Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma.

BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

Identification of an individualized therapy prognostic signature for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are the most common cancers in the head and neck. Therapeutic response-related genes (TRRGs) are closely associated with carcinogenesis and prognosis in HNSCC. However, the clinical value and prognostic significance of TRRGs are still unclear. We aimed to construct a prognostic risk model to predict therapy response and prognosis in TRRGs-defined subgroups of HNSCC. METHODS: The multiomics data and clinical information of HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA). The profile data GSE65858 and GSE67614 chip was downloaded from public functional genomics data Gene Expression Omnibus (GEO). Based on TCGA-HNSC database, patients were divided into a remission group and a non-remission group according to therapy response, and differentially expressed TRRGs between those two groups were screened. Using Cox regression analysis and Least absolute shrinkage and selection operator (LASSO) analysis, candidate TRRGs that can predict the prognosis of HNSCC were identified and used to construct a TRRGs-based signature and a prognostic nomogram. RESULT: A total of 1896 differentially expressed TRRGs were screened, including 1530 upregulated genes and 366 downregulated genes. Then, 206 differently expressed TRRGs that was significantly associated with the survival were chosen using univariate Cox regression analysis. Finally, a total of 20 candidate TRRGs genes were identified by LASSO analysis to establish a signature for risk prediction, and the risk score of each patient was calculated. Patients were divided into a high-risk group (Risk-H) and a low-risk group (Risk-L) based on the risk score. Results showed that the Risk-L patients had better overall survival (OS) than Risk-H patients. Receiver operating characteristic (ROC) curve analysis revealed great predictive performance for 1-, 3-, and 5-year OS in TCGA-HNSC and GEO databases. Moreover, for patients treated with post-operative radiotherapy, Risk-L patients had longer OS and lower recurrence than Risk-H patients. The nomogram involves risk score and other clinical factors had good performance in predicting survival probability. CONCLUSIONS: The proposed risk prognostic signature and Nomogram based on TRRGs are novel promising tools for predicting therapy response and overall survival in HNSCC patients.

Plasma Epstein-Barr Virus MicroRNA BART8-3p as a Diagnostic and Prognostic Biomarker in Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-associated tumor that is highly common in southern China. Our previous sequencing data demonstrated that the EBV-encoded microRNA BART8-3p was most upregulated in nasopharyngeal carcinoma (NPC) and was closely associated with the metastasis of NPC. However, the values of plasma BART8-3p in NPC patients have not yet been well characterized. MATERIAL AND METHODS: We quantified plasma BART8-3p expression by quantitative real-time PCR in 205 newly diagnosed NPC patients. Kaplan-Meier analysis was used to compare overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) between the groups. RESULTS: Plasma pretreatment BART8-3p was highly expressed in NPC patients compared with healthy controls. Pretreatment BART8-3p yielded a 92% predictive value for detecting NPC. Importantly, BART8-3p decreased dramatically after therapy relative to pretreatment levels. High levels of pretreatment or post-treatment BART8-3p were associated with worse OS, DMFS, and LRRFS. Multivariate analysis showed that high pretreatment or post-treatment BART8-3p was an independent unfavorable prognostic marker for OS (HR 3.82, 95% CI 1.77-8.24, P = .001 or HR 2.74, 95% CI 1.27-5.91, P = .010), DMFS (HR 2.82, 95% CI 1.36-5.85, P = .005 or HR 3.27, 95% CI 1.57-6.81, P = .002), and LRRFS (HR 1.94, 95% CI 1.12-3.35, P = .018 or HR 2.03, 95% CI 1.14-3.62, P = .016) in NPC. Subgroup analysis revealed that for patients with locally advanced NPC with high levels of pretreatment BART8-3p (n = 58), more cycles of chemotherapy (≥6 cycles) tended to prolong OS (P = .070). Over 50% (6/11) patients with high levels of post-treatment BART8-3p presented distant metastasis. CONCLUSION: Plasma BART8-3p is a promising biomarker for the detection and prognosis of NPC.

RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma.

BACKGROUND: Accumulated evidence suggests that RING finger proteins (RNFs) are involved in the carcinogenesis of cancers. However, RNF38, a member of the RNF protein family, has not been studied in nasopharyngeal carcinoma (NPC). METHODS: RNF38 expression was analyzed by RT-PCR, Western blotting and Immunohistochemistry. Biological functions of RNF38 were evaluated by cell growth, colony formation, apoptosis, migration and invasion assays in vitro. Xenograft growth and lung metastasis models were conducted to investigate the effect of RNF38 in vivo. Liquid chromatography coupled with tandem mass spectrometry, co-immunoprecipitation, and CHX assay were implemented to detect the interaction among RNF38 and ACTN4. RESULTS: RNF38 was significantly downregulated in NPC cells and tissues. Immunohistochemistry implied that loss of RNF38 was an independent prognostic factor for poor outcomes of NPC patients. Gain- and loss-of-function experiments showed that RNF38 inhibited proliferation and metastasis in NPC in vitro and in vivo. Upregulation of RNF38 promoted apoptosis of NPC cells to etoposide but not cisplatin. ACTN4 was upregulated in NPC and negatively correlated with RNF38. Mechanistic investigations suggested that RNF38 inactivates the NF-𝛋B and ERK1/2 signaling pathways by inducing ubiquitination and degradation of ACTN4. RNF38 suppress the development of NPC by interacting with ACTN4. CONCLUSIONS: RNF38 plays a potential cancer suppressor gene role in NPC tumorigenesis and is a prognostic biomarker in NPC.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Circulating Epstein-Barr virus microRNAs BART7-3p and BART13-3p as novel biomarkers in nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) BamHI A rightward transcripts (BART) encoded microRNAs (EBV-miR-BARTs) are abnormally highly expressed in nasopharyngeal carcinoma (NPC). This study aims to investigate the diagnostic and prognostic performance of miR-BART7-3p and miR-BART13-3p. Plasma levels of EBV DNA, miR-BART7-3p, and miR-BART13-3p were examined by quantitative PCR in 483 treatment-naïve NPC patients and 243 controls without NPC. The prognostic performance was examined by comparing plasma levels with rates of distant metastasis during follow-up. The area under the receiver operating characteristic curve for diagnosing NPC was 0.926 for EBV DNA, 0.964 for plasma miR-BART7-3p, 0.973 for miR-BART13-3p, and 0.997 for all three indices. Among 465 NPC patients without distant metastasis, the above-median miR-BART7-3p and EBV DNA were independent risk for shorter distant metastasis-free survival (DMFS) (hazard ratio [HR] = 2.94, 95% confidence interval [CI], 1.44-5.97, P = .003; HR = 2.27, 95% CI, 1.26-4.10, P = .006) in multivariate Cox regression. Epstein-Barr virus DNA, miR-BART7-3p, and miR-BART13-3p after radiotherapy were detectable in 28.6%, 17.6%, and 54.7% of patients, respectively. In multivariate Cox regression, detectable miR-BART7-3p and EBV DNA were independent risks for shorter DMFS (HR = 4.13, 95% CI, 1.89-9.01, P < .001; HR = 2.14, 95% CI, 1.04-4.42, P = .039). The 4-year DMFS rate was 92.0% in subjects (n = 156) with neither detectable miR-BART7-3p nor EBV DNA, 80.0% in subjects (n = 65) with either detectable miR-BART7-3p or EBV DNA, and 52.9% in subjects (n = 24) with both detectable miR-BART7-3p and EBV DNA after radiotherapy (P < .001). Circulating levels of miR-BART7-3p and miR-BART13-3p show excellent diagnostic performance for NPC. The combination of plasma levels of miR-BART7-3p and EBV DNA at diagnosis and after radiotherapy could help stratify patients by risk of poor DMFS.

NF-κB Signaling Regulates Expression of Epstein-Barr Virus BART MicroRNAs and Long Noncoding RNAs in Nasopharyngeal Carcinoma.

UNLABELLED: Epstein-Barr virus (EBV) expresses few viral proteins in nasopharyngeal carcinoma (NPC) but high levels of BamHI-A rightward transcripts (BARTs), which include long noncoding RNAs (lncRNAs) and BART microRNAs (miRNAs). It is hypothesized that the mechanism for regulation of BARTs may relate to EBV pathogenesis in NPC. We showed that nuclear factor-κB (NF-κB) activates the BART promoters and modulates the expression of BARTs in EBV-infected NPC cells but that introduction of mutations into the putative NF-κB binding sites abolished activation of BART promoters by NF-κB. Binding of p50 subunits to NF-κB sites in the BART promoters was confirmed in electrophoretic mobility shift assays (EMSA) and further demonstrated in vivo using chromatin immunoprecipitation (ChIP) analysis. Expression of BART miRNAs and lncRNAs correlated with NF-κB activity in EBV-infected epithelial cells, while treatment of EBV-harboring NPC C666-1 cells with aspirin (acetylsalicylic acid [ASA]) and the IκB kinase inhibitor PS-1145 inhibited NF-κB activity, resulting in downregulation of BART expression. Expression of EBV LMP1 activates BART promoters, whereas an LMP1 mutant which cannot induce NF-κB activation does not activate BART promoters, further supporting the idea that expression of BARTs is regulated by NF-κB signaling. Expression of LMP1 is tightly regulated in NPC cells, and this study confirmed that miR-BART5-5p downregulates LMP1 expression, suggesting a feedback loop between BART miRNA and LMP1-mediated NF-κB activation in the NPC setting. These findings provide new insights into the mechanism underlying the deregulation of BARTs in NPC and identify a regulatory loop through which BARTs support EBV latency in NPC. IMPORTANCE: Nasopharyngeal carcinoma (NPC) cells are ubiquitously infected with Epstein-Barr virus (EBV). Notably, EBV expresses very few viral proteins in NPC cells, presumably to avoid triggering an immune response, but high levels of EBV BART miRNAs and lncRNAs which exhibit complex functions associated with EBV pathogenesis. The mechanism for regulation of BARTs is critical for understanding NPC oncogenesis. This study provides multiple lines of evidence to show that expression of BARTs is subject to regulation by NF-κB signaling. EBV LMP1 is a potent activator of NF-κB signaling, and we demonstrate that LMP1 can upregulate expression of BARTs through NF-κB signaling and that BART miRNAs are also able to downregulate LMP1 expression. It appears that aberrant NF-κB signaling and expression of BARTs form an autoregulatory loop for maintaining EBV latency in NPC cells. Further exploration of how targeting NF-κB signaling interrupts EBV latency in NPC cells may reveal new options for NPC treatment.

Pretreatment Serum Lactate Dehydrogenase Level as an Independent Prognostic Factor of Nasopharyngeal Carcinoma in the Intensity-Modulated Radiation Therapy Era.

BACKGROUND The aims of this study were to analyze the prognostic value of baseline lactate dehydrogenase (LDH) among nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT), and to evaluate the potential application of LDH in monitoring treatment efficacy dynamically. MATERIAL AND METHODS From June 2005 to December 2010, 1188 patients with non-metastatic NPC who underwent IMRT with or without chemotherapy were reviewed. Univariate and multivariate analyses were performed to evaluate the predictive value of baseline LDH. Wilcoxon signed-rank test was used to analyze the difference between baseline and post-radiotherapy LDH, and to compare post-radiotherapy LDH with the LDH in cases of distant failure. RESULTS Patients with elevated LDH had significant inferior survival rates, in terms of overall survival (70.0% vs. 83.2%, p=0.010), disease-specific survival (71.1% vs. 85.7%, p=0.002), and distant metastasis-free survival (71.1% vs. 83.4%, p=0.009), but not correlated with locoregional relapse-free survival (p=0.275) or progression-free survival (p=0.104). Subgroup analysis demonstrated that this predictive effect was more significant with advanced stage. Sixty-five post-radiotherapy LDH levels were available from the 90 patients with high LDH at initial diagnosis, and these levels fell in 65 patients, with 62 cases (95.4%) falling within the normal range. Of the 208 patients who experienced distant metastasis, 87 had an available LDH level at that time. Among them, 69 cases (79.3%) had an increased level compared with the post-radiotherapy LDH level. CONCLUSIONS Pretreatment LDH is a simple, cost-effective biomarker that could predict survival rates and might be used in individualized treatment. It is also a potential biomarker that might reflect tumor burden and be used to monitor therapy efficacy.

Long-term survival of nasopharyngeal carcinoma patients with Stage II in intensity-modulated radiation therapy era.

OBJECTIVES: To evaluate the long-term survival and the role of chemotherapy in nasopharyngeal carcinoma (NPC) patients in Stage II treated by intensity-modulated radiation therapy (IMRT). METHODS: Three hundred and eleven NPC patients in Stage II were reviewed. All were treated with IMRT with or without chemotherapy, with 191, 20 and 100 patients being defined as T1N1M0, T2N0M0 and T2N1M0 stage, respectively. RESULTS: At a median follow-up of 57 months, the 5-year overall survival, disease-specific survival, distant metastasis-free survival, loco-regional relapse-free survival (LRRFS) and progression-free survival were 91.1, 93.5, 90.6, 95.9 and 87.6%, respectively. T2N1 patients had significant poorer survival outcomes than T1N1 patients, with T2N0 patients in between. Further analysis showed that the addition of chemotherapy could only improve LRRFS [hazard ratio (HR) 0.263, 95% confidence interval (CI) 0.083-0.839, P = 0.024], especially for T1N1 patients (HR 0.209, 95% CI 0.046-0.954, P = 0.043). For those in the T2N1M0 group, chemotherapy, as used in our series, added no benefit to any endpoint. CONCLUSIONS: IMRT in NPC patients in Stage II was quite therapeutic; however, different subgroups have distinct survival outcomes. Distant metastasis was the main failure pattern, especially for those with T2N1 disease, and the chemotherapy currently in use failed to treat subclinical metastatic foci effectively. Further prospective study is warranted to find out the role and the optimal schedule of chemotherapy in this subgroup of patients.

Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment.

More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein-Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV-harboring NPC and noncancerous NP cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n = 89), and healthy (n = 28) and non-NPC tumor patient controls (n = 18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miR-BART13, but not miR-BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR-BART7 and miR-BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy.

[Prognostic analysis of nasopharyngeal carcinoma patients with distant metastasis after curative radiotherapy].

OBJECTIVE: To analyze the prognosis and its influencing factors for nasopharyngeal carcinoma patients with distant metastasis after radical radiotherapy. METHODS: Clinical data of 184 cases of nasopharyngeal carcinoma after radical radiotherapy with distant metastases were retrospectively reviewed and the factors affecting prognosis were analyzed. RESULTS: The median survival time was 12 months for the whole group, and the 1-, 2-, and 3-year survival rates were 50.6%, 30.7% and 20.9%, respectively. Cox univariate analysis showed that the prognosis of patients with metastasis after radiotherapy was significantly related with The N stage, chemotherapy, time interval between the end of radiotherapy and occurrence of distant metastasis, metastatic sites, chemotherapy after metastasis, cycles of chemotherapy and palliative radiotherapy after metastasis (P<0.05), but not significantly related with sex, age, T stage, clinical stage, cycles of chemotherapy, radiation technique and radiation dose for initial treatment (P>0.05). Advanced N stage, no chemotherapy, short time interval between the end of radiotherapy and occurrence of distant metastasis, multiple metastases, no radiotherapy or chemotherapy for metastases were predictive for poor prognosis (P<0.05). Multivariable analysis indicated that factors including N stage at initial diagnosis, metastatic sites, whether or not chemotherapy was given, the time interval between the end of radiotherapy and the occurrence of distant metastasis were independent factors affecting the prognosis of nasopharyngeal carcinoma patients with distant metastasis after radiotherapy. CONCLUSIONS: N stage at initial diagnosis, metastatic sites, whether or not chemotherapy was given, the time interval between the end of radiotherapy and the occurrence of distant metastasis are independent factors affecting the prognosis for nasopharyngeal carcinoma patients with distant metastasis after radiotherapy. Systemic chemotherapy and local palliative radiotherapy are the primary treatment for nasopharyngeal carcinoma patients with metastasis.

Risk-adapted locoregional radiotherapy strategies based on a prognostic nomogram for de novo metastatic nasopharyngeal carcinoma patients treated with chemoimmunotherapy.

To develop a prognostic nomogram for individualized strategies on locoregional radiation therapy (LRRT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) treated with chemoimmunotherapy. Ninety patients with dmNPC treated with chemoimmunotherapy and diagnosed between 2019 and 2022 were included in our study. Cox regression analysis was performed to identify independent prognostic factors for overall survival (OS) and progression-free survival (PFS) to establish a nomogram. With a median follow-up of 17.5 months, the median PFS and OS were 24.9 months and 29.4 months, respectively. Sixty-nine patients and twenty-one patients were included in the LRRT group and without LRRT group, respectively. Multivariate analysis revealed that younger age, lower EBV DNA copy number before treatment, a single metastatic site, more cycles of chemotherapy and immunotherapy were significantly associated with better OS. A prognostic nomogram was constructed incorporating the above 5 independent factors, with a C-index of 0.894. Patients were divided into low- and high-risk cohorts based on nomogram scores. A significant improvement in OS was revealed in the LRRT group compared with the without-LRRT group for patients in the high-risk cohort (HR = 2.46, 95% CI 1.01-6.00, P = 0.049), while the OS was comparable between the two groups in the low-risk cohort. Our study indicates that LRRT may be associated with better prognosis in high-risk patients with dmNPC in the era of immunotherapy.

Failure patterns and individualized treatment plans of reirradiation for inoperable locally recurrent nasopharyngeal carcinoma.

Re-irradiation with intensity-modulated radiotherapy (IMRT) remains the primary treatment modality for inoperable locally recurrent nasopharyngeal carcinoma (NPC). However, the rate of radiation-related late adverse effects is often substantially high. Therefore, we aimed to explore failure patterns and individualized treatment plans of re-irradiation for inoperable locally recurrent NPC. Ninety-seven patients who underwent IMRT were retrospectively analyzed. Sixty-two patients had clinical target volume of recurrence (rCTV) delineated, and thirty-five patients had only gross tumor volume of recurrence (rGTV) delineated. Twenty-nine patients developed second local failures after re-irradiation with IMRT (28 cases available). Among those patients, 64.3% (18/28) of patients and 35.7% (10/28) developed in-field or out-field, respectively. No statistical correlation was observed between target volume (rGTV or rCTV) and the local recurrence rate, local failure patterns, grade ≥ 3 toxicity, and survival. Multivariate analysis showed that recurrent T (rT) stage (HR 2.62, P = 0.019) and rGTV volume (HR 1.73, P = 0.037) were independent prognostic factors for overall survival (OS). Risk stratification based on rT stage and rGTV volume revealed that low risk group had a longer 3-year OS rate (66.7% vs. 23.4%), lower total grade ≥ 3 toxicity (P = 0.004), and lower re-radiation associated mortality rates (HR 0.45, P = 0.03) than high risk group. This study demonstrates that the delineation of rCTV may not be beneficial for re-irradiation using IMRT in locally recurrent NPC. Patients with low risk were most suitable for re-irradiation, with maximizing local salvage and minimizing radiation-related toxicities. More precise and individualized plans of re-irradiation are warranted.

Plasma Epstein-Barr virus microRNA BART8-3p as a potential biomarker for detection and prognostic prediction in early nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) encoded microRNA BART8-3p (miR-BART8-3p) was significantly associated with the metastasis in nasopharyngeal carcinoma (NPC). To explore the clinical values of plasma miR-BART8-3p in patients with early NPC. We retrospectively analyzed 126 patients with stage I and II NPC. A receiver operating characteristic curve was used to examine the diagnostic performance. Kaplan‒Meier analysis was applied to determine survival differences. Cox regression was used for univariate and multivariate analyses. Compared to healthy subjects, plasma EBV miR-BART8-3p was highly expressed in early NPC patients. The sensitivity, specificity, and area under the curve value of plasma miR-BART8-3p combined with plasma EBV DNA was up to 88.9%, 94.4%, and 0.931. Compared to patients with low expression of miR-BART8-3p, patients with high expression of miR-BART8-3p had poorer 5-year overall survival (OS) (98.9% vs. 91.1%, P = 0.025), locoregional recurrence-free survival (LRRFS) (100% vs. 83.9%, P < 0.001) and distant metastasis-free survival (DMFS) (98.9% vs. 88.0%, P = 0.006). Risk stratification analysis revealed that high-risk patients (with high levels of EBV DNA and miR-BART8-3p) had inferior OS, LRRFS, and DMFS than low-risk patients (without high levels of EBV DNA and miR-BART8-3p). Multivariate analysis verified that the high-risk group was an unfavorable factor for OS, LRRFS, and DMFS. A combination of plasma EBV miR-BART8-3p and EBV DNA could be a potential biomarker for the diagnosis and prognosis in early NPC.

Selectively sparing of the supraclavicular area during intensity-modulated radiotherapy in nasopharyngeal carcinoma: A double-center observation study.

BACKGROUND AND PURPOSE: This study was aimed at evaluating the feasibility of sparing the supraclavicular area, namely levels IVb and Vc, during intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC) patients with N1-2 disease[except N1 disease with purely restropharyngeal lymph nodes(RPN) involvement], and providing a basis for the revision of International Guideline for the delineation of the clinical target volume (CTV). PATIENTS AND MATERIALS: Patients with NPC (stage TanyN1-2M0) diagnosed pathologically in Fujian Cancer Hospital (Center 1, Only Lin SJ's attending group) from January 2014 to March 2018 and Jiangxi Cancer Hospital(Center 2) from January 2014 to December 2015 were included. According to our principle, the supraclavicular area (levels IVb and Vc) were excluded from the CTVnd. Survival outcomes focused on regional recurrence-free survival (RRFS) and recurrence rates of levels IVb and Vc were analysed. RESULTS: A total of 672 eligible patients were recruited (Center 1, n = 362; Center 2, n = 310). There was no significant difference in 5-year RRFS (97.33 % vs. 97.24 %, p = 0.980), overall survival (OS) (89.14 % vs. 88.56 %, p = 0.327), local recurrence-free survival (LRFS) (94.90 % vs. 95.30 %, p = 0.593) and distant metastasis-free survival (DMFS) (89.38 % vs. 86.60 %, p = 0.130) between Center 1 and Center 2. Twenty patients developed regional failure (median: 36 months), among them, only one case (0.15 %) was recorded as levels IVb and Vc recurrence. CONCLUSION: Omitting the supraclavicular area (levels IVb and Vc) during IMRT should be safe and feasible for N1-2 disease (except N1 disease with purely RPN involvement). Well-designed multicenter prospective trials should be conducted to confirm our findings.

Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China.

BACKGROUND: The objective of this study was to evaluate the long-term survival and late toxicities of concurrent-adjuvant chemotherapy in patients with stage III through IVB nasopharyngeal carcinoma (NPC) from endemic regions of China. METHODS: Patients with stage III to IVB NPC were assigned randomly to receive radiotherapy (RT) alone (the RT group) or RT plus concurrent adjuvant chemotherapy (the CRT group). CRT patients received concurrent cisplatin (40 mg/m2) weekly during RT followed by cisplatin (80 mg/m2) and fluorouracil (800 mg/m(2) daily for 5 days) every 4 weeks for 3 cycles. The primary endpoint was overall survival. RESULTS: In total, 316 patients underwent randomization, with 158 to each group. At a median follow-up of 70 months, the 5-year overall survival rate was 72% for the CRT group and 62% for the RT group (hazard ratio, 0.69; 95% confidence interval, 0.48-0.99; P = .043). Failure-free survival was significantly higher in the CRT group (P = .020). Most late toxicities were similar (33% vs. 26%; P = .089), except for cranial neuropathy (P = .042), peripheral neuropathy (P = .041), and ear damage (P = .048), which were significantly increased in the CRT group. CONCLUSIONS: The addition of concurrent adjuvant chemotherapy to RT provides survival benefits to patients with stage III through IVB NPC in endemic regions of China, and it does not increase most late toxicities apart from cranial neuropathy, peripheral neuropathy, and ear damage.

Lack of association between XRCC1 SNPs and acute radiation­induced injury or prognosis in patients with nasopharyngeal carcinoma.

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC.

Individualized Concurrent Chemotherapy for Patients with Stage III-IVa Nasopharyngeal Carcinoma Receiving Neoadjuvant Chemotherapy Combined with Definitive Intensity-Modulated Radiotherapy.

PURPOSE: This retrospective study aimed to re-evaluate the effect of concurrent chemotherapy in patients with locally advanced nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: A total of 498 patients who received neoadjuvant chemotherapy (NCT) combined with concurrent chemoradiotherapy (CCRT) or IMRT were retrospectively reviewed. The distribution of baseline characteristics was balanced using propensity score matching. Additionally, the results of NCT+IMRT and NCT+CCRT were compared using Kaplan-Meier survival analysis, and differences in survival rates were analyzed using the log rank test. RESULTS: There were no significant differences in overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and local progression-free survival (LRFS) between the two groups. Patients were further categorized into risk subgroups based on pretreatment Epstein-Barr virus (EBV) DNA cutoff values using receiver operating characteristic curve analysis. There were no statistically significant differences in OS, PFS, DMFS, and LRFS between patients who received NCT+CCRT and NCT+IMRT in the high-risk group. In the low-risk group, although there were no differences between NCT+CCRT and NCT+IMRT in OS, PFS, and LRFS, patients who received NCT+CCRT had better DMFS than those who received NCT+IMRT. CONCLUSION: Pretreatment EBV DNA level can be used to individualize concurrent chemotherapy for patients with locally advanced NPC. Patients with low pretreatment EBV DNA levels may benefit from concurrent chemotherapy, whereas those with high levels may not. Other treatment modalities need to be explored for high-risk patients to improve their prognosis.

Prioritizing sufficient dose to gross tumor volume over normal tissue sparing in intensity-modulated radiotherapy treatment of T4 nasopharyngeal carcinoma.

BACKGROUND: In intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC), priority is often given minimize dose to the critical organs at risk (OARs) to avoid potential morbid sequelae. However, in T4 NPC, dosimetric inadequacy enforced by dose constraints on OARs may significantly impact tumor control. METHODS: This was a single-institute cohort that patients diagnosed between July 2005 and December 2010 with T4 NPC treated with IMRT. All patients were re-classification according to the 7th-AJCC stage. RESULTS: Overall, the average doses such as Dmax , D1% , D2% and D1cc for various Central nervous system (CNS) OARs including brainstem, optic nerve, chiasm, temporal lobes and spinal cord were found to exceed published guidelines as RTOG0225. However, no clinical toxicities were seen during the follow-up period except for 13% patients with temporal lobe necrosis. CONCLUSION: Our retrospective review showed that its feasible to maximize gross tumor volume dose coverage while exceeding most CNS OAR constraint standards, with ideal local control and no obvious increase of craniocerebral toxicity.

Constructing an individualized surveillance framework for nasopharyngeal carcinoma based on a dynamic risk-adapted approach.

BACKGROUND AND PURPOSE: This study aims to evaluate the dynamic survival and recurrence hazard of nasopharyngeal carcinoma(NPC) patients after definitive chemoradiotherapy utilizing conditional survival(CS) analysis, and to propose a personalized surveillance strategy at different clinical stages. MATERIALS AND METHODS: Non-metastatic NPC patients who received curative chemotherapy between June 2005 and December 2011 were included. The Kaplan-Meier method was used to calculate the CS rate. RESULTS: A total of 1616 patients were analyzed. With the prolongation of survival time, both conditional locoregional recurrence free survival and distant metastatic free survival increased gradually. Changing pattern of annual recurrence risk over time varied among different clinical stages. The annual locoregional recurrence(LRR) risk in stage I-II was always less than 2%, while in stage III-IVa, it was greater than 2% for the first three years and decreased to below 2% only after the third year. The annual distant metastases (DM) risk was always less than 2% in stage I, but higher than 2% in stage II for the first 3 years (2.5-3.8%). For those with stage III-IVa, the annual DM risk retained at a high level(>5%), and only decreased to < 5% after the third year. Based on the dynamic changes in survival probability over time, we established a surveillance plan with different follow-up intensities and frequencies for different clinical stages. CONCLUSION: The annual risk of LRR and DM decrease over time. Our individual surveillance model will provide critical prognostic information to optimize clinical decision-making, and promote to formulate surveillance counseling and help with resources allocation.