The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3-36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9-7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Simultaneous integrated boost intensity-modulated radiotherapy post breast-conserving surgery: clinical efficacy, adverse effects, and cosmetic outcomes in breast cancer patients.

BACKGROUND: Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) is an innovative technique delivering a higher dose to the tumor bed while irradiating the entire breast. This study aims to assess the clinical outcomes, adverse effects, and cosmetic results of SIB-IMRT following breast-conserving surgery in breast cancer patients. METHODS: We conducted a retrospective analysis of 308 patients with stage 0-III breast cancer who underwent breast-conserving surgery and SIB-IMRT from January 2016 to December 2020. The prescribed doses included 1.85 Gy/27 fractions to the whole breast and 2.22 Gy/27 fractions or 2.20 Gy/27 fractions to the tumor bed. Primary endpoints included overall survival (OS), local-regional control (LRC), distant metastasis-free survival (DMFS), acute and late toxicities, and cosmetic outcomes. RESULTS: The median follow-up time was 36 months. The 3-year OS, LRC, and DMFS rates were 100%, 99.6%, and 99.2%, respectively. Five patients (1.8%) experienced local recurrence or distant metastasis, and one patient succumbed to distant metastasis. The most common acute toxicity was grade 1-2 skin reactions (91.6%). The most common late toxicity was grade 0-1 skin and subcutaneous tissue reactions (96.7%). Five patients (1.8%) developed grade 1-2 upper limb lymphedema, and three patients (1.1%) had grade 1 radiation pneumonitis. Among the 262 patients evaluated for cosmetic outcomes at least 2 years post-radiotherapy, 96.9% achieved excellent or good results, while 3.1% had fair or poor outcomes. CONCLUSIONS: SIB-IMRT after breast-conserving surgery in breast cancer patients demonstrated excellent clinical efficacy, mild acute and late toxicities, and satisfactory cosmetic outcomes in our study. SIB-IMRT appears to be a feasible and effective option for breast cancer patients suitable for breast-conserving surgery.

Efficacy and Safety of Nimotuzumab in Combination with Radiotherapy or Chemoradiotherapy for Local Advanced Head and Neck Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The present meta-analysis aimed to evaluate the efficacy and safety of adding nimotuzumab to radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Prospective randomized controlled studies at EMBASE, PubMed, and the Cochrane Library from January 1, 2010, to October 1, 2022, were searched. Data on the overall survival (OS), progress-free survival (PFS), disease-free survival (DFS), complete response rate (CRR), objective response rate (ORR), and all grade adverse events were collected from the enrolled publications. OS was the primary measurement indicator. Pooled analysis was performed with relative risks (RRs), hazard risks (HRs), and their corresponding 95% confidence intervals (CIs) in the software Stata SE 16.0. RESULTS: Six randomized controlled studies were included in the analysis of the overall pooled effect. As compared to the control group, the nimotuzumab intervention group exhibited improved OS by 21% (pooled HR=0.79,95% CI: 0.64-0.98, P=0.028), along with PFS up to 31% (HR=0.69, 95% CI: 0.55-0.86, P=0.001) and DFS up to 29% (HR=0.71, 95% CI: 0.56-0.91, P=0.006), increased CRR as 50% (RR=1.50, 95%CI:1.09-2.04; P=0.012), and ORR as 35% (RR=1.35, 95%- CI:1.04-1.73; P=0.022). Regarding safety, nimotuzumab in combination with RT or CRT did not increase the incidence of all grade adverse events (pooled-RD=-1.27, 95%CI:-2.78-0.23, P=0.099). CONCLUSION: The present meta-analysis has demonstrated that nimotuzumab, in combination with RT or CRT, could provide survival benefits and increase response rates. Its safety profile has been found to be controllable.

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

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

Nutritional Status and Incidence of Radiation-Induced Oral Mucositis in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy.

Malnutrition is prevalent among patients with nasopharyngeal carcinoma undergoing radiotherapy. This study examined the nutritional status and incidence of radiation-induced oral mucositis (RIOM) in patients with nasopharyngeal carcinoma. A retrospective analysis was conducted to compare the incidence of RIOM, Nutritional Risk Screening (NRS) 2002 score, weight, body mass index (BMI), and hemoglobin levels in 338 patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) or treated with CCRT alone. The IC + CCRT group exhibited an increase in weight and BMI but a decrease in hemoglobin levels after IC compared with baseline (p < 0.001). Both groups showed differences in weight at Week 0 and BMI at Weeks 0-2 of radiotherapy (p < 0.05). The IC + CCRT group experienced an increase in NRS 2002 scores from Week 2 to Week 6 (p < 0.05). The hemoglobin levels of the IC + CCRT group were consistently lower throughout radiotherapy (p < 0.001). However, no significant difference was observed in the incidence of RIOM between the two groups (p = 0.246). Patients treated with IC + CCRT exhibited a higher nutritional risk during radiotherapy. Although the incidence of Grade III RIOM was high, no significant difference was found between the groups.

Anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To identify anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma (M1-NPC). MATERIALS AND METHODS: All M1-NPC treated with chemotherapy and/or radiotherapy between 2010 and 2019 from two centers (training and validation cohort) were included. The prognostic value of metastatic disease extent and involved organs for overall survival (OS) were assessed by several multivariable analyses (MVA) models. A new M1 classification was proposed and validated in a separate cohort who received immuno-chemotherapy. RESULTS: A total of 197 M1-NPC in the training and 307 in the validation cohorts were included for M1 subdivision study with median follow-up of 46 and 57 months. MVA model with "≤2 organs/≤5 lesions" as the definition of oligometastasis had the highest C-index (0.623) versus others (0.606-0.621). Patients with oligometastasis had better OS versus polymetastasis (hazard ratio [HR] 0.47/0.63) while liver metastases carried worse OS (HR 1.57/1.45) in MVA in the training/validation cohorts, respectively. We proposed to divide M1-NPC into M1a (oligometastasis without liver metastases) and M1b (liver metastases or polymetastasis) with 3-year OS of 66.5%/31.7% and 64.9%/35.0% in the training/validation cohorts, respectively. M1a subset had a better median progress-free survival (not reach vs. 17 months, p < 0.001) in the immuno-chemotherapy cohort (n = 163). CONCLUSION: Oligometastasis (≤2 organs/≤5 lesions) and liver metastasis are prognostic for M1-NPC. Subdivision of M1-NPC into M1a (oligometastasis without liver metastasis) and M1b (liver metastasis or polymetastasis) depicts the prognosis well in M1-NPC patients who received immuno-chemotherapy.

Dual-responsive probe and DNA interstrand crosslink precursor target the unique redox status of cancer cells.

Elevated GSH and H2O2 in cancer cells is sometimes doubted due to their contrary reactivities. Here, we construct a dual-responsive fluorescent probe to confirm the conclusion, and employ this to exploit a redox-inducible DNA interstrand crosslink (ICL) precursor. It crosslinks DNA upon activation by GSH and H2O2, affording an alternative dual-responsive strategy.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

A Novel Prognostic Model Predicts Outcomes in Non-Metastatic Nasopharyngeal Carcinoma Based on Inflammation, Nutrition, and Coagulation Signature.

Purpose: This study aimed to assess the prognostic and predictive value of a circulating hematological signature (CHS) and to develop a CHS-based nomogram for predicting prognosis and guiding individualized chemotherapy in non-metastatic nasopharyngeal carcinoma (NPC) patients. Patients and Methods: NPC patients were recruited between January 2014 and December 2017 at the Jiangxi Cancer Hospital. The CHS was constructed based on a series of hematological indicators. The nomogram was developed by CHS and clinical factors. Results: A total of 779 patients were included. Three biomarkers were selected by least absolute shrinkage and selection operator regression, including prognostic nutritional index, albumin-to-fibrinogen ratio, and prealbumin-to-fibrinogen ratio, were used to construct the CHS. The patients in the low-CHS group had better 5-year DMFS and OS than those in the high-CHS group in the training (DMFS: 85.0% vs 56.6%, p<0.001; OS: 90.3% vs 65.4%, p<0.001) and validation cohorts (DMFS: 92.3% vs 43.6%, p<0.001; OS: 92.1% vs 65.5%, p<0.001). The nomogram_CHS showed better performance than clinical stage in predicting distant metastasis (concordance index: 0.728 vs 0.646). In the low-TRS (total risk scores) group, the patients received RT alone, CCRT and IC plus CCRT had similar 5-year DMFS and OS (p>0.05). In the middle-TRS group, the patients received RT alone had worse 5-year DMFS (58.7% vs 80.8% vs 90.8%, p=0.002) and OS (75.0% vs 94.1% vs 95.0%, p=0.001) than those received CCRT or IC plus CCRT. In the high-TRS group, the patients received RT alone and CCRT had worse 5-year DMFS (18.6% vs 31.3% vs 81.5%, p<0.001) and OS (26.9% vs 53.2% vs 88.8%, p<0.001) than those received IC plus CCRT. Conclusion: The developed nomogram_CHS had satisfactory prognostic accuracy in NPC patients and may individualize risk estimation to facilitate the identification of suitable IC candidates.

Involved site radiation therapy in stage I-III nasopharyngeal carcinoma with limited lymph node burden (ISRT-NPC) or elective region irradiation: a study protocol for a multicenter non-inferiority randomized controlled phase III clinical trial.

BACKGROUND: Current radiotherapy guidelines and consensus statements uniformly recommend elective region irradiation (ERI) as the standard strategy for nasopharyngeal carcinoma (NPC). However, given the scarcity of skip-metastasis, the improved assessment accuracy of nodal involvement, and the striking advancements in chemotherapy for NPC, a one-fits-all delineation scheme for clinical target volumes of the nodal region (CTVn) may not be appropriate anymore, and modifications of the CTVn delineation strategy may be warranted. Involved site irradiation (ISI) covering merely the initially involved nodal site and potential extranodal extension has been confirmed to be as effective as ERI with decreased radiation-related toxicities in some malignancies, but has not yet been investigated in NPC. This study aims to compare the regional control, survival outcomes, radiation-related toxicities, and quality of life (QoL) of ISI with conventional ERI in NPC patients with a limited nodal burden. METHODS: ISRT-NPC is a prospective, multicenter, open-label, noninferiority, phase III randomized controlled trial. A total of 414 patients will be randomly assigned in a 1:1 ratio to receive ISI or ERI. Randomization will be stratified by institution scale and N stage. Generally, in the ISI group, the high-risk CTV1 (dose: 60 Gy) includes a 1-cm expansion of the positive LN as well as the VIIa and the retrostyloid space above the bilateral transverse process of the atlantoaxial spine (C1), regardless of N status. The low-risk CTV2 (dose: 50 Gy) covers the cervical nodal region with a 3-cm caudal expansion below the transverse process of C1 for N0 disease and a 3-cm expansion below the positive LN for positive LNs. DISCUSSION: The results of this trial are expected to confirm that ISI is a non-inferior strategy to ERI in stage I-III patients with low LN burden, enabling the minimization of treatment-related toxicity and improvement of long-term QoL without compromising regional control. TRIAL REGISTRATION: ClinicalTrails.gov, NCT05145660. Registered December 6, 2021.

MRI-based deep learning model predicts distant metastasis and chemotherapy benefit in stage II nasopharyngeal carcinoma.

Chemotherapy remains controversial for stage II nasopharyngeal carcinoma because of its considerable prognostic heterogeneity. We aimed to develop an MRI-based deep learning model for predicting distant metastasis and assessing chemotherapy efficacy in stage II nasopharyngeal carcinoma. This multicenter retrospective study enrolled 1072 patients from three Chinese centers for training (Center 1, n = 575) and external validation (Centers 2 and 3, n = 497). The deep learning model significantly predicted the risk of distant metastases for stage II nasopharyngeal carcinoma and was validated in the external validation cohort. In addition, the deep learning model outperformed the clinical and radiomics models in terms of predictive performance. Furthermore, the deep learning model facilitates the identification of high-risk patients who could benefit from chemotherapy, providing useful additional information for individualized treatment decisions.

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

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

An Automated Skill Assessment Framework Based on Visual Motion Signals and a Deep Neural Network in Robot-Assisted Minimally Invasive Surgery.

Surgical skill assessment can quantify the quality of the surgical operation via the motion state of the surgical instrument tip (SIT), which is considered one of the effective primary means by which to improve the accuracy of surgical operation. Traditional methods have displayed promising results in skill assessment. However, this success is predicated on the SIT sensors, making these approaches impractical when employing the minimally invasive surgical robot with such a tiny end size. To address the assessment issue regarding the operation quality of robot-assisted minimally invasive surgery (RAMIS), this paper proposes a new automatic framework for assessing surgical skills based on visual motion tracking and deep learning. The new method innovatively combines vision and kinematics. The kernel correlation filter (KCF) is introduced in order to obtain the key motion signals of the SIT and classify them by using the residual neural network (ResNet), realizing automated skill assessment in RAMIS. To verify its effectiveness and accuracy, the proposed method is applied to the public minimally invasive surgical robot dataset, the JIGSAWS. The results show that the method based on visual motion tracking technology and a deep neural network model can effectively and accurately assess the skill of robot-assisted surgery in near real-time. In a fairly short computational processing time of 3 to 5 s, the average accuracy of the assessment method is 92.04% and 84.80% in distinguishing two and three skill levels. This study makes an important contribution to the safe and high-quality development of RAMIS.

Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study.

Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. This phase 2 study aimed to evaluate the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Methods: This was a multicentre, single-arm, phase 2 study of KL-A167 in R/M NPC (KL167-2-05-CTP) (NCT03848286), conducted at 42 hospitals across the People's Republic of China. Eligible patients had histologically confirmed non-keratinising R/M NPC, and had failed at least two lines of chemotherapy. Patients received KL-A167 900mg intravenously once every 2 weeks until confirmed disease progression, intolerable toxicity, or withdrawal of informed consent. The primary endpoint was objective response rate (ORR) assessed by the independent review committee (IRC) according to RECIST v1.1. Findings: Between Feb 26th, 2019 and Jan 13th, 2021, 153 patients were treated. Totally, 132 patients entered full analysis set (FAS) and were evaluated for the efficacy. As of data cutoff date on Jul 13th, 2021, the median follow-up time was 21.7 months (95%CI 19.8-22.5). For FAS population, the IRC-assessed ORR was 26.5% (95%CI 19.2-34.9%), and disease control rate (DCR) was 56.8% (95%CI 47.9-65.4%). Median progression-free survival (PFS) was 2.8 months (95%CI 1.5-4.1) . Median duration of response was 12.4 months (95%CI 6.8-16.5), and median overall survival (OS) was 16.2 months (95%CI 13.4-21.3). When using the cutoff of 1000 copies/ml, 5000 copies/ml and 10,000 copies/ml for plasma EBV DNA titer, baseline low plasma EBV DNA was consistently related with better DCR, PFS and OS. Dynamic change of plasma EBV DNA was significantly associated with ORR and PFS. Among 153 patients, treatment related-adverse events (TRAEs) occurred in 73.2% of patients, and grade ≥3 TRAEs were in 15.0% of patients. No TRAE leading to death was reported. Conclusion: In this study, KL-A167 showed promising efficacy and an acceptable safety profile in patients with previously treated R/M NPC. Baseline plasma EBV DNA copy number might be a potentially useful prognostic biomarker for KL-A167 treatment, and post-treatment EBV DNA decrease might be correlated with better response to KL-A167. Funding: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., China National Major Project for New Drug Innovation (2017ZX09304015).

Impaired geriatric 8 score is associated with worse survival after radical intensity modulated radiation therapy in elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Geriatric 8 score (G8) was an independent prognostic factor for survival and toxicities in various malignancies, but it has never been tested in nasopharyngeal carcinoma (NPC). OBJECTIVES: To evaluate the value of G8 in predicting survival in elderly patients with NPC. MATERIAL AND METHODS: Patients with NPC aged ≥70 who received intensity-modulated radiation therapy were recruited into this study. The overall survival (OS), progression-free survival (PFS), locoregional recurrence rate (LRR), and distant metastasis rate (DMR) between the patients with G8 > 14 and G8 ≤ 14 were calculated using the Kaplan-Meier method and compared with the Log-rank test. Cox proportional hazards model was applied to perform univariate and multivariate analysis. RESULTS: G8 ≤ 14 had significantly reduced OS (p = .001) and PFS (p = .032) than those with G8 > 14 by log-rank test. G8 score remained an independent prognosticator for OS (HR = 0.490, 95% CI = 0.267-0.900, p = .021) and was a borderline significance towards PFS (HR = 0.639, 95% CI = 0.386-1.058, p = .082) in multivariate analysis. Grade 3-4 acute toxicities were significantly more common in patients with G8 ≤ 14 than in those with G8 > 14. CONCLUSIONS AND SIGNIFICANCE: G8 is useful in predicting the OS in elderly patients with NPC. Further prospective study stratified by G8 is needed to explore the value of CT in elderly patients with NPC.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

Serum and urine metabolomics analyses reveal metabolic pathways and biomarkers in relation to nasopharyngeal carcinoma.

RATIONALE: Nasopharyngeal carcinoma (NPC) is a malignant tumor that is endemic in Southeast Asia, North Africa, and southern China. There is an urgent need for effective early diagnosis and treatment of this disease since NPC is currently often detected at advanced stages. METHODS: To reveal the underlying metabolic mechanisms and discover potential diagnostic biomarkers of NPC, we employed ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and UHPLC-Q-Exactive Orbitrap MS, respectively, to analyze 54 serum samples and 54 urine samples from 27 patients with NPC and 27 healthy control individuals. RESULTS: A total of 1230 metabolites were determined in serum samples, and 181 of the 1230 metabolites were significantly changed in NPC patients. The 181 metabolites were enriched in 16 pathways, including biosynthesis of unsaturated fatty acids, cholesterol metabolism, and ferroptosis. A total of 2509 metabolites were detected in the urine samples. Among them, 179 metabolites were significantly altered in NPC patients, and these metabolites were enriched in eight pathways, including the tricarboxylic acid (TCA) cycle and caffeine metabolism. Seven metabolites, including creatinine and paraxanthine, were found to be significantly changed in both NPC serum and urine samples. Based on them, further biomarker analysis revealed that the panel of three serum metabolites, octanoylcarnitine, creatinine, and decanoyl-l-carnitine, displayed a perfect diagnostic performance (area under the curve [AUC] = 0.973) to distinguish NPC patients from controls, while the other three-metabolite biomarker panel, consisting of stachydrine, decanoyl-l-carnitine, and paraxanthine, had an AUC = 0.809 to distinguish NPC and control in urine samples. CONCLUSION: This work highlights the key metabolites and metabolic pathways disturbed in NPC and presents potential biomarkers for effective diagnosis of this disease.

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study.

BACKGROUND AND PURPOSE: This multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. MATERIALS AND METHODS: We included 1,082 patients treated in 2005-2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE - ) subset separately. RESULTS: Centers 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE-, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE - groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). CONCLUSION: Unequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE - patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing.

OBJECTIVES: While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. MATERIALS AND METHODS: pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. RESULTS: Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. CONCLUSION: Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.