantification of RFS in patients with stage II-IVa NPC treated with IC followed by IMRT. Patients with low risk could benefit from CC, whereas patients with high risk may require additional AC.

A nomogram for predicting late radiation-induced xerostomia among locoregionally advanced nasopharyngeal carcinoma in intensity modulated radiation therapy era.

BACKGROUND: Dry mouth sensation cannot be improved completely even though parotids are spared correctly. Our purpose is to develop a nomogram to predict the moderate-to-severe late radiation xerostomia for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) in intensity modulated radiation therapy (IMRT) / volumetric modulated arc radiotherapy (VMAT) era. METHODS: A dataset of 311 patients was retrospectively collected between January 2010 and February 2013. The binary logistic regression was to estimate each factor's prognostic value for development of moderate-to-severe patient-reported xerostomia at least 2 years (Xer2y) after completion of radiotherapy. Therefore, we can develop a nomogram according to binary logistic regression coefficients. This novel model was validated by bootstrapping analyses. RESULTS: Contralateral Parotid mean dose (coMD<24.4Gy), VMAT (yes), and platinum-based concurrent chemoradiotherapy (no) were significantly related to patient-reported xerostomia at least 2 years (Xer2y) (all p < 0.001), and were included in the nomogram. Receiver operating characteristic (ROC) analysis revealed AUC (area under the ROC curve) with the value of 0.811 (0.710-0.912) of the nomogram, which was significantly higher than coMD 0.698 (0.560-0.840) from QUANTEC2010 (p<0.001). Calibration plots illustrated that the predicted Xer2y was close to the actual observation, and decision curve analyses (DCA) indicated valid positive net benefits. CONCLUSION: We developed a feasible nomogram to predict patient-rated Xer2y based on comprehensive individual data in patients with LA-NPC in the real world. The proposed model is able to facilitate the development of treatment plan and quality of life improvement.

Prognostic Value of Survivin in Nasopharyngeal Carcinoma: A Systematic Review and Meta-analysis.

Background: Previous studies have shown that survivin has potential prognostic value in nasopharyngeal carcinoma. However, the results remained controversial until now. Thus, to investigate the influence of survivin expression on prognosis and clinical characteristics in nasopharyngeal carcinoma, we performed this meta-analysis. Methods: We searched PubMed, PMC, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure electronic databases from their establishment to 1 March 2021. The pooled hazard ratio (HR) and the pooled odds ratio (OR) were used to evaluate the prognostic and clinicopathological values of survivin in nasopharyngeal carcinoma. We used the I2 statistic and the Q test to evaluate heterogeneity. Meta-regression, publication bias, and sensitivity analyses were also conducted. Results: A total of 26 eligible studies with 2278 patients were included in our meta-analysis. We found that the expression of survivin is connected with poor overall survival (HR=1.94; 95% confidence interval (CI)=1.52-2.48; P<0.001), lymph node metastasis (OR=3.01; 95% CI=2.31- 3.91; P<0.001), local recurrence (OR=2.40; 95% CI=1.60-3.61, P<0.001), distant metastasis (OR=2.58; 95% CI=1.74-3.84, P<0.001), and a higher clinical stage (OR=4.58; 95% CI=2.81-7.47, P<0.001). However, no significant correlations were found between survivin expression and radio-sensitivity (OR=1.33; 95% CI=0.25-7.17, P=0.737) or gender (OR=1.02; 95% CI=0.75-1.39, P=0.887). Conclusions: This meta-analysis indicates that survivin could be used as a biomarker for predicting prognosis in nasopharyngeal carcinoma.

Nomograms Forecasting Long-Term Overall and Cancer Specific Survival of Patients With Head and Neck Neuroendocrine Carcinoma.

BACKGROUND: The purpose of this retrospective analysis was to build and validate nomograms to predict the cancer-specific survival (CSS) and overall survival (OS) of head and neck neuroendocrine carcinoma (HNNEC) patients. METHODS: A total of 493 HNNEC patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015, and 74 HNNEC patients were collected from the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital (HCH) between 2008 and 2020. Patients from SEER were randomly assigned into training (N=345) and internal validation (N=148) groups, and the independent data group (N=74) from HCH was used for external validation. Independent prognostic factors were collected using an input method in a Cox regression model, and they were then included in nomograms to predict 3-, 5-, and 10-year CSS and OS rates of HNNEC patients. Finally, we evaluated the internal and external validity of the nomograms using the consistency index, while assessing their prediction accuracy using calibration curves. A receiver operating curve (ROC) was also used to measure the performance of the survival models. RESULTS: The 3-, 5-, and 10-year nomograms of this analysis demonstrated that M classification had the largest influence on CSS and OS of HNNEC, followed by the AJCC stage, N stage, age at diagnosis, sex/gender, radiation therapy, and marital status. The training validation C-indexes for the CSS and OS models were 0.739 and 0.713, respectively. Those for the internal validation group were 0.726 and 0.703, respectively, and for the external validation group were 0.765 and 0.709, respectively. The area under the ROC curve (AUC) of 3-, 5-, and 10-year CSS and OS models were 0.81, 0.82, 0.82, and 0.78, 0.81, and 0.82, respectively. The C-indexes were all higher than 0.7, indicating the high accuracy ability of our model's survival prediction. CONCLUSIONS: In this study, prognosis nomograms in HNNEC patients were constructed to predict CSS and OS for the first time. Clinicians can identify patients' survival risk better and help patients understand their survival prognosis for the next 3, 5, and 10 years more clearly by using these nomograms.

Nomograms for predicting survival outcomes in intensity-modulated radiotherapy era of nasopharyngeal carcinoma: A study based on Epstein-Barr virus DNA biological responses.

BACKGROUND: Treatment of nasopharyngeal carcinoma (NPC) is evolving toward Intensity-modulated radiotherapy (IMRT) era, which requires patient-specific reestimation of survival outcomes in modern health care. METHODS: A total of 488 detectable pre-treatment Epstein-Barr virus (EBV) DNA patients (stage II-IVa) treated with induction chemotherapy (IC) and IMRT were examined (training set, n = 325; validation set, n = 163). RESULTS: Concurrent chemotherapy (CC) was still an independent prognosticator for overall survival (OS) and progression-free survival (PFS). Both nomograms included age, T classification, N classification, post-IC EBV DNA, and CC. Predictions correlated well with observed 3-/5-year OS and PFS. The concordance index was 0.776 (95% confidence interval (CI) 0.69-0.86) for OS and 0.742 (95% CI 0.65-0.83) for PFS in the validation cohort. The nomograms can successfully classify patients into low- and high-risk groups. CONCLUSION: The validated nomograms provided useful prediction of OS and PFS for detectable pre-treatment EBV DNA patients with NPC in IMRT era.

LncRNA LINC00641 Sponges miR-497-5p to Ameliorate Neural Injury Induced by Anesthesia via Up-Regulating BDNF.

INTRODUCTION: Ketamine, which is widely used in anesthesia, can induce cortical neurotoxicity in patients. This study aims to investigate the effects of long non-coding RNA LINC00641 on the ketamine-induced neural injury. MATERIALS AND METHODS: In this study, rat pheochromocytoma cells (PC12 cells) were used as a cell model and Sprague-Dawley postnatal day 7 rats were used for experiments in vivo. Ketamine-induced aberrant expression levels of LINC00641, miR-497-5p and brain-derived neurotrophic factor (BDNF) were examined by qRT-PCR. The effects of LINC00641 and miR-497-5p on ketamine-induced neural injury were then examined by MTT assays and TUNEL analysis. In addition, the activity of ROS and caspase-3 was measured. The regulatory relationships between LINC00641 and miR-497-5p, miR-497-5p and BDNF were detected by dual-luciferase reporter assay, respectively. RESULTS: Ketamine induced the apoptosis of PC12 cells, accompanied by down-regulation of LINC00641 and BDNF, and up-regulation of miR-497-5p. LINC00641 overexpression enhanced the resistance to the apoptosis of PC12 cells, while transfection of miR-497-5p had opposite effects. Furthermore, LINC00641 could bind to miR-497-5p and reduce its expression, but indirectly increase the BDNF expression, which was considered as a protective factor in neural injury and activated TrkB/PI3K/Akt pathway. CONCLUSION: Collectively, LINC00641/miR-497-5p/BDNF axis was validated to be an important signaling pathway in modulating ketamine-induced neural injury.

A multidimensional nomogram combining overall stage, dose volume histogram parameters and radiomics to predict progression-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVES: To develop a multidimensional nomogram for predicting the progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) (stage III-IVa). MATERIALS AND METHODS: A total of 224 patients with locoregionally advanced NPC (training cohort, n = 149; validation cohort, n = 75) were retrospectively included. We extracted 260 radiomic features from the primary tumor and lymph nodes on the axial contrast-enhanced T1 weighted and T2 weighted MRI. Radiomic signatures of the gross tumor volume (RSnx) and lymph node (RSnd), Dose Volume Histogram (DVH) signature reflecting planning score (PS), and clinical characteristics were included as potential predictors of PFS. The least absolute shrinkage and selection operator (LASSO) regression were applied for feature selection and data dimension reduction. A nomogram was developed by incorporating the selected predictors. The C-index and calibration curve were used to assess discrimination and calibration power of the nomogram, respectively. RESULTS: RSnd, PS, and tumor-node-metastasis (TNM) stage were the independent predictors for PFS (all p < 0.05). The nomogram integrating the three factors achieved a C-index of 0.811 (95% CI: 0.74-0.882) in the validation cohort for predicting PFS, which outperformed than that of the TNM stage alone (C-index, 0.613, 95% CI: 0.532-0.694). Subgroup analysis showed Epstein-Barr virus (EBV) DNA status improved the predictive accuracy of the nomogram (C-index, 0.86, 95% CI: 0.787-0.933). CONCLUSIONS: The multidimensional nomogram incorporating RSnd, PS, and TNM stage showed high performance for predicting PFS in patients with locoregionally advanced NPC.

Diagnostic accuracy and prognostic applications of CYFRA 21-1 in head and neck cancer: A systematic review and meta-analysis.

Cytokeratin fraction 21-1 (CYFRA 21-1) has been widely studied as an important biomarker in non-small cell lung cancer for both diagnosis and prognosis. Many studies have also assessed the clinical applications of CYFRA 21-1 in head and neck cancer, but the diagnostic and prognostic values of CYFRA 21-1 are not yet fully established. This pooled analysis aims at evaluating the diagnostic accuracy and prognostic applications of CYFRA 21-1 in patients with head and neck cancer. A systematic retrieval of literatures was conducted without time or language restrictions by searching PubMed, EMBASE, Web of Science, Cochrane library and China National Knowledge Infrastructure. Twenty studies were eligible for systematic review, of which 14 conformed for diagnostic analysis and 7 for prognostic analysis. The pooled sensitivity and specificity of CYFRA 21-1 analysis were 0.53 (95% CI: 0.39-0.67) and 0.97 (95% CI: 0.93-0.99), respectively. A high level of CYFRA 21-1 was significantly correlated with shorter overall survival (HR 1.33, 95% CI: 1.13-1.56) and disease-free survival (HR 1.48; 95%CI: 1.10-1.97). Current evidence indicates that the level of CYFRA 21-1 in the serum could be used as an indicator for monitoring tumor status and evaluating its curative effects.

Administration of Curcumin Alleviates Neuropathic Pain in a Rat Model of Brachial Plexus Avulsion.

BACKGROUND/AIMS: Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. METHODS: Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. RESULTS: After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. CONCLUSIONS: Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes.

Prognostic value of hypoxia-inducible factor-1 alpha in nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: Over the past 5 years, many studies have reported the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1α) in nasopharyngeal carcinoma. However, the results have not reached a consensus until now. Therefore, we performed this meta-analysis to investigate the influence of HIF-1α expression on the prognosis and clinical characteristics in nasopharyngeal carcinoma. METHODS: We searched PubMed, the Cochrane Library, Embase (via Ovid interface), Web of Science, and China National Knowledge Infrastructure electronic databases from their establishment to 6 December 2017. We calculated the hazard ratio (HR) and the odds ratio (OR) to assess the prognostic and clinicopathological values of HIF-1α, respectively. Q test and I2 statistic were applied to evaluate heterogeneity. We also conducted publication bias and sensitivity analyses. RESULTS: A total of 18 studies with 1476 patients were included in our meta-analysis. We found HIF-1α expression was associated with poor overall survival (HR=1.77; 95% confidence interval (CI) 1.35, 2.32; P<0.001), poor progression-free survival (HR=1.72; 95% CI 1.22, 2.44; P=0.002), a higher rate of lymph node metastasis (OR=3.81; 95% CI 2.60, 5.58, P<0.001), and more advanced tumor stage (OR=2.98; 95% CI 1.79, 4.97; P<0.001). CONCLUSIONS: Our study demonstrated that HIF-1α could be an appropriate prognostic biomarker for nasopharyngeal carcinoma patients.

Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats.

PURPOSE OF THE RESEARCH: Post operational cognitive dysfunction (POCD) occurs in patients after anesthesia and surgery. Abnormal histone acetylation and neuroinflammation are key factors in the pathogenesis of cognitive impairment. Apigenin not only has an anti-inflammatory activity but also modifies histone acetylation. We aimed to investigate whether apigenin can attenuate isoflurane exposure-induced cognitive decline by regulating histone acetylation and inflammatory signaling. MATERIALS AND METHODS: Spatial learning and memory were assessed by Morris water maze test. Levels of histone acetylation, BDNF and downstream signaling, and inflammatory components were analyzed. PRINCIPAL RESULTS: Isoflurane exposure in aged rats lead to impaired spatial learning and memory. These rats exhibited dysregulated histone H3K9 and H4K12 acetylation, which was accompanied by reduced BDNF expression and suppressed BDNF downstream signaling pathway. Apigenin restored histone acetylation and BDNF signaling. Apigenin also suppressed isoflurane exposure induced upregulation of proinflammatory cytokines and NFκB signaling pathway. MAJOR CONCLUSIONS: Memory impairment induced by isoflurane exposure is associated with dysregulated histone acetylation in the hippocampus, which affects BDNF expression and hence BDNF downstream signaling pathway. Apigenin recovers cognitive function by restoring histone acetylation and suppressing neuroinflammation.