Comparison of long-term quality of life and their predictors in survivors between paediatric and adult nasopharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND: To compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL. METHODS: We enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared. RESULTS: The paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P < 0.001), role function (paediatric: 97.0 ± 9.2; adult: 90.5 ± 15.2; P < 0.001), social function (paediatric: 96.0 ± 8.9; adult: 93.5 ± 11.8; P = 0.038), insomnia (paediatric: 1.9 ± 7.8; adult: 13.1 ± 22.3; P < 0.001), constipation (paediatric: 1.3 ± 7.5; adult: 8.0 ± 17.4; P < 0.001), diarrhea (paediatric: 0.7 ± 4.6; adult: 2.8 ± 9.3; P = 0.010), and financial difficulties (paediatric: 1.9 ± 7.8; adult: 11.0 ± 19.8; P < 0.001), but poorer cognitive function (paediatric: 88.3 ± 9.9; adult: 93.8 ± 12.6; P < 0.001) than the adult group. Pretreatment clinical factors, including T stage, N stage, and pre-treatment EBV (Epstein-Barr Virus) DNA, showed a strong association with QoL. However, the factors that affected the QoL outcomes differed between the two groups. In survivors of paediatric cancer, global health status/QoL was strongly correlated with T stage (P < 0.001) and clinical stage (P = 0.018), whereas it was strongly correlated with pre-treatment EBV DNA (P = 0.008) in adults. CONCLUSION: Paediatric survivors of NPC have a significantly better QoL than adult NPC survivors. Moreover, pre-treatment T stage, N stage, and EBV DNA significantly influenced the overall health status of the survivors. These results highlight the need to tailor care to both age groups to promote better long-term health outcomes.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Clinical characteristics and prognostic factors affecting survival after radical radiotherapy for early and late post-treatment metastatic nasopharyngeal carcinoma.

OBJECTIVE: We compared the clinical characteristics and survival outcomes after radical radiotherapy between nasopharyngeal carcinoma (NPC) with early and late metastases based on a relatively large cohort, which provides valuable data for the planning of clinical surveillance strategies. METHODS: This was a single-center retrospective analysis of 10,566 patients who received radical radiotherapy in China from January 2000 to December 2016. Overall survival was the primary endpoint. Kaplan-Meier survival analysis and log-rank tests were applied to investigate the association between early or late metastasis and the endpoints. The prognostic value of clinicopathological features was identified using univariate and multivariate Cox proportional hazards models. RESULTS: The cutoff value for time to metastasis was based on ROC analysis. A total of 559 (5.3%) patients developed distant metastases, 297 (53.1%) of which developed early metastatic disease, with the rest (46.9%) developing late metastatic disease. The K-M analysis showed that the patients with late metastatic foci had significantly better post-metastatic OS (P = 0.0056). Multivariate analysis indicated that age, liver metastasis, the number of metastatic foci and time to metastasis (P = 0.013) are independent prognostic factors for OS. After analyzing the impact of different treatment methods, we found that local treatment was an independent protective factor for LM, while local treatment was not associated with a survival benefit for EM disease. CONCLUSIONS: The time to metastasis after radical radiotherapy affected the prognosis of NPC patients and local treatment was an independent protective factor that could improve the survival of late metastatic NPC patients.

Nasopharyngeal necrosis contributes to overall survival in nasopharyngeal carcinoma without distant metastasis: a comprehensive nomogram model.

OBJECTIVES: This study focused on developing and validating a nomogram to predict the overall survival (OS) of patients with nasopharyngeal carcinoma (NPC) without distant metastasis based on their clinical characteristics, serum biomarkers, and presence of nasopharyngeal (NP) necrosis. METHODS: This study included 9298 patients with NPC. Patients from January 2009 to December 2014 were randomly categorized into the training cohort and validation cohort A. Validation cohort B, whose data were collected from January 2015 to December 2017, was also included. OS was the primary endpoint of this study. Cox regression analysis was used to detect independent risk variables. Decision curve analysis, calibration curve, time-dependent receiver operating characteristic (ROC) curve, and concordance index (C-index) were used to evaluate the performance of the nomogram model. RESULTS: A total of 267 patients developed NP necrosis after the first routine radiotherapy. After radiotherapy, patients with NP necrosis had significantly lower OS than other patients in all three cohorts (p < 0.001). Eleven factors, including NP necrosis, were involved in the nomogram, which had favorable discrimination and calibration with a C-index of 0.768 in the training cohort, 0.749 in validation cohort A, and 0.739 in validation cohort B. The nomogram exhibited a significantly larger area under the ROC curve for predicting OS than the TNM stage and Epstein-Barr virus (EBV) DNA (p < 0.001). CONCLUSION: Compared with the TNM system and EBV DNA, we established a nomogram model with an accurate prognostic prediction for patients with NPC, which might help with patient management in NPC. KEY POINTS: • This study included 9298 patients with NPC, and 11 factors were involved in the final model. • The nomogram had a significantly higher C-index and area under the ROC curve than the TNM stage and EBV DNA. • We established the first nomogram model for NPC involving the occurrence of NP necrosis, which was valuable for providing individual counseling and clinical assessments.

Head and neck MRI-based T stage and [18F]FDG PET/CT-based N/M stage improved prognostic stratification in primary nasopharyngeal carcinoma.

OBJECTIVES: To evaluate whether MRI-based T stage (TMRI), [18F]FDG PET/CT-based N (NPET/CT), and M stage (MPET/CT) are superior in NPC patients' prognostic stratification based on long-term survival evidences, and whether TNM staging method involving TMRI + NPET/CT + MPET/CT could improve NPC patients' prognostic stratification. METHODS: From April 2007 to December 2013, 1013 consecutive untreated NPC patients with complete imaging data were enrolled. All patients' initial stages were repeated based on (1) the NCCN guideline recommended "TMRI + NMRI + MPET/CT" ("MMP") staging method; (2) the traditional "TMRI + NMRI + Mconventional work-up (CWU)" ("MMC") staging method; (3) the single-step "TPET/CT + NPET/CT + MPET/CT" ("PPP") staging method; or (4) the "TMRI + NPET/CT + MPET/CT" ("MPP") staging method recommended in present research. Survival curve, ROC curve, and net reclassification improvement (NRI) analysis were used to evaluate the prognosis predicting ability of different staging methods. RESULTS: [18F]FDG PET/CT performed worse on T stage (NRI = - 0.174, p < 0.001) but better on N (NRI = 0.135, p = 0.004) and M stage (NRI = 0.126, p = 0.001). The patients whose N stage upgraded by [18F]FDG PET/CT had worse survival (p = 0.011). The "TMRI + NPET/CT + MPET/CT" ("MPP") method performed better on survival prediction when compared with "MMP" (NRI = 0.079, p = 0.007), "MMC" (NRI = 0.190, p < 0.001), or "PPP" method (NRI = 0.107, p < 0.001). The "TMRI + NPET/CT + MPET/CT" ("MPP") method could reclassify patients' TNM stage to a more appropriate stage. The improvement is significant in patients with more than 2.5-years follow-up according to the time-dependent NRI values. CONCLUSIONS: The MRI is superior to [18F]FDG PET/CT in T stage, and [18F]FDG PET/CT is superior to CWU in N/M stage. The "TMRI + NPET/CT + MPET/CT" ("MPP") staging method could significantly improve NPC patients' long-term prognostic stratification. CLINICAL RELEVANCE STATEMENT: The present research provided long-term follow-up evidence for benefits of MRI and [18F]FDG PET/CT in TNM staging for nasopharyngeal carcinoma, and proposes a new imaging procedure for TNM staging incorporating MRI-based T stage and [18F]FDG PET/CT-based N and M stage, which significantly improves long-term prognostic stratification for patients with NPC. KEY POINTS: • The long-term follow-up evidence of a large-scale cohort was provided to evaluate the advantages of MRI, [18F]FDG PET/CT, and CWU in the TNM staging of nasopharyngeal carcinoma. • A new imaging procedure for TNM stage of nasopharyngeal carcinoma was proposed.

Identifying optimal candidates for postoperative adjuvant therapy among regional persistent/recurrent nasopharyngeal carcinoma patients after neck dissection.

PURPOSE: To analyze the clinical outcomes of patients with regional persistent/recurrent nasopharyngeal carcinoma (NPC) who received neck dissection, and to evaluate the clinical benefit of postoperative adjuvant therapy (PAT) based on patients' positive lymph node counts (PLNs), extracapsular spread (ECS) and preoperative plasma EBV DNA levels. METHODS: From 2003 to 2017, 342 patients with regional persistent/recurrent NPC were included in this study. All patients were treated with neck dissection and 76 patients received PAT. Progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were compared between groups using propensity score matching (PSM). RESULTS: 152 patients without PAT treatment and 76 patients with PAT treatment were selected by the PSM. There was no significant difference in 2-year PFS (52.4% vs. 61.3%, P = 0.371), 2-year OS (91.9% vs. 90.5%, P = 0.097) or 2-year LRFS (66.3% vs. 67.9%, P = 0.872) between the two groups. However, the application of PAT brought survival benefits to patients in terms of 2-year DMFS (76.5% vs. 84.7%, P = 0.020). PLN, ECS and preoperative EBV DNA level remained independent risk factors for poorer PFS. Accordingly, patients were divided into low-risk and high-risk groups using receiver operating characteristic (ROC) curve; the 2-year PFS rates for two risk groups were 73.4% and 59.1% (P < 0.0001) respectively. The results showed that low-risk patients didn't benefit from the addition of PAT. However, the 2-year DMFS rate was significantly improved in high-risk PAT-treated patients than those treated by neck dissection alone (83.7% vs. 71.7%, P = 0.023). CONCLUSIONS: PLNs, ECS and preoperative EBV DNA level are associated with the prognosis of patients with regional persistent/recurrent NPC. High-risk patients identified by PLNs, ECS and preoperative EBV DNA level may benefit from the addition of PAT after neck dissection.

Pulmonary Metastasectomy in Patients with Lung Metastases from Nasopharyngeal Carcinoma.

BACKGROUND: Approximately 10% of patients with nasopharyngeal carcinoma (NPC) develop lung-only metastases. Data regarding the potential role of lung metastasectomy are limited. OBJECTIVE: The aim of this case-control study was to determine whether lung metastasectomy prolongs survival in patients with NPC with lung-only metastases. METHODS: The resectability of 215 consecutive patients diagnosed with lung-only metastases from 2001 to 2018 was reviewed by doctors blinded to the patient groups. The propensity score matching method was used to balance the potential probability of being assigned to treatment groups based on pretherapeutic information. Postmetastatic survival (PMS) and cumulative incidence of local failure were compared between the surgical and nonsurgical arms. RESULTS: Overall, 120 potentially resectable cases were enrolled, and 45 and 22 patients who underwent and did not undergo metastasectomy, respectively, were included in the propensity-matched cohort. Patients who underwent pulmonary resection had better PMS and a lower cumulative incidence of local failure than those who did not undergo surgery. The 5-year PMS rates were 75.53% and 47.81% in the surgical and nonsurgical arms, respectively (difference 27.72%; 95% confidence interval 3.95-51.49%). Younger patients (≤ 45 years), and those with a lower primary N stage (N0-1), longer disease-free interval (> 2 years), smaller total diameter of the metastatic lesions (≤ 3 cm), unilateral distribution of metastases, no mediastinal/hilar lymph node involvement, and adjuvant chemotherapy showed a significantly longer PMS after metastasectomy by multivariable analysis. CONCLUSIONS: Lung metastasectomy may improve PMS and decrease the chance of local treatment failure in NPC patients with potentially resectable lung-only metastases.

Nomogram for the prediction of primary distant metastasis of nasopharyngeal carcinoma to guide individualized application of FDG PET/CT.

PURPOSE: This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT. METHODS: In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed. RESULTS: A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76-0.83) and 0.779 (95% CI, 0.74-0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses. CONCLUSION: This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.

Subdivision of de-novo metastatic nasopharyngeal carcinoma based on tumor burden and pretreatment EBV DNA for therapeutic guidance of locoregional radiotherapy.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy predominantly associated with infection by the Epstein-Barr virus (EBV). Approximately 12,900 new cases of NPC occur each year, with more than 70% of cases occurring in the east and southeast Asia. NPC is different from ordinary head and neck squamous cell carcinoma due to its particular biological properties and it is highly sensitive to radiotherapy. With the development of RT technology, the 3-year local control rate and survival rates of non-metastatic NPC reached 80-90% in the intensity-modulated RT (IMRT) era. However, whether distant metastatic NPC (de novo mNPC, dmNPC) should receive locoregional RT (LRRT) needs to be clarified. RESULTS: Multivariate analysis identified three independent prognostic factors: Epstein-Barr virus (EBV) DNA, number of metastatic lesions, and number of metastatic organs. Through these factors, all patients were successfully divided into 3 subgroups: low-risk (single metastatic organ, EBV DNA ≤ 25,000 copies/ml, and ≤ 5 metastatic lesions), intermediate-risk (single metastatic organ, EBV DNA > 25,000 copies/ml, and ≤ 5 metastatic lesions), and high-risk (multiple metastatic organs or > 5 metastatic lesions or both). By comparing LRRT and non-LRRT groups, statistical differences were found in OS in the low-risk and intermediate-risk subgroups (p = 0.039 and p = 0.010, respectively) but no significant difference was found in OS in the high-risk subgroup (p = 0.076). Further multivariate analysis of different risk stratifications revealed that LRRT can improve OS of low- and intermediate-risk subgroups. CONCLUSIONS: The risk stratification of dmNPC may be used as a new prognostic factor to help clinicians organize individualized LRRT treatment to improve the survival outcomes of dmNPC patients.

Percent change in apparent diffusion coefficient and plasma EBV DNA after induction chemotherapy identifies distinct prognostic response phenotypes in advanced nasopharyngeal carcinoma.

BACKGROUND: To evaluate the prognostic value of the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI) and monitor the early treatment response to induction chemotherapy (IC) with plasma EBV DNA in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). RESULTS: A total of 307 stage III-IVb NPC patients were prospectively enrolled. All patients underwent MRI examinations to calculate ADC and plasma EBV DNA measurements pretreatment and post-IC. The participants' ADC value of 92.5% (284/307) increased post-IC. A higher percent change in ADC value (ΔADC%high group) post-IC was associated with a higher 5-year OS rate (90.7% vs 74.9%, p < 0.001) than those in the ΔADC%low group. Interestingly, ΔADC% was closely related to the response measured by RECIST 1.1 (p < 0.001) and plasma EBV DNA level (p = 0.037). The AUC significantly increased when post-IC plasma EBV DNA was added to ΔADC% to predict treatment failure. Thus, based on ΔADC% and plasma EBV DNA, we further divided the participants into three new prognostic response phenotypes (early response, intermediate response, and no response) that correlated with disparate risks of death (p = 0.001), disease progression (p < 0.001), distant metastasis (p < 0.001), and locoregional relapse (p < 0.001). CONCLUSION: The percentage change in ADC post-IC is indicative of treatment response and clinical outcome. ΔADC% and plasma EBV DNA-based response phenotypes may provide potential utility for early termination of treatment and allow guiding risk-adapted therapeutic strategies for LA-NPC.

Low value of whole-body dual-modality [18f]fluorodeoxyglucose positron emission tomography/computed tomography in primary staging of stage I-II nasopharyngeal carcinoma: a nest case-control study.

OBJECTIVES: The value of using PET/CT for staging of stage I-II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical therapy. METHODS: A total of 1003 patients with pathologically confirmed NPC of stages I-II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup ([CWU], head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat. RESULTS: Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% [62.3-82.1] vs. 91.1% [84.8-97.4], p = 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% [92.8-100.0] vs. 76.4% [67.6-85.2], p < 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival. CONCLUSIONS: This study showed PET/CT is of little value for staging of stage I-II NPC patients at initial imaging. KEY POINTS: • PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions. • No association existed between pre-treatment PET/CT use and improved survival in stage I-II NPC patients.

Molecular cloning, the characterization of metallothionein and catalase, and the evaluation of testicular toxicity of Cd in the Chinese fire-bellied newt (Cynops orientalis).

Cadmium (Cd) is an environmental toxicant and a nonessential metal. Cd can attack a wide range of organs, such as the liver, kidney, lung, ovary, testis, brain, and muscle in vertebrates. Among these organs, the testis might be the most sensitive organ to Cd toxicity. Metallothionein (MT) is a cysteine-rich protein with a low molecular weight, that can bind with Cd and eliminate reactive oxygen species (ROSs). Hydrogen peroxide, which as a crucial type of ROS that is induced by Cd, can be eliminated by catalase (CAT) in the self-protection of cells and to realize Cd toxicity resistance. To investigate the functions of MT and CAT in the testis of Cynops orientalis, we cloned the full-length MT and CAT genes of C. orientalis for the first time. Immunofluorescence results demonstrated that MT and CAT were expressed in Sertoli cells and all spermatogenic cells in the testis of C. orientalis. The results of the ultrastructural damage assay demonstrated that there were various impairments, which included organelle vacuolization, abnormal chromatin distribution, and apoptotic bodies, in somatic cells that were exposed to Cd. However, the anomalies of spermatozoa were located mainly in the mid-piece and head, many of which showed severely impaired structures. The results demonstrated that MT and CAT expression had distinct patterns in response to various Cd concentrations: an increase in MT mRNA levels with elevated Cd levels and a persistent increase in CAT mRNA levels with elevated Cd levels. These results suggested that MT and CAT play roles in Cd toxicity resistance in the testis and that the expression of CAT may be a better biomarker than the expression of MT for assessing Cd pollution.

Comparing three induction chemotherapy regimens for patients with locoregionally advanced nasopharyngeal carcinoma based on TNM stage and plasma Epstein-Barr virus DNA level.

BACKGROUND: We compared the efficacy and toxicity of three IC regimens (TPF: taxanes, cisplatin, and 5-fluorouracil; TP: taxanes and cisplatin; and PF: cisplatin and 5-fluorouracil) followed by CCRT in locoregionally advanced NPC. METHODS: The retrospective study involved 1354 patients with newly diagnosed stage III-IVA NPC treated with IC and CCRT. The median follow-up time in our cohort was 50 months. Based on EBV DNA level, all the patients with stage IV were divided into low- (pre-EBV DNA < 1500 copies) and high-risk group (pre-EBV DNA ≥ 1500 copies). Progression free survival (PFS), overall survival (OS), locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS) and grade 3-4 toxicities were compared among different IC regimens. The survival rates were compared using log-rank test and a Cox proportional hazards model was used to perform multivariate analyses. RESULTS: A multivariate analysis revealed TPF to be more effective than TP. Among stage III patients, no significant difference in clinical outcome between the different IC regimens was showed, while TPF was associated with significantly better survival conditions in the stage IV patients. A further subgroup analysis revealed that only patients with pre-EBV DNA ≥ 1500 copies could benefit from the application of TPF among stage IV NPC. In terms of acute toxicities, PF was associated with fewer grade 3/4 acute toxicities. CONCLUSIONS: In low-risk NPC patients, PF-based IC showed similar efficacy as TPF and TP but was associated with fewer grade 3/4 acute toxicities. In high-risk patients, however, the TPF regimen was superior to PF and TP, although grade 3/4 toxicities were more common with the TPF regimen.

Identifying optimal candidates for local treatment of the primary tumor among patients with de novo metastatic nasopharyngeal carcinoma: a retrospective cohort study based on Epstein-Barr virus DNA level and tumor response to palliative chemotherapy.

BACKGROUND: To evaluate the clinical outcome in patients with de novo metastatic nasopharyngeal carcinoma (NPC) treated or not treated with locoregional radiotherapy (LRRT) based on plasma Epstein-Barr virus (EBV) DNA level and tumor response after palliative chemotherapy (PCT). METHODS: From 2007 to 2016, 502 patients with de novo metastatic NPC were included in this study. All patients were treated with PCT and 315 patients received LRRT. Our primary study endpoint was overall survival (OS). RESULTS: EBV DNA was detected in 461 patients (91.8%) before treatment but was undetectable in 249 patients (49.6%) after PCT. Three hundred and seventeen patients (63.1%) achieved satisfactory response (complete response or partial response) to PCT. Both the post-PCT EBV DNA level and tumor response were independent prognostic factors. Among low-risk patients (patients with undetectable EBV DNA and satisfactory tumor response after PCT), the 3-year OS rate was 80.4% in LRRT-treated patients and 45.3% in patients not treated with LRRT (P < 0.001). Multivariate analyses demonstrated that LRRT was an independent prognostic factor of OS in the low-risk patients (P < 0.001). However, among the high-risk patients (patients with detectable EBV DNA and/or unsatisfactory response after PCT), no statistically significant survival differences were observed between the LRRT and non-LRRT groups. CONCLUSIONS: EBV DNA level and tumor response after PCT both correlate with the prognosis of de novo metastatic NPC. In such cases, LRRT may benefit the patients with undetectable EBV DNA levels and satisfactory tumor response after PCT.

Maximal standard uptake values of 18F-fluoro-2-deoxy-D-glucose positron emission tomography compared with Epstein-Barr virus DNA as prognostic indicators in de novo metastatic nasopharyngeal carcinoma patients.

BACKGROUND: This study aimed to evaluate the prognostic value of maximal standard uptake values (SUVmax) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) comparing with Epstein-Barr virus (EBV) DNA levels in de novo metastatic nasopharyngeal carcinoma (NPC) patients. METHODS: From December 2006 to December 2016, 253 de novo metastatic NPC patients assessed by PET/ computed tomography were involved in current study. SUVmax-T, SUVmax-N, and SUVmax-M referred to the SUVmax at the primary tumor, cervical lymph nodes, and metastatic lesions respectively. Overall survival (OS) was the primary endpoint. RESULT: Patients who died during the follow-up had significantly higher SUVmax-N, SUVmax-M, and EBV DNA level than those in the patients who were alive. SUVmax-N and SUVmax-M were positively correlated with EBV DNA level. The cut-off values of SUVmax-T, SUVmax-N, SUVmax-M, and EBV DNA were 17.0, 12.7, and 6.9, and 13,800 copies/mL respectively, which were determined by receiver operating characteristic (ROC) curve analysis. Patients with elevated SUVmax-N, SUVmax-M, and EBV DNA levels had a lower 3-year OS rate. In multivariate analysis, the independent prognostic factors of OS included EBV DNA, metastatic site, and locoregional radiotherapy application, while SUVmax was not an independent prognostic factor. CONCLUSION: In de novo metastatic NPC patients, higher SUVmax-N and SUVmax-M were associated with worse prognosis. However, the predictive ability of SUVmax-N and SUVmax-M was poorer than that of EBV DNA.

Neoadjuvant or Adjuvant Chemotherapy Plus Concurrent CRT Versus Concurrent CRT Alone in the Treatment of Nasopharyngeal Carcinoma: A Study Based on EBV DNA.

BACKGROUND: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. PATIENTS AND METHODS: A total of 2,263 eligible patients with stage III-IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis-free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. RESULTS: Patients in the low-risk group (stage N0-1 disease and Epstein-Barr virus [EBV] DNA <4,000 copies/mL) who received NACT followed by CCRT achieved significantly better 5-year DMFS than those treated with CCRT alone (96.2% vs 91.3%; P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22-0.80; P=.009). In both the intermediate-risk group (stage N0-1 disease and EBV DNA ≥4,000 copies/mL and stage N2-3 disease and EBV DNA <4,000 copies/mL) and the high-risk group (stage N2-3 disease and EBV DNA ≥4,000 copies/mL), comparison of NACT or ACT + CCRT versus CCRT alone indicated no significantly better survival for all end points. CONCLUSIONS: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.

Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.

Symptomatic venous thromboembolism associated with peripherally inserted central catheters predicts a worse survival in nasopharyngeal carcinoma: results of a large cohort, propensity score-matched analysis.

BACKGROUND: Despite increasing use, symptomatic venous thromboembolism (VTE) associated with peripherally inserted central catheter (PICC) is a common complication in nonmetastatic nasopharyngeal carcinoma (NPC) patients. METHODS: A total of 3012 nonmetastatic NPC patients were enrolled in this retrospective study, and we applied Cox regression and log-rank tests to assess the association between PICC-VTE and survival using the propensity score method (PSM) to adjust for gender, age, radiotherapy technique, tumor stage, node stage, UICC clinical stage and pre-treatment EBV DNA. RESULTS: 217 patients developed PICC-VTE, with an incidence of 7.20%. PSM identified 213 patients in the cohort with VTE and 852 in that without. Patients who developed PICC-VTE had a shorter 5-year PFS (77.5% vs 87.6%, p < 0.001), DMFS (85.0% vs 91.2%, p < 0.001), LRRFS (93.9% vs 97.7%, p < 0.001) and OS (85.4% vs 87.6%, p < 0.001). Subgroup analyses indicated that no significant survival difference was found between PICC-related superficial venous thrombosis and deep vein thrombosis, nor did different anticoagulant treatment methods. CONCLUSIONS: PICC-VTE was associated with a worse survival outcome in nonmetastatic NPC patients. A prospective randomized clinical trial is required to verify the results.

Liposomal paclitaxel versus docetaxel in induction chemotherapy using Taxanes, cisplatin and 5-fluorouracil for locally advanced nasopharyngeal carcinoma.

BACKGROUND: We wished to evaluate the efficacy and safety of liposomal paclitaxel and docetaxel for induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC). METHODS: A total of 1498 patients with newly-diagnosed NPC between 2009 and 2017 treated with IC plus concurrent chemotherapy were included in our observational study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and grade-3-4 toxicities were compared between groups using propensity score matching (PSM). RESULTS: In total, 767 patients were eligible for this study, with 104 (13.6%) and 663 (86.4%) receiving a liposomal paclitaxel-based and docetaxel-based taxanes, cisplatin and 5-fluorouracil (TPF) regimen, respectively. PSM identified 103 patients in the liposomal-paclitaxel group and 287 patients in the docetaxel group. There was no significant difference at 3 years for OS (92.2% vs. 93.9%, P = 0.942), PFS (82.6% vs. 81.7%, P = 0.394), LRFS (94.7% vs. 93.3%, P = 0.981) or DMFS (84.6% vs. 87.4%, P = 0.371) between the two groups after PSM. Significant interactions were not observed between the effect of chemotherapy regimen and sex, age, T stage, N stage, overall stage, or Epstein-Barr virus DNA level in the subgroup multivariate analysis. The prevalence of grade-3-4 leukopenia and neutropenia in the liposomal-paclitaxel group was significantly lower than that of the docetaxel group (P < 0.05 for all). CONCLUSIONS: Compared with docetaxel, liposomal paclitaxel has identical anti-tumor efficacy, but causes fewer and milder adverse reactions in IC for NPC.

[Ambient VOCs Characteristics and Reactivity During O3 Pollution in Autumn in Urban Beijing].

In order to understand the effect of volatile organic compounds (VOCs) on ozone pollution, the concentrations, chemical composition variations, and ozone formation potential (OFP) were studied under different O3 concentrations, using high-resolution online monitoring data obtained in the urban site of Beijing in autumn of 2019. The results showed that the average concentration of VOCs was (22.22±10.10)×10-9, with the largest contribution of VOCs from alkanes (55.65%), followed by that of oxygenated volatile organic compounds (OVOCs) (16.23%) and alkenes (8.13%). Three ozone pollution episodes were captured during the observation period. The average concentration of VOCs on pollution days was (26.22±12.52)×10-9, which was 60.17%higher than that on clear days (16.37±7.19)×10-9. The value of ozone formation potential (OFP) on pollution days was 113.63 µg·m-3, which was 56.55%higher than that on clear days. The contributions of OVOCs and aromatics to OFP on pollution days increased by 6.51%and 1.55%, respectively, whereas that of alkenes declined (8.72%). The ratios of toluene to benzene (T/B) and benzene, toluene, and ethylbenzene (B:T:E) were 1.55 and 0.36:0.55:0.09, respectively, indicating that vehicle exhaust had significant effects on VOCs in autumn in urban Beijing. The back-trajectory results indicated a high contribution of southern air masses to atmospheric VOCs variations in autumn in urban Beijing.