Lin-Quan Tang

The impact of plasma epstein–barr virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis: an observational study

Background:The impact of combining plasma fibrinogen levels with Epstein–Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated.Methods:In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS).Results:Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (⩾3.34u2009gu2009l−1) presented with worse DFS, regardless of EBV DNA ⩾4000 or <4000 copiesu2009ml−1 subgroup. Similar findings were observed for DMFS and OS.Conclusions:Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.

The Prognostic Value of Plasma Epstein-Barr Viral DNA and Tumor Response to Neoadjuvant Chemotherapy in Advanced-Stage Nasopharyngeal Carcinoma

PURPOSEnTo 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).nnnPATIENTS AND METHODSnIn 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).nnnRESULTSnEBV 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).nnnCONCLUSIONnDetectable 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.

Is Hemoglobin Level in Patients with Nasopharyngeal Carcinoma Still a Significant Prognostic Factor in the Era of Intensity-Modulated Radiotherapy Technology?

Background Hemoglobin (Hb) levels are regarded as an important determinant of outcome in a number of cancers treated with radiotherapy. However, for patients treated with intensity modulated radiotherapy (IMRT), information regarding the prognostic value of hemoglobin level is scarce. Patients and Methods A total of 650 patients with nasopharyngeal carcinoma (NPC), enrolled between May, 2005, and November, 2012, were included in this study. The prognostic significance of hemoglobin level (anemia or no-anemia) at three different time points was investigated, including before treatment, during treatment and at the last week of treatment. Univariate and multivariate analyses were conducted using the log–rank test and the Cox proportional hazards model, respectively. Results The 5-year OS (overall survival) rate of patients who were anemia and no-anemia before treatment were 89.1%, and 80.7% (P = 0.01), respectively. The 5-year DMFS (distant metastasis-free survival) rate of patients who were anemia and no-anemia before treatment were 88.9%, and 78.2% (P = 0.01), respectively. The 5-year OS rate of patients who were anemia and no-anemia during treatment were 91.7% and 83.3% (P = 0.004). According to multivariate analysis, the pre-treatment Hb level predicted a decreased DMFS (P = 0.007, HR = 2.555, 95% CI1.294–5.046). Besides, the mid-treatment Hb level predicted a decreased OS (P = 0.013, HR = 2.333, 95% CI1.199–4.541). Conclusions Hemoglobin level is a useful prognostic factor in NPC patients receiving IMRT. It is important to control the level of hemoglobin both before and during chemoradiotherapy.

Combination of Tumor Volume and Epstein-Barr Virus DNA Improved Prognostic Stratification of Stage II Nasopharyngeal Carcinoma in the IMRT Era: A Large-Scale Cohort Study

Purpose Little is known about combination of the circulating Epstein-Barr viral (EBV) DNA and tumor volume in prognosis of stage II nasopharyngeal carcinoma (NPC) patients in the intensity modulated radiotherapy (IMRT) era. We conducted this cohort study to evaluate the prognostic values of combining these two factors. Materials and Methods By Kaplan-Meier, we compare the differences of survival curves between 385 patients with different EBV DNA or tumor volume levels, or with the combination of two biomarkers mentioned above. Results Gross tumor volume of cervical lymph nodes (GTVnd, p < 0.001) and total tumor volume (GTVtotal, p < 0.001) were both closely related to pretreatment EBV DNA, while gross tumor volume of nasopharynx (GTVnx, p=0.047) was weakly related to EBV DNA. EBV DNA was significantly correlated with progress-free survival (PFS, p=0.005), locoregional-free survival (LRFS, p=0.039), and distant metastasis-free survival (DMFS, p=0.017), while GTVtotal, regardless of GTVnx and GTVnd, had a significant correlation with PFS and LRFS. The p-values of GTVtotal for PFS and LRFS were 0.008 and 0.001, respectively. According to GTVtotal and pretreatment EBV DNA level, patients were divided into a low-risk group (EBV DNA 0 copy/mL, GTVtotal < 30 cm3; EBV DNA 0 copy/mL, GTVtotal ≥ 30 cm3; or EBV DNA > 0 copy/mL, GTVtotal < 30 cm3) and a high-risk group (EBV DNA > 0 copy/mL, GTVtotal ≥ 30 cm3). When patients in the low-risk group were compared with those in the high-risk group, 3-year PFS (p=0.003), LRFS (p=0.010), and DMFS (p=0.031) rates were statistically significant. Conclusion Pretreatment plasma EBV DNA and tumor volume were both closely correlated with prognosis of stage II NPC patients in the IMRT era. Combination of EBV DNA and tumor volume can refine prognosis and indicate for clinical therapy.

FMNL1 mediates nasopharyngeal carcinoma cell aggressiveness by epigenetically upregulating MTA1

It has been suggested that formin-like protein 1 (FMNL1) plays an important role in the pathogenic process of several hematopoietic malignancies. In this study, we performed a series of in vivo and in vitro assays to elucidate the biological functions of FMNL1 and underlying mechanisms in human nasopharyngeal carcinoma (NPC) pathogenesis. Herein, we report that high expression of FMNL1 in NPC is positively associated with an aggressive disease and/or poor patient survival. Ectopic overexpression of FMNL1 in NPC cells substantially promoted cell invadopodia formation, epithelial-mesenchymal transition (EMT) and invasiveness, whereas depletion of FMNL1 potently suppressed NPC cells invadopodia formation, EMT, and invasive/metastatic capacities. We further show that FMNL1 could enhance NPC cell aggressiveness by increasing a key downstream target, the metastasis-associated protein 1 (MTA1) gene. Importantly, ectopic overexpression of FMNL1 in NPC cells markedly improved the binding of HDAC1 with Profilin2 in the cytoplasm and suppressed the enrichment of HDAC1 on the promoter of MTA1 and thereby, leading to an increased MTA1 transcription and expression. Furthermore, in addition to the amplification of FMNL1 gene, decreased level of miR-16 in NPCs is another critical mechanism to upregulate FMNL1 expression. These results, collectively, provide first-line of evidences that high expression of FMNL1, resulted from decreased miR-16 and/or MTA1 amplification, has a potent oncogenic role to drive the development and aggressive process of NPC by upregulating MTA1, and FMNL1 might be employed as a new prognostic biomarker and therapeutic target for human NPC.

Development and validation of an endoscopic images-based deep learning model for detection with nasopharyngeal malignancies

BackgroundDue to the occult anatomic location of the nasopharynx and frequent presence of adenoid hyperplasia, the positive rate for malignancy identification during biopsy is low, thus leading to delayed or missed diagnosis for nasopharyngeal malignancies upon initial attempt. Here, we aimed to develop an artificial intelligence tool to detect nasopharyngeal malignancies under endoscopic examination based on deep learning.MethodsAn endoscopic images-based nasopharyngeal malignancy detection model (eNPM-DM) consisting of a fully convolutional network based on the inception architecture was developed and fine-tuned using separate training and validation sets for both classification and segmentation. Briefly, a total of 28,966 qualified images were collected. Among these images, 27,536 biopsy-proven images from 7951 individuals obtained from January 1st, 2008, to December 31st, 2016, were split into the training, validation and test sets at a ratio of 7:1:2 using simple randomization. Additionally, 1430 images obtained from January 1st, 2017, to March 31st, 2017, were used as a prospective test set to compare the performance of the established model against oncologist evaluation. The dice similarity coefficient (DSC) was used to evaluate the efficiency of eNPM-DM in automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images, by comparing automatic segmentation with manual segmentation performed by the experts.ResultsAll images were histopathologically confirmed, and included 5713 (19.7%) normal control, 19,107 (66.0%) nasopharyngeal carcinoma (NPC), 335 (1.2%) NPC and 3811 (13.2%) benign diseases. The eNPM-DM attained an overall accuracy of 88.7% (95% confidence interval (CI) 87.8%–89.5%) in detecting malignancies in the test set. In the prospective comparison phase, eNPM-DM outperformed the experts: the overall accuracy was 88.0% (95% CI 86.1%–89.6%) vs. 80.5% (95% CI 77.0%–84.0%). The eNPM-DM required less time (40xa0s vs. 110.0u2009±u20095.8xa0min) and exhibited encouraging performance in automatic segmentation of nasopharyngeal malignant area from the background, with an average DSC of 0.78u2009±u20090.24 and 0.75u2009±u20090.26 in the test and prospective test sets, respectively.ConclusionsThe eNPM-DM outperformed oncologist evaluation in diagnostic classification of nasopharyngeal mass into benign versus malignant, and realized automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images.

Induction Chemotherapy Plus Concurrent Chemoradiotherapy Versus Concurrent Chemoradiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma in Children and Adolescents: A Matched Cohort Analysis

Purpose The purpose of this study was to evaluate the long-term clinical outcome and toxicity of induction chemotherapy (IC) followed by concomitant chemoradiotherapy (CCRT) compared with CCRT alone for the treatment of children and adolescent locoregionally advanced nasopharyngeal carcinoma (LACANPC). Materials and Methods A total of 194 locoregionally advanced nasopharyngeal carcinoma patients youngerthan 21 years who received CCRT with or without IC before were included in the study population. Overall survival (OS) rate, progression-free survival (PFS) rate, locoregional recurrence-free survival (LRFS) rate, and distant metastasis-free survival (DMFS) rate were assessed by the Kaplan-Meier method and a log-rank test. Treatment toxicities were clarified and compared between two groups. Results One hundred and thiry of 194 patients received IC+CCRT. Patients who were younger and with more advanced TNM stage were more likely to receive IC+CCRT and intensive modulated radiotherapy. The addition of IC before CCRT failed to improve survival significantly. The matched analysis identified 43 well-balanced patients in both two groups. With a median follow-up of 51.5 months, no differences were found between the IC+CCRT group and the CCRT group in 5-year OS (83.7% vs. 74.6%, p=0.153), PFS (79.2% vs. 73.4%, p=0.355), LRFS (97.7% vs. 88.2%, p=0.083), and DMFS (81.6% vs. 81.6%, p=0.860). N3 was an independent prognostic factor predicting poorer OS, PFS, and DMFS. The addition of IC was associated with increased rates of grade 3 to 4 neutropenia. Conclusion This study failed to demonstrate that adding IC before CCRT could provide a significant additional survival benefit for LACANPC patients. Further investigations are warranted.

Pretreatment Serum Amyloid A and C-reactive Protein Comparing with Epstein-Barr Virus DNA as Prognostic Indicators in Patients with Nasopharyngeal Carcinoma: A Prospective Study

Purpose The measuring Epstein-Barr virus (EBV) DNA is an important predictor of nasopharyngeal carcinoma (NPC). This study evaluated the predictive value of pretreatment serum amyloid A (SAA) and C-reactive protein (CRP) comparing with EBV DNA in patients with NPC. Materials and Methods In an observational study of 419 non-metastatic NPC patients, we prospectively evaluated the prognostic effects of pretreatment SAA, CRP, and EBV DNA on survival. The primary end-point was progress-free survival (PFS). Results The median level of SAA and CRP was 4.28 mg/L and 1.88 mg/L, respectively. For the high-SAA group (> 4.28 mg/L) versus the low-SAA (≤ 4.28 mg/L) group and the high-CRP group (> 1.88 mg/L) versus the low-CRP (≤ 1.88 mg/L) group, the 5-year PFS was 64.5% versus 73.1% (p=0.013) and 65.2% versus 73.3% (p=0.064), respectively. EBV DNA detection showed a superior predictive result, the 5-year PFS in the EBV DNA ≥ 1,500 copies/mL group was obviously different than the EBV DNA < 1,500 copies/mL group (62.2% versus 77.8%, p < 0.001). Multifactorial Cox regression analysis confirmed that in the PFS, the independent prognostic factors were including EBV DNA (hazard ratio [HR], 1.788; p=0.009), tumour stage (HR, 1.903; p=0.021), and node stage (HR, 1.498; p=0.049), but the SAA and CRP were not included in the independent prognostic factors. Conclusion The results of SAA and CRP had a certain relationship with the prognosis of NPC, and the prognosis of patients with high level of SAA and CRP were poor. However, the predictive ability of SAA and CRP was lower than that of EBV DNA.