Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Currently, it is not known whether patients with different EBV-associated diseases have different methylation ...profiles of circulating EBV DNA. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. We further analyse the plasma EBV DNA methylome of NPC and non-NPC subjects from a prospective screening cohort. Plasma EBV DNA fragments demonstrate differential methylation patterns between NPC and non-NPC subjects. Combining such differential methylation patterns with the fractional concentration (count) and size of plasma EBV DNA, population screening of NPC is performed with an improved positive predictive value of 35.1%, compared to a count- and size-based only protocol.
Background and Aims
The albumin–bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence‐based alternative to the Child–Pugh (CP) score for hepatocellular carcinoma (HCC). ...We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC.
Methods
An international multicentre cohort (n = 3696) was accrued to compare the prognostic performance of the CP‐based and ALBI‐based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi‐squares, and c‐indices, respectively.
Results
The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP‐based and ALBI‐based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI‐based BCLC upstaged 83 (2.2%) patients from lower CP‐based BC LC stages to ALBI‐based BCLC stage D, whose median overall survival was only 3 months.
Conclusions
The overall prognostic performance of ALBI‐based and CP‐based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents.
Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as ...an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis.
Systemic therapy is an integral part of the management of non‐keratinizing nasopharyngeal carcinoma (NPC). The purposes of this review are to provide the latest results and future directions of ...clinical and translational research for this disease, and to illustrate how some of these new therapies have improved the treatment outcome for patients with NPC. Particular attention will be paid to the clinical application of chemotherapy in the adjunctive treatment of locoregionally advanced NPC, novel targeted drugs, Epstein–Barr virus‐targeted vaccine therapies, and the use of plasma Epstein–Barr virus DNA as a biomarker for selecting patients for adjunctive therapies. (Cancer Sci 2008; 99: 1311–1318)
Epstein-Barr virus (EBV) is associated with several malignancies including nasopharyngeal carcinoma, a high incidence tumor in Chinese populations, in which tumor cells express the two EBV antigens ...EB nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). Here, we report the phase I trial of a recombinant vaccinia virus, MVA-EL, which encodes an EBNA1/LMP2 fusion protein designed to boost T-cell immunity to these antigens. The vaccine was delivered to Hong Kong patients with nasopharyngeal carcinoma to determine a safe and immunogenic dose. The patients, all in remission more than 12 weeks after primary therapy, received three intradermal MVA-EL vaccinations at three weekly intervals, using five escalating dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming unit (pfu). Blood samples were taken during prescreening, immediately before vaccination, one week afterward and at intervals up to one year later. Immunogenicity was tested by IFN-γ ELIspot assays using complete EBNA1 and LMP2 15-mer peptide mixes and known epitope peptides relevant to patient MHC type. Eighteen patients were treated, three per dose level one to four and six at the highest dose, without dose-limiting toxicity. T-cell responses to one or both vaccine antigens were increased in 15 of 18 patients and, in many cases, were mapped to known CD4 and CD8 epitopes in EBNA1 and/or LMP2. The range of these responses suggested a direct relationship with vaccine dose, with all six patients at the highest dose level giving strong EBNA1/LMP2 responses. We concluded that MVA-EL is both safe and immunogenic, allowing the highest dose to be forwarded to phase II studies examining clinical benefit.
Background
Folate level was proposed to be a predictor for fluoropyrimidine‐related toxicity. We conducted a prospective study to determine the association between serum and red‐cell folate and ...capecitabine‐related toxicity in patients with colorectal cancers.
Materials and Methods
Eligibility criteria included diagnosis of colorectal cancers; eligible patients who were scheduled to undergo capecitabine monotherapy or capecitabine‐oxaliplatin (CAPOX) for adjuvant or palliative purposes. Exclusion criteria included concomitant radiotherapy or chemotherapy other than capecitabine or CAPOX and creatinine clearance <30 mL/min. Fasting serum and red‐cell folate were measured prior to chemotherapy. Capecitabine was administered at 2,500 mg/m2 per day (monotherapy) or 2,000 mg/m2 per day (CAPOX) for 14 days every 3 weeks. The toxicity of the first four cycles was documented by clinical investigators who were blinded to folate levels.
Results
A total of 144 patients were recruited, of whom 126 were eligible; 40 patients had capecitabine alone, and 86 patients received CAPOX. The rates of grade 2 and grade 3 toxicity were 63.5% and 14.3%, respectively. Nausea and vomiting were the most common grade ≥2 adverse event (47.7%), followed by hand‐foot syndrome (25.4%), diarrhea (23.1%), and neutropenia (22.3%). Combination with oxaliplatin (odds ratio OR, 2.77; p = .043) and serum folate (OR, 10.33; p = .002) were independent predictors of grade ≥2 toxicity. Red‐cell folate was not predictive of toxicity. For every 10 nmol/L increment in serum folate, the risk of grade ≥2 toxicity increased by 9%.
Conclusion
Serum folate level, but not red‐cell folate, was associated with higher rate of grade ≥2 toxicity during capecitabine‐based treatment. Excessive folate intake may be avoided before and during capecitabine‐based chemotherapy.
Implications for Practice
This is the first prospective study to evaluate the association between serum folate level and capecitabine‐related toxicity in patients with colon cancers. It shows that higher serum folate level is associated with increased risks of moderate to severe toxicity during capecitabine‐based treatment. Excessive folate intake should be avoided before and during capecitabine‐based chemotherapy.
摘要
背景。有人提出将叶酸水平用作氟尿嘧啶相关毒性的预测因素。我们进行了一项前瞻性研究,旨在确定结直肠癌患者中的血清和红细胞叶酸与卡培他滨相关毒性之间的关系。
材料和方法。入选标准包括确诊结直肠癌;计划接受卡培他滨单药治疗或者卡培他滨‐奥沙利铂 (CAPOX) 辅助治疗或姑息治疗的符合条件的患者。排除标准包括除卡培他滨或 CAPOX 治疗之外的同步放疗或化疗以及肌酐清除率<30 mL/min。在化疗之前测量空腹血清和红细胞叶酸。卡培他滨每3周给药14 天,每天给药剂量为 2 500 mg/m2(单药治疗)或 2 000 mg/m2(CAPOX 治疗)。由不知晓叶酸水平的临床研究人员记录前四个周期的毒性情况。
结果。一共招募 144 名患者,其中,126 名患者符合条件;40 名患者接受卡培他滨单药治疗,86 名患者接受CAPOX 治疗。2 级和 3 级毒性的比率分别为 63.5% 和 14.3%。最常见的 >2 级的不良反应为恶心和呕吐 (47.7%),其次是手足综合征 (25.4%)、腹泻 (23.1%) 以及嗜中性白血球减少症 (22.3%)。联合奥沙利铂比值比(OR,2.77;p=0.043)和血清叶酸(OR,10.33;p=0.002)是 >2 级毒性的独立预测因素。红细胞叶酸不能预测毒性。血清叶酸每增加10 nmol/L,>2 级毒性的风险就会升高9%。结论。在基于卡培他滨的治疗期间,血清叶酸水平(而非红细胞叶酸)与 >2 级毒性的较高比率相关。在基于卡培他滨的化疗之前及期间,可以避免摄入过多的叶酸
This article evaluates the association between capecitabine‐related toxicity and serum/red cell folate level in a group of patients who underwent capecitabine‐based chemotherapy for the treatment of colorectal cancer. The rate and type of capecitabine‐related toxicity was examined, with a goal of identifying other clinical predictive parameters for capecitabine‐related toxicity.
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