The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

Potential Gains in Health-Adjusted Life Expectancy by Reducing Burden of Noncommunicable Diseases in 188 Countries: A Population-Based Study.

OBJECTIVES: This article quantifies the potential gains in health-adjusted life expectancy for people aged 30 to 70 years (HALE[30-70]) by examining the reductions in disability in addition to premature mortality from noncommunicable diseases (NCDs). METHODS: We extracted data from the Global Burden of Disease Study 2019 for 4 major NCDs (cancers, cardiovascular diseases, chronic respiratory diseases, and diabetes mellitus) in 188 countries from 2010 to 2019. Estimates of the potential gains in HALE[30-70] were based on a counterfactual analysis involving 3 alternative future scenarios: (1) achieve Sustainable Development Goals target 3.4 but do not make any progress on disability reduction, (2) achieve Sustainable Development Goals target 3.4 and eliminate NCD-related disability, and (3) eliminate all NCD-related mortality and disability. RESULTS: In all scenarios, the high-income group has the greatest potential gains in HALE[30-70], above the global average. For all specific causes, potential gains in HALE[30-70] decrease as income levels fall. Across these 3 scenarios, the potential gains in HALE[30-70] globally of reducing premature mortality for 4 major NCDs are 3.13 years, 4.53 years, and 7.32 years, respectively. In scenario A, all income groups have the greatest potential gains in HALE[30-70] from diabetes and chronic respiratory diseases. In scenarios B and C, the high-income group has the greatest potential gains in HALE[30-70] from cancer intervention, and the other income groups have the greatest potential gains in HALE[30-70] from cardiovascular diseases intervention. CONCLUSION: Reducing premature death and disability from 4 major NCDs at once and attaching equal importance to each lead to a sizable improvement in HALE[30-70].

Impact of cumulative cisplatin dose in childhood nasopharyngeal carcinoma based on neoadjuvant chemotherapy response in the intensity-modulated radiotherapy era: a real-world study.

BACKGROUND: We aimed to comprehensively investigate the optimal cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) for locoregionally advanced nasopharyngeal carcinoma (CA-LANPC) with different tumor responses after neoadjuvant chemotherapy (NAC). METHODS: Patients with CA-LANPC who underwent NAC followed by cisplatin-based concurrent chemoradiotherapy were retrospectively analyzed. Evaluation of tumor response in patients was conducted by Response Evaluation Criteria for Solid Tumor (RECIST) 1.1 after two to four cycles NAC. Multivariate Cox proportional hazards models were used for prognosis. Recursive partitioning analysis (RPA) was conducted to classify participates and predict disease-free survival (DFS). RESULTS: One hundred and thirty-two patients with favorable response after NAC were included. The median CC-CCD was 163 mg/m2 (IQR, 145-194 mg/m2), and 160 mg/m2 was selected as the cutoff point to group patients into low and high CC-CCD groups (< 160 vs. ≥ 160 mg/m2). There was significant improvement in 5-year DFS (91.2% vs. 72.6%; P = 0.003) for patients receiving high CC-CCD compared to those receiving low CC-CCD. Multivariate analysis revealed that CC-CCD, T stage, and Epstein-Barr virus (EBV) DNA were independent prognostic factors for DFS (P < 0.05 for all). Patients were further categorized into two prognostic groups by RPA: the low-risk group (T1-3 disease with regardless of EBV DNA, and T4 disease with EBV DNA < 4000 copy/mL), and the high-risk group (T4 disease with EBV DNA ≥ 4000 copy/mL). Significant 5-year DFS improvement was observed for the high-risk group (P = 0.004) with high CC-CCD. However, DFS improvement was relatively insignificant in the low-risk group (P = 0.073). CONCLUSIONS: CC-CCD was a positive prognostic factor for responders after NAC in CA-LANPC. Furthermore, CC-CCD ≥ 160 mg/m2 could significantly improve DFS in the high-risk group with CA-LANPC, but the benefit of high CC-CCD in the low-risk group needs further study.

Prognostic value of neutrophil-to-lymphocyte ratio in advanced nasopharyngeal carcinoma: a large institution-based cohort study from an endemic area.

BACKGROUND: Findings remain unclear whether neutrophil-to-lymphocyte ratio (NLR) detrimentally affects advanced nasopharyngeal carcinoma (NPC) prognosis. We aim to evaluate the prognostic value of NLR in patients with NPC based on a large-scale cohort from an endemic area. METHODS: We selected patients retrospectively from a cohort examining long-term cancer outcomes following diagnosis. Neutrophil counts and lymphocyte counts were assessed prior to treatment. Kaplan-Meier method and log-rank test were used to calculate and compare survival outcomes. Additionally, Cox proportional hazards model was utilized to carry out univariate and multivariate analyses. RESULTS: Between October 2009 and August 2012, we enrolled 1550 consecutive NPC patients staged II-IVB. The median value of NLR was 2.27 (interquartile range [IQR], 1.71-3.12). Determined by operating characteristic curve using overall survival (OS) as an endpoint, the cutoff value for NLR was 2.50. At 5 years, NLR > 2.50 was associated with inferior OS (90.3% vs 82.5%; P < 0.001), distant metastasis-free survival (DMFS, 89.4% vs 85.0%; P = 0.014), and progression-free survival (PFS, 80.9% vs 76.5%; P = 0.031) than NLR ≤2.50. In multivariate analysis, NLR was found to be a significant prognostic factor for OS (HR, 1.72; 95% CI, 131-2.24; P < 0.001), DMFS (HR, 1.45; 95% CI, 1.10-1.92; P = 0.009), and PFS (HR, 1.29; 95% CI, 1.04-1.59; P = 0.021). CONCLUSION: Pretreatment NLR independently affects survival. Our findings suggest that NLR measurements will be of great clinical significance in the management of NPC.

Prognostic Value of Circulating Lipoprotein in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

BACKGROUND/AIMS: Lipoproteins have been reported to be associated with prognosis in various cancers; however, the prognostic value of lipoproteins in patients with nasopharyngeal carcinoma (NPC) remains largely unknown. We aim to asses the role of circulating lipoproteins in locoregionally advanced NPC patients. METHODS: Between October 2009 and August 2012, a total of 1,081 patients with stage III-IVB NPC were included in the analysis. Circulating high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are the two key lipoproteins, which were measured at baseline. Receiver operating characteristic (ROC) curve analysis was used to evaluate different cut-off points for lipoproteins. Actuarial rates were performed using Kaplan-Meier methods and the log-rank test. RESULTS: The cutoff points of HDL, LDL, and LDL/HDL ratio were 1.17 mmol/L, 3.75 mmol/L, and 2.73, respectively. At 5 years, high HDL (> 1.17 mmol/L) was significantly associated with better overall survival (OS, 86.6% vs. 78.9%; P=0.004), distant metastasis-free survival (DMFS, 86.9% vs. 80.8%; P=0.004), locoregional relapse-free survival (LRFS, 90.8% vs. 85.4%; P=0.010), and progression-free survival (PFS, 79.1% vs. 70.2%; P= 0.001) than low HDL (≤1.17 mmol/L). In contrast, high LDL (> 3.75 mmol/L) tend to be inferior OS (79.1% vs. 84.9%; P= 0.016) in compassion with low LDL (≤3.75 mmol/L). Likewise, patients with high LDL/HDL ratio (> 2.73) tend to be inferior OS (79.3% vs. 86.9%; P=0.001), DMFS (81.9% vs. 86.5%; P=0.030), and PFS (72.6% vs. 77.8%; P= 0.034) than those of low LDL/HDL ratio (≤2.73). In multivariate analysis, baseline HDL was found to be a significant prognostic factor for LRFS (HR= 0.65; 95% CI, 0.45-0.93; P= 0.019) and PFS (HR=0.75; 95% CI, 0.58-0.98; P= 0.034). CONCLUSIONS: Circulating HDL is significantly associated with treatment outcomes in patients with locoregionally advanced NPC. We suggest that HDL measurements will be of great clinical significance in the management of NPC.

The detrimental effects of radiotherapy interruption on local control after concurrent chemoradiotherapy for advanced T-stage nasopharyngeal carcinoma: an observational, prospective analysis.

BACKGROUND: Previous studies have reported radiotherapy interruption (RTI) is associated with poor local control in two-dimensional radiotherapy (2DRT) era. However, it remains unclear whether RTI still affects local control for advanced T stage (T3-4) in the intensity-modulated radiation therapy (IMRT) era. We aim to evaluate whether RTI affects local control for T3-4 NPC treated with definitive IMRT. METHODS: In this observational prospective study, 447 T3-4 NPC patients treated with IMRT plus concurrent chemotherapy were included. All patients completed the planned radiotherapy course, and RTI was defined as the actual time taken to finish the prescribed course of radiotherapy minus the planned radiotherapy time. Receiver operating characteristic (ROC) curve was used for determined the cutoff point of RTI. The effects of RTI on local control were analyzed in multivariate analysis. RESULTS: At 5 years, the local relapse-free survival (LRFS) and overall survival (OS) rates were 93.7 and 85.7%, respectively. The cutoff RTI for LRFS was 5.5 days by ROC curve. Compared to patients with RTI >  5 days, patients with RTI ≤ 5 days had a significantly lower rate of LRFS (97% vs. 83%; P < 0.001). In multivariate analysis, RTI was a risk factor independently associated with LRFS (HR = 9.64, 95% CI, 4.10-22.65), but not for OS (HR = 1.09, 95% CI, 0.84-1.64). CONCLUSIONS: The current analysis demonstrates a significant correlation between prolonged RTI and local control in NPC, even when concurrent chemotherapy is used. We consider that attention to RTI seems to be warranted for patients with advanced T-stage NPC in the era of IMRT.

Prognostic value of serum Epstein-Barr virus antibodies in patients with nasopharyngeal carcinoma and undetectable pretreatment Epstein-Barr virus DNA.

Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA-IgA) and viral capsid antigen (VCA-IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA-IgA and VCA-IgA in patients with NPC is less clear. We hypothesize that serum EA-IgA and VCA-IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non-metastatic NPC and undetectable pEBV DNA were included. Serum EA-IgA and VCA-IgA were determined by ELISA. After analysis, serum EA-IgA and VCA-IgA loads correlated positively with T, N, and overall stage (all P < 0.05). Serum EA-IgA was not associated with survival outcome in univariable analyses. But patients with serum VCA-IgA >1:120 had significantly inferior 5-year progression-free survival (80.4% vs 89.6%, P = 0.025), distant metastasis-free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse-free survival (88.4% vs 95.6%, P = 0.023; log-rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P < 0.05), but the VCA-IgA became insignificant. Further analyses revealed that serum VCA-IgA was not an independent prognostic factor in early N (N0-1) or advanced N (N2-3) stage NPC. In summary, although both EA-IgA and VCA-IgA correlate strongly with TNM stage, our analyses do not suggest that these antibodies are prognostic biomarkers in patients with NPC and undetectable pEBV DNA.

Prognostic value of primary gross tumor volume and standardized uptake value of 18F-FDG in PET/CT for distant metastasis in locoregionally advanced nasopharyngeal carcinoma.

Distant metastasis has become the predominant model of treatment failures in patients with locoregionally advanced nasopharyngeal carcinoma. Effort should therefore be made to stratify locoregionally advanced nasopharyngeal carcinoma patients into different groups based on the risk of metastasis to improve prognosis and tailor individualized treatments. This study aims to assess the value of primary gross tumor volume and the maximum standardized uptake value for predicting distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. A total of 294 locoregionally advanced nasopharyngeal carcinoma patients who were identified from prospectively maintained database and underwent fluor-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging before treatment were included. The maximum standardized uptake value was recorded for the primary tumor (SUVmax-P) and neck lymph nodes (SUVmax-N). Computed tomography-derived primary gross tumor volume was measured using the summation-of-area technique. At 5 years, the distant metastasis-free survival rate was 83.7%. The cut-off of the SUVmax-P, SUVmax-N, and primary gross tumor volume for distant metastasis-free survival was 8.95, 5.75, and 31.3 mL, respectively, by receiver operating characteristic curve. In univariate analysis, only SUVmax-N (hazard ratio: 7.01; 95% confidence interval: 1.70-28.87; p < 0.01) and clinical stage (hazard ratio: 3.03; 95% confidence interval: 1.67-5.47; p = 0.007) were confirmed as independent predictors of distant metastasis-free survival. A prognostic model was derived by SUVmax-N and clinical stage: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75). Multivariate analysis revealed that SUVmax-N and the prognostic model remained independent prognostic factors for distant metastasis-free survival (p = 0.023 and p < 0.001, respectively), but the clinical stage became insignificant (p = 0.133). Furthermore, the adjusted hazard ratios for the prognostic model were higher than SUVmax-N (hazard ratio = 6.27 vs 5.21, respectively). In summary, compared with SUVmax-P, SUVmax-N may be a better predictor of distant metastasis-free survival for patients with locoregionally advanced nasopharyngeal carcinoma. Combining SUVmax-N with clinical stage gives a more precise picture in predicting distant metastasis.

Neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in elderly patients with stage III-IVa nasopharyngeal carcinoma: A real-world study based on medical comorbidities.

PURPOSE: To evaluate the outcomes and toxicities of adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) in elderly (≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (LANPC, stage III-IVa). METHODS AND MATERIALS: Using an NPC-specific database, 245 elderly patients with stage III-IVa NPC, receiving CCRT +/- NAC, and an Adult Co-morbidity Evaluation 27 (ACE-27) score <2 were included. Recursive partitioning analysis (RPA) based on TNM stage and Epstein-Barr virus (EBV) DNA were applied for risk stratification. The primary end point was disease-free survival (DFS). RESULTS: Two risk groups were generated by the RPA model. In the high-risk group (EBV DNA < 4000 copy/ml with stage IVa & EBV DNA ≥4000 copy/ml with stage III-IVa), patients treated with NAC plus CCRT achieved improved 5-year DFS rates compared to those who received CCRT alone (56.9% vs. 29.4%; p = 0.003). But we failed to observe the survival benefit of additional NAC in the low-risk group (EBV DNA <4000 copy/ml with stage III). The most common severe acute toxic effects were leucopenia (46.8% vs. 24.4%) and neutropenia (43.7% vs. 20.2%) in the NAC plus CCRT group versus CCRT group with statistically significant differences. CONCLUSIONS: The addition of NAC to CCRT was associated with better DFS for the high-risk group of elderly LANPC patients with ACE-27 score <2. However, the survival benefit of additional NAC was not observed in low-risk patients.

The feasibility of reduced-dose radiotherapy in childhood nasopharyngeal carcinoma with favorable response to neoadjuvant chemotherapy.

BACKGROUND: To assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Using an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2-4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RDstandard, 66-72 Gy) and the reduced RD on primary tumors (PT-RDreduced, 60-65.9 Gy). RESULTS: A total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2-98.7 months) for the entire cohort. The PT-RDreduced group had a significantly decreased incidence of severe mucositis (51.3 % vs 32.1 %; P = 0.034) when compared to the PT-RDstandard group. The total incidence of severe sequela in the PT-RDstandard group were significantly higher than those in the PT-RDreduced group (31.8 % vs 13.7 %; P = 0.029). In the propensity-matched analysis, the PT-RDreduced group resulted in parallel 5-year survival with the PT-RDstandard group from the matched cohort (disease-free survival, 82.7 % vs 80.3 %, P = 0.841; overall survival, 91.7 % vs 91.3 %, P = 0.582; distant metastasis-free survival, 87.5 % vs 82.8 %, P = 0.573; and locoregional relapse-free survival, 95.6 % vs 97.3 %, P = 0.836). In multivariate analysis, the impact of PT-RDreduced on all survival end points remained insignificant. CONCLUSIONS: Chemoradiotherapy with RD at levels of 60-65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC.

Concurrent chemoradiotherapy with or without neoadjuvant chemotherapy in pediatric patients with stage III-IVa nasopharyngeal carcinoma: a real-world propensity score-matched cohort study.

OBJECTIVES: To compare neoadjuvant chemotherapy (NAC) plus concurrent chemoradiotherapy (CCRT) to CCRT alone in children and adolescents (age ≤ 18 years) with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC, stage III-IVA). MATERIALS AND METHODS: 195 CA-LANPC patients who were treated through CCRT with or without NAC between 2008 and 2018 were enrolled in this study. A matched cohort composed of CCRT patients and NAC-CCRT patients was generated by propensity score matching (PSM) at a 1:2 ratio. Survival outcomes and toxicities were compared between the CCRT group and NAC-CCRT group. RESULTS: Of the 195 patients, 158 (81%) received NAC plus CCRT, and 37 (19%) received CCRT alone. The NAC-CCRT group had higher EBV DNA levels (≥ 4000 copy/mL), more advanced TNM stage (stage IV disease), and lower incidence of a high radiation dose (> 6600 cGy) than the CCRT group. To avoid bias in treatment selection within retrospectively analysis, 34 patients from the CCRT group were matched with 68 patients from the NAC-CCRT group. In the matched cohort, the 5-year DMFS rate was 94.0% in the NAC-CCRT group versus 82.4% in the CCRT group, with marginal statistical significance (HR = 0.31; 95%CI 0.09-1.10; P = 0.055). During treatment, the accumulate incidence of severe acute toxicities (65.8% vs 45.9%; P = 0.037) in the NAC-CCRT group was higher than the CCRT group. However, the CCRT group had significantly higher accumulate incidence of severe late toxicities (30.3% vs 16.8%; P = 0.041) than the NAC-CCRT group. CONCLUSIONS: Addition of NAC to CCRT tended to improve long-term DMFS in CA-LANPC patients with acceptable toxicity. However, relative randomized clinical trial is still needed in the future.

The association between childhood adiposity in northeast China and anthropogenic heat flux: A new insight into the comprehensive impact of human activities.

Anthropogenic heat has been reported to have significant health impacts, but research on its association with childhood adiposity is still lacking. In this study, we matched the 2008-2012 average anthropogenic heat flux, as simulated by a grid estimation model using inventory methods, with questionnaire and measurement data of 49,938 children randomly recruited from seven cities in Northeast China in 2012. After adjusting for social demographic and behavioral factors, we used generalized linear mixed-effect models to assess the association between anthropogenic heat flux and adiposity among children. We also examined the effect modification of various social demographic and behavioral confounders. We found that each 10 W/m2 increase in total anthropogenic heat flux and that from the industry source was associated with an increase of 5.82% (95% CI = 0.84%-11.05%) and 6.62% (95% CI = 0.87%-12.70%) in the odds of childhood adiposity. Similarly, the excess rate of adiposity among children were 5.26% (95% CI = -1.33%-12.29%) and 8.51% (95% CI = 2.24%-15.17%) per 1 W/m2 increase in the anthropogenic heat flux from transportation and buildings, and was 7.94% (95% CI = 2.28%-13.91%) per 0.001 W/m2 increase in the anthropogenic heat flux from human metabolism. We also found generally greater effect estimates among female children and children who were exposed to passive smoking during pregnancy, born by caesarean section, non-breastfed/mixed-fed, or lived within 20 m adjacent to the main road. The potential deleterious effect of anthropogenic heat exposure on adiposity among children may make it a new but major threat to be targeted by future mitigation strategies.

Does three cycles of neoadjuvant chemotherapy prior to concurrent chemoradiotherapy provide benefits for all childhood patients with locoregionally advanced nasopharyngeal carcinoma?

BACKGROUND: Adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) is the main strategy in treatment of children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). Yet, an optimal number of NAC cycles remains unknown. We aimed to optimize the NAC cycle and potentially contribute to clinical decision making for the individual treatment of CA-LANPC. PATIENTS AND METHODS: Utilizing an NPC-specific database through an acknowledged big-data information system at our center, we identified 143 CA-LANPC treated with NAC followed by CCRT between September 2007 through April 2018. Recursive partitioning analysis (RPA) was performed to categorize the patients and predict disease-free survival (DFS). The clinical benefits of NAC cycles (two cycles vs three cycles) were assessed in each risk group. RESULTS: Independent factors derived from multivariable analysis to predict DFS were T stage (T1-3 vs T4) and plasma Epstein-Barr virus (EBV) DNA (< 4000 vs ≥ 4000 copies/mL) for risk stratification. Consequently, 87 (61%) participants were classified as low-risk group (T1-3 with low or high EBV DNA, and T4 with low EBV DNA) and the other 56 patients (39%) were classified as a high-risk group (T4 with high EBV DNA) through RPA, and corresponding 5-year DFS rates of 91.9% and 71.2%, respectively (p = 0.001). Among the high-risk group, patients receiving three cycles of NAC had statistically significant improvement in 5-year DFS over those who received two cycles of NAC (86.7% vs 59.1%; p = 0.020), while the survival benefit of three cycles NAC for low-risk groups were not observed (94.7% vs 89.7%; p = 0.652). CONCLUSIONS: We found three cycles of NAC with CCRT was a positive prognostic indicator for improved DFS for the high-risk group among CA-LANPC. However, whether low-risk patients could benefit from three cycles NAC needs further study.

Development of a web-based prognostic model to quantify the survival benefit of cumulative cisplatin dose during concurrent chemoradiotherapy in childhood nasopharyngeal carcinoma.

PURPOSE: To quantify and predict the survival benefits of cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). MATERIALS AND METHODS: Patients with CA-LANPC who received first-line neoadjuvant chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) between September 2007 and April 2018 were evaluated. Recursive partitioning analyses (RPAs) helped identify the ideal thresholds of CC-CCD on disease-free survival (DFS). We then developed a web-based predictive model to quantify the survival benefit of CC-CCD for CA-LANPC. RESULTS: In total, 139 patients were eligible for the analysis. The median CC-CCD was 162 mg/m2 (IQR, 138-192 mg/m2). The optimum cut-off point of CC-CCD was 160 mg/m2 for DFS. Hence, we selected 160 mg/m2 as the cut-off to classify CA-LANPC into either high or low CC-CCD groups for survival analysis. The 5-year DFS rates were 91.6% in the high (≥160 mg/m2) CC-CCD group and 77.8% in the low (<160 mg/m2) CC-CCD group (P = 0.011). Multivariate analysis indicated CC-CCD (HR, 0.34; 95%CI, 0.13-0.87; P = 0.024), T stage (HR, 3.72; 95%CI, 1.35-10.22; P = 0.011), and EBV DNA (HR, 3.00; 95%CI, 1.00-8.97; P = 0.049) were independent prognostic factors and were incorporated into the prognostic model. N stage was also included due to its clinical importance. The predictive model was demonstrably accurate (C-index, 0.741) when predicting 5-year DFS rates. CONCLUSIONS: We built a predictive model to quantify the survival benefit of CC-CCD for CA-LANPC treated with NAC plus CCRT. This tool may improve individual treatment consultations and facilitate evidence-based decision-making.

The prognostic value of adding systemic inflammation response index to Epstein-Barr virus DNA in childhood nasopharyngeal carcinoma: A real-world study.

BACKGROUND: To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC). METHODS: A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS). RESULTS: Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p < 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p < 0.05). CONCLUSIONS: The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC.

Establishing a Predictive Nomogram for Cervical Lymph Node Metastasis in Patients With Papillary Thyroid Carcinoma.

OBJECTIVES: The purpose of this study was to establish a nomogram for predicting cervical lymph node metastasis (CLNM) in patients with papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: A total of 418 patients with papillary thyroid carcinoma undergoing total thyroidectomy with cervical lymph node dissection were enrolled in the retrospective study from January 2016 to September 2019. Univariate and multivariate Logistic regression analysis were performed to screen the clinicopathologic, laboratory and ultrasound (US) parameters influencing cervical lymph nodes metastasis and develop the predicting model. RESULTS: CLNM was proved in 34.4% (144/418) of patients. In the multivariate regression analysis, Male, Age < 45 years, Tumor size > 20mm, multifocality, ambiguous boundary, extracapsular invasion and US-suggested lymph nodes metastasis were independent risk factors of CLNM (p < 0.05). Prediction nomogram showed an excellent discriminative ability, with a C-index of 0.940 (95% confidence interval [CI], 0.888-0.991), and a good calibration. CONCLUSION: The established nomogram showed a good prediction of CLNM in patients with PTC. It is conveniently used and should be considered in the determination of surgical procedures.

Development and Validation of Web-Based Nomograms to Precisely Predict Survival Outcomes of Non-metastatic Nasopharyngeal Carcinoma in an Endemic Area.

PURPOSE: This study aimed to develop web-based nomograms to precisely predict survival outcomes in patients with non-metastatic nasopharyngeal carcinoma (NPC) in an endemic area. MATERIALS AND METHODS: A total of 10,126 patients who underwent radical intensity-modulated radiotherapy at Sun Yat-sen University Cancer Center (SYSUCC) from 2009 to 2015 were analyzed. We assigned patients into a training cohort (SYSUCC-A, n=6,751) and an internal validation cohort (SYSUCC-B, n=3,375) based on computer-generated random numbers. Patients collected from Wuzhou Red Cross Hospital (WZRCH) between 2012 and 2015 were used as the independent external validation cohort (WZRCH, n=450). Concordance index (C-index) was used to determine predictive accuracy and discriminative ability for the nomogram. The web-based clinicopathologic prediction models for predicting survival were based on Cox regression. RESULTS: The C-indexes for SYSUCC-A, SYSUCC-B, and WZRCH cohorts for the established nomograms to predict 3-year overall survival (OS) was 0.736, 0.715, and 0.691. Additionally, C-indexes to predict 3-year distant metastasis-free survival (DMFS) was 0.717, 0.706, and 0.686, disease-free survival (DFS) was 0.713, 0.697, and 0.656, local relapse-free survival was 0.695, 0.684, and 0.652, and regional relapse-free survival was 0.672, 0.650, and 0.616. The calibration plots showed great agreement between nomogram-predicted 3-year survival outcomes and actual 3-year survival outcomes. Moreover, C-indexes of the nomograms for OS, DMFS, and DFS were significantly superior than TNM stage (p< 0.001 for all). CONCLUSION: These user-friendly nomograms can precisely predict survival endpoints in patients with non-metastatic NPC. They may serve as a useful tool for providing patient counseling and help physicians to make individual follow-up plans.

Optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma: A real-world data study.

PURPOSE: To identify an optimal cumulative cisplatin dose along with concurrent chemoradiotherapy (CC-CCD) for children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC) using real-world data. MATERIALS AND METHODS: Using an NPC-specific database at our center, 157 patients younger than 19 years old with non-disseminated CALANPC and receiving neoadjuvant chemotherapy (NAC) plus cisplatin-based concurrent chemoradiotherapy (CCRT) were enrolled. Confounding factors were controlled by conducting propensity score matching analysis. Primary endpoints include disease-free survival (DFS) and distant metastasis-free survival (DMFS). RESULTS: The optimal threshold for CC-CCD with respect to DFS was 160 mg/m2 based on recursive partitioning analyses (RPA). Therefore, a uniform threshold of 160 mg/m2 (≥160 vs. <160 mg/m2) was selected to classify patients between high and low CC-CCD groups for survival analysis. Patients receiving low CC-CCD showed a significant decrease in 5-year DFS (76.6% vs 91.3%; P = 0.006) and DMFS (81.3% vs 93.5%; P = 0.009) compared to those receiving high CC-CCD. Multivariate analyses indicated that high CC-CCD as an favorable prognostic influence for DFS (P = 0.007) and DMFS (P = 0.008). Further matched analysis identified 65 pairs in both high and low CC-CCD groups. In the matched cohort, high CC-CCD was still identified as a favorable factor for prognosis in DFS (HR, 0.23; 95% CI, 0.08-0.70; P = 0.010) and DMFS (HR, 0.23; 95% CI, 0.06-0.82; P = 0.023). CONCLUSION: CC-CCD exerts significant treatment effects and 160 mg/m2 CC-CCD may be adequate to provide antitumor effects for CALANPC receiving NAC plus CCRT.

Relationships between Long-Term Ozone Exposure and Allergic Rhinitis and Bronchitic Symptoms in Chinese Children.

Numerous studies have demonstrated that exposure to ambient ozone (O3) could have adverse effects on children's respiratory health. However, previous studies mainly focused on asthma and wheezing. Evidence for allergic rhinitis and bronchitic symptoms (e.g., persistent cough and phlegm) associated with O3 is limited, and results from existing studies are inconsistent. This study included a total of 59,754 children from the seven northeastern cities study (SNEC), who were aged 2 to 17 years and from 94 kindergarten, elementary and middle schools. Information on doctor-diagnosed allergic rhinitis (AR), persistent cough, and persistent phlegm was collected during 2012-2013 using a standardized questionnaire developed by the American Thoracic Society (ATS). Information for potential confounders was also collected via questionnaire. Individuals' exposure to ambient ozone (O3) during the four years before the investigation was estimated using a satellite-based random forest model. A higher level of O3 was significantly associated with increased risk of AR and bronchitic symptoms. After controlling for potential confounders, the OR (95% CI) were 1.13 (1.07-1.18), 1.10 (1.06-1.16), and 1.12 (1.05-1.20) for AR, persistent cough, and persistent phlegm, respectively, associated with each interquartile range (IQR) rise in O3 concentration. Interaction analyses showed stronger adverse effects of O3 on AR in children aged 7-17 years than those aged 2-6 years, while the adverse association of O3 with cough was more prominent in females and children aged 7-12 years than in males and children aged 2-6 and 13-17 years. This study showed that long-term exposure to ambient O3 was significantly associated with higher risk of AR and bronchitic symptoms in children, and the association varies across age and gender. Our findings contribute additional evidence for the importance of controlling O3 pollution and protecting children from O3 exposure.

Projecting life-cycle environmental impacts of corn production in the U.S. Midwest under future climate scenarios using a machine learning approach.

Climate change is exacerbating environmental pollution from crop production. Spatially and temporally explicit estimates of life-cycle environmental impacts are therefore needed for suggesting location and time relevant environmental mitigations strategies. Emission factors and process-based mechanism models are popular approaches used to estimate life-cycle environmental impacts. However, emission factors are often incapable of describing spatial and temporal heterogeneity of agricultural emissions, whereas process-based mechanistic models, capable of capturing the heterogeneity, tend to be very complicated and time-consuming. Efficient prediction of life-cycle environmental impacts from agricultural production is lacking. This study develops a rapid predictive model to quantify life-cycle global warming (GW) and eutrophication (EU) impacts of corn production using a novel machine learning approach. We used the boosted regression tree (BRT) model to estimate future life-cycle environmental impacts of corn production in U.S. Midwest counties under four emissions scenarios for years 2022-2100. Results from BRT models indicate that the cross-validation (R2) for predicting life cycle GW and EU impacts ranged from 0.78 to 0.82, respectively. Furthermore, results show that future life-cycle GW and EU impacts of corn production will increase in magnitude under all four emissions scenarios, with the highest environmental impacts shown under the high-emissions scenario. Moreover, this study found that changes in precipitation and temperature played a significant role in influencing the spatial heterogeneity in all life-cycle impacts across Midwest counties. The BRT model results indicate that machine learning can be a useful tool for predicting spatially and temporally explicit future life-cycle environmental impacts associated with corn production under different climate scenarios.