Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Associations between serum trace elements and the risk of nasopharyngeal carcinoma: a multi-center case-control study in Guangdong Province, southern China.

Background: Associations between trace elements and nasopharyngeal carcinoma (NPC) have been speculated but not thoroughly examined. Methods: This study registered a total of 225 newly diagnosed patients with NPC and 225 healthy controls matched by sex and age from three municipal hospitals in Guangdong Province, southern China between 2011 and 2015. Information was collected by questionnaire on the demographic characteristics and other possibly confounding lifestyle factors. Eight trace elements and the level of Epstein-Barr virus (EBV) antibody were measured in casual (spot) serum specimens by inductively coupled plasma-mass spectrometry (ICP-MS) and enzyme-linked immunosorbent assay (ELISA), respectively. Restricted cubic splines and conditional logistic regression were applied to assess the relationship between trace elements and NPC risk through single-and multiple-elements models. Results: Serum levels of chromium (Cr), cobalt (Co), nickel (Ni), arsenic (As), strontium (Sr) and molybdenum (Mo) were not associated with NPC risk. Manganese (Mn) and cadmium (Cd) were positively associated with NPC risk in both single-and multiple-element models, with ORs of the highest tertile compared with the reference categories 3.90 (95% CI, 1.27 to 7.34) for Mn and 2.30 (95% CI, 1.26 to 3.38) for Cd. Restricted cubic splines showed that there was a linear increasing trend between Mn and NPC risk, while for Cd there was a J-type correlation. Conclusion: Serum levels of Cd and Mn was positively related with NPC risk. Prospective researches on the associations of the two trace elements with NPC ought to be taken into account within the future.

New insights into the composition and diversity of endophytic bacteria in cultivated Huperzia serrata.

Endophytic bacteria play crucial roles in the growth and bioactive compound synthesis of host plants. In this study, the composition and diversity of endophytic bacteria in the roots, stems, and leaves from 3-year-old artificially cultivated Huperzia serrata were investigated using Illumina HiSeq sequencing technology. Total effective reads were assigned to 936 operational taxonomic units (OTUs), belonging to 12 phyla and 289 genera. A total of 28, 3, and 2 OTUs were exclusive to the roots, stems, and leaves, respectively. The bacterial richness and diversity in the roots were significantly lower than those in the leaves and stems. The dominant genera with significant distribution differences among these plant tissue samples were Burkholderia-Caballeronia-Paraburkholderia, Sphingomonas, Acidibacter, Bradyrhizobium, Bryobacter, Methylocella, Nocardioides, Acidothermus, and Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium. Furthermore, the differences in the bacterial communities associated with these plant tissue samples were visualized using principal coordinate analysis and cluster pedigree diagrams. Linear discriminant analysis effect size explained statistically significant differences among the endophytic bacterial microbiota in these plant tissue samples. Overall, this study provides new insights into the diversity and distribution patterns of endophytic bacteria in the different tissues of H. serrata.

Dietary intakes of trihalomethanes and haloacetic acids from ready-to-eat vegetables in taiwan.

BACKGROUND: Chlorine-based disinfectants are often used to sanitize fruit and vegetables to produce a product called ready-to-eat (RTE) vegetables. During the disinfection process, disinfection byproducts (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs), might be formed via chlorination. OBJECTIVE: To determine the amounts of DBPs that occur in RTE vegetables in Taiwan, an analytical method which can detect THMs and HAAs simultaneously was developed for this study. METHODS: For HAAs, dimethyl sulfate (DMS) was first added into the sample as derivatization reagent and tetrabutylammonium hydrogen sulfate (TBA-H2SO4) was used as the ion-pairing agent to improve the derivatization process. Afterwards, the solid-phase microextraction (SPME) procedure coupled with gas chromatography with tandem mass spectrometers (GC/MS/MS) was performed to measure the HAAs derivatives and THMs in the sample. RESULTS: A total of 92 single RTE ingredients were analyzed in this study. Among various THMs and HAAs, the results showed that dibromochloromethane (21%) and dichloroacetic acid (12%) had the highest detection rates, respectively. Compared with fruits, vegetables were more easily to contain DBPs. For adults in Taiwan, the maximum daily exposure of THMs and HAAs estimated via the consumption of RTE vegetables were 28.53 and 77.83 µg, respectively. SIGNIFICANCE: The findings from this study suggest that the exposure of DBPs from RTE vegetables is an important food safety issue in Taiwan.

Association Between Traditional Herbal Diet and Nasopharyngeal Carcinoma Risk: A Prospective Cohort Study in Southern China.

INTRODUCTION: Prospective evidence for herbal diet and nasopharyngeal carcinoma (NPC) development is absent. We therefore evaluated the associations of herbal soup and herbal tea with NPC in a prospective cohort study in southern China. METHODS: Based on an NPC screening cohort established in 2008-2015, information on herbal diet consumption, potential confounding factors, and Epstein-Barr virus (EBV) antibody levels were collected from 10,179 individuals aged 30-69 years in Sihui city, southern China. Cox regression models were performed to examine herbal diet with NPC risk, and logistic regression models were used to examine herbal diet with EBV reactivation. RESULTS: During a median of 7.54 years of follow-up, 69 participants developed NPC. Herbal soup consumption was associated with decreased NPC risk, with HRs of 0.31 (95% confidence interval (CI): 0.15-0.62) for the highest intake frequency and 0.29 (95% CI: 0.16-0.51) for a longer duration. However, herbal tea was not significantly associated. Moreover, we identified herbal soup was inversely associated with EBV seropositivity among all the participants at baseline, with the adjusted ORs being 0.78 (95% CI: 0.65-0.93) for immunoglobulin A antibodies against EBV capsid antigens (VCA-IgA) and 0.76 (95% CI: 0.64-0.91) for nuclear antigen 1 (EBNA1-IgA) in those with the highest frequency and 0.70 (95% CI: 0.59-0.84) for VCA-IgA and 0.64 (95% CI: 0.54-0.77) for EBNA1-IgA in those with the longer duration. Inverse associations were also observed in non-NPC individuals. CONCLUSIONS: With inhibition of EBV reactivation by plants, herbal soup could significantly decrease the risk of NPC in endemic areas.

Validity and reliability of the simplified Chinese patient-reported outcomes version of the common terminology criteria for adverse events.

BACKGROUND: The psychometric properties of the simplified Chinese version of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) have not been assessed. Therefore, we aimed to assess its validity, reliability, and responsiveness. PATIENTS AND METHODS: A Chinese version of the PRO-CTCAE and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) were distributed to 1580 patients from four cancer hospitals in China. Validity assessments included construct validity, measured by Pearson's correlations and confirmatory factor analysis (CFA), and known-groups validity, measured by t-tests. The assessment of reliability included internal consistency, measured by Cronbach's ɑ, and test-retest reliability, measured by the intraclass correlation (ICC). Responsiveness was assessed by standardized response means (SRMs). RESULTS: Data from 1555 patients who completed the instruments were analyzed. The correlations were high between PRO-CTCAE items and parallel QLQ-C30 symptom scales (r > 0.60, p < 0.001), except for fatigue (severity: r = 0.49). Moreover, CFA showed the PRO-CTCAE structure was a good fit with the data (Root Mean Square Error of Approximation = 0.046). Known-groups validity was also confirmed. Cronbach's ɑ of all item clusters were greater than 0.9 and the median test-retest reliability coefficients of the 38 items were 0.85 (range = 0.71-0.91). In addition, the SRMs of PRO-CTCAE items were greater than 0.8, indicating strong responsiveness. CONCLUSION: The simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

Evolving landscape and academic attitudes toward the controversies of global immuno-oncology trials.

This cross-sectional and longitudinal descriptive analysis aimed to track the evolving landscape of global immuno-oncology (IO) trials and provide insight into the resolution of IO-related controversies. Clinical trials (n = 4510) registered on ClinicalTrials.gov in 2007 to 2019 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), cancer vaccines and immune modulators were included. Most of IO trials are Phase 2 and focus on ICIs and multiple IO therapies. The United States leads global IO research, with stable growth and the best methodological quality. Mainland China ranks first in the number of ACT trials but has the lowest article publication rate (6.2%). A multiple-arm comparative design is often adopted in multiple IO therapies trials (44.0%). Trials studying ICIs and multiple IO therapies are likely to use early registration (80.0% and 86.6%) and stringent corticosteroid-/infection-related criteria. Hospitals have provided the most extensive and strongest support for all IO categories. Big pharma prefers to fund Phase 3-4 ICI trials (6.98%), while small pharma has a wider sponsorship favoring Phase 1-2 trials. The "partial-use-of-corticosteroids" strategy is generally well accepted in ICI trials with a definitive trend (32.5%; P < .001) but is associated with the poor dissemination of results (P ≤ .020), while the complete disclosure and standardization of dose/timing limits are still lacking. Disparities in design features and dissemination of results are widespread in IO trials and are modulated by IO category, cancer type and sponsor. We propose policy reforms to redefine the timely publication of IO trials and standardize the resolution of corticosteroid-/infection-related issues.

Combining tumor response and personalized risk assessment: Potential for adaptation of concurrent chemotherapy in locoregionally advanced nasopharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND AND PURPOSE: In the intensity-modulated radiotherapy (IMRT) era, the role of concurrent chemoradiotherapy (CCRT) after induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is undetermined, while concerns exist about CCRT-associated excessive toxicity. We aimed to combine tumor response and risk assessment to guide decisions about concurrent chemotherapy. MATERIALS AND METHODS: From April 2009 to December 2015, 744 LANPC patients treated with CCRT/IMRT after IC were included. Matching techniques were performed for treatment effect evaluation. Tumor response to IC was used for patient stratification. A nomogram was built based on multivariable Cox regression analysis to predict overall survival (OS). RESULTS: After IC, 508 patients (68.3%) had favorable tumor response (complete or partial response), among whom IC + CCRT achieved significantly superior 5-year disease-free survival and OS than IC + IMRT (82.2% vs. 72.5%, P = 0.025; 89.2% vs. 79.9%, P = 0.025). However, no significant difference was found in patients with unfavorable response (both P > 0.05). For favorable responders, a nomogram was built integrating age, smoking, T category, N category, pretreatment Epstein-Barr virus DNA and treatment modality. The concordance index was 0.713 and calibration was good. The nomogram determined three risk groups with distinct OS. High-risk patients benefited from CCRT after IC regarding disease-free survival, OS and distant metastasis-free survival, whereas low- and intermediate-risk patients did not. CONCLUSIONS: For LANPC patients with unfavorable response to IC, subsequent CCRT seems inadequate, rendering intensification necessary. For favorable responders with low risk, IC + IMRT represents a reasonable de-intensification approach, although confirmation by prospective data is needed.

p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD.

BACKGROUND: Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive impairment. The aggregation of amyloid ß (Aß) and hyperphosphorylated tau protein are two major pathological features of AD. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) has been indicated in Aß pathology; however, whether and how it affects tau pathology are not yet clear. METHODS: The role of NOX2 in cognitive function, amyloid plaque formation, and tau hyperphosphorylation were examined in APP/PS1 transgenic mice mated with p47phox-deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1) and/or in p47phox-deficient mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The cognitive and non-cognitive functions in these mice were assessed by Morris water maze, Rotarod test, open field, and elevated plus maze. Aß levels, amyloid plaques, p47phox expression, and astrocyte activation were evaluated using immunofluorescence staining, ELISA, and/or Western blotting. Cultured primary neuronal cells were treated with okadaic acid or conditioned media (CM) from high glucose-stimulated primary astrocytes. The alteration in tau pathology was determined using Western blotting and immunofluorescence staining. RESULTS: Deletion of the gene coding for p47phox, the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47phox deficiency decreased the activation of astrocytes but had no effect on Aß levels and amyloid plaque formation in the brains of aged APP/PS1 mice, which displayed markedly increased expression of p47phox in neurons and astrocytes. Cell culture studies found that neuronal p47phox deletion attenuated okadaic acid-induced tau hyperphosphorylation at specific sites in primary cultures of neurons. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in primary neurons, whereas this effect was absent from p47phox-deficient astrocytes. CONCLUSIONS: These results suggest that p47phox is associated with cognitive function and tau pathology in AD. p47phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affect tau hyperphosphorylation by activating astrocytes indirectly. Our results provide new insights into the role of NOX2 in AD and indicate that targeted inhibition of p47phox may be a new strategy for the treatment of AD.

Association between outcome disparities and pragmatic features related to clinical trial and real-world settings in nasopharyngeal carcinoma: A population-based retrospective cohort study, 2006-2016.

BACKGROUND: Prognosis often differs between trial participants and nontrial (pragmatic) patients in similar clinical scenarios, raising a concern that results of trials may not represent those in real-world practice. METHODS AND MATERIALS: Individual patient data were extracted from three phase III randomized controlled trials and a big-data real-world database (n = 10,126). Patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy (CCRT [control]: 2438 vs. 519) or induction chemotherapy plus CCRT (experimental) were included. Propensity score matching and correspondence analysis were used for data mining. RESULTS: Compared with the real-world CCRT cohort, clinical trials preferred to include cases with T4 (25.3-43.3% vs. 18.8%) and N2 (44.4-60.7% vs. 38.9%) categories. Real-world patients were more likely to undergo shorter irradiation time (44 vs. 46-49 days), inadequate chemotherapy cycles (70.6% vs. 25.2-43.9%), other chemotherapy (36.4% vs. 0.0%), and flexible regimens (≥3 vs. 1). Although real-world patients had better survival than trial participants, the survival disparities disappeared in the matched cohorts, except for in one trial with the lowest pragmatism assessment caused by stringent eligibility criteria and low flexibility of delivery. Stage specification, year of treatment, and Epstein-Barr virus DNA were related to survival disparities (all P ≤ 0.034). The influence of pragmatic features on survival mainly affected the control (all P ≤ 0.043) rather than the experimental group. CONCLUSION: Special attention should be paid to the control group when interpreting trial results. Assessing whether the pragmatic features of studies deviate from routine practice will lead to better conversion of trial findings into clinical guidelines.

Prognostic value of MRI-determined cervical lymph node size in nasopharyngeal carcinoma.

OBJECTIVES: To investigate the prognostic value of magnetic resonance imaging (MRI)-determined cervical lymph node (CLN) size in nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed 2066 patients with NPC treated with intensity-modulated radiotherapy, and randomly divided them into two groups, in a 1:1 ratio. One group was used for training (the training group), and the other one was for internal validation (the validation group). All patients had undergone MRI examination and the maximal axial diameters (MAD) of the axial plane of all positive nodes had been measured and recorded. RESULTS: Of 683 patients with CLN metastases in the training group (n = 1033), MAD = 4 cm was associated with worse OS (64.7% vs 84.6%, P < .001), DFS (55.9% vs 76.3%, P = .001), and DMFS (67.6% vs 86.1%, P = .001). Multivariate analysis showed that MAD = 4 cm was a significant negative prognostic factor for OS (HR = 2.058; P = .025), DFS (HR = 1.727; P = .049), and DMFS (HR = 2.034; P = .036). When MRI-determined MAD = 4 cm was classified as N3 in the N classification, the OS, DFS, DMFS, and RRFS survival curves were well separated. The OS, DFS, DMFS, and RRFS concordance indexes were not statistically different between the proposed N staging system and the UICC/AJCC staging system in the training group, or between the training group and the validation group (all P = .05). CONCLUSION: MAD = 4 cm on axial MRI slices can be recommended as a prognostic factor in future versions of the UICC/AJCC NPC staging system.

Nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: clinical outcomes and patterns of failure among subsets of 8th AJCC stage IVa.

OBJECTIVES: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. RESULTS: T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). CONCLUSIONS: In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. KEY POINTS: • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.

Thyroid dose-volume thresholds for the risk of radiation-related hypothyroidism in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy-A single-institution study.

BACKGROUND: To identify thyroid dose-volume thresholds for radiotherapy (RT)-related hypothyroidism (HT) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated RT (IMRT). In this way, we desired to guide the design of treatment plans and, finally, lower HT prevalence. METHODS: In total, 345 NPC patients treated with IMRT were evaluated retrospectively during a median follow-up of 45.2 (range, 11.3-64.9) months. Serum-based assessments of thyroid function before and after IMRT were monitored periodically. Thyroid dose-volume parameters were analyzed for their association with HT risk. RESULTS: In total, 44.1% of patients (152/345) developed primary HT. Analyses of thyroid dose-volume parameters identified a stringent dose-volume histogram (DVH) threshold defined by V25Gy (the percentage thyroid volume that receives >25 Gy, not the absolute volume) ≤60%, V35Gy  ≤ 55%, and V45Gy  ≤ 45%. Patients whose thyroid DVHs satisfied these constraints had a lower prevalence of 2-year HT compared with the overall prevalence (13.2% vs 25.8%, P < .001). Another DVH was defined by V25Gy  > 95%, V35Gy  > 90%, and V45Gy  > 75%, and patients whose thyroid DVHs satisfied with these constraints had a higher prevalence of 2-year HT than the overall incidence (36.0% vs 25.8%, P < .001). CONCLUSION: We recommend V25Gy  ≤ 60%, V35Gy  ≤ 55%, and V45Gy  ≤ 45% as the "stringent" DVH line, and V25Gy  > 95%, V35Gy  > 90%, and V45Gy  > 75% as the "inhibition" DVH line, under the precondition of not compromising the target coverage. These findings could help in the design of individual treatment plans and, eventually, to lowering of HT prevalence.

Relationship of circulating tumor cells and Epstein-Barr virus DNA to progression-free survival and overall survival in metastatic nasopharyngeal carcinoma patients.

We analyzed the number of circulating tumor cells (CTCs) and Epstein-Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The levels of CTCs and EBV DNA were measured at baseline and after first-line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non-mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first-line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first-line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first-line chemotherapy was associated with significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first-line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first-line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.

Prognostic Value of Deep Learning PET/CT-Based Radiomics: Potential Role for Future Individual Induction Chemotherapy in Advanced Nasopharyngeal Carcinoma.

PURPOSE: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA. RESULTS: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709-0.800] in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC. CONCLUSIONS: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

The development and external validation of simplified T category classification for nasopharyngeal carcinoma to improve the prognostic value in the intensity-modulated radiotherapy era.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) provides excellent local control in nasopharyngeal carcinoma (NPC). We investigated whether simplifying 8th American Joint Committee on Cancer staging system T categories improves prognostic value. METHODS: We used 2191 NPC patients as a training set and 414 patients separately as an independent, external validation cohort. RESULTS: In the training set, local relapse-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were not significantly different between the 8th edition T2/T3 (P = 0.610, 0.380 and 0.353, respectively). Merging T2 and T3 to proposed T2 (proT2) provided significant differences in LRFS, DFS, and OS between proposed T categories. Proposed T categories had similar c-indices for LRFS, DFS, and OS (vs the 8th edition), which was validated in the external cohorts. Moreover, for DFS, the adjusted HRs of the proT2N0 (3.8), proT1N1 (3.8), and proT2N1 (6.0) subsets were similar; the adjusted HRs of the proT3N0 (7.0), proT3N1 (11.4), proT1N2 (11.0), proT2N2 (11.6), and proT3N2 (13.3) subsets were similar; the adjusted HRs of the proT1N3 (17.8), proT2N3 (15.3), and proT3N3 (26.4) subsets were similar; the results of the adjusted HRs for OS had the same rule. Defining proT1N0 as stage I; proT1N1/proT2N0-1 as stage II; proT3N0-2/proT1-2N2 as stage III; and proT1-3N3 as stage IVa generated orderly, significant differences in DFS and OS between stages in the training set and external validation cohort. CONCLUSIONS: In the IMRT era, three T categories are more reasonable (merging T2/T3 into T2) and proT3N0-2 (the 8th edition T4N0-2) should be down-staged to stage III.

Effect of prior cancer on trial eligibility and treatment outcomes in nasopharyngeal carcinoma: Implications for clinical trial accrual.

OBJECTIVE: In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC. METHODS: We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database.Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer. RESULTS: There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival. CONCLUSIONS: Many NPC trials excluded patients with prior cancer, whichimpacts trialaccrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials.

Patterns of EBV-positive cervical lymph node involvement in head and neck cancer and implications for the management of nasopharyngeal carcinoma T0 classification.

OBJECTIVES: Epstein-Barr virus (EBV)-positive cervical lymph node (CLN) metastasis of unknown primary origin is classified as nasopharyngeal carcinoma (NPC) T0 by the American Joint Committee on Cancer staging manual (8th edition). We aimed to investigate the possible primary sites and patterns of EBV-positive CLN metastases and to provide implications for the management of NPC T0 classification. MATERIALS AND METHODS: We retrospectively reviewed 269 patients with newly diagnosed EBV-positive CLN metastatic disease who underwent EBV detection via EBV-encoded RNA in situ hybridization. Fifteen patients with unknown primary tumors underwent follow-up after initial treatment. RESULTS: In patients with EBV-positive CLNs, the most common primary sites after the nasopharynx (51.7%) were the salivary gland (24.5%), lung (7.8%), oropharynx (3.3%), nasal cavity/maxillary (3.3%), oral cavity (2.2%), orbit (1.1%), and liver (0.4%). No primary site was found in 15 patients (5.6%). For salivary gland malignancies, level II and I were the most frequently involved regions. Tumors arising from the lung or liver metastasized to the lower neck (level IV, V, and VI) rather than the upper neck. After initial treatment, 2/15 patients with EBV-positive CLNs of unknown primary exhibited primary NPC and oropharyngeal tumor, respectively. Further, even without prophylactic irradiation to the nasopharynx, only one of 13 unknown primary patients developed NPC. CONCLUSIONS: The origins of EBV-positive CLNs may not be restricted to the nasopharynx alone, and are likely to involve the head and neck or non-head and neck regions. NPC T0 classification should be cautiously assigned to such tumors.

Plasma Epstein-Barr Virus DNA Load After Induction Chemotherapy Predicts Outcome in Locoregionally Advanced Nasopharyngeal Carcinoma.

PURPOSE: To investigate whether plasma Epstein-Barr virus (EBV) DNA load at induction chemotherapy (ICT) completion (postICT-DNA) is a useful outcome predictor in locoregionally advanced nasopharyngeal carcinoma (NPC) and to compare the prognostic value of postICT- DNA and post-chemoradiation therapy (CCRT) DNA (postRT-DNA). METHODS AND MATERIALS: We retrospectively reviewed 278 patients with stage III-IV NPC treated with ICT followed by concurrent CCRT. The EBV DNA load was measured by quantitative polymerase chain reaction pre-ICT (pre-DNA), at ICT completion (postICT-DNA), and 1 week after CCRT completion (postRT-DNA). RESULTS: PostICT-DNA was associated with significantly worse 3-year overall survival (86.4% vs. 93.4%, P = .023), distant metastasis-free survival (69.2% vs. 93.9%, P < .001), and disease-free survival (64.6% vs. 88.7%, P < .001) than was undetectable postICT-DNA. In multivariate analysis, postICT-DNA was an independent predictor of overall survival (hazard ratio [HR], 2.567; 95% confidence interval [CI], 1.104-5.967; P = .029), distant metastasis-free survival (HR, 5.618; 95% CI, 2.781-11.348; P < .001), and disease-free survival (HR, 3.672; 95% CI, 2.064-6.533; P < .001). The postICT-DNA and postRT-DNA areas under the curve were 0.584 and 0.561 (P < .001), respectively, for predicting 3-year death; 0.717 and 0.649 (P < .001), respectively, for predicting 3-year metastasis; and 0.659 and 0.602 (P < .001), respectively, for predicting 3-year disease failure. CONCLUSIONS: Plasma EBV DNA load at ICT completion is a powerful and earlier outcome predictor in locoregionally advanced NPC that would facilitate further risk stratification and early treatment modification.

Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types.

We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6658 human samples were analyzed. The tumor melatonergic system was characterized by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism Index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1]). Samples of each cancer type were classified into two subgroups (high vs low) based on median values. Clinical outcomes, mutational burden, and neoepitope abundance were analyzed and compared. We found that the ability of the tumor microenvironment to synthesize and accumulate melatonin varied across cancer types and negatively correlated with tumor burden. Kaplan-Meier survival analyses and multivariable modeling showed that the three indexes played different roles across different cancers and harbored prognostic values in breast cancer (adjusted hazard ratio [AHR]Index-II  = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHRIndex-I  = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHRIndex-III  = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHRIndex-I  = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHRIndex-III  = 0.68 [0.41-0.94]; P = 0.02). We further investigated its clinical relevance with tumor immunogenic features (mutational burden and neoantigen abundance), which may predict immunotherapy benefits. We observed significant negative correlations with mutational burden in the majority of tumors (P < 0.05), except cervical cancer, pancreatic adenocarcinoma, and thyroid carcinoma. Our study provides a systematic overview of the oncostatic values of the melatonergic system and highlights the utilization of this simple and promising gene signature as a prognosticator and potential predictor of response to immunotherapy.