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Title: The time frame of Epstein-Barr virus latent membrane protein-1 gene to disappear in nasopharyngeal swabs after initiation of primary radiotherapy is an independently significant prognostic factor predicting local control for patients with nasopharyngeal carcinoma

Abstract

Purpose: The presence of Epstein-Barr virus latent membrane protein-1 (LMP-1) gene in nasopharyngeal swabs indicates the presence of nasopharyngeal carcinoma (NPC) mucosal tumor cells. This study was undertaken to investigate whether the time taken for LMP-1 to disappear after initiation of primary radiotherapy (RT) was inversely associated with NPC local control. Methods and Materials: During July 1999 and October 2002, there were 127 nondisseminated NPC patients receiving serial examinations of nasopharyngeal swabbing with detection of LMP-1 during the RT course. The time for LMP-1 regression was defined as the number of days after initiation of RT for LMP-1 results to turn negative. The primary outcome was local control, which was represented by freedom from local recurrence. Results: The time for LMP-1 regression showed a statistically significant influence on NPC local control both univariately (p < 0.0001) and multivariately (p = 0.004). In multivariate analysis, the administration of chemotherapy conferred a significantly more favorable local control (p = 0.03). Advanced T status ({>=} T2b), overall treatment time of external photon radiotherapy longer than 55 days, and older age showed trends toward being poor prognosticators. The time for LMP-1 regression was very heterogeneous. According to the quartiles of the time for LMP-1more » regression, we defined the pattern of LMP-1 regression as late regression if it required 40 days or more. Kaplan-Meier plots indicated that the patients with late regression had a significantly worse local control than those with intermediate or early regression (p 0.0129). Conclusion: Among the potential prognostic factors examined in this study, the time for LMP-1 regression was the most independently significant factor that was inversely associated with NPC local control.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [2];  [1];  [1];  [1];  [2];  [6]
  1. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan (China)
  2. Department of Otolaryngology, Chang Gung Memorial Hospital, Linkou, Taiwan (China)
  3. (China)
  4. Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan (China)
  5. Department of Anatomic Pathology, Chang Gung Memorial Hospital, Linkou, Taiwan (China)
  6. Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan (China). E-mail: rt3126@adm.cgmh.org.tw
Publication Date:
OSTI Identifier:
20788224
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 63; Journal Issue: 5; Other Information: DOI: 10.1016/j.ijrobp.2005.05.051; PII: S0360-3016(05)00963-6; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARCINOMAS; CHEMOTHERAPY; CONTROL; GENES; MEMBRANE PROTEINS; ONCOGENIC VIRUSES; PATIENTS; RADIOTHERAPY; TUMOR CELLS

Citation Formats

Lin, S.-Y., Chang, K.-P., Graduate Institute of Clinical Medical Sciences, Chang Gung University, Linkou, Taiwan, Hsieh, M.-S., Ueng, S.-H., Hao, S.-P., Tseng, C.-K., Pai, P.-C., Chang, F.-T., Tsai, M.-H., and Tsang, N.-M. The time frame of Epstein-Barr virus latent membrane protein-1 gene to disappear in nasopharyngeal swabs after initiation of primary radiotherapy is an independently significant prognostic factor predicting local control for patients with nasopharyngeal carcinoma. United States: N. p., 2005. Web. doi:10.1016/J.IJROBP.2005.0.
Lin, S.-Y., Chang, K.-P., Graduate Institute of Clinical Medical Sciences, Chang Gung University, Linkou, Taiwan, Hsieh, M.-S., Ueng, S.-H., Hao, S.-P., Tseng, C.-K., Pai, P.-C., Chang, F.-T., Tsai, M.-H., & Tsang, N.-M. The time frame of Epstein-Barr virus latent membrane protein-1 gene to disappear in nasopharyngeal swabs after initiation of primary radiotherapy is an independently significant prognostic factor predicting local control for patients with nasopharyngeal carcinoma. United States. doi:10.1016/J.IJROBP.2005.0.
Lin, S.-Y., Chang, K.-P., Graduate Institute of Clinical Medical Sciences, Chang Gung University, Linkou, Taiwan, Hsieh, M.-S., Ueng, S.-H., Hao, S.-P., Tseng, C.-K., Pai, P.-C., Chang, F.-T., Tsai, M.-H., and Tsang, N.-M. Thu . "The time frame of Epstein-Barr virus latent membrane protein-1 gene to disappear in nasopharyngeal swabs after initiation of primary radiotherapy is an independently significant prognostic factor predicting local control for patients with nasopharyngeal carcinoma". United States. doi:10.1016/J.IJROBP.2005.0.
@article{osti_20788224,
title = {The time frame of Epstein-Barr virus latent membrane protein-1 gene to disappear in nasopharyngeal swabs after initiation of primary radiotherapy is an independently significant prognostic factor predicting local control for patients with nasopharyngeal carcinoma},
author = {Lin, S.-Y. and Chang, K.-P. and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Linkou, Taiwan and Hsieh, M.-S. and Ueng, S.-H. and Hao, S.-P. and Tseng, C.-K. and Pai, P.-C. and Chang, F.-T. and Tsai, M.-H. and Tsang, N.-M.},
abstractNote = {Purpose: The presence of Epstein-Barr virus latent membrane protein-1 (LMP-1) gene in nasopharyngeal swabs indicates the presence of nasopharyngeal carcinoma (NPC) mucosal tumor cells. This study was undertaken to investigate whether the time taken for LMP-1 to disappear after initiation of primary radiotherapy (RT) was inversely associated with NPC local control. Methods and Materials: During July 1999 and October 2002, there were 127 nondisseminated NPC patients receiving serial examinations of nasopharyngeal swabbing with detection of LMP-1 during the RT course. The time for LMP-1 regression was defined as the number of days after initiation of RT for LMP-1 results to turn negative. The primary outcome was local control, which was represented by freedom from local recurrence. Results: The time for LMP-1 regression showed a statistically significant influence on NPC local control both univariately (p < 0.0001) and multivariately (p = 0.004). In multivariate analysis, the administration of chemotherapy conferred a significantly more favorable local control (p = 0.03). Advanced T status ({>=} T2b), overall treatment time of external photon radiotherapy longer than 55 days, and older age showed trends toward being poor prognosticators. The time for LMP-1 regression was very heterogeneous. According to the quartiles of the time for LMP-1 regression, we defined the pattern of LMP-1 regression as late regression if it required 40 days or more. Kaplan-Meier plots indicated that the patients with late regression had a significantly worse local control than those with intermediate or early regression (p 0.0129). Conclusion: Among the potential prognostic factors examined in this study, the time for LMP-1 regression was the most independently significant factor that was inversely associated with NPC local control.},
doi = {10.1016/J.IJROBP.2005.0},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 63,
place = {United States},
year = {Thu Dec 01 00:00:00 EST 2005},
month = {Thu Dec 01 00:00:00 EST 2005}
}
  • Purpose: To evaluate the long-term prognostic impact of plasma Epstein-Barr virus (EBV) DNA concentration measured by real-time quantitative polymerase chain reaction (RTQ-PCR) in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT). Methods and Materials: Epstein-Barr virus DNA was retrospectively measured from stock plasma of 152 biopsy-proven NPC patients with Stage II-IV (M0) disease with a RTQ-PCR using the minor groove binder-probe. All patients received CCRT with a median follow-up of 78 months. We divided patients into three subgroups: (1) low pretreatment EBV DNA (<1,500 copies/mL) and undetectable posttreatment EBV DNA (pre-L/post-U) (2) high pretreatment EBV DNA ({>=}1,500 copies/mL) and undetectablemore » posttreatment EBV DNA (pre-H/post-U), and (3) low or high pretreatment EBV DNA and detectable posttreatment EBV DNA (pre-L or H/post-D) for prognostic analyses. Results: Epstein-Barr virus DNA (median concentration, 573 copies/mL; interquartile range, 197-3,074) was detected in the pretreatment plasma of 94.1% (143/152) of patients. After treatment, plasma EBV DNA decreased or remained 0 for all patients and was detectable in 31 patients (20.4%) with a median concentration 0 copy/mL (interquartile range, 0-0). The 5-year overall survival rates of the pre-L/post-U, pre-H/post-U, and pre-L or H/post-D subgroups were 87.2%, 71.0%, and 38.7%, respectively (p < 0.0001). The relapse-free survival showed similar results with corresponding rates of 85.6%, 75.9%, and 26.9%, respectively (p < 0.0001). Multivariate Cox analysis confirmed the superior effects of plasma EBV DNA compared to other clinical parameters in prognosis prediction. Conclusion: Plasma EBV DNA is the most valuable prognostic factor for NPC. More chemotherapy should be considered for patients with persistently detectable EBV DNA after CCRT.« less
  • Raji cells, an EBV genome carrying and nonproducer cell line, treated with tetradecanoyl-phorbol-13-acetate (TPA) and n-butyrate could induce a special DNA polymerase which has properties that are similar to the EBV-DP induced by TPA in P/sub 3/HR-I cells, an EBV producer cell line. Since EBV was found to have a strong association with NPC, and antibodies against EBV proteins or enzymes were found in high levels in sera from these patients, the possible presence of serum antibody against EBV-DP was examined. The serum titer of antibody to EBV-DP was found to have 190 +/- 84 units/ml serum (mean +/- S.D.)more » in 48 sera from patients with NPC. The titer in 52 healthy donors was 31.4 +/- 28 unit/ml serum (p < 0.01). The antibody was found to be associated with the IgG but not the IgA fraction. The antibody titers against EBV-DP were not correlated with the titer against EBV-DNase or VCA-IgA. Whether the antibody observed is against an EBV-DP core protein or its stimulating protein, as demonstrated by this laboratory previously, is still being investigated. This study demonstrated the high frequency and high titer of antibody against EBV-DP in serum from patients with NPC, and suggested the potential of utilizing this antibody titer to compliment other methods for the early diagnosis or prognosis of NPC.« less
  • Purpose: To investigate the effects of adjuvant chemotherapy in nasopharyngeal carcinoma (NPC) patients with persistently detectable plasma Epstein-Barr virus DNA (pEBV DNA) after curative radiation therapy plus induction/concurrent chemotherapy. Methods and Materials: The study population consisted of 625 NPC patients with available pEBV DNA levels before and after treatment. Eighty-five patients with persistently detectable pEBV DNA after 1 week of completing radiation therapy were eligible for this retrospective study. Of the 85 patients, 33 were administered adjuvant chemotherapy consisting of oral tegafur-uracil (2 capsules twice daily) for 12 months with (n=4) or without (n=29) preceding intravenous chemotherapy of mitomycin-C, epirubicin, and cisplatin.more » The remaining 52 patients who did not receive adjuvant chemotherapy served as the control group. Results: Baseline patient characteristics at diagnosis (age, sex, pathologic type, performance status, T classification, N classification, and overall stage), as well as previous treatment modality, were comparable in both arms. After a median follow-up of 70 months for surviving patients, 45.5% (15 of 33 patients) with adjuvant chemotherapy and 71.2% (37 of 52 patients) without adjuvant chemotherapy experienced tumor relapses (P=.0323). There were a significant reduction in distant failure (P=.0034) but not in local or regional recurrence. The 5-year overall survival rate was 71.6% for patients with adjuvant chemotherapy and 28.7% for patients without adjuvant chemotherapy (hazard ratio 0.27; 95% confidence interval 0.17-0.55; P<.0001). Conclusions: Our retrospective data showed that adjuvant chemotherapy can reduce distant failure and improve overall survival in NPC patients with persistently detectable pEBV DNA after curative radiation therapy plus induction/concurrent chemotherapy.« less
  • Purpose: To evaluate the effects of combining the assessment of circulating high-sensitivity C-reactive protein (hs-CRP) with that of Epstein-Barr virus DNA (EBV DNA) in the pretherapy prognostication of nasopharyngeal carcinoma (NPC). Patients and Methods: Three independent cohorts of NPC patients (training set of n=3113, internal validation set of n=1556, and prospective validation set of n=1668) were studied. Determinants of disease-free survival, distant metastasis–free survival, and overall survival were assessed by multivariate analysis. Hazard ratios and survival probabilities of the patient groups, segregated by clinical stage (T1-2N0-1M0, T3-4N0-1M0, T1-2N2-3M0, and T3-4N2-3M0) and EBV DNA load (low or high) alone, and alsomore » according to hs-CRP level (low or high), were compared. Results: Elevated hs-CRP and EBV DNA levels were significantly correlated with poor disease-free survival, distant metastasis–free survival, and overall survival in both the training and validation sets. Associations were similar and remained significant after excluding patients with cardiovascular disease, diabetes, and chronic hepatitis B. Patients with advanced-stage disease were segregated by high EBV DNA levels and high hs-CRP level into a poorest-risk group, and participants with either high EBV DNA but low hs-CRP level or high hs-CRP but low EBV DNA values had poorer survival compared with the bottom values for both biomarkers. These findings demonstrate a significant improvement in the prognostic ability of conventional advanced NPC staging. Conclusion: Baseline plasma EBV DNA and serum hs-CRP levels were significantly correlated with survival in NPC patients. The combined interpretation of EBV DNA with hs-CRP levels led to refinement of the risks for the patient subsets, with improved risk discrimination in patients with advanced-stage disease.« less
  • The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) transforms cells activating signal transduction pathways such as NF-{kappa}B, PI3-kinase, or c-Jun N-terminal kinase (JNK). Here, we investigated the functional role of the LMP1-induced JNK pathway in cell transformation. Expression of a novel dominant-negative JNK1 allele caused a block of proliferation in LMP1-transformed Rat1 fibroblasts. The JNK-specific inhibitor SP600125 reproduced this effect in Rat1-LMP1 cells and efficiently interfered with proliferation of EBV-transformed lymphoblastoid cells (LCLs). Inhibition of the LMP1-induced JNK pathway in LCLs caused the downregulation of c-Jun and Cdc2, the essential G2/M cell cycle kinase, which was accompanied bymore » a cell cycle arrest of LCLs at G2/M phase transition. Moreover, SP600125 retarded tumor growth of LCLs in a xenograft model in SCID mice. Our data support a critical role of the LMP1-induced JNK pathway for proliferation of LMP1-transformed cells and characterize JNK as a potential target for intervention against EBV-induced malignancies.« less