局部晚期鼻咽癌治疗新进展

目前局部晚期鼻咽癌的治疗热点主要有4个方面：非常规分割照射；三维适形放疗（3-DCRT）与调强放疗（IMRT）；放化疗综合治疗；放疗与靶向药物综合治疗。IMRT是精确放疗发展的主要方向，其有更好的适形度和靶区剂量分布，可将局控率提高至90％以上，且能较好地保护肿瘤周围的正常组织。但远处转移率仍为20％-25％，限制着总生存率（overall survival，OS）的提高。为进一步巩固IMRT对肿瘤的局控率和降低远处转移率，采取放化综合治疗仍为必需。从目前发表的临床随机研究以及Meta分析的结果可知，化疗能在放疗的基础上将局部晚期鼻咽癌的OS提高6％以上，其中同期放化疗疗效最为显著。     

Systemic treatment strategies and therapeutic monitoring for advanced nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is endemic in Asia and is etiologically associated with the Epstein-Barr virus. Although radiotherapy can cure most patients with early-stage disease, those with advanced disease often develop recurrences following radiotherapy. The past decade has witnessed significant advances in the systemic treatment of advanced NPC. This article reviews the latest literature regarding: combined modality therapy for locoregionally advanced NPC; clinical trials of novel biologic and cytotoxic therapies for metastatic NPC; and disease monitoring with the plasma Epstein-Barr virus DNA assay.     

Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.     

Cancer patterns in nasopharyngeal carcinoma multiplex families in Taiwan

Genetic and environmental factors have been implicated in the etiology of nasopharyngeal carcinoma (NPC), a tumor known to be closely associated with Epstein‐Barr virus (EBV) infection. Studies have reported familial aggregation of NPC and have suggested the possible aggregation of NPC and other cancers. We evaluated familial aggregation of cancer in 358 high‐risk families with two or more NPC cases enrolled in a NPC genetics study in Taiwan. Participants were linked to the Taiwan National Cancer Registry to identify incident cancers diagnosed after study enrollment (started in 1996) and before December 31, 2005, or death. In total, 2,870 individuals from the NPC Multiplex Family Study contributed 15,151 person‐years over an average of 5.3 years of follow‐up. One hundred ten incident cancers were identified. Multiple‐primary standardized incidence ratios (MP‐SIRs) were computed to evaluate overall cancer risk associated with infectious agents and with other tumors. The overall MP‐SIR was 1.3 (95% CI: 1.1–1.6), which was largely explained by an excess in NPC (MP‐SIR = 15; 95% CI: 10–23). Exclusion of incident NPC diagnoses led to an overall MP‐SIR of 1.0 (95% CI: 0.83–1.3). Similarly, the observed excess risk of cancers associated with infectious agents (MP‐SIR = 2.0; 95% CI: 1.5–2.6) was driven by the excess in NPC; exclusion of NPC cases led to a reduced MP‐SIR that did not differ from 1.0. Analysis of the largest NPC multiplex family study to date confirms the presence of coaggregation of NPC within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. © 2008 Wiley‐Liss, Inc.     

奈达铂联合紫杉醇和顺铂联合紫杉醇同步放化疗局部晚期鼻咽癌的临床随机对照实验

目的 通过临床随机对照实验观察奈达铂是否能够替代顺铂与紫杉醇联合同步放化疗局部晚期鼻咽癌,是否能够提高治疗的耐受性.方法 实验组(TN组)30例,采用紫杉醇135 mg/m2ivgtt d1+奈达铂10 mg/m2 ivgttd1诱导化疗,每3周为1个化疗周期,共2个疗程,以后行同样方案同期放化疗,仍然每3周为1个化疗...     

Early detection of nasopharyngeal carcinoma by plasma Epstein‐Barr virus DNA analysis in a surveillance program

BACKGROUND:

Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia. Over the last decade, plasma Epstein‐Barr virus (EBV) DNA has been developed as a tumor marker for NPC. In this study, the authors investigated whether plasma EBV DNA analysis is useful for NPC surveillance.

METHODS:

In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow‐up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC.

RESULTS:

Three individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow‐up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2‐fold increase in plasma EBV DNA on the follow‐up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks.

CONCLUSIONS:

Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false‐positive results. Cancer 2013. © 2013 American Cancer Society.     

Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP-1), is expressed in the majority of NPCs. LMP-1 upregulates antiapoptotic genes, including bcl-2, and Bcl-2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl-2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666-1 line, a stably infected NPC-derived line that co-expresses LMP-1 and Bcl-2. We have shown that G3139 treatment of C666-1 in vitro caused sequence-dependent suppression of Bcl-2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days x 5 doses) delayed engraftment and significantly inhibited growth of established C666-1 xenografts in SCID mice compared to control oligo-treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days x 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real-time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl-2 levels were significantly decreased in G3139-treated animals. Our studies have demonstrated that the Bcl-2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666-1, and in combination with CDDP, is curative in C666-1 NPC xenograft tumors in vivo. The sequence-dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl-2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC.     

Systematic comparison of plasma EBV DNA,anti-EBV antibodies and miRNA levels for early detection and prognosis of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is originated from the epithelial cells of nasopharynx, Epstein–Barr virus (EBV)-associated and has the highest incidence and mortality rates in Southeast Asia. Late presentation is a common issue and early detection could be the key to reduce the disease burden. Sensitivity of plasma EBV DNA, an established NPC biomarker, for Stage I NPC is controversial. Most newly reported NPC biomarkers have neither been externally validated nor compared to the established ones. This causes difficulty in planning for cost-effective early detection strategies. Our study systematically evaluated six established and four new biomarkers in NPC cases, population controls and hospital controls. We showed that BamHI-W 76 bp remains the most sensitive plasma biomarker, with 96.7% (29/30), 96.7% (58/60) and 97.4% (226/232) sensitivity to detect Stage I, early stage and all NPC, respectively. Its specificity was 94.2% (113/120) against population controls and 90.4% (113/125) against hospital controls. Diagnostic accuracy of BamHI-W 121 bp and ebv-miR-BART7-3p were validated. Hsa-miR-29a-3p and hsa-miR-103a-3p were not, possibly due to lower number of advanced stage NPC cases included in this subset. Decision tree modeling suggested that combination of BamHI-W 76 bp and VCA IgA or EA IgG may increase the specificity or sensitivity to detect NPC. EBNA1 99 bp could identify NPC patients with poor prognosis in early and advanced stage NPC. Our findings provided evidence for improvement in NPC screening strategies, covering considerations of opportunistic screening, combining biomarkers to increase sensitivity or specificity and testing biomarkers from single sampled specimen to avoid logistic problems of resampling.     

单药顺铂在局部晚期鼻咽癌同步放化疗中的临床应用分析

目的：评价局部晚期鼻咽癌PDD同步化疗的疗效及毒副反应。方法：52例局部晚期鼻咽癌接受顺铂同步放疗,PDD化疗的第1天就开始实施同步放疗,顺铂30 mg/m2静脉滴注,每周1次,共7次;鼻咽部病灶及阳性的淋巴结给予放疗总量为70Gy,颈部预防性照射给予放疗量50Gy,每周5次,每次2Gy。结果：全部患者均可评价,近期有效率为100%;1年、3年和5年OS分别为100%、88.5%、25%;3年、5年的无病生存率分别为80.8%和19.2%;平均生存时间和中位生存时间分别为48.7月和47月。无病平均生存时间和无病中位生存时间分别为45.7月和45月。结论：局部晚期鼻咽癌含PDD方案的CCRT有较好的疗效,毒性反应可耐受,长期生存需要进一步观察。     

Spontaneous T cell responses to Epstein-Barr virus-encoded BARF1 protein and derived peptides in patients with nasopharyngeal carcinoma: bases for improved immunotherapy

Immunotherapy approaches targeting Epstein-Barr virus (EBV)-encoded antigens induce objective clinical responses only in a fraction of patients with undifferentiated nasopharyngeal carcinoma (UNPC). In the present study, we have characterized the immunogenicity of the EBV-encoded BARF1 oncogene with the aim to assess whether this protein could constitute a new target antigen for immunotherapy in this setting. Spontaneous CD4+ and CD8+ T cell responses specific for the recombinant p29 BARF1 protein were detected by IFNgamma-ELISPOT in both EBV-seropositive donors and UNPC patients, but not in EBV-seronegative individuals. Using immunoinformatic prediction tools, we have selected 5 different candidate BARF1 T cell epitopes presented by HLA-A*0201. Although only one of these peptides was able to bind HLA-A2 with low affinity in the T2 stabilization assay, all 5 BARF1 nonamers readily elicited specific CD8+ T cell responses in EBV-seropositive HLA-A*0201+ donors and UNPC patients. Notably, the magnitude of CD8+ T cell responses to the whole BARF1 protein and derived A*0201 peptides was significantly higher in UNPC patients than in healthy donors. Moreover, cytotoxic T lymphocytes specific for the p2-10, p23-31, or p49-57 BARF1 peptides were easily obtained from HLA-A*0201+ donors. These cultures were not only able to lyse autologous targets loaded with the antigenic peptide, but also recognized tumor cells endogenously expressing BARF1 in an antigen-specific and HLA-A2-restricted manner. These findings, indicate that BARF1 is a particularly attractive antigen with immunogenic properties in most UNPC patients and provide valuable information to develop new strategies to improve the efficacy of EBV-targeting immunotherapy of UNPC patients.     

Distribution of Epstein-Barr viral load in serum of individuals from nasopharyngeal carcinoma high-risk families in Taiwan

The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests that it might also serve as a screening test for individuals who are at high risk for developing NPC. We previously demonstrated that unaffected individuals from high-risk families had elevated anti-EBV antibody levels compared to community controls. In this study, we measured EBV load using 2 different real-time PCR assays (targeting BamH1W and polymerase gene sequences, respectively) carried out in 2 independent research labs in serum samples from 19 untreated NPC cases, 11 healthy community controls and 100 unaffected individuals from families in which 2 or more individuals were affected with NPC. EBV genomes were detectable in 68% of NPC cases by the EBV BamH1W assay and in 74% by the EBV polymerase assay (kappa = 0.64). Patients with stage III or IV disease had significantly higher EBV load compared to those with stage I or II disease (p = 0.008). EBV DNA was detected in a single community control sample by the EBV BamH1W assay and in none of the samples by the EBV polymerase assay. Only one of 100 unaffected family members tested positive by both assays. An additional 14 were positive by only one of the 2 EBV load assays used and usually in only one of the duplicate wells tested, all with very low viral loads (3-50 copies/ml). In addition, EBV load did not correlate with EBV serology results (anti-VCA, anti-DNase, anti-EBNA-1) among these unaffected family members. In conclusion, our study suggests limited clinical utility of the EBV load test, in its current configuration, to screen individuals from high-risk families. Should a more sensitive or specific molecular assay be developed that is capable of detecting and distinguishing tumor-derived EBV genomes or gene products from true negatives, it could be evaluated as a possible screening tool for asymptomatic and early-stage NPC.     

局部晚期鼻咽癌同步放化疗临床疗效分析(英文)

Objective  

The prognosis of patients with nasopharyngeal carcinoma (NPC) depends on the stage of the disease at diagnosis. Unfortunately, at diagnosis, most of patients have locally advanced, non-metastatic stage III or IVa disease. The study was to evaluate the efficacy and toxicities of cisplatin plus 5-fluorouracil combined with concurrent radiotherapy for locally advanced nasopharyngeal carcinoma.     

EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma

Background:

Approximately 10% of gastric carcinomas are associated with Epstein–Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma.

Methods:

We conducted a population-based case–control study comparing gastric carcinomas in Greenland and in Denmark.

Results:

The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations.

Conclusion:

The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit.     

5-Aza-CdR 联合EBNA1-DC 疫苗诱导的淋巴细胞对鼻咽癌C666-1细胞的杀伤作用

目的：探讨EB病毒核抗原1（EBNA1） mRNA修饰的DC（EBNA1-DC）诱导的淋巴细胞联合甲基化抑制剂5-Aza-CdR对鼻咽癌C666-1细胞的杀伤作用。方法：以构建的EBNA1-pCDNA3.1质粒为模板,体外转录获得EBNA1 mRNA,通过脂质体转染至健康人外周血来源DC,构建EBNA1-DC疫苗。流式细胞术检测转染后DC表型及5-Aza-CdR 处理后的C666-1 细胞凋亡情况。实时无标记动态细胞分析技术检测EBNA1-DC 疫苗诱导的淋巴细胞联合5-Aza-CdR 的特异性抗肿瘤活性。结果：转染EBNA1 mRNA 后EBNA1-DC 表面EBNA1 阳性率为（59.3±5.85）%,HLA-DR 的表达与未转染DC 相比显著升高[（84.9±5.5）% vs（68.0±5.8）%,P=0.026],CD80 的表达也显著升高[（88.2±3.9）% vs （61.1±4.4）%,P=0.015]。低剂量5-Aza-CdR 处理后的C666-1细胞凋亡情况与未处理的细胞相比无显著差异。经低浓度5-Aza-CdR 预处理的C666-1细胞中IRF7基因表达与未处理的细胞相比显著升高（P=0.000 1）。与空载的DC相比,EBNA1-DC诱导的淋巴细胞对EBV 阳性表达的C666-1细胞具有更强的特异性杀伤活性（P=0.049）;经低浓度5-Aza-CdR 预处理的C666-1 细胞对EBNA1-DC 诱导的特异性免疫杀伤更敏感（P=0.019）。结论：5-Aza-CdR 与EBNA1-DC疫苗联合可显著增强对C666-1细胞的特异性免疫杀伤,本研究为开拓以mRNA为基础的DC疫苗及其在临床综合治疗中的应用转化提供前期研究基础。     

鼻咽癌患者血浆游离EBV-DNA的研究进展

近年来,研究人员发现血浆游离EB病毒DNA对鼻咽癌的诊断、分期、疗效监测及判断预后方面都具有重要作用,并且优于目前较为普遍的抗体的检测,是新一代的有效检测指标。     

鼻咽癌患者血浆游离EBV-DNA的研究进展

近年来,研究人员发现血浆游离EB病毒DNA对鼻咽癌的诊断、分期、疗效监测及判断预后方面都具有重要作用,并且优于目前较为普遍的抗体的检测,是新一代的有效检测指标。