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1.
Seven American juvenile patients with undifferentiated or nonkeratinizing nasopharyngeal carcinoma (NPC) were examined serially for Epstein-Barr virus (EBV)-specific antibody spectra and titers in sera. At diagnosis, all showed antibody patterns characteristic of NPC: i.e., high titers of IgG antibodies to viral capsid antigen (VCA) and to the diffuse (D) component of the early antigen complex. Six patients had IgA antibodies to VCA, and four to the D component. In the patients who responded to therapy with complete and maintained remissions, the IgG antibodies to D and the IgA antibodies to VCA and D decreased to undetectable levels within 12 to 30 months. By contrast, of the four patients who responded only transiently to therapy, three showed substantial increases and one continuously high titers of IgG anti-D and IgA anti-VCA. The increases in antibody titers preceded clinical recognition of recurrent tumors by 1 to 6 months. Three of these patients have died and the fourth is alive with disease. These data indicate that American juvenile NPC does not differ from the adult disease observed anywhere in the World. They reaffirm the potential usefulness of EBV-specific serology in the diagnosis and prognosis of NPC and the monitoring of patients following therapy.  相似文献   

2.
Stimulated by a report on elevated IgA levels in nasopharyngeal carcinoma (NPC), we tested a total of 372 sera from patients with NPC, other carcinomas of head and neck or elsewhere, Burkitt's lymphoma (BL), infectious mononucleosis (IM) or healthy controls. The sera were titrated in indirect immunofluorescence tests for IgA antibodies to Epstein-Barr virus (EBV) capsid antigen (VCA) and to the diffuse (D) or restricted (R) components of the EBV-induced early antigen (EA) complex. The results proved NPC to be outstanding in that prior to therapy 93% of the patients tested revealed IgA antibodies to VCA and 73% to D, often at high titers which occasionally matched the corresponding IgG antibody levels. The EBV-specific IgA titers increased from stages I or II to stages III or IV; i.e. with the total tumor burden. Conversely, many of the NPC patients examined 2-6 years after initial therapy had only low levels of EBV-specific IgA or none at all, and the majority of those with high titers were known to have residual or recurrent disease. In contrast to untreated NPC patients, less than 5% of 73 patients with other carcinomas or of 76 healthy donors revealed VCA-specific IgA and even fewer EA-specific IgA; only 28% and 4% of 54 BL patients tested at admission had IgA antibodies to VCA and R, respectively, and 38% and 3% of 37 IM patients showed transient VCA- or D-specific IgA responses, all at generally low titers. While sera from untreated NPC patients often contained IgA antibodies also to herpes simplex type 1 virus, their incidence and range of low titers were similar to those obtained with sera from patients with other carcinomas or from healthy donors. It thus appears that the elevated IgA levels in NPC might be due to EBV-specific antibodies. Possible reasons for this unique response in NPC have been discussed.  相似文献   

3.
Nasopharyngeal carcinomas (NPC) from 2 black patients and 1 Caucasian patient were positive for Epstein-Barr virus (EBV) DNA. Of the tumors, 2 were lymphoepitheliomas (undifferentiated NPC) and 1 was a moderately differentiated NPC. All 3 patients had high IgG titers against EBV early antigen and high IgG and IgA titers against virus capsid antigen (VCA). In one patient, the levels of anti-VCA IgA were different than those of anti-VCA IgG over the course of the disease. Our data support the association of EBV and NPC in North America.  相似文献   

4.
Since patients with nasopharyngeal carcinoma were first reported to have elevated levels of IgA antibody to Epstein-Barr virus (EBV) in their sera, workers in a number of countries have studied the possibility that this assay could be used in the diagnosis and monitoring of patients with this disease. In the United States, a collaborative project involving seven centers has been established to investigate the potential value of IgA antibody to EBV viral capsid antigen (VCA) as a clinical tool. In this report, we will summarize the results obtained from three studies: a comparison of EBV serology in three laboratories; a retrospective study of 37 nasopharyngeal carcinoma (NPC) patients and controls, and a prospective study of 126 NPC patients and 683 controls, including 149 patients with other malignancies involving the head and neck. The study of testing comparability in three laboratories demonstrated the feasibility of using this assay in a number of laboratories. The retrospective study confirmed the difference in IgA antibody titers between NPC patients and matched controls. The prospective study showed a relationship between IgA antibody titers and histopathology but not disease stage. IgA antibody titers were elevated more frequently in patients with nonkeratinizing or poorly differentiated types of NPC than for the well-differentiated squamous cell carcinomas. While IgA antibodies to EBV VCA appear to be of value in the early detection and diagnosis of NPC, it is possible that additional serologic tests for immunity to EBV, such as IgG antibody to VCA or early antigen (EA), will improve even further the clinical value of EBV serology in the management of NPC.  相似文献   

5.
We have examined serial sera from 17 juvenile patients with nasopharyngeal carcinoma (NPC) for their capacity to neutralize the activity of Epstein-Barr virus (EBV)-specific DNase. The results revealed that NPC patients who became long-term survivors (LTS) without evidence of the disease either never possessed significant levels of antibodies to the enzyme or showed a gradual decline in the number of EBV DNase units neutralized from an elevated level at diagnosis to an insignificant figure several years later. All the 10 LTS neutralized less than 4, and some neutralized less than 2 units of the enzyme 3 or more years after the initial diagnosis. In contrast, serial sera from juvenile patients who died of NPC neutralized over 10 and as many as 25 units of EBV DNase either persistently until death occurred or with transient declines during unmaintained remissions. Rises and declines in the neutralizing activity were, with few exceptions, accompanied by corresponding changes in the titers of IgA and IgG antibodies to EB viral capsid antigen and to the diffuse component of the early antigens. Although the number of juvenile NPC cases available for study was small, the observations suggest that the EBV DNase neutralization test may serve to provide information on the prognosis of the patients.  相似文献   

6.
A Tamada  K Makimoto  H Yamabe  J Imai  Y Hinuma  A Oyagi  T Araki 《Cancer》1984,53(3):430-440
It is thought that nonkeratinizing or undifferentiated squamous cell carcinoma in the nasopharynx (NPC) is intimately correlated with Epstein-Barr Virus (EBV). Twenty-one patients with NPC were followed in Kyoto University Hospital and 4 in Osaka Red Cross Hospital during the past 2 years from 1980 to 1981. These patients were classified histopathologically according to the WHO classification in 1978 and staged with the TNM classification in Union Internationale Contre le Cancer (UICC) in 1978. The incidence rate of NPC among the head and neck tumors was 5.6% in the authors' university from 1980 to 1981. The sex ratio of male to female was nearly equal. The mean age of NPC patients was 56.7 years. Sera from these 25 patients with nasopharyngeal carcinoma were collected at intervals of 3 to 8 months over a 2-year period, and were examined for their spectra and titers of antibodies of EBV-related antigens. They were titrated for IgG, IgA and IgM antibodies to EB viral capsid antigen (VCA), for IgG and IgA antibodies to early antigen-DR component (EA) and for antibodies to EBV-associated nuclear antigen (EBNA). All of these patients were primarily treated with radiation, while a few who did not respond to this therapy were subsequently treated with surgery or chemotherapy. EBV antibodies of VCA-IgG, -IgA, EA(DR)-IgG, and -IgA and EBNA were elevated in 73% and 90% of the nonkeratinizing and undifferentiated NPC patients, respectively. The VCA-IgM was elevated in almost none of the cases. In contrast to this, these values were all in a normal range in the NPC patients with keratinizing squamous cell carcinoma and malignant lymphoma. Also 9% and 10% of nonkeratinizing and undifferentiated carcinomas showed the normal ranges of EBV antibodies, possibly indicating a nonassociation with EBV. When NPC disappeared with radiation therapy, EBV antibodies became normal for 6-18 months. However, those whose NPC did not respond to the combined therapy with radiation, surgery and chemotherapy maintained high titers of EBV antibodies. The prognosis was the poorest in the patients with undifferentiated carcinoma, 40% of whom died within 4 years after diagnosis.  相似文献   

7.
Epstein-Barr virus (EBV) is an important causal factor of human nasopharyngeal carcinoma (NPC). High levels ‍of serum IgA and IgG antibodies to EBV early and viral capsid antigens (IgA/EA, IgA/VCA, IgG/EA and IgG/VCA) ‍have been reported in NPC patients. Since specific serum IgA/EA, IgA/VCA and IgG/EA are claimed to be useful ‍serological markers for NPC. In order to evaluate whether plasma IgA/EA, IgA/VCA, IgG/EA and IgG/VCA antibody ‍levels are useful markers for diagnosis and prognosis of Thai NPC, we examined the prevalence of these antibodies ‍in 79 NPC patients, and 127 age-matched controls (47 healthy subjects (HS), 32 cases of other disease (OD) and 48 ‍cases of other cancer (OC)) by using an indirect immunofluorescence assay. The prevalence of plasma IgA/EA, IgA/ ‍VCA, and IgG/EA in NPC patients (55.7, 68.4 and 68.4%) was significantly higher than in the HS (0.0, 0.0 and ‍20.5%,), OD (0.0, 0.0 and 3.1%) and OC (0.0, 0.0 and 20.8%) groups (p<0.05). The prevalence of plasma IgG/VCA ‍in NPC patients (93.7%) was significantly different from those for the OD and OC groups (71.9 and 43.8%) but not ‍for the HS group (89.4%). In NPC patients, the geometric mean titers (GMT) of plasma IgA/EA, IgA/VCA and IgG/ ‍EA were increased with an advanced clinical stage of disease but not IgG/VCA. In contrast, GMT of IgG/VCA was ‍increased with aggressive type of disease (histological type) but not IgA/EA, IgA/VCA, and IgG/VCA. The results of ‍our study suggest that plasma IgA/EA, IgA/VCA and IgG/EA antibodies may be useful markers for diagnosis and ‍assessing prognosis of Thai NPC. ‍  相似文献   

8.
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) generally occurs in adults, especially in high-prevalence populations such as the Chinese and Eskimos. In Maghrebian populations, young patients affected with this malignancy represent 25% of the total NPC cases. In adults with NPC, relatively high titers of IgA antibodies to the EBV viral capsid antigen (VCA) and early antigen (EA) represent important markers. However, nearly 50% of young NPC patients are negative for IgA-anti-VCA and -EA or exhibit very low titers of these antibodies. We report here that 92% of sera from young NPC patients negative for IgA-EA and 89% of those negative for IgA-VCA were positive for IgG antibodies to the EBV transactivator protein (ZEBRA) at very high titers. Our results show that in young patients with NPC these antibodies represent the most reliable marker for diagnosis and prognosis, particularly when compared with conventional NPC markers, i.e., IgA-VCA (58%) and anti-EA (25%). The titers of IgG-ZEBRA antibodies increased along with lymph node involvement only in the young patient group, suggesting a prognostic value of this marker in this patient group.  相似文献   

9.
Shao JY  Li YH  Gao HY  Wu QL  Cui NJ  Zhang L  Cheng G  Hu LF  Ernberg I  Zeng YX 《Cancer》2004,100(6):1162-1170
BACKGROUND: Serologic measurement of antibodies to Epstein-Barr virus (EBV) immunoglobulin A/viral capsid antigen (IgA/VCA) and early antigen (IgA/EA) has been used widely to screen for nasopharyngeal carcinoma (NPC) in China. Recently, it was found that plasma EBV DNA concentration is an indicator for the staging and prognosis of patients with NPC. To determine whether there is a correlation between plasma EBV DNA levels and serum levels of IgA/VCA, the authors measured both in patients with NPC and in a control group. METHODS: Real-time polymerase chain reaction was used for quantitative analysis of plasma EBV DNA concentration, and enzyme-linked immunoadsorbent assay was used to measure EBV VCA/IgA in patients with primary NPC (n = 120 patients), locally recurrent NPC (n = 8 patients), and distant metastatic NPC (n = 21 patients) among 76 patients with NPC after the completion of radiotherapy, in 60 patients with NPC in clinical remission, in 38 patients with non-NPC tumors, and in 47 control individuals. RESULTS: The median plasma EBV DNA levels were 6200 copies/mL, 9200 copies/mL, and 2050 copies/mL in patients with primary, locally recurrent, and distant metastatic NPC, respectively, but declined to 0 copies/mL in patients with clinically remissive NPC, in patients who completed radiotherapy, in patients with non-NPC tumors, and in the control group. In contrast, EBV VCA/IgA titers and detection rates remained high in all NPC groups. Plasma EBV DNA levels were significantly higher in patients who had serum VCA/IgA titers > or = 1:640 (median, 83,450 copies/mL) compared with the levels in patients who had titers < or = 1:320 (median, 17,200 copies/mL). Patients with NPC who had advanced TNM stage (Stages III and IV; median, 8530 copies/mL) and T classification (T3 and T4 tumors; median, 8530 copies/mL) had significantly higher plasma EBV DNA levels compared with patients who had early TNM stage (Stages I and II; median, 930 copies/mL) and T classification (T1 and T2 tumors; median, 3700 copies). Patients who had advanced TNM stage NPC had significantly higher mean VCA/IgA titers (1:424) compared with patients who had early TNM stage NPC (1:246), but there was no correlation between IgA/VCA titer and T or N classification of NPC. CONCLUSIONS: The results suggest that plasma EBV DNA detection is a more sensitive and specific marker than the serum IgA/VCA titer for the diagnosis and monitoring of patients with NPC. These findings provide convincing evidence for the use of plasma EBV DNA measurements for the early diagnosis and staging of NPC as well as for monitoring recurrence and metastasis of this tumor.  相似文献   

10.
Antibody titers to Epstein-Barr virus (EBV)-associated early antigens (EA) and the viral capsid antigen (VCA) were determined by ELISA on 263 sera obtained from healthy donors, patients with Hodgkin's disease (HD), non-Hodgkin lymphomas (NHL), infectious mononucleosis (IM), Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC). As expected, most lymphoma patients showed markedly elevated anti-VCA IgG and anti-EA IgG antibody titers. Only one patient in the NHL group (n = 56) consisting of patients with lymphomas other than chronic lymphocytic leukemia (CLL) and hairy-cell leukemia (HCL), and 3 patients with HCL (n = 19) had high antibody titers of the IgA class to VCA and EA. Seventeen out of 48 patients (36%) with CLL had high IgA anti-VCA titers and 10 of these sera (21%) also contained IgA anti-EA. The geometric mean titer (GMT) of IgA anti-VCA was 2,510, the GMT of IgA anti-EA was 780. These antibody titers were about 10 times lower than the corresponding GMT of the NPC patients investigated in this study. The elevated IgG and IgA antibody titers to VCA and EA in CLL and HCL patients seem to reflect an immunodeficiency secondary to the malignant disease leading to reactivation of latent EBV infection. The possibility that at least some of these B-cell lymphomas are associated with EBV cannot be excluded.  相似文献   

11.
Epstein-Barr virus (EBV) is present within the tumor cells of most cases of nasopharyngeal carcinoma (NPC). Recent studies suggest that tumor burden is proportional to the level of EBV DNA in blood and that rapid blood testing can be used to guide therapeutic intervention. The relative utility of viral load vs. serology has been insufficiently studied. In our study, EBV viral load was measured by quantitative PCR using either real-time or end-point detection systems in serum samples from 124 NPC patients (93 pretreatment, 13 relapsed, 18 in remission) and 40 controls. Serologic titers against EBV early antigen were measured in the same serum samples. EBV DNA was detectable in 64 of 93 untreated NPC patients (69%; mean viral load 11,211 copies/ml), 11 of 13 relapsed NPC patients (85%; mean 53,039 copies/ml) and 0 of 18 remission patients. EBV DNA was detectable in only 1 of 40 non-NPC controls (3%). In 34 instances where paired plasma and serum samples were available for testing, both were effective sample types, and there was no significant difference between end-point and real-time methods for measuring viral load. Early antigen (EA) IgA and IgG titers were elevated in most NPC patients regardless of whether their disease was active or in remission. EBV viral load was more informative than was EA serology for distinguishing remission from relapsed disease. EBV DNA measurement appears to be a noninvasive way to monitor tumor burden after therapy.  相似文献   

12.
In a comparative study of populations at high and low risk of nasopharyngeal carcinoma (NPC), sera from 442 Eskimo and 770 Danish children and adolescents were tested for the presence of antibodies against Epstein-Barr virus (EBV). Eskimo children in Greenland were seropositive at an early age and showed significantly higher titers of IgG antibody to the viral capsid antigen (VCA) (p<0.0001) and soluble (S) antigen (p<.005) than Danes matched for age and sex, but had similar levels of IgA antibody to VCA and IgG antibody to the early antigen (EA). The high geometric mean VCA (IgG) titers found in certain age groups of Eskimo children were as high as those previously reported from areas in Africa highly endemic for Burkitt's lymphoma. In Greenland, neither location nor household size was a determining factor for prevalence or titer of VCA (IgG). The high antibody titers among Eskimo children probably reflect exposure to a large inoculum of EBV at the time of primary infection, infection early in life and/or re-exposure due to the higher incidence of EBV infection in Greenland. In view of the high incidence of NPC in Greenland and the known association of this tumor with EBV, we speculate that the time and quantitative aspects of the primary infection are also factors of relevance in the etiology of NPC.  相似文献   

13.
IgG and IgA antibodies to Epstein-Barr virus (EBV) membrane antigen (MA) were detected in sera from 96 NPC patients and normal individuals by the indirect immunofluorescence test. For MA/IgG antibody, 100% of NPC patients were positive with a GMT of 1:439.7 and 97.9% of normal individuals were positive with a GMT of 1:94.7. In contrast, for MA/IgA antibody, 58.3% of NPC patients were positive with a GMT of 1:7.3 and none of the normal individuals were positive. There was no difference in the detection of antibodies to EBV MA when other P3HR-1 or B95-8 cell lines, differing in their major membrane antigen, were used.  相似文献   

14.
Nasopharyngeal carcinoma (NPC) is a human neoplasm closely associated with Epstein-Barr virus (EBV). Human leukocyte interferon (IFN) has known antiviral and antineoplastic properties. After initial IFN treatment in one NPC patient demonstrated acceptably low toxicity, 12 additional patients were treated on a protocol with IFN, 10 X 10(6) units intramuscularly (IM) daily for 30 days. IFN did not affect serum anti-EBV antibody titers (IgA and IgG antiviral capsid and early antigens). Of six patients tested, none was found to excrete EBV in saliva before, during, or after IFN. Four patients had measurable tumor regression (two partial responses and two minor responses), three had stable disease, and five patients plus the initial preprotocol patient had progressive disease. Toxicity included fever, fatigue, and myalgias in all patients, thrombocytopenia in two patients, and neutropenia in three patients. Three patients were withdrawn from the study, one each for severe fatigue, neutropenia, and hypotension. This study demonstrates that IFN has sufficient activity in advanced NPC to justify further investigation.  相似文献   

15.
本文报道,用正丁酸和巴豆油激活人类类淋巴母细胞株—B95—8细胞株、诱导产生早期膜抗原(EMA)和晚期膜抗原(LMA),应用间接免疫荧光法检测鼻咽癌(NPC)病人血清中膜抗原(MA)抗体。MA/IgA在正常人阴性,而在NPC病人阳性率55.96%,GMT 1:20.1。经过葡萄球菌蛋白A(SPA)吸附病人血清后,能提高2~3个血清稀释度。对诊断NPC有意义。  相似文献   

16.
The sera of 73 patients with nasopharyngeal carcinoma (NPC), 28 patients with other carcinomas (OC) and 89 healthy subjects (HS) were tested for IgG and IgA antibodies to Epstein-Barr virus (EBV) viral capsid antigen (VCA). The majority of the NPC sera had IgG titres of 160 or above, whereas the majority of the other sera had titres below 160. For IgA reactivity to EBV-VCA, 68 of 73 (93-2%) NPC sera had titres of greater than or equal to 10. In contrast, only 6 of 28 (21-4%) OC sera and none of the HS sera had such titres. The mean serum concentrations of IgG, IgA, IgM and C3' were also determined in 55 NPC and 20 OC patients and 18 HS. They were all significantly higher in the NPC sera than in the HS. Although the concentrations of IgG and C3' were not significantly different in the two carcinoma groups, the concentrations of IgA and IgM were significantly higher in the NPC group than in OC. These findings appear to reflect the intensity of EBV-specific antigenic stimulation in NPC, and the EBV-specific serum IgA reactivity may be a sueful aid to the diagnosis of NPC, especially in cases with an occult primary tumour. It may be also of value as a screening test in people at high risk.  相似文献   

17.
背景与目的:Epstein-Barr病毒VCA/IgA抗体(serum immunoglobulin Aagainst Epstein-Barr vires capsid antigen,EBV—VCA/IgA)是目前应用最广泛的鼻咽癌诊断指标之一,但它对鼻咽癌预后判断的意义尚不明确。本研究探讨VCA/IgA抗体水平与鼻咽癌患者长期生存的关系,为确立VCA/IgA能否作为鼻咽癌独立的预后指标提供依据。方法:根据广东省四会市肿瘤发病与死亡登记资料,选择1990至2003年在中山大学肿瘤防治中心治疗的全部317例四会籍初诊鼻咽癌患者,收集患者的临床与病理资料,分析患者治疗前血清VCA/IgA抗体不同水平与生存期的关系。结果:在临床分期中Ⅲ、Ⅳ期的抗体水平率较Ⅰ、Ⅱ期为高,P=0.01。抗体滴度越高的患者生存时间越短,低水平组(〈1:160)的患者(n=170)与高水平组(≥1:160)患者(n=147)的5年生存率分别为65.0%和43.0%,P=0.01。多因素分析显示患者的临床分期、性别、治疗年代和EBV-VCA/IgA水平是影响生存期的独立因素。结论:鼻咽癌患者治疗前VCA/IgA抗体水平可能是影响患者生存的独立预后指标。  相似文献   

18.
J Shepherd  C G Woodward  L Turnbull 《Cancer》1987,59(6):1150-1153
Nigerian patients with tumors of the jaw were compared with controls in respect of antibodies to the viral capsid antigens of Epstein-Barr Virus (EBV) and of total immunoglobulin levels. Immunoglobulin levels did not differ between patients and controls but increased two weeks postsurgery. Immunoglobulin A (IgA) antibodies to EBV were detected in a small number of patients, and mean titers of IgG antibodies to EBV were lower in the patient group, indicating a lack of association between EBV and tumor formation. An association was noted between the presence of Hepatitis B surface antigen, and depressed antibody titers to EBV in patients with tumors. Of 78 patients studied, 12% were Hepatitis B surface antigen positive.  相似文献   

19.
Between December 1979 and April 1982, 373 patients with untreated, undifferentiated carcinoma of the nasopharynx (NPC), 99 in Hong Kong, 120 in Tunis and 154 in Villejuif, entered a longitudinal study aimed at determining the clinical prognostic value of EBV serology after radiotherapy. A minimum of 3 years' follow-up was achieved for 319 patients (83 in Tunis, 95 in Hong Kong and 141 in Villejuif) who had regular clinical and serological testing at intervals of 6-8 months. No significant difference in initial serology (i.e., before any treatment) or variations of antibody titers at time of first follow-up was observed between patients who achieved complete remission after radiotherapy and those who did not. This included IgG and IgA antibodies to VCA, EA or EBNA. However, when patients with confirmed clinical remission 1 year after completion of radiotherapy were studied, the value of IgG/EA and mainly of IgA/EA increasing titers became highly significant for prediction of relapse, regardless of the initial titers. This demonstrated the clinical usefulness of EBV serology for NPC patients who have confirmed clinical remission after radiotherapy.  相似文献   

20.
To evaluate applications of highly purified recombinant EBV DNAase in the diagnosis and prognosis of NPC, we tested sera from patients with NPC, other EBV-associated diseases and EBV-seropositive and -seronegative healthy subjects by immunoblotting and DNAase inhibitory assay. The results were compared with those obtained by the conventional immunofluorescence assays against the EBV-specified early antigens and capsid antigens. The antigenic specificity of the immunoblotting assay for IgG antibody against the viral enzyme, but not that for the IgA antibody, was correlated with DNAase-inhibitory activity of the sera and their titers of IgG antibodies against the viral early antigens. Purified IgA as well as IgG from NPC sera inhibited enzyme activity with similar efficiency. The use of highly purified viral DNase has increased the sensitivity of detection of the corresponding antibodies by immunoblotting, with the IgG antibody being detected in all but one, and IgA antibody in all but 2, of the 174 NPC sera tested. The IgG antibody was also commonly detected in the other groups of control sera, while the IgA antibody was detected in about 10% of African Burkitt's lymphoma and Algerian Hodgkin's lymphoma patients and less than 3% of the other control subjects. These results suggest that IgA antibody against recombinant EBV DNAase may be useful in the diagnosis of NPC, but the level of this antibody did not appear to be related to clinical stages of this cancer. © 1996 Wiley-Liss, Inc.  相似文献   

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