Familial Nasopharyngeal Carcinoma 6

106 J-C. Linradiotherapy became highly significant for predictionof relapse, regardless of the initial titers. Yip et al. (1994)investigated the prognostic role of the IgG antibodyagainst EBV BZLF-1 replication activators and foundno significant difference in patients’ survival betweenthe low and high titers for sera taken before treatment(p = 0.331). In contrast, for sera taken 10 months afterradiation therapy, the high titer group predicted significantlyworse overall survival rates (p = 0.0019). Hsuet al. (1988) investigated the prognostic impact of twoantibodies (VCA-IgA and anti-DNase) measured atdifferent time-points on 179 NPC patients. The resultsshowed that the last anti-DNase titer correlated withlocal recurrence and distant metastasis, the last VCA-IgA and initial anti-DNase predicted distant metastasis,the initial VCA-IgA had no correlation with localrecurrence or distant metastasis. A recent study comparedthe prognostic impact of serum IgA and IgGantibodies titer against VCA and plasma EBV DNAlevel in 114 advanced NPC patients (Twu et al. 2007)and showed that both pre and posttreatment VCA antibodiestiter could not predict overall and relapse-freesurvivals. Because of lack of evidence regarding pretreatmentantibody titers on the prognosis prediction,longitudinal follow-up data of clinical results and seriesblood tests when disease status changed for the samepatient groups, the prognostic role of anti-EBV antibodiesin NPC seems to be less clear, and the precisepoint of blood sampling has not been well established.The lack of prognostic effect of antibody assays isthought to be attributable to individual differences inthe immune responses to various antigens. This maybe explained by the fact that antibody is a markerwhich essentially is a host response to viral tumor antigens.This kind of marker inevitably lags behind withregard to kinetics upon treatment. Also, the dynamicrange of antibody responses is fairly limited in general,with only weak correlations observed between theextent of exposure and the level (titer) of the response.On the other hand, unlike conventional protein markerssuch as CEA or PSA, released mostly from tumorcells, EBV can be found in patients with EBV-relateddiseases or even in normal population in high concentration,especially after an EBV infection.9.4.2Tumor-Associated Genesin Peripheral Blood CellsDistant metastasis is associated with worse prognosis.Cancer cells usually enter into circulation beforeestablishment of a metastatic lesion in distant organs.Micrometastasis refers as occult disseminated tumorcells in peripheral blood, bone marrow, or lymphnodes that cannot be detected by conventional histopathologicalmethods. Smith et al. (1991) first developeda nested reverse transcriptase-polymerase chainreaction (rt-PCR) assay for the detection of circulatingmelanoma cells by the amplification of tyrosinasemRNA, which is exclusively expressed in melanocytesand melanoma cells. Since then, this method has beenwidely applied in the early detection of occult metastasisfrom different specimens. The most importantissue of an rt-PCR assay is to select a target moleculewith high specificity and sensitivity. Cytokeratin 19(CK19) is an intermediate filament protein expressedby all simple epithelia, their corresponding malignancies,and a small number of other tissues (Moll et al.1982). It has been reported earlier that CK19 is notexpressed by lymphoid or hematopoietic cells (Dattaet al. 1994; Schoenfeld et al. 1997) and, therefore,may be a useful marker of occult metastasis in theperipheral blood, bone marrow, and lymph nodes ofpatients with cancer of epithelial origin. So far, CK19mRNA is one of the most frequently studied targetgenes in the early detection of micrometastasis. Bymeticulous design of a nested rt-PCR system to detectcirculating CK19 mRNA expression cells, Lin et al.(2002) found that 33.3% (19/57) clinically nonmetastaticNPC patients had CK19 mRNA in their pretreatmentblood. The positive detection rates of CK19mRNA in the peripheral blood increase as clinicalstage increase (20.0% for Stage II, 31.6% Stage III, and43.5% Stage IV, p = 0.1335). After a median follow-uptime of 35 months, 9 of 19 (47.4%) CK19 mRNA positivepatients and 5 of 38 (13.2%) CK19 mRNA negativepatients developed distant metastasis (p = 0.00826).The 3-year metastasis-free survival rates were 49.9%for patients with detectable CK19 mRNA, and 85.9%for those with undetectable CK19 mRNA (p = 0.0089).They concluded that the presence of circulating CK19mRNA positive cells before treatment indicated occurrenceof micrometastasis and was a poor prognosticsign for NPC.The EBV DNA has been shown in tumor cells ofnearly all patients with NPC. Circulating peripheralblood cells that carry EBV DNA may be a sign of disseminatedtumor cells for NPC. Based on this hypothesis,Lin et al. (2001) explored whether the presence ofEBV DNA in the peripheral blood cells can serve as aprognostic indicator for NPC. The DNA extractedfrom peripheral blood cells of 124 previously untreatedNPC patients with no evidence of distant metastasis