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1.  Familial nasopharyngeal carcinomas possess distinguished clinical characteristics in southern China 
Objective
To compare clinical characteristics between familial nasopharyngeal carcinomas (NPCs) and sporadic NPCs in Guangdong province, China, a high-risk area.
Methods
Between 1991 and 2001, 993 NPC patients treated at the Cancer Center of Sun Yat-Sen University in Guangdong were randomly selected as probands. Information about NPC among the probands’ relatives and other information were obtained from a retrospective review of the patients’ medical records. The patients were divided into sporadic NPC, low-frequency familial NPC (one NPC patient in addition to the proband in three generations), and high-frequency familial NPC (2 or more additional NPC patients in three generations) groups. Pathological and clinical characteristics were compared among these groups.
Results
Of the 993 patients, 131 (13.2%) had a familial history of NPC. The average age at diagnosis was the lowest in the high-frequency familial NPC group (39 years; P=0.048). Although the overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates did not differ between familial and sporadic NPCs, the locoregional recurrence-free survival (LRFS) rate increased in the order sporadic NPCs, low-frequency familial NPCs, and high-frequency familial NPCs (P=0.009), with 5-year rates of 70%, 83%, and 87%, respectively. Multivariate analysis showed that family history of NPC was an independent favorable prognostic factor for LRFS, with adjusted hazard ratio (aHR) of 0.548, 95% CI (0.342-0.878). The high LRFS for familial NPCs was mainly noted among young, advanced-stage patients who received continuous radiation treatment.
Conclusions
Genetic factors may play an important role in the etiology of high-frequency familial NPC and underlie the early age of onset and sensitivity to radiotherapy.
doi:10.3978/j.issn.1000-9604.2014.10.03
PMCID: PMC4220253  PMID: 25400419
Nasopharyngeal carcinoma (NPC); familial; clinical behavior
2.  MiRNA-125a-5p: a regulator and predictor of gefitinib’s effect on nasopharyngeal carcinoma 
Background
Nasopharyngeal carcinoma (NPC) is a common malignancy in China and Southeast Asia. Radiotherapy is the major treatment modality for patients with NPC, but does not always achieve fully satisfactory outcomes. Studies have shown that epidermal growth factor receptor (EGFR) is highly expressed in NPC, and EGFR-targeted treatment is expected to be a new strategy for NPC. Recently, clinical trials have shown that NPC patients have different responses to gefitinib. Thus, the identification of indicators that can regulate and predict the sensitivity of NPC to gefitinib is very valuable. MiRNAs (MicroRNAs) are closely related to cancer development. We studied miRNAs in NPC cell lines to identify those that can regulate and predict the effectiveness of gefitinib on NPC.
Methods
CCK8, Annexin V-FITC assays and animal models were carried out to evaluate the inhibitory effect of gefitinib on NPC cell lines HNE-1 and HK-1. MiRNA microarrays were used to detect and compare the miRNAs expression levels in the two cells with gefitinib or not, and qRT-PCR was used to evaluate miR-125a-5p expression in NPC cells and in serum of the tumor animal models. Loss-of-function and gain-of-function experiments were taken to evaluate the effect of miR-125a-5p on gefitinib effectiveness. Western blots were used to evaluate the effect of miR-125a-5p on p53 and Her2 in HNE-1 and HK-1 cells.
Results
Gefitinib inhibited two NPC cell lines proliferation in vitro and in vivo,and HNE-1 cells were less sensitive than HK-1 cells to gefitinib.MiR-125a-5p expression levels were increased by geftinib in the two cell lines and in the serum of NPC tumor bearing-mice. This phenomenon was weak in HNE-1 cells and strong in HK-1 cells. MiR-125a-5p over expression improved anti-proliferative and pro-apoptotic effects of gefitinib on the NPC cells and that miR-125a-5p down-regulation decreased those effects. MiR-125a-5p also increased p53 protein expression in HNE-1 cells, and decreased Her2 protein expression in HNE-1 and HK-1 cells.
Conclusions
Our results indicate that gefitinib sensitivity and some miRNAs expressions varied in NPC cell lines. The miR-125a-5p is a possible candidate that can regulate and predict the effect of gefitinib on NPC.
doi:10.1186/1475-2867-14-24
PMCID: PMC3973965  PMID: 24602316
miRNA; miR-125a-5p; Nasopharyngeal carcinoma; Gefitinib
3.  Stat3 Inhibitor Stattic Exhibits Potent Antitumor Activity and Induces Chemo- and Radio-Sensitivity in Nasopharyngeal Carcinoma 
PLoS ONE  2013;8(1):e54565.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia, Africa and Alaska. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin and radiotherapy. Signal transducer and activator of transcription 3 (Stat3) has been implicated in the development and progression of various solid tumors. In this study, we assessed the activation and expression of Stat3 in NPC cells. We found that Stat3 was activated and could be blocked by the small molecule inhibitor Stattic. The inhibition of Stat3 in NPC cells by Stattic decreased the expression of cyclin D1 in a dose- and time-dependent manner. Thus, Stattic was used to target Stat3 in NPC cell lines. We found that Stattic could inhibit cell viability and proliferation in NPC cells and significantly induced apoptosis. Additionally, Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of Stattic upon cell viability inhibition and apoptosis induction. Furthermore, Stattic sensitized NPC cells to cisplatin and ionizing radiation (IR) by preventing cell proliferation and inducing apoptosis. Taken together, Stattic inhibit Stat3 and display antitumor effect in NPC, and enhanced chemosensitivity and radiosensitivity in NPC. Therefore, our findings provide the base for more rational approaches to treat NPC in the clinic.
doi:10.1371/journal.pone.0054565
PMCID: PMC3558509  PMID: 23382914
4.  Analysis of late toxicity in nasopharyngeal carcinoma patients treated with intensity modulated radiation therapy 
Purpose
To observe the late toxicities in nasopharyngeal carcinoma (NPC) patients who achieved long-term survival after intensity modulated radiation therapy (IMRT).
Methods
208 untreated NPC patients who received IMRT and survived more than five years with locoregional disease control and no metastasis were evaluated in this study. The prescription dose to the gross target volume of nasopharynx (GTVnx), positive neck lymph nodes (GTVnd), clinical target volume 1 (CTV1) and 2 (CTV2) was 68Gy/30f, 60-66Gy/30f, 60 Gy/30f and 54Gy/30f, respectively. The nasopharynx and upper neck targets were irradiated using IMRT, and the lower neck and supraclavicular fossae targets were irradiated using the half-beam technique with conventional irradiation. The late toxicities were evaluated according to the LENT/SOMA criteria of 1995.
Results
The median follow-up time was 78 months (60–96 months). The occurrence rates of cervical subcutaneous fibrosis, hearing loss, skin dystrophy, xerostomia, trismus, temporal lobe injury, cranial nerve damage, cataract, and brain stem injury induced by radiotherapy were 89.9%, 67.8%, 47.6%, 40.9%, 7.21%, 4.33%, 2.88%, 1.44%, and 0.48%, respectively. No spinal cord injury and mandible damage were found. Grade 3–4 late injuries were observed as follows: 1 (0.48%) skin dystrophy, 4 (1.92%) cervical subcutaneous fibrosis, 2 (0.96%) hearing loss, 2 (0.96%) cranial nerve palsy, and 1 (0.48%) temporal lobe necrosis. No grade 3–4 late injuries occurred in parotid, temporomandibular joints and eyes. Xerostomia decreased gradually over time and then showed only slight changes after 4 years. The change in the incisor distance stabilised by 1 year after RT, however, the incidence of hearing loss, skin dystrophy, subcutaneous fibrosis and nervous system injuries increased over time after RT.
Conclusion
The late injuries in most NPC patients who had long-term survivals after IMRT are alleviated. Within the 5 years of follow-up, we found xerostomia decreased gradually; The change in the incisor distance stabilised by 1 year after RT; while hearing loss, nervous system injuries increased over time after RT.
doi:10.1186/s13014-014-0326-z
PMCID: PMC4302701  PMID: 25582731
Nasopharyngeal neoplasm/radiotherapy; Intensity-modulated radiotherapy; Radiation injury; Late toxicity
5.  Curcumin analogue T83 exhibits potent antitumor activity and induces radiosensitivity through inactivation of Jab1 in nasopharyngeal carcinoma 
BMC Cancer  2013;13:323.
Background
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.
Methods
NPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting.
Results
A growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy.
Conclusion
Our data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC.
doi:10.1186/1471-2407-13-323
PMCID: PMC3706359  PMID: 23815987
Nasopharyngeal carcinoma; Tumorigenesis; Epstein-Barr virus–associated malignancy; Jab1/CSN5; Curcumin
6.  Phosphorylated Mnk1 and eIF4E Are Associated with Lymph Node Metastasis and Poor Prognosis of Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(2):e89220.
Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. The phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 promotes cellular proliferation, survival, malignant transformation and metastasis. However, whether the alterations of the expression of p-eIF4E and p-Mnk1 protein are associated with clinicopathologic/prognostic implication for NPC has not been reported. The purposes of the present study are to examine the expression of p-eIF4E and p-Mnk1 protein in NPC and non-cancerous nasopharyngeal epithelial tissues by immunohistochemistry and evaluate the association between the expression of p-eIF4E and p-Mnk1 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of p-Mnk1 and p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was significantly higher than that in non-cancerous nasopharyngeal epithelium (40.0% and 32.9%, respectively). The positive expression of p-eIF4E and p-Mnk1 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis. Additionally, p-eIF4E expression was more pronouncedly increased in metastatic NPC than the matched primary NPC. Increase of p-eIF4E and p-Mnk1 expression was significantly correlated inversely with overall survival. Spearman’s rank correlation test further showed that expression of p-Mnk1 was strongly positive correlated with expression of p-eIF4E in NPC. The expression of p-Mnk1 and p-eIF4E in NPC was proved to be the independent prognostic factors regardless of lymph node metastasis, clinical stages and combination of radiotherapy and chemotherapy, histological type, age and gender by multivariate analysis. Taken together, high expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict poor prognosis of NPC and therapeutic targets for developing the valid treatment strategies.
doi:10.1371/journal.pone.0089220
PMCID: PMC3925237  PMID: 24551240
7.  Nasopharyngeal carcinoma in Indonesia: epidemiology, incidence, signs, and symptoms at presentation 
Chinese Journal of Cancer  2012;31(4):185-196.
Among all head and neck (H&N) cancers, nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology, clinical presentation, biological markers, carcinogenic risk factors, and prognostic factors. NPC is endemic in certain regions of the world, especially in Southeast Asia, and has a poor prognosis. In Indonesia, the recorded mean prevalence is 6.2/100 000, with 13 000 yearly new NPC cases, but otherwise little is documented on NPC in Indonesia. Here, we report on a group of 1121 NPC patients diagnosed and treated at Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia between 1996 and 2005. We studied NPC incidence among all H&N cancer cases (n=6000) observed in that period, focusing on age and gender distribution, the ethnic background of patients, and the disease etiology. We also analyzed most prevalent signs and symptoms and staging of NPC patients at first presentation. In this study population, NPC was the most frequent H&N cancer (28.4%), with a male-to-female ratio of 2.4, and was endemic in the Javanese population. Interestingly, NPC appeared to affect patients at a relatively young age (20% juvenile cases) without a bimodal age distribution. Mostly, NPC initiated in the fossa of Rosenmuller and spreaded intracranially or locally as a mass in the head. Occasionally, NPC developed at the submucosal level spreading outside the anatomic limits of the nasopharynx. At presentation, NPC associated with hearing problems, serous otitis media, tinnitus, nasal obstruction, anosmia, bleeding, difficulty in swallowing and dysphonia, and even eye symptoms with diplopia and pain. The initial diagnosis is difficult to make because early signs and symptoms of NPC are not specific to the disease. Early-age Epstein-Barr virus (EBV) infection combined with frequent exposure to environmental carcinogenic co-factors is suggested to cause NPC development. Undifferentiated NPC is the most frequent histological type and is closely associated with EBV. Expression of the EBV-encoded latent membrane protein 1(LMP1) Oncogene in biopsy material was compared between NPC patients of < 30 years old and those of ≥ 30 years old, matched for sex and tumor stage. Higher LMP1 expression in patients of <30 years old was observed, which was related to more locoregional progressivity. Increased medical awareness of prevailing early stage signs and symptoms coupled to use of EBV-related diagnostic tumor markers may lead to down-staging and timely treatment to improve survival of patients with this aggressive disease.
doi:10.5732/cjc.011.10328
PMCID: PMC3777476  PMID: 22313595
Nasopharyngeal carcinoma; incidence; epidemiology; Indonesia
8.  Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology ▿ ‡  
Journal of Virology  2011;85(21):11291-11299.
Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis. However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.
doi:10.1128/JVI.00823-11
PMCID: PMC3194977  PMID: 21880770
9.  Radiation induced temporal lobe necrosis in patients with nasopharyngeal carcinoma: a review of new avenues in its management 
Temporal lobe necrosis (TLN) is the most debilitating late-stage complication after radiation therapy in patients with nasopharyngeal cancer (NPC). The bilateral temporal lobes are inevitably encompassed in the radiation field and are thus prone to radiation induced necrosis. The wide use of 3D conformal and intensity-modulated radiation therapy (IMRT) in the treatment of NPC has led to a dwindling incidence of TLN. Yet, it still holds great significance due to its incapacitating feature and the difficulties faced clinically and radiologically in distinguishing it from a malignancy. In this review, we highlight the evolution of different imaging modalities and therapeutic options. FDG PET, SPECT and Magnetic Spectroscopy are among the latest imaging tools that have been considered. In terms of treatment, Bevacizumab remains the latest promising breakthrough due to its ability to reverse the pathogenesis unlike conventional treatment options including large doses of steroids, anticoagulants, vitamins, hyperbaric oxygen and surgery.
doi:10.1186/1748-717X-6-128
PMCID: PMC3195720  PMID: 21961805
Nasopharyngeal cancer; radiation therapy; temporal lobe necrosis; Bevacizumab
10.  Neurosurgery and prognosis in patients with radiation-induced brain injury after nasopharyngeal carcinoma radiotherapy: a follow-up study 
Background
Radiotherapy is the standard radical treatment for nasopharyngeal carcinoma (NPC) and may cause radiation-induced brain injury (RI). Treatment for RI remains a challenge. We conducted this study to investigate the indications of neurosurgery, operation time and prognosis of patients with RI after NPC radiotherapy who underwent neurosurgical management.
Methods
This was a follow-up study between January 2005 and July 2011. Fifteen NPC cases of RI who underwent neurosurgery were collected. Brain Magnetic resonance imaging (MRI), surgery and histology were studied. The outcome was assessed by LENT/SOMA scales and modified Rankin scale.
Results
Brain lesion resection (86.7%) was more common than decompressive craniotomy (13.3%). According to LENT/SOMA scale before and six months after surgery, 13 of 15, 12 of 15, 14 of 15, and 14 of 15 cases showed improvement at subjective, objective, management and analytic domains, respectively. 12 of 15 patients showed improvement of modified Rankin scale after surgery. Three patients who underwent emergency surgery showed significant improvement (average score increment of 2, 2.7, 2.7, 3 and 2 at LENT/SOMA scale subjective, objective, management, analytic, and modified Rankin scale, respectively), as compared with 12 cases underwent elective surgery (average score increment of 1, 1, 1.4, 1.8 and 1 at LENT SOMA scale subjective, objective, management, analytic, and modified Rankin scale, respectively).
Conclusions
Neurosurgery, including brain necrotic tissue resection and decompressive craniotomy, improves the prognosis for RI patients, especially for those with indications of emergency surgery.
doi:10.1186/1748-717X-8-88
PMCID: PMC3653741  PMID: 23578338
Radiotherapy; Nasopharyngeal carcinoma; Radiation-induced brain injury; Neurosurgery
11.  Serum proteome analysis for profiling protein markers associated with carcinogenesis and lymph node metastasis in nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC), one of the most common cancers in population with Chinese or Asian progeny, poses a serious health problem for southern China. It is unfortunate that most NPC victims have had lymph node metastasis (LNM) when first diagnosed. We believe that the 2D based serum proteome analysis can be useful in discovering new biomarkers that may aid in the diagnosis and therapy of NPC patients. To filter the tumor specific antigen markers of NPC, sera from 42 healthy volunteers, 27 non-LNM NPC patients and 37 LNM NPC patients were selected for screening study using 2D combined with MS. Pretreatment strategy, including sonication, albumin and immunoglobulin G (IgG) depletion, was adopted for screening differentially expressed proteins of low abundance in serum. By 2D image analysis and MALDI-TOF-MS identification, twenty-three protein spots were differentially expressed. Three of them were further validated in the sera using enzyme-linked immunosorbent assay (ELISA). Our research demonstrates that HSP70, sICAM-1 and SAA, confirmed with ELISA at sera and immunohistochemistry, are potential NPC metastasis-specific serum biomarkers which may be of great underlying significance in clinical detection and management of NPC.
doi:10.1007/s10585-008-9152-8
PMCID: PMC2413104  PMID: 18357507
Nasopharyngeal carcinoma; Serum proteome; Carcinogenesis; Lymph node metastasis
12.  Comparative serum proteomic analysis involving liver organ-specific metastasis-associated proteins of nasopharyngeal carcinoma 
Metastasis is the main cause of cancer-related mortality; patients with liver metastases (LM) have the worst prognosis among patients with nasopharyngeal carcinoma (NPC). However, at present, few biomarkers for detecting organ-specific metastasis have been identified. Proteomics, an ultra-sensitive analytical technique, can detect molecular changes before organ-specific metastasis occurs. Analysis with matrix-assisted, laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS), combined with magnetic chemical affinity beads is a new technique for evaluating protein separation. We sought to identify potential liver-specific, metastasis-associated proteomic printing in patients with NPC. We examined 64 serum samples from 50 patients who had pathologically confirmed NPC and 14 who had pathologically confirmed non-NPC with LM using MALDI-TOF-MS with weak cation bead protein chips. During follow-up of at least 37 months (maximum, 176 months) following radiotherapy, we confirmed 16 cases of LM (LM NPC), 16 cases without LM (non-LM NPC) and 18 cases without metastasis (non-M NPC). Using comparison analysis, 4 protein mass peaks, 4155.34, 4194.87, 4210.78 and 4249.56 m/z were identified as liver-specific, metastasis-associated protein peaks in NPC and two of them (4155 and 4249 m/z) met two different statistical criteria in both ClinProt software analyses and discriminant analyses. Models based on the 4 potential serum markers of NPC discriminated between LM NPC, non-LM NPC, non-M NPC and non-NPC LM analyzed with sieved markers. The recognition capability and cross-validation of these models for differentiating the above 4 groups are all approximately 80%. MALDI-TOF-MS combined with tree analysis models may provide a clinical diagnostic platform for detecting potential liver-specific, metastasis-associated proteomic printing in NPC. However, markedly differential proteins still need to be identified.
doi:10.3892/etm.2012.526
PMCID: PMC3438645  PMID: 22970016
nasopharyngeal carcinoma; organ-specific metastasis; liver metastasis; proteomics
13.  Increased expression of SHP-1 is associated with local recurrence after radiotherapy in patients with nasopharyngeal carcinoma 
Radiology and Oncology  2014;48(1):40-49.
Background
Nasopharyngeal carcinoma (NPC) is a major cancer in southern China. Src homology phosphatase-1 (SHP-1) is a tyrosine phosphatase that regulates growth, differentiation, cell cycle progression, and oncogenesis. We determined the clinical significance of SHP-1 expression in the tumours of NPC patients from southern China who were treated with radiotherapy.
Patients and methods.
SHP-1 expression was determined by real-time polymerase chain reaction (PCR) and western blotting of NPC tissue samples of 50 patients and nasopharyngeal tissues of 50 non-NPC patients who had chronic nasopharyngeal inflammation. SHP-1 expression was measured in NPC tissue samples of 206 patients by immunohistochemistry and survival analysis was performed.
Results
The tumours of NPC patients had significantly increased expression of SHP-1 at mRNA and protein levels relative to patients with chronic nasopharyngeal inflammation. Survival analysis of NPC patients indicated that SHP-1 expression was significantly associated with poor local recurrence-free survival (p = 0.008), but not with nodal recurrence-free survival, distant metastasis-free survival, or overall survival.
Conclusions
SHP-1 appears to be associated with radiation resistance of NPC cells and can be considered as a candidate marker for prognosis and/or therapeutic target in patients with this type of cancer.
doi:10.2478/raon-2014-0001
PMCID: PMC3908846  PMID: 24587778
SHP-1; nasopharyngeal carcinoma; real-time quantitative PCR; Western blotting; immunohistochemistry; radiation resistance
14.  Neurosurgical interventions for patients with nasopharyngeal carcinoma: a single institution experience 
Background
Nasopharyngeal carcinoma (NPC) is a frequent head and neck cancer in southern China and Southeast Asia. The majority of NPC patients are managed by radiation oncologists, medical oncologists and head and neck surgeons. Actually, neurosurgical interventions are warranted under specific circumstances. In this article, we described our experience as neurosurgeons in the management of NPC patients.
Methods
Medical records of NPC patients who received neurosurgical procedure at Sun Yat-sen University Cancer Center were reviewed.
Results
Twenty-seven patients were identified. Among 27 cases, neurosurgical procedures were performed in 18 (66.7%) with radiation-induced temporal necrosis, 2 (7.4%) with radiation-induced sarcoma, 4 (14.8%) with synchronous NPC with primary brain tumors, 2 (7.4%) with recurrent NPC involving skull base, and 1 (3.7%) with metachronous skull eosinophilic granuloma, respectively. The diagnosis is challenging in specific cases and initial misdiagnoses were found in 6 (22.2%) patients.
Conclusions
For NPC patients with intracranial or skull lesions, the initial diagnosis can be occasionally difficult because of the presence or a history of NPC and related treatment. Unawareness of these entities can result in misdiagnosis and subsequent improper treatment. Neurosurgical interventions are necessary for the diagnosis and treatment for these patients.
doi:10.1186/1477-7819-11-227
PMCID: PMC3847299  PMID: 24034781
Nasopharyngeal carcinoma; Radiation-induced temporal necrosis; Radiation-induced sarcoma; Multiple primary tumor
15.  Retrospective analysis of results of treatment for nasopharyngeal carcinoma in Macao 
Background
Nasopharyngeal carcinoma (NPC) is a common malignancy in Southeast Asia, however, a full consensus has not yet been reached as to the value of comprehensive treatment for NPC. This study was designed to evaluate the epidemiological characteristics of NPC and their prognostic value, as well as the long-term efficacy of NPC treatment.
Patients and methods
A total of 248 patients, with different stages of NPC, were included in this study.
Results
The 5-year overall survival (OS) rates for patients in stages I, II, III and IV were 90.48%, 76.71%, 76.89% and 33.87%, respectively (P=0.000), while the respective 5-year progression-free survival (PFS) rates were 85.15%, 72.36%, 63.88% and 26.26% (P=0.000). The respective 5-year OS rates, according to stage, for the group that received radiotherapy combined with chemotherapy and for the group that received radiotherapy only were as follows: stages I and II, 81.67% and 79.59% (P=0.753); stage III, 79.91% and 70.38% (P=0.143); stage IV, 35.22% and 0% (P=0.000). The respective 5-year PFS rates in these groups were as follows: stages I and II, 75.83% and 74.98% (P=0.814); stage III, 74.08% and 42.25% (P=0.027); stage IV, 27.31% and 0% (P=0.000).
Conclusions
Clinical staging appears to be the most important prognostic factor for NPC. As the stage number increases, both the 5-year OS and PFS significantly decrease. Adding chemotherapy to radiotherapy was not advantageous for patients with stage I or II NPC, however the addition of chemotherapy to radiotherapy significantly improved OS and PFS in patients with stage IV NPC. The addition of chemotherapy improved PFS, but not OS in patients with stage III NPC.
doi:10.3978/j.issn.1000-9604.2014.03.01
PMCID: PMC4000909  PMID: 24826055
Nasopharyngeal carcinoma (NPC); treatment; retrospective analysis; Macao
16.  Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy 
Background
The radiation tolerance dose-volume in brain remains unclear for nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiotherapy (IMRT). We performed this study to investigate dosimetric factors associated with temporal lobe necrosis (TLN) in NPC patients treated with IMRT.
Methods
From 2001 to 2008, 870 NPC patients were treated with IMRT. For the whole group, 40 patients have developed MRI-diagnosed TLN, and 219 patients were followed-up more than 60 months. Predictive dosimetric factors for TLN were identified by using univariate and multivariate analysis in these 259 patients.
Results
By univariate analyses, rVX ( percent of temporal lobes receiving ≥ X Gy) and aVX ( absolute volumes of temporal lobes receiving ≥ X Gy, values of X considered were 10, 20, 30, 40, 50, 60, 66 and 70) were all significantly associated with TLN. Multivariate analysis by logistic regression showed that rV40 and aV40 were significant factors for TLN. All dosimetric factors in current serials were highly correlated one another (p < 0.001). The 5-year incidence of TLN for rV40 <10% or aV40 <5 cc is less than 5%. The incidence for rV40 ≥ 15% or aV40c ≥ 10c is increased significantly and more than 20%.
Conclusions
In this study, all dosimetric factors were highly correlated, rV40 and aV40 were independent predictive factors for TLN, IMRT with rV40 <10% or aV40 <5 cc in temporal lobe is relatively safe.
doi:10.1186/1748-717X-8-17
PMCID: PMC3573909  PMID: 23336282
Nasopharyngeal carcinoma; Temporal lobe necrosis; Intensity modulated radiotherapy
17.  TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness 
Molecular Cancer  2014;13:51.
Background
MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.
Methods
We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation.
Results
TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC.
Conclusion
The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
doi:10.1186/1476-4598-13-51
PMCID: PMC4016586  PMID: 24606633
miR-93; TGFβR2; Aggressiveness; PI3K/Akt; Nasopharyngeal carcinoma
18.  Endoscope-Guided Interstitial Intensity-Modulated Brachytherapy and Intracavitary Brachytherapy as Boost Radiation for Primary Early T Stage Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(3):e90048.
Background
Intracavitary brachytherapy (ICBT) is usually applied as boost radiotherapy for superficial residual of nasopharyngeal carcinoma (NPC) after primary extern-beam radiptherapy (ERT). Here, we evaluated the outcome of endoscope-guided interstitial intensity-modulated brachytherapy (IMBT) boost radiation for deep-seated residual NPC.
Methodology/Principal Findings
Two hundred and thirteen patients with residual NPC who were salvaged with brachytherapy boost radiation during 2005–2009 were analyzed retrospectively. Among these patients, 171 patients had superficial residual NPC (≤1 cm below the nasopharyngeal epithelium) were treated with ICBT boost radiation, and interstitial IMBT boost radiation was delivered to 42 patients with deep-seated residual NPC (>1 cm below the nasopharyngeal epithelium). We found that IMBT boost subgroup had a higher ratio of T2b (81.0% VS 34.5%, P<0.001) and stage II (90.5% VS 61.4%, P = 0.001) than that of ICBT boost subgroup. The dosage of external-beam radiotherapy in the nasopharyngeal (63.0±3.8 VS 62.6±4.3 Gray (Gy), P = 0.67) and regional lymph nodes (55.8±5.0 VS 57.5±5.7 Gy, P = 0.11) was comparable in both groups. For brachytherapy, IMBT subgroup had a lower boost radiation dosage than ICBT subgroup (11.0±2.9 VS 14.8±3.2 Gy, P<0.01). Though the IMBT group had deeper residual tumors and received lower boost radiation dosages, both subgroups had the similar 5-year actuarial overall survival rate (IMBT VS ICBT group: 96.8% VS 93.6%, P = 0.87), progression-free survival rate (92.4% VS 86.5%, P = 0.41) and distant metastasis-free survival rate (94.9% VS 92.7%, P = 0.64). Moreover, IMBT boost radiation subgroup had a similar local (97.4% VS 94.4%, P = 0.57) and regional (95.0% VS 97.2%, P = 0.34) control to ICBT subgroup. The acute and late toxicities rates were comparable between the both subgroups.
Conclusions/Significance
IMBT boost radiation may be a promising therapeutic selection for deep-seated residual NPC.
doi:10.1371/journal.pone.0090048
PMCID: PMC3940723  PMID: 24595299
19.  A Study of Radiation-Induced Cerebral Vascular Injury in Nasopharyngeal Carcinoma Patients with Radiation-Induced Temporal Lobe Necrosis 
PLoS ONE  2012;7(8):e42890.
Purpose
To investigate radiation-induced carotid and cerebral vascular injury and its relationship with radiation-induced temporal lobe necrosis in nasopharyngeal carcinoma (NPC) patients.
Methods and Materials
Fifty eight NPC patients with radiation-induced temporal lobe necrosis (TLN) were recruited in the study. Duplex ultrasonography was used to scan bilateral carotid arterials to evaluate the intima-media thickness (IMT) and occurrence of plaque formation. Flow velocities of bilateral middle cerebral arteries (MCAs), internal carotid arteries (ICAs) and basal artery (BA) were estimated through Transcranial Color Doppler (TCD). The results were compared with data from 33 patients who were free from radiation-induced temporal lobe necrosis after radiotherapy and 29 healthy individuals.
Results
Significant differences in IMT, occurrence of plaques of ICAs and flow velocities of both MCAs and ICAs were found between patients after radiotherapy and healthy individuals (p<0.05). IMT had positive correlation with post radiation interval (p = 0.049). Compared with results from patients without radiation-induced TLN, the mean IMT was significantly thicker in patients with TLN (p<0.001). Plaques were more common in patients with TLN than patients without TLN (p = 0.038). In addition, flow velocities of MCAs and ICAs in patients with TLN were much faster (p<0.001, p<0.001). Among patients with unilateral TLN, flow velocity of MCAs was significantly different between ipsilateral and contralateral sides to the lesion (p = 0.001).
Conclusion
Thickening of IMT, occurrence of plaque formation and hemodynamic abnormality are more common in patients after radiotherapy, especially in those with TLN, compared with healthy individuals.
doi:10.1371/journal.pone.0042890
PMCID: PMC3418223  PMID: 22912759
20.  Suppression of Jab1/CSN5 induces radiation- and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways 
Oncogene  2012;32(22):2756-2766.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin. Increased DNA damage repair is one of the mechanisms contributing to this resistance. Jab1/CSN5 is a multifunctional protein that participates in controlling cell proliferation and the stability of multiple proteins. Jab1 overexpression has been found to correlate with poor prognosis in several tumor types. However, the biological significance of Jab1 activity in response to cancer treatment is unclear. In this study, we used three NPC cell lines (CNE1, CNE2, and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA-damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV). We found that Jab1 was overexpressed in two relatively cisplatin-, IR- and UV-resistant NPC cell lines, and knocking down its expression conferred sensitivity to cisplatin, IR and UV. By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV Moreover, we provide a mechanism by which Jab1 positively regulated Rad51 through p53-dependent pathway, and increased ectopic expression of Rad51 conferred cellular resistance to cisplatin, IR and UV in Jab1-deficient cells. Taken together, our findings suggest that Jab1 plays an important role in the cellular response to cisplatin and irradiation by regulating DNA damage and repair pathways. Therefore, Jab1 is a novel biomarker for predicting the outcome of patients with NPC who are treated with DNA-damaging agents.
doi:10.1038/onc.2012.294
PMCID: PMC3566273  PMID: 22797071
nasopharyngeal carcinoma; Epstein-Barr virus-associated malignancy; cisplatin; ultraviolet radiation; ionizing radiation; RPPA
21.  Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease 
PLoS Genetics  2005;1(1):e7.
Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.
Synopsis
Niemann-Pick disease type C is a deadly neurodegenerative disease that is most often due to mutations in a gene called npc1. As a consequence of intracellular lipid trafficking defects, patients with Niemann-Pick type C, and mice with the same disease, lose an important class of cerebellar neurons called Purkinje cells (PCs). Npc1 (the protein coded by npc1) might be needed in other cell types to produce substances that nourish PCs or within the PCs themselves. To see which is true, the researchers constructed genetically mosaic mice in which some cells have mutant Npc1 and some have normal Npc1 function. In the cerebella of these mosaic mice, PCs lacking Npc1 continued to die even while surrounded by normal cells, while normal PCs appeared unaffected by their partially mutant surroundings. From these findings, the researchers concluded that the neurodegeneration is due to a problem within PCs and not due to a lack of supporting factors provided by other cells or an extrinsic toxic or inflammatory insult. Npc1 probably functions within PCs to allow critical transport processes necessary for cell survival. The researchers also found that the degenerating PCs undergo a complex process called autophagy in which the cells sense a lack of key nutrients and start to break down their own structures to feed themselves. By identifying exactly which cells require Npc1 function, the researchers set the stage for investigating the exact molecular roles of Npc1 protein in the cells where it is most needed.
doi:10.1371/journal.pgen.0010007
PMCID: PMC1183526  PMID: 16103921
22.  Comparison of single versus fractionated dose of stereotactic radiotherapy for salvaging local failures of nasopharyngeal carcinoma: a matched-cohort analysis 
Head & Neck Oncology  2009;1:13.
Background
wLocal failure is an important cause of morbidity and mortality in nasopharyngeal carcinoma (NPC). Although surgery or brachytherapy may be feasible in selected cases, most patients with local failure require external beam re-irradiation. Stereotactic radiation using single or multiple fractions have been employed in re-irradiation of NPC, but the optimal fractionation scheme and dose are not clear.
Methods
Records of 125 NPC patients who received salvage stereotactic radiation were reviewed. A matched-pair design was used to select patients with similar prognostic factors who received stereotactic re-irradiation using single fraction (SRS) or multiple fractions (SRM). Eighty-six patients were selected with equal number in SRS and SRM groups. All patients were individually matched for failure type (persistent or recurrent), rT stage (rT1-2 or rT3-4), and tumor volume (≤ 5 cc, >5–10 cc, or >10 cc). Median dose was 12.5 Gy in single fraction by SRS, and 34 Gy in 2–6 fractions by SRM.
Results
Local control rate was better in SRM group although overall survival rates were similar. One- and 3-year local failure-free rates were 70% and 51% in SRS group compared with 91% and 83% in SRM group (p = 0.003). One- and 3-year overall survival rates were 98% and 66% in SRS group compared with 78% and 61% in SRM group (p = 0.31). The differences in local control were mainly observed in recurrent or rT2-4 disease. Incidence of severe late complications was 33% in SRS group vs. 21% in SRM group, including brain necrosis (16% vs. 12%) and hemorrhage (5% vs. 2%).
Conclusion
Our study showed that SRM was superior to SRS in salvaging local failures of NPC, especially in the treatment of recurrent and rT2-4 disease. In patient with local failure of NPC suitable for stereotactic re-iradiation, use of fractionated treatment is preferred.
doi:10.1186/1758-3284-1-13
PMCID: PMC2694191  PMID: 19463191
23.  Increased Expression of Flotillin-2 Protein as a Novel Biomarker for Lymph Node Metastasis in Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(7):e101676.
Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC.
doi:10.1371/journal.pone.0101676
PMCID: PMC4094483  PMID: 25014228
24.  Validity of the Age-Adjusted Charlson Comorbidity Index on Clinical Outcomes for Patients with Nasopharyngeal Cancer Post Radiation Treatment: A 5-Year Nationwide Cohort Study 
PLoS ONE  2015;10(1):e0117323.
Purpose
To characterize the impact of comorbidity on survival outcomes for patients with nasopharyngeal carcinoma (NPC) post radiotherapy (RT).
Methods
A total of 4095 patients with NPC treated by RT or RT plus chemotherapy (CT) in the period from 2007 to 2011 were included through Taiwan’s National Health Insurance Research Database. Information on comorbidity present prior to the NPC diagnosis was obtained and adapted to the Charlson Comorbidity Index (CCI), Age-Adjusted Charlson Comorbidity Index (ACCI) and a revised head and neck comorbidity index (HN-CCI). The prevalence of comorbidity and the influence on survival were calculated and analyzed.
Results
Most of the patients (75%) were male (age 51±13 years) and 2470 of them (60%) had at least one comorbid condition. The most common comorbid condition was diabetes mellitus. According to these three different comorbidity index (CCI, ACCI and HN-CCI), higher scores were associated with worse overall survival (P< 0.001). The Receiver Operating Characteristic (ROC) curve was used to assess the discriminating ability of CCI, AACI and HN-CCI scores and it demonstrated the predictive ability for mortality with the ACCI (0.693, 95% CI 0.670–0.715) was superior to that of the CCI (0.619, 95% CI 0.593–0.644) and HN-CCI (0.545, 95%CI 0.519–0.570).
Conclusion
Comorbidities greatly influenced the clinical presentations, therapeutic interventions, and outcomes of patients with NPC post RT. Higher comorbidity index scores accurately was associated with worse survival. The ACCI seems to be a more appropriate prognostic indicator and should be considered in further clinical studies.
doi:10.1371/journal.pone.0117323
PMCID: PMC4305297  PMID: 25617629
25.  Elevated expressions of survivin and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma 
Background
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. The China 1992 TNM staging system has been widely used for prognosis prediction of NPC patients in China. Although NPC patients can be classified according to their clinical stage in this system, their prognosis may vary significantly.
Method
280 cases of NPC with clinical follow-up data were collected and expressions of survivin and VEGF in tumor tissues were investigated by immunohistochemistry (IHC). Apoptosis index (AI) in 100 cases of NPC was detected by the TUNEL method.
Results
Expression of survivin and VEGF were significantly associated with TNM stage, T-stage and metastasis of NPC. The patients with survivin and VEGF over-expression presented lower 5-year survival rate, as compared to those of low-expression (42.32% vs. 70.54%, 40.1% vs. 67.8%, respectively, P < 0.05), especially in advanced stage patients (36.51% vs. 73.41%, 35.03% vs. 65.22%, respectively, P < 0.05). The 5-year survival rate in NPC patients with survivin and VEGF dual over-expression was significantly lower than that of patients with dual low-expression (18.22% vs. 73.54%, respectively; P = 0.0003). Multivariate analysis indicated that both survivin and VEGF over-expression in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. The mean AI in the 39 survivin low-expression cases was 144.7 ± 39.9, which was significantly higher than that in 61 survivin over-expression cases (111.6 ± 39.8) (T test, P < 0.05).
Conclusion
Survivin and VEGF over-expression are independent prognostic factors for the patients with NPC. These results also suggest that tumor survivin and VEGF expressions are valuable prognostic markers for prognosis prediction in NPC patients.
doi:10.1186/1479-5876-6-1
PMCID: PMC2254380  PMID: 18171482

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