Virus de Epstein-Barr: más que una mononucleosis infecciosa / Epstein-Barr virus: more than infectious mononucleosis

El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados

Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet

Epstein-Barr Virus LMP1-Activated mTORC1 and mTORC2 Coordinately Promote Nasopharyngeal Cancer Stem Cell Properties.

Epstein-Barr virus (EBV) is associated with several malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. The virus-encoded oncoprotein, LMP1, induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring cancer stem cell (CSC) characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 coregulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients. IMPORTANCE LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 coregulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.

Combined radiotherapy and chemotherapy versus radiotherapy alone in elderly patients with nasopharyngeal carcinoma: A SEER population-based study.

ABSTRACT: Currently, the impact of chemotherapy (CT) on survival outcomes in elderly patients with nasopharyngeal carcinoma (NPC) receiving radiation therapy (RT) remains controversial. This retrospective study aims to investigate survival outcomes in a cohort of elderly NPC patients receiving RT alone or together with CT.Clinical data on 529 NPC patients aged 65 years and older extracted from the Surveillance, Epidemiology, and End Results registry (2004-2015) was collected and retrospectively reviewed. In this cohort, 74 patients were treated with RT alone and 455 individuals received RT and CT. We used propensity score matching with a 1:3 ratio to identify correlations between patients based on 6 different variables. Kaplan-Meier analysis was used to evaluate overall (OS) and cancer-specific survival (CSS). The differences in OS and CSS between the 2 treatment groups were compared using the Log-rank test and Cox proportional hazards models.The estimated 5-year OS and CSS rates for all patients were 49.5% and 59.3%, respectively. The combination of RT and CT provided longer OS than RT alone (53.7% vs 36.9%, P = .002), while no significant difference was observed in CSS (61.8% vs 51.7%, P = .074) between the 2 groups. Moreover, multivariate analysis demonstrated that the combination of CT and RT correlated favorably with OS and CSS. Subgroup analyses showed that the combination of RT and CT correlated better with both OS and CSS in patients with stage T3 or N2 or stage III.Among NPC patients aged 65 years and older, treatment with RT and CT provided longer OS than RT alone. Furthermore, the combination of RT and CT showed a better correlation with OS and CSS in NPC patients with stage T3 or N2 or stage III.

Treatment outcomes of induction chemotherapy combined with intensity-modulated radiotherapy and adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma in Southeast China.

ABSTRACT: Induction chemotherapy (IC) and adjuvant chemotherapy (AC) are used to enhance tumor locoregional control and support early treatment for distant metastases. However, optimum combinatorial treatment of these chemoradiotherapy regimens with radiotherapy in curing locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. Here, we evaluate the efficacy and therapeutic outcome of a combinatorial treatment strategy involving IC, intensity-modulated radiotherapy (IMRT), and AC, by retrospectively analyzing 243 NPC patients who were treated by IC followed by IMRT and AC. The rates of 3-/5-year local-regional control rate, distant failure-free rate (DFFR), progression-free survival (PFS), and overall survival (OS) were 93.3%/90.3%, 84.2%/79.4%, 79.6%/74.4%, and 84.0%/72.6%, respectively. The 3-/5-year OS rates of patients in stage III or IVA were 91.5%/75.1% and 86.5%/56.5%, respectively. Combination cisplatin with paclitaxel showed no significance in OS as compared to cisplatin plus 5-fluorouracil (P-value = .17). Total four-cycle IC and AC was significantly beneficious versus three-cycle in DFFR (P-value = .04), as well as total 6 chemotherapy cycles compared to 4 in DFFR and PFS (P-value = .03 and P-value = .01, respectively). All survival indicators were adversely affected by T-category, while N-category could only predict DFFR and PFS. Radiation dosage represented as a second prognostic factor for local control. We propose that IC combined with IMRT and AC for locoregionally advanced NPC shows effective treatment outcomes.

Functional aspects of the Eustachian tube by means of 3D-modeling.

The extent of dysfunction of the Eustachian tube (ET) is relevant in understanding the pathogenesis of secondary otological diseases such as acute or chronic otitis media. The underlying mechanism of ET dysfunction remains poorly understood except for an apparent genesis such as a nasopharyngeal tumor or cleft palate. To better describe the ET, its functional anatomy, and the biomechanical valve mechanism and subsequent development of diagnostic and interventional tools, a three-dimensional model based on thin-layer histology was created from an ET in this study. Blackface sheep was chosen as a donor. The 3-D model was generated by the coherent alignment of the sections. It was then compared with the cone-beam computed tomography dataset of the complete embedded specimen taken before slicing. The model shows the topographic relation of the individual components, such as the bone and cartilage, the muscles and connective tissue, as well as the lining epithelium with the lumen. It indicates a limited spiraling rotation of the cartilaginous tube over its length and relevant positional relationships of the tensor and levator veli palatine muscles.

Excessive vitamin B6 during treatment is related to poor prognosis of patients with nasopharyngeal carcinoma: A U-shaped distribution suggests low dose supplement.

BACKGROUND & AIM: Several studies explored the association of vitamin B6 intake with the risk of cancers. However, it is unclear whether different doses of vitamin B6 have distinct effects on the prognosis of nasopharyngeal carcinoma (NPC) patients. This study investigated the relationship between different doses of B6 intake and the prognosis of NPC patients. METHODS: This retrospective cohort analysis included 792 newly diagnosed NPC patients with a median follow-up of 62.05 months. Restricted cubic spline and maximally selected rank statistics were performed to determine the cut-off value of vitamin B6 during treatment (VB6DT). Kaplan-Meier method and log-rank tests were performed to analyze survival outcomes. A multivariable Cox proportional hazard model was performed to determine the independent prognostic factors. RESULTS: NPC patients were divided into three groups according to the cut-off value of VB6DT: non-users (0 mg/d), VB6DT > 8.6 mg/d, and VB6DT ≤ 8.6 mg/d. Patients with VB6DT > 8.6 mg/d had significantly lower 5-year overall survival (OS) (83.5% vs. 90.8%, p = 0.006), distant metastasis-free survival (DMFS) (83.5% vs. 91.0%, p = 0.004), and progression-free survival (PFS) (73.7% vs. 81.7%, p = 0.011) and slightly but not significantly lower 5-year local recurrence-free survival (LRFS) (87.7% vs. 90.7%, p = 0.214) than the non-users. Patients with VB6DT ≤ 8.6 mg/d had slightly but not significantly better 5-year OS (93.3% vs. 90.8%, p = 0.283) than the non-users, while all other primary endpoints were similar (p > 0.50). Multivariable analyses confirmed that VB6DT > 8.6 mg/d was an independent negative prognostic factor of OS (p = 0.010), DMFS (p = 0.017), and PFS (p = 0.030) but not of LRFS (p = 0.428). CONCLUSIONS: Excessive VB6DT higher than the cut-off value is an independent negative prognostic factor for NPC patients. Additionally, low dose intake improved OS only slightly but not significantly.

LncRNA SNHG6 accelerates nasopharyngeal carcinoma progression via modulating miR-26a-5p/ARPP19 axis.

OBJECTIVES: Long noncoding RNAs (lncRNAs) have been reported to be involved in multiple cancer progression, yet the biological role of lncRNA SNHG6 in nasopharyngeal carcinoma (NPC) is still unclear. This research aims to explore the molecular mechanism of SNHG6 in the development and progression of NPC. DESIGN: Prospective feasibility study. SETTING: The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital. Long noncoding RNAs (lncRNAs) have been reported to be involved in multiple cancer progression, yet the biological role of lncRNA SNHG6 in nasopharyngeal carcinoma (NPC) is still unclear. This research aims to explore the molecular mechanism of SNHG6 in the development and progression of NPC. RT-qPCR assay was used to examine the expression of SNHG6, miR-26a-5p, and ARPP19 in NPC. CCK-8 and transwell assays were employed to detect NPC cell viability, migration, and invasion. The interaction between miR-26a-5p and SNHG6 or ARPP19 was determined by the luciferase reporter, RIP and RNA pull-down assays. We observed that SNHG6 expression was enhanced in NPC tissues and cells. SNHG6 deletion attenuated NPC cell viability and metastasis. MiR-26a-5p was predicted and validated to interact with SNHG6, and miR-26a-5p expression was markedly elevated in NPC after SNHG6 silence. Moreover, miR-26a-5p inhibitor rescued the suppressive effect of SNHG6 depletion on NPC cell viability, migration and invasion. Besides, ARPP19 was a target of SNHG6 and positively regulated by SNHG6. ARPP19 overexpression neutralized the repressive effect of SNHG6 knockdown on NPC progression. Our results indicated that SNHG6 regulated NPC progression through modulating miR-26a-5/ARPP19 axis, which might provide new insights into NPC diagnosis and treatment.

Is skeletal muscle loss associated with chemoradiotherapy toxicity in nasopharyngeal carcinoma patients? A prospective study.

BACKGROUND: Our study explored to investigate whether skeletal muscle loss before concurrent chemoradiotherapy (CCRT) can predict treatment-related toxicity in this population. METHODS: Computed tomography (CT) scan of the third lumbar were used to assess and calculate the SMA (skeletal muscle area), SMI (skeletal muscle index), SMD (skeletal muscle density), SMG (skeletal muscle gauge) and estimate LBM (lean body mass). Handgrip strength (HGS) and daily walk speed were evaluated. Predictive factors linked to toxicity were assessed by logistic regression models and adjusted odds ratios (OR) of treatment toxicity were reported. RESULTS: A total of 82 patients were evaluated (67.1% males, 45.7 ± 10.7 years). Skeletal muscle loss was not associated with severe radiotherapy toxicity. In males, sarcopenia increases the risk of dose-limiting toxicity (DLT) (OR: 4.00, 95% CI = 1.20-13.36, p = 0.024). DLT is associated with reduced SMA (OR: 0.97, 95% CI = 0.94-1.00, p = 0.041), SMI (OR: 0.91, 95% CI = 0.84-0.99, p = 0.042) and LBM (OR: 0.90, 95% CI = 0.81-0.99, p = 0.041). Reduced HGS was significantly associated with grade 3-4 leukopenia (OR: 0.92, 95% CI = 0.86-0.98, p = 0.007), and was associated with any grade 3-4 toxicity (OR: 0.94, 95% CI = 0.89-0.99, p = 0.013). There is a strong correlation between LBM and HGS (Pearson's r = 0.71, p < 0.001). CONCLUSIONS: Skeletal muscle loss was not associated with severe radiation oral mucositis and dermatitis but associated with any grade 3-4 toxicity and severe gastrointestinal reactions in NPC patients. In males, sarcopenia before treatment is predictive of DLT. Increased HGS is independently associated with a reduced risk of hematological toxicity.

Baseline Low Prognostic Nutritional Index Predicts Poor Survival in Locally Advanced Nasopharyngeal Carcinomas Treated With Radical Concurrent Chemoradiotherapy.

BACKGROUND: To retrospectively assess the impact of prognostic nutritional index (PNI) on survival outcomes of patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated with concurrent chemoradiotherapy (CCRT). METHODS: This study incorporated 154 patients with LA-NPC who received exclusive cisplatinum-based CCRT. Receiver operating characteristic (ROC) curve analysis was utilized for accessibility of pretreatment PNI cutoffs influencing survival results. The primary end point was the interaction between the overall survival (OS) and PNI values, while cancer-specific survival (CSS) locoregional progression-free survival (LR-PFS), distant metastasis-free survival (DMFS), and PFS were the secondary end points. RESULTS: A rounded PNI cutoff value of 51 was identified in ROC curve analyses to exhibit significant link with CSS, OS, DMFS, and PFS outcomes, but not LR-PFS. Patients grouping per PNI value (≥51 [N = 95] vs <51 [N = 49]) revealed that PNI < 51 group had significantly shorter median CSS (P < .001), OS (P < .001), DMFS (P < .001), and PFS (P < .001) times than the PNI ≥ 51 group, and the multivariate results confirmed the PNI < 51 as an independent predictor of poor outcomes for each end point (P < .05 for each). The unfavorable impact of the low PNI was also continued at 10-year time point with survival rates of 77.9% versus 42.4%, 73.6% versus 33.9%, 57.9% versus 27.1%, and 52.6% versus 23.7% for CSS, OS, DMFS, and PFS, respectively. Additionally, we found that PNI < 51 was significantly associated with higher rates of weight loss >5% over past 6 months (49.2% versus 11.6%; P = .002) compared to PNI < 51 group. CONCLUSION: Low pre-CCRT PNI levels were independently associated with significantly reduced CSS, OS, DMFS, and PFS outcomes in patients with LA-NPC treated with definitive CCRT.

Effects of Dicer1 targeted by EBV-miR-BART6-5p on biological properties and radiosensitivity of nasopharyngeal carcinoma.

OBJECTIVE: To discuss the effects of Epstein-Barr virus (EBV)-encoded BamHI A rightward transcript (BART) microRNA (miR-BART6-5p) by targeting Dicer1 on biological properties and radiosensitivity of nasopharyngeal carcinoma (NPC). METHODS: NPC patients (n = 96) treated with radiotherapy were collected from Jan 2010 to Jan 2011. Real-time quantitative PCR (qRT-PCR) and western blot were carried out to measure the expression of miR-BART6-5p and Dicer1. Dual luciferase reporter gene assay verified that miR-BART6-5p targeted Dicer1. CCK8, wound-healing, Transwell and Annexin-FITC/PI were employed to evaluate the effects of Dicer1 mediated by miR-BART6-5p on biological characteristics of NPC cells. The radiosensitivity of miR-BART6-5p targeting Dicer1 was assessed in vitro and in vivo. RESULTS: Increased miR-BART6-5p and decreased Dicer1 were discovered in NPC patients, displaying a close association with T-stage, clinical stage, as well as Pre-DNA of NPC. While elevated Dicer1 and miR-BART6-5p down-regulation in NPC patients were found after effective radiotherapy. Both miR-BART6-5p and Dicer1 were prognostic factors of NPC. Down-regulation of miR-BART6-5p could enhance Dicer1 expression and inhibit NPC cell proliferation, invasion and migration with promoted apoptosis. Clone formation assay also showed miR-BART6-5p down-regulation reduced planting efficiency (PE), which further decreased with the increased dose of irradiation. Injection with miR-BART6-5p inhibitors in nude mice after 6-Gy irradiation contributed to the overexpression of Dicer1 and the inhibition of tumor growth. CONCLUSIONS: EBV-miR-BART6-5p may target Dicer1 to facilitate proliferation and metastasis of NPC cells and suppress apoptosis, thus being a new target for NPC therapy.

Association of body composition with survival and inflammatory responses in patients with non-metastatic nasopharyngeal cancer.

OBJECTIVES: It is unknown whether or not the body composition is correlated with the prognosis and inflammatory response in patients with nasopharyngeal cancer (NPC). MATERIALS AND METHODS: This cohort included 1767 patients with NPC. Visceral, subcutaneous and intra muscular adipose tissues (VAT, SAT and IMAT), and skeletal muscle index were quantified with computed tomography. We used the optimal stratification to select cut points for VAT, SAT and IMAT. We defined sarcopenia according to a widely used cut-point. The primary endpoint was overall survival (OS). The association between body composition and inflammatory response was also examined. RESULTS: Low VAT, SAT, IMAT and sarcopenia were observed in 260 (14.7%), 451 (25.5%), 773 (43.7%) and 683 (38.7%) patients, respectively. Low VAT (P < 0.001, hazard ratio [HR], 1.884; 95% confidence interval [CI], 1.436-2.473,) and SAT (P = 0.022, HR, 1.334, 95%CI, 1.043-1.706) were both associated worse survival. IMAT and sarcopenia were not with prognostic value. In multivariate analysis, we found the prognostic value of the VAT (HR: 1.544, 95% CI: 1.128-2.114; P = 0.007) was independent of T stage, N stage, disease stage, lactic dehydrogenase, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), the systemic immune-inflammation index (SII), EBV-DNA and body mass index. We observed higher NLR (P = 0.028) and PLR (P < 0.001) in patients with low SAT. Both low VAT (P = 0.009) and SAT (P = 0.005) were associated with decreased stromal lymphocyte infiltrating intensity. CONCLUSIONS: Among body composition parameters, VAT was an independent prognostic factor, especially in patients with locally advanced NPC.

Olfaction in Juvenile Nasopharyngeal Angiofibroma: The first study.

BACKGROUND: To study the pattern of olfactory dysfunction/recovery in juvenile nasopharyngeal angiofibroma (JNA). METHODS: Olfactory assessment was undertaken in 30 patients (category1) both pre- & post-operatively and in another 18 (category 2) only postoperative. All patients underwent transpalatal excision and variables of interest included age, radiological stage/parameters & tumor size. RESULTS: Objective olfactory dysfunction was seen in 60% while involvement of olfactory strip was suggested in 50%. Despite some marginal trends only noted between size/age with change of olfaction, Pearson's correlation test did not reveal any significance amongst multiple variables. However a better recovery of olfaction following surgery was evident in Category-2 where Chi-Square test (p < 0.05) significantly revealed this to be a function of postoperative duration. This regenerative course in JNA suggests an optimum period of 4 years for full recovery after surgery. CONCLUSION: In this first study of olfaction in JNA many new trends have been appreciated. In general, deteriorations of olfaction were seen due to 'vascular-concussion' effect in early postoperative phase where post-surgical clearance of airway showed minimal effect in terms of improvement. The hypervascularity of olfactory epithelium with possible hormonal effects may be responsible for the unique pattern of olfactory function and recovery in JNA.

The efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

BACKGROUND: A systemic review and meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy, toxicity and safety of concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) for locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Research searching was performed in Web of Science, PubMed, The Cochrane Library, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chongqing VIP Database for Chinese Technical Periodicals and Wanfang Database. RCTs including patients diagnosed with locoregionally advanced NPC without metastasis and randomly treated with IC plus CCRT and CCRT alone were included. Survival and outcome data were extracted and meta-analysis was performed using the Revman 5.3.0 software. RESULTS: Ten RCTs (2280 patients) were selected and used for pooled meta-analysis. In comparison with CCRT, IC plus CCRT treatment significantly improved the overall survival (OS; HR = 0.70, 95%CI 0.56-0.87, P = .002), progression-free survival (PFS; HR = 0.75, 95%CI 0.65-0.87, P < .0001), distant metastasis failure-free survival (DMFS; HR = 0.71, 95%CI 0.58-0.85, P = .0003) and loco-regional failure-free survival (LFES; HR = 0.72, 95%CI 0.59-0.88, P = .002) of patients with locoregionally advanced NPC. Patients treated with IC and CCRT had higher incidence of grade 3-4 leucopenia and thrombocytopenia than patients treated with CCRT alone (P < .0001). No significant difference in other grade 3-4 adverse events and radiation toxicity was observed between the two groups. IC combined with CCRT improved the survival of patients with locoregionally advanced NPC. CONCLUSIONS: Combined IC and CCRT therapy was an efficacy treatment regimen for locoregionally advanced NPC.

Pre-symptomatic local brain activity and functional connectivity alterations in nasopharyngeal carcinoma patients who developed radiation encephalopathy following radiotherapy.

Radiation encephalopathy (RE) is a common complication in patients with nasopharyngeal carcinoma (NPC) who have received radiotherapy (RT), and recent neuroimaging studies have shown brain alterations in Post-RT patients prior to RE. However, whether there are functional alterations between those Post-RT patients who are proved to have RE in follow-up and those who do not develop it remains largely unknown. Here, we used resting state functional MRI to explore regional homogeneity (ReHo) and functional connectivity (FC) alterations in Post-RT patients with (Post-RT RE proved; n = 18) or without (Post-RT non-RE; n = 22) RE at follow-up, also making comparisons with a Pre-RT group (n = 23). Compared with the Pre-RT group, patients in Post-RT non-RE and Post-RT RE proved groups showed concurrent increased and decreased ReHo values in different brain regions inside and/or outside the radiation field, with the alterations in ReHo tending to increase if RE occurred. Seed-based FC analysis showed that compared with the Post-RT non-RE group, patients in the Post-RT RE proved group had different changing patterns of FC between a region of interest (ROI) in the right temporal lobe and distant brain regions (mainly in the sensorimotor system and default mode network). Receiver operating characteristic (ROC) curve analysis showed that the altered ReHo value in the ROI had excellent diagnostic performance for differentiating NPC patients who developed RE in follow-up from those who did not, with an area under the curve (AUC) value of 0.94. These ReHo and FC findings may provide new insights into the early diagnosis of RE.

Prevalence and Associated Impacts of Cervical Esophageal Clearance Issues Post Chemoradiotherapy for Nasopharyngeal Carcinoma (NPC).

At present, the nature and extent of upper esophageal stage clearance issues following nonsurgical management of nasopharyngeal cancer (NPC) is not well elucidated. The aim of this study was to conduct an initial retrospective study of the prevalence and severity of upper esophageal clearance impairments in a cohort of patients post-NPC management. A secondary aim was to explore any observed relationship between severity of impairment with both (a) aspiration and (b) temporal oropharyngeal swallowing measures. A cohort of 134 NPC patients who received curative intent (chemo)radiotherapy (C/RT) and completed a videofluoroscopic swallowing study (VFSS) between 2012 and 2015 were reviewed. An Esophageal Clearance parameter, based on the scale used in MBSImP was used to classify the presence and severity of esophageal impairment on thin liquid and semisolids. Data on oral and pharyngeal temporal measures, pharyngeal constriction, and penetration/aspiration were also collected. The prevalence of cervical esophageal clearance impairment was high with ratings > 0 observed among 83% and 97% of patients on thin liquid and semisolids, respectively. With the increasing impairment, significantly (p < 0.05) increased oral transit times were observed for liquid swallows, and increased pharyngeal transit times for semisolids. Significantly higher proportions of patients presented with penetration/aspiration in the group with more severe esophageal clearance impairment. Results confirm that cervical esophageal clearance impairment is highly prevalent post-C/RT treatment for NPC. Causality cannot be determined from this study; however, this initial evidence supports that esophageal impairment may coexist in patients post NPC, presenting with more severe oral/pharyngeal deficits, and the impact of this on swallow function needs to be considered. Further systematic research is required.

Epstein-Barr virus latent membrane protein 1 (LMP1) regulates the aldehyde dehydrogenase (ALDH) positive cell population in nasopharyngeal carcinoma cell lines.

Nasopharyngeal carcinoma (NPC) is one of the severe head and neck carcinomas, which are rare in western countries but with high incidence in Southern Asia especially South China. NPC is relatively sensitive to radiotherapy, but the prognosis of patients in late stage is poor. The development of NPC is closely related to genetic background, Epstein-Barr virus (EBV) infection and life style. EBV latent membrane protein 1 (LMP1) is an oncoprotein, which plays important roles in the tumorigenesis of NPC. LMP1 was reported to be involved in the regulation of cancer stem cells (CSCs) by immunohistochemistry (IHC) and other surface marker staining methods, but not shown by aldehyde dehydrogenase 1 (ALDH-1) functional assay yet. In this study, we overexpressed LMP1 in two NPC cell lines and found elevated level of cytokeratin 19 (CK19) expression. CK19 is an undifferentiated keratin and a stem cell marker. We also have found an increased number of ALDH positive cells along with LMP1 overexpression in both cell lines. Our data demonstrate that LMP1 regulates the maintenance of ALDH-1 positive NPC cancer stem cells, thus shedding light on target therapy of NPC in clinical application. Keywords: nasopharyngeal carcinoma; latent membrane protein 1; aldehyde dehydrogenase; cancer stem cells.

[Research of chewing efficiency in patients with extensive acquired defects of the upper jaw after resections of nasopharyngeal zone tumors and various terms of orthopedic rehabilitation]. / Zhevatel'naia éffektivnost' u patsientov s obshirnymi priobretennymi defektami verkhnei cheliusti posle ortopedicheskoi reabilitatsii.

The aim of the study was to estimate how the quality and terms of rational dental orthopedic treatment affects masticatory efficiency in patients using obturators after extensive resections of nasopharyngeal area tumors. The analysis of indicators of masticatory efficiency in dynamics with the use of masticatory probe of V.N. Trezubov considering prosthetics terms, functional and age features was conducted in 14 patients. The results of the research show that high-quality substitution of obturating structures positively affects masticatory efficiency dynamics and therefore has positive impact on the general health state and also on the level of physical and psychological comfort of patients.

Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma.

Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes. New innovative targets are urgently needed. KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene. Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1. Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC. Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis. Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4. The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined. Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC. Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling. We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop. Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion: Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop. The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC. These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.