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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

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.

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56–0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57–0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51–0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48–1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824–33. ©2018 AACR.

Supplementary Method

Figure S1. Flow chart of patient inclusion. NPC, nasopharyngeal carcinoma; PET/CT, positron emission tomography with computed tomography; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; IMRT, intensity-modulated radiotherapy. Figure S2. The manual segmentation of (A) a patient with disease progression and (B) a patient without disease progression. Red region, the segmented tumors; green region, the segmented lymph nodes. Figure S3. DCNN architectures used in the study. (A) DCNN for CT image in training step; (B) DCNN for CT image in feature extraction step; (C) DCNN for PET image in training step; (D) DCNN for PET image in feature extraction step. Figure S4. Time-dependent ROC curves of radiomics nomogram in the training (A) and test (B) sets. ROC, receiver operating characteristic; AUC, area under the curve. Figure S5. Radiomics nomogram score for each patients in the training (A) and test (B) sets. Figure S6. Kaplan-Meier survival curves of disease-free survival between high-risk and low-risk groups stratified by age, gender, overall stage, and pre-DNA. Figure S7. Kaplan-Meier survival curves of overall survival between high-risk and low-risk groups stratified by age, gender, overall stage and pre-DNA. Figure S8. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for the whole 707 patients. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; OS, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S9. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for the 521 patients with low risk. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. DFS, disease-free survival; OS, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S10. An example of the feature maps generated from the DCNNs. Figure S11. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram A-defined low-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S12. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram A-defined high-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S13. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram B-defined low-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S14. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram B-defined high-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival.

Table S1. Numbers of features remained after each selection step for CT-based signature building. Table S2. Numbers of features remained after each selection step for PET-based signature building. Table S3. Results of radiomics feature selection and Rad-score building. Table S4. Comparison of signatures combining features of different categories. Table S5. Results of univariate analysis. Table S6. Multivariate analysis results for disease-free survival in training set. Table S7. Baseline information of nomogram-defined high-risk and low-risk groups. Table S8. Survival outcomes between radiomics nomogram-defined high and low risk groups. Table S9. Results of multivariate analysis for the whole cohort. Table S10. Results of multivariate analysis within the high-risk group. Table S11. Results of multivariate analysis within the low-risk group. Table S12. Results of multivariate analysis within the low-risk group defined by nomogram A. Table S13. Results of multivariate analysis within the high-risk group defined by nomogram A. Table S14. Results of multivariate analysis within the low-risk group defined by nomogram B. Table S15. Results of multivariate analysis within the high-risk group defined by nomogram B.

Supplementary materials including supplementary figures and tables Supplementary Figure S1. Flowchart of randomized controlled trial selection. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; PWH, Prince of Wales Hospital; RCT, randomized controlled trial Supplementary Figure S2. Forest plots for (A) progression-free survival and (B) overall survival. The estimated hazard ratio (HR) for each individual trial is indicated by the center of the square and the horizontal line gives the 95% confidence interval (CI). The closed diamonds show the overall HR and 95% CI. HR < 1 and 95% CI excluding 1 indicate improved survival for the experimental versus control arm. A fixed effect model was used. CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; O-E, observed minus expected deaths or events; PWH, Prince of Wales Hospital. Supplementary Figure S3. Multiple treatment comparison network. Each treatment area is proportional to the cumulative number of patients (in parentheses). Solid lines between treatments represent direct comparisons. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; CEP, cisplatin, epirubicin and paclitaxel; GCP, gemcitabine, carboplatin and paclitaxel; IC, induction chemotherapy; PF, cisplatin and fluorouracil; PX, cisplatin and capecitabine; TP, docetaxel and cisplatin; TPF, TP and fluorouracil. Supplementary Table S1. Description of the Two Trials Included in the Supplementary Analysis Supplementary Table S2. Description of Patient Characteristics Supplementary Table S3. Disease Status and Pattern of FailureSupplementary Table S4. Compliance with Induction Chemotherapy and Concurrent Chemoradiotherapy Supplementary Table S5. Summary of Major Grade 3-4 Adverse Events*

Supplementary Result

Purpose To explore the peripheral blood cells (neutrophil/monocyte/lymphocyte/platelet) to apolipoprotein AI or high‐density lipoprotein‐cholesterol ratio (NAR, MAR, LAR, PAR, NHR, MHR, LHR, and PHR) as independent prognostic indicators for stage III nasopharyngeal carcinoma (NPC). Patients and methods Between 2009 and 2014, 562 patients diagnosed with stage III NPC who were treated with a concomitant chemotherapy and intensity‐modulated radiotherapy with cumulative cisplatin dose ≥200 mg/m2 were included in this retrospective study. Routine blood and biochemical variables and baseline clinical characteristics (T and N stage, age, sex, and induction chemotherapy) were collected. After inserting 19 hematological parameters into a set, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and restricted cubic splines regression to select valuable parameters for predicting 5‐year overall survival (OS). Subsequently, univariate and multivariate survival analyses were used to assess independent indicators of 5‐year OS, distant metastasis survival, regional recurrence‐free survival (RRFS), and disease‐free survival. Results NAR, MAR, serum lactated dehydrogenase (LDH), and Epstein‐Barr virus (EBV)‐DNA were selected using LASSO regression, and the optimal cut‐off values for NAR, MAR, EBV‐DNA, and, LDH were 4.39, 0.3, 1590 copies/mL, and 218.4 IU/L, respectively. In multivariate survival analysis, higher NAR was associated with both poor 5‐year OS and RRFS (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.09‐3.25, P = .024; HR, 3.13; 95% CI, 1.42‐6.91, P = .005, respectively). Conclusion NAR could be an attractive indicator for evaluating the 5‐year OS in patients with stage III NPC, which is closely related to inflammation and circulating lipid metabolism. Level of Evidence: 4, The neutrophil‐to‐apolipoprotein A‐I ratio, which is closely related to inflammation and circulating lipid metabolism, could be an attractive indicator for evaluating the 5‐year overall survival in patients with stage III NPC.

We analyzed the patterns of lymph node (LN) failure and prognosis in patients with regional recurrent nasopharyngeal carcinoma (rNPC) alone after primary intensity-modulated radiotherapy (IMRT).A total of 175 patients who were treated with IMRT between 2010 and 2015 and who experienced regional recurrence alone were included. Recurrent LNs were re-located in the initial pretreatment imaging and IMRT plan and failures were classified as in-field or out-field based on target volume delineation. All patients underwent curative salvage treatment. Independent prognostic factors for overall survival (OS) were selected by multivariate Cox analysis.Level IIb (49.1%, 86/175) was the most frequent recurrence site, followed by level IIa (36%), level III (18.9%), level IVa (12%), the retropharyngeal region (8%), level Va (6.9%), and the parotid region (6.9%). A total of 264 recurrent LNs were recorded: 149 (56.4%) were classified as in-field failure with a prescribed dose ≥66 Gy, 60 (22.7%) with 60 to66 Gy, 32 (12.1%) with 50 to60 Gy, and 23 (8.7%) as an out-field failure, which mainly occurred in the parotid region and level Ib. After a median follow-up of 52.8 months, the estimated 5-year OS rate was 66.9%. Multivariate analysis showed that age, plasma Epstein-Barr virus DNA level, extranodal extension, lower neck involvement, and parotid LN recurrence were independent prognostic factors of OS.In-field failure represented the main pattern of regional recurrence and out-field failure mainly occurred in the parotid gland and level Ib. Patients with regional rNPC alone had a good prognosis after salvage treatment.

e15110 Background: Immune checkpoint inhibitors (ICIs) yield remarkable clinical efficacy in the treatment of cancer. With the increasing use of ICI therapies, the dissemination of immune-related adverse events (irAEs) data is essential. This study aimed to investigate the pattern of onset and resolution of ICI-induced irAEs in cancer. Methods: Phase II–III clinical trials with single or multiple arms studying ICI-based treatments in cancer published between January 2007 and December 2019 were included. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were analyzed based on irAE categories and severity grades using the metamedian package of the R software. Subgroup analyses were performed based on different ICI drugs, ICI doses, and cancer types. Results: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. On average, irAEs occurred at 6.1 weeks (95% confidence interval [95% CI], 5.7–7.4) after the initial ICI-based treatment. The first four irAEs with the shortest PMT-O were hypersensitivity/infusion reaction (3.1 weeks), neurological (4.0 weeks), skin (4.1 weeks), and gastrointestinal (6.1 weeks) events. IrAEs were resolved within 4.5 weeks (95% CI, 4.0–6.1), with the shortest and longest PMT-R for hypersensitivity/infusion reaction (0.1 weeks) and endocrine events (28.7 weeks), respectively. The application of immune-modulation drugs prolonged the general resolution time to 5.9 weeks, with the shortest and longest PMT-IMR for hypersensitivity/infusion reaction (0.2 weeks) and endocrine events (56.6 weeks), respectively. Grade ≥ 3 irAEs showed a significantly longer PMT-O (7.9 vs. 6.1 weeks; P < 0.01) compared with all grade irAEs. Nivolumab + ipilimumab had a significantly shorter PMT-O than nivolumab alone (6.0 vs. 8.2 weeks; P < 0.01). A significantly shorter PMT-O was observed for lung cancer compared with that for melanoma (4.7 vs. 6.1 weeks; P = 0.02). Conclusions: This study revealed the pattern and kinetics of the time to onset and resolution of irAEs in pan-cancers, which will promote the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

Objectives : To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. Methods : All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case–control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. Results : rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. Conclusions : FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients.Key Points• FKBP5 gene polymorphisms were associated with depression of SLE patients.• FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients.• FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients.• FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

Objectives To address whether sparing the medial retropharyngeal lymph node (MRLN) region from elective irradiation volume provides non-inferior local relapse-free survival versus standard radiotherapy in patients with nasopharyngeal carcinoma. Design Open-label, non-inferiority, multicentre, randomised, phase 3 trial. Setting Three Chinese hospitals between 20 November 2017 and 3 December 2018. Participants Adults (18-65 years) with newly diagnosed, non-keratinising, non-distant metastatic nasopharyngeal carcinoma without MRLN involvement. Interventions Randomisation was done centrally by the Clinical Trials Centre at Sun Yat-sen University Cancer Center. Eligible patients were randomly assigned (1:1; block size of four) to receive MRLN sparing radiotherapy or standard radiotherapy (both medial and lateral retropharyngeal lymph node groups), and stratified by institution and treatment modality as follows: radiotherapy alone; concurrent chemoradiotherapy; induction chemotherapy plus radiotherapy or concurrent chemoradiotherapy. Main outcome measures Non-inferiority was met if the lower limit of the one sided 97.5% confidence interval of the absolute difference in three year local relapse-free survival (MRLN sparing radiotherapy minus standard radiotherapy) was greater than −8%. Results 568 patients were recruited: 285 in the MRLN sparing radiotherapy group; 283 in the standard radiotherapy group. Median follow-up was 42 months (interquartile range 39-45), intention-to-treat analysis showed that the three year local relapse-free survival of the MRLN sparing radiotherapy group was non-inferior to that of the standard radiotherapy group (95.3% v 95.5%, stratified hazard ratio 1.04 (95% confidence interval 0.51 to 2.12), P=0.95) with a difference of −0.2% ((one sided 97.5% confidence interval –3.6 to ∞), P non-inferiority v 35.1%, P=0.01) and late dysphagia (24.0% v 34.3%, P=0.008). Patient reported outcomes at three years after MRLN sparing radiotherapy were better in multiple domains after adjusting for the baseline values: global health status (mean difference −5.6 (95% confidence interval –9.1 to –2.0), P=0.002), role functioning (−5.5 (–7.4 to –3.6), P10 points difference). Conclusion Compared with standard radiotherapy, MRLN sparing radiotherapy showed non-inferiority in terms of risk of local relapse with fewer radiation related toxicity and improved patient reported outcomes in patients with non-metastatic nasopharyngeal carcinoma. Trial registration ClinicalTrials.gov NCT03346109

Purpose. To quantify the long-term evaluation of optic chiasma (OC) and/or optic nerve(s) (ONs) and to develop predictive models for radiation-induced optic neuropathy (RION) in nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). Methods and Materials. A total of 3,662 patients’ OC/ONs with full visual acuity and dosimetry data between 2010 and 2015 were identified. Critical dosimetry predictors of RION were chosen by machine learning and penalized regression for survival. A nomogram containing dosimetry and clinical variables was generated for predicting RION-free survival. Results. The median follow-up was 71.79 (2.63–120.9) months. Sixty-six eyes in 51 patients (1.39%) developed RION. Two patients were visual field deficient, and 49 patients had visual acuity of less than 0.1 (20/200). The median latency time was 36 (3–90) months. The 3-, 5-, and 8-year cumulative incidence of RION was 0.78%, 1.19%, and 1.97%, respectively. Dmax was the most critical dosimetry variable for RION (AUC: 0.9434, the optimal cutoff: 64.48 Gy). Patients with a Dmax ≥64.48 Gy had a significantly higher risk of RION (HR = 102.25; 95%CI, 24.86–420.59; P < 0.001 ). Age (>44 years) (HR = 2.234, 95% CI = 1.233–4.051, p = 0.008), advanced T stage (T3 vs. T1-2: HR = 7.516, 95% CI = 1.725–32.767, p = 0.007 ; T4 vs. T1-2: HR = 37.189, 95% CI = 8.796–157.266, P < 0.001 ), and tumor infiltration/compression of the OC/ONs (HR = 4.572, 95% CI = 1.316–15.874, p = 0.017 ) were significant clinical risk factors of RION. A nomogram comprising age, T stage, tumor infiltration/compression of the OC/ON, and Dmax significantly outperformed the model, with only Dmax predicting RION (C-index: 0.916 vs. 0.880, P < 0.001 in the training set; 0.899 vs. 0.874, P = 0.038 in the test set). The nomogram-defined high-risk group had a worse 8-year RION-free survival. Conclusions. In the IMRT era, Dmax

Purpose Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy. Methods and materials 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits. Results The median follow-up was 59.3 (0.39–170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1–2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3–4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184–0.517; P P = 0.002). In the poor-prognosis group, a significantly improved OS for chemoradiotherapy (CRT) compared with RT alone was observed (HR = 0.70, 95% CI 0.55–0.88; P = 0.003). Patients who received induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and CCRT had a significantly improved OS compared with RT alone (IC + CCRT vs. RT alone: P = 0.002; CCRT vs. RT alone: P = 0.008) but not in the IC + RT group (P = 0.306). The 5-year OS for CRT versus RT-alone with ACE-27 scores of 0, 1 and 2 were 76.0% versus 70.0% (P = 0.014), 80.5% versus 68.2% (P = 0.150) and 58.5% versus 62.2% (P = 0.490), respectively; for those aged 60–64, 65–70 and ≥ 70 years old they were 80.9% versus 75.9% (P = 0.068), 73.3% versus 63.4% (P = 0.270) and 64.8% versus 67.1% (P = 0.820), respectively. Conclusions For elderly NPC patients a simple screening cutoff for chemotherapy beneficiaries might be EBV DNA 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy.

ImportanceMicrobiota-tumor interactions have qualified microbiota as a promising prognostic biomarker in various types of cancers. Although the nasopharynx acts as a crucial niche of the upper respiratory tract microbiome, whether the intratumoral microbiota exists and its clinical significance in nasopharyngeal carcinoma (NPC) remain uncertain.ObjectiveTo evaluate the clinical significance of intratumoral microbiota for individual prognostication in patients with NPC.Design, Setting, and ParticipantsThis retrospective cohort study included NPC biopsy samples from 2 hospitals: Sun Yat-sen University Cancer Center (Guangzhou, China) and Zhejiang Cancer Hospital (Hangzhou, China) between January 2004 and November 2016, with follow-up through November 2020. A total of 802 patients were included according to the following criteria: with histologically proven NPC, without distant metastasis at initial diagnosis, had not received antitumor treatment before biopsy sampling, aged between 18 and 70 years, with complete medical records and regular follow-up, without a history of cancer, and successfully extracted enough DNA for experiments.Main Outcomes and MeasuresThe primary end point was disease-free survival, and the secondary end points included distant metastasis–free survival and overall survival. To assess the existence and load of intratumoral microbiota in 96 patients with NPC with or without tumor relapse, 16S rRNA sequencing and quantitative polymerase chain reaction were used. The associations between intratumoral bacterial load and clinical outcome were evaluated in 241 fresh-frozen NPC samples (training cohort) and validated in paraffin-embedded NPC samples of internal (n = 233) and external (n = 232) validation cohorts. Metagenomic and transcriptome analyses were performed to ascertain the origin and underlying mechanism of intratumoral bacteria.ResultsA total of 802 patients with NPC (mean [SD] age, 46.2 [10.6] years; 594 [74.1%] male) were enrolled. Microbiota presented within NPC tumor tissues, among which Corynebacterium and Staphylococcus predominated. Patients with a high bacterial load in the training cohort had inferior rates of disease-free survival (hazard ratio [HR], 2.90; 95% CI, 1.72-4.90; P P P Conclusions and RelevanceIntratumoral bacterial load was a robust prognostic tool for patients with NPC in this cohort study, indicating potential guidance for treatment decisions in patients at different levels of risk of malignant progression.

Background The impact of radiotherapy interruption due to the Spring Festival holidays in China on the survival of patients with nasopharyngeal carcinoma (NPC) is unclear. Methods Nontrial patients with locoregionally advanced NPC receiving radiotherapy plus induction chemotherapy (IC) and/or concurrent chemotherapy (CC) were included (N = 5035) and divided into two groups based on the Spring Festival-induced radiotherapy interruption. Kaplan–Meier curves for overall survival (OS) and failure-free survival (FFS) were compared between rival groups. Impact of the timing of radiotherapy interruption (during or outside the Spring Festival) on survival was investigated in a propensity score-matched dataset. We adopted ordination correspondence analysis to determine the cut-off of radiotherapy prolongation for prognostic prediction, and accordingly performed subgroup analysis based on delayed days and chemotherapy details. Individual patient data of three phase III NPC trials (NCT00677118, NCT01245959, NCT01872962) were used for validation (N = 1465). Results Radiotherapy interruption was most frequently observed between December to January of the following year. Significantly lower OS and FFS were associated with the Spring Festival-induced interruption of radiotherapy (P = 0.009 and 0.033, respectively), but not that interruption of IC. In two matched comparison groups, the timing of radiotherapy interruption during the Spring Festival was more likely to lead to a decrease in FFS than outside the Spring Festival (P = 0.046), which was not observed in the validation using clinical trial data or in the subgroup analysis based on the 5-day delayed time. The absence of CC and the accumulated dose of cisplatin P = 0.002) and OS (P = 0.010), respectively. Conclusions The poor survival of patients with NPC is associated with the Spring Festival-induced interruption of radiotherapy. We recommend that these patients receive adequate doses of cisplatin concurrently with radiotherapy.

Background Depression has been reported to be associated with some types of cancer in observational studies. However, the direction and magnitude of the causal relationships between depression and different types of cancer remain unclear. Methods We performed the two-sample bi-directional mendelian randomization with the publicly available GWAS summary statistics to investigate the causal relationship between the genetically predicted depression and the risk of multiple types of cancers, including ovarian cancer, breast cancer, lung cancer, glioma, pancreatic cancer, lymphoma, colorectal cancer, thyroid cancer, bladder cancer, and kidney cancer. The total sample size varies from 504,034 to 729,150. Causal estimate was calculated by inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the causal relationship. Results After correction for heterogeneity and horizontal pleiotropy, we only detected suggestive evidence for the causality of genetically predicted depression on breast cancer (OR = 1.09, 95% CI: 1.03–1.15, P = 0.0022). The causal effect of depression on breast cancer was consistent in direction and magnitude in the sensitivity analysis. No evidence of causal effects of depression on other types of cancer and reverse causality was detected. Conclusions The result of this study suggests a causative effect of genetically predicted depression on specific type of cancer. Our findings emphasize the importance of depression in the prevention and treatment of breast cancer.

Colorectal cancer (CRC) is the most common form of gastrointestinal malignancies. A growing number of reports focusing on oxaliplatin (OXA) resistance in CRC treatment have revealed that drug resistance is an urgent issue in clinical applications, especially for finding effective therapeutic targets. Recently, microRNAs (miRNAs) are reported to play a critical role in tumor progressions and multi-drug resistance. The main aim of this study is to establish whether miR-5000-3p is an oncogene that is resistant to OXA and further confirm its underlying regulatory role in CRC. The OXA-associated gene expression dataset in CRC cells was downloaded from Gene Expression Omnibus (GEO) database. Statistical software R was used for significance analysis of differentially expressed genes (DEGs) between OXA-resistant (OR)-CRC cells and CRC cells, and results indicated ubiquitin-specific peptidase 49 (USP49) was upregulated in OR-CRC cells. Luciferase reporter assay showed that USP49 was verified to act as a downstream target gene of miR-5000-3p. From the results of TCGA database, miR-5000-3p expression was upregulated and USP49 was downregulated in patients with CRC. The function of miR-5000-3p was detected using MTT assay, wound healing, Transwell, and flow cytometry assays. Moreover, through in vitro and in vivo experiments, miR-5000-3p expression was confirmed to be upregulated in CRC cells or OR-CRC cells comparing to normal cell lines. Molecular mechanism assays revealed that USP49 binds to the miR-5000-3p promoter to increase the expression of miR-5000-3p, resulting in cancer cells sensitized to OXA. To sum up, these results suggest that miR-5000-3p may be a novel biomarker involved in drug-resistance progression of CRC. Moreover, the drug-resistance mechanism of miR-5000-3p/USP49 axis provides new treatment strategies for CRC in clinical trials.

Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Genistein is an important isoflavone that has been widely used to prevent blood disease and cancer. In this work, a novel genistein electrochemical sensor was developed based on the composite of molecularly imprinted polymer (MIP) and carboxylated multiwalled carbon nanotubes (cMWCNTs). The MIP layer was electropolymerizated on the cMWCNTs modified electrode using carbazole as functional monomer and genistein as template molecule. The morphology and electrochemical performance of MIP/cMWCNTs were characterized by scanning electron microscopy (SEM) and cyclic voltammetry (CV), respectively. A series of experimental conditions were optimized, including the pH value of supporting electrolyte, electropolymerization potential range, molar ratio of functional monomers to template molecules, numbers of cycle, accumulation potential and accumulation time. Under the optimal conditions, the resulting electrochemical sensor (MIP/cMWCNTs/GCE) showed high performance, such as high sensitivity and selectivity towards genistein, a wide linear range (0.02–7.00 μM) and a low limit detection of 0.006 μM (S/N = 3). The electrochemical sensor was applied to determination of genistein in tablets and human urine samples with satisfactory recoveries (97.9%–102.8%), and the accuracy of the sensor was demonstrated with the HPLC method.

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.