We analyzed the number of circulating tumor cells (CTCs) and Epstein–Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The ...levels of CTCs and EBV DNA were measured at baseline and after first‐line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non‐mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first‐line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first‐line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first‐line chemotherapy was associated with significantly longer progression‐free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first‐line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first‐line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
What's new?
Endemic nasopharyngeal carcinoma (NPC) is associated with latent infection of the oncogenic Epstein‐Barr virus (EBV) and frequently metastasizes to distant lymph nodes and organs. Metastatic NPC is treated by serial administration of cytotoxic or targeted therapies and treatment response is generally assessed with serial imaging, which often fails to detect changes in tumor burden. Here, the authors show that the number of circulating tumor cells (CTCs) and EBV DNA levels before, after, and during first‐line chemotherapy are strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in ...nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.
Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.
Median follow-up was 5.0 years. The HR for PFS was 0.70 95% confidence interval (CI), 0.56-0.86;
= 0.0009; 9.3% absolute benefit at 5 years in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57-0.99;
= 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51-0.90;
= 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48-1.01;
= 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.
This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control.
.
Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as ...gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II–IVB nasopharyngeal carcinoma.
We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18–65 years with non-keratinising stage II–IVB (T1–4N1–3 or T3–4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up.
Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8–94·0) in the cisplatin group and 88·0% (83·5–94·5) in the nedaplatin group, with a difference of 1·9% (95% CI −4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4–94·0) in the cisplatin group and 88·7% (84·2–94·5) in the nedaplatin group, with a difference of 1·0% (95% CI −5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 18% of 198 in the cisplatin group vs 12 6% of 200 in the nedaplatin group, p<0·0001), nausea (18 9% vs four 2%, p=0·0021), and anorexia (53 27% vs 26 13%, p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three 2% in the nedaplatin group vs 11 6% in the cisplatin group, p=0·030). No patients died from treatment-related causes.
Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents.
National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.
The impact of variation of Epstein-Barr virus (EBV) antibody titers before the development of nasopharyngeal carcinoma (NPC) is still unclear. We analyzed the fluctuations of antibodies against EBV ...before histopathological diagnosis to assess the risk of NPC and aimed to provide a reliable basis for screening in high risk populations.
This study was based on a population-based screening program in Sihui County in Guangdong Province of China. A total of 18,986 subjects were recruited in 1987 and 1992, respectively. Baseline and repeated serological tests were performed for IgA antibodies against EBV capsid antigen (VCA/IgA) and early antigen (EA/IgA). Follow-up until the end of 2007 was accomplished through linkage with population and health registers. Cox proportional hazards regression model was used to estimate the relative risk of NPC in association with EBV antibodies. Time-dependent receiver operating characteristic curve (ROC) analysis was used to further evaluate the predictive ability.
A total of 125 NPCs occurred during an average of 16.9 years of follow-up. Using baseline information alone or together with repeated measurements, serological levels of VCA/IgA and EA/IgA were significantly associated with increased risks for NPC, with a striking dose-response relationship and most prominent during the first 5 years of follow-up. Considering the fluctuant types of serological titers observed during the first three tests, relative risk was highest among participants with ascending titers of EBV VCA/IgA antibodies with an adjusted hazard ratio (HR) of 21.3 (95% confidence interval CI 7.1 to 64.1), and lowest for those with decreasing titers (HR = 1.5, 95% CI 0.2 to 11.4), during the first 5 years of follow-up. Time-dependent ROC analysis showed that VCA/IgA had better predictive performance for NPC incidence than EA/IgA.
Our study documents that elevated EBV antibodies, particularly with ascending titers, are strongly associated with an increased risk for NPC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Salvage ENPG and IMRT are more effective treatments for rNPC than traditional 2-dimensional radiotherapy. However, compared with IMRT, the benefits of ENPG have not yet been ...clearly described. Methods We defined a resectable area in which the disease could be radically removed using ENPG and our imaging specialists selected eligible patients with tumors confined to this resectable area from a database of rNPC patients. Using propensity scores to adjust for some potential prognostic factors, a well-balanced cohort of 144 limited rNPC patients was created by matching each patient who underwent ENPG (study group) with one who underwent IMRT (control group). Morbidity, long-term oncological results, treatment-related complications, medical costs, and quality of life were compared. Results Compared with IMRT, ENPG was associated with a relatively good overall survival (5-year OS, 77.1% vs 55.5%, P = .003), QOL conservation (mean global health status score, 57.6 vs 29.8, P < .001), and significant decreases in post-treatment complications (12.5% vs 65.3%, P < .001), medical costs (23 645.90 vs 118 122.53 Yuan, P < .001) ≈ (€2371.71 vs 11,847.80, P < .001). Conclusions Salvage ENPG may be more effective for maximizing survival and QOL benefits and minimizing treatment-related complications and medical costs for limited rNPC patients, as compared with IMRT.
Concurrent chemoradiotherapy (CCRT) has been shown to improve outcomes for stage III-IV nasopharyngeal carcinoma (NPC) patients compared with radiotherapy (RT) alone, but the effectiveness of the ...combined therapy for stage II NPC patients is unknown.
Patients with Chinese 1992 stage II NPC were randomly assigned to receive either RT alone (n = 114) or CCRT (n = 116). The CCRT patients were given concurrent cisplatin (30 mg/m(2) on day 1) weekly during RT. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), distant metastasis-free survival, and locoregional relapse-free survival. All patients were analyzed by the intent-to-treat principle. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) and in multivariable analyses to test the independent statistical significance of treatment intervention. Toxic effects and the response to treatment were analyzed using the χ(2) test. All statistical tests were two-sided.
With a median follow-up of 60 months, adding chemotherapy statistically significantly improved the 5-year OS rate (94.5% vs 85.8%; HR of death = 0.30, 95% CI = 0.12 to 0.76; P = .007), PFS (87.9% vs 77.8%; HR of progression = 0.45, 95% CI = 0.23 to 0.88; P = .017), and distant metastasis-free survival (94.8% vs 83.9%; HR of distant relapse = 0.27, 95% CI = 0.10 to 0.74; P = .007); however, there was no statistically significant difference in the 5-year locoregional relapse-free survival rate (93.0% vs 91.1%; HR of locoregional relapse = 0.61, 95% CI = 0.25 to 1.51; P = .29). Multivariable analysis showed that the number of chemotherapy cycles was the only independent factor that was associated with OS, PFS, and distant control in stage II NPC. The CCRT arm experienced statistically significantly more acute toxic effects (P = .001), although the rate of late toxic effects did not increase statistically significantly.
Concurrent chemotherapy and radiotherapy is associated with a considerable survival benefit for patients with stage II NPC.
Despite evidence suggesting the utility of Epstein‐Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high‐risk regions, no validated NPC risk ...prediction model exists. We aimed to validate an EBV‐based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver‐operator‐characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross‐validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV‐based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93‐0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0‐92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9‐3.0%) to 12.5% (9.9‐15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255‐290) to 50 (41‐59). Combining the score with other risk factors (sex, first‐degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5‐year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high‐risk population. Adding nonviral risk factors did not improve NPC prediction.
What's new?
Evidence suggests that markers of Epstein‐Barr virus (EBV) infection are useful in screening for nasopharyngeal carcinoma (NPC). Few prospective studies, however, have validated the performance of EBV‐based risk scores for NPC. In this prospective validation study with data for more than 51 000 participants, EBV‐based risk score based on the combination of IgA antibodies against viral capsid antigen and EBV nuclear antigen 1 was found to be highly discriminating for NPC over follow‐up periods lasting five years. The findings indicate that EBV‐based scores could be valuable risk‐prediction tools for early NPC diagnosis, leading to improved clinical outcomes.
Abstract
Background
Hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide, ranks as the fifth most common cancer and has been the second most frequent cause of ...cancer-related death. RNA binding proteins (RBPs) are proteins that interact with different classes of RNA and are commonly detected in cells.
Methods
We used RNA sequencing data from TCGA to display dysfunctional RBPs microenvironments and provide potential useful biomarkers for HCC diagnosis and prognosis.
Results
330 differently expressed RBPs (208 upregulated and 122 downregulated) were identified. KEGG were mainly enriched in RNA degradation, Influenza A, Hepatitis C, RIG-I-like receptor signaling pathway, Herpes simplex virus 1 infection and RNA transport. CBioPortal results demonstrated that these genes were altered in 50 samples out of 357 HCC patients (14%) and the amplification of
BRCA1
was the largest frequent copy-number alteration.
Conclusion
Based on the online database, we identified novel RBPs markers for the prognosis of hepatocellular carcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To explore the prognostic value of the plasma load of Epstein-Barr viral (EBV) DNA and the tumor response to neoadjuvant chemotherapy (NACT) in advanced-stage nasopharyngeal carcinoma (NPC).
In all, ...185 consecutive patients with stage III to IVb NPC treated with NACT followed by concurrent chemoradiation therapy (CCRT) were prospectively enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS).
EBV DNA was detected in 165 (89%) patients before treatment but was undetectable in 127 (69%) patients after NACT. Detectable EBV DNA levels after NACT were correlated with poor prognosis (3-year PFS 71.8% vs 85.2%, P=.008 and 3-year DMFS 82.5% vs 92.3%, P=.013). An unsatisfactory tumor response (stable disease or disease progression) after NACT was also correlated with poor clinical outcome (3-year PFS 71.1% vs 85.9%, P=.005 and 3-year LRFS 82.7% vs 93.5%, P=.012). Multivariate analysis showed that the EBV DNA level after NACT (hazard ratio HR 2.31, 95% CI 1.18-4.54, P=.015) and the tumor response to NACT (HR 2.84, 95% CI 1.42-5.67, P=.003) were both significant prognostic factors for PFS. Multivariate analysis also showed that EBV DNA after NACT was the only significant predictor of DMFS (HR 2.99, 95% CI 1.25-7.15, P=.014) and that tumor response to NACT was the only significant predictor of LRFS (HR 3.31, 95% CI 1.21-9.07, P=.020).
Detectable EBV DNA levels and an unsatisfactory tumor response (stable disease or disease progression) after NACT serve as predictors of poor prognosis for patients with advanced-stage NPC. These findings will facilitate further risk stratification, early treatment modification, or both before CCRT.
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