GmTCP40 Promotes Soybean Flowering under Long-Day Conditions by Binding to the GmAP1a Promoter and Upregulating Its Expression.

Soybean [Glycine max (L.) Merr.] is a short-day (SD) plant that is sensitive to photoperiod, which influences flowering, maturity, and even adaptation. TEOSINTE-BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factors have been shown to regulate photoperiodic flowering. However, the roles of TCPs in SD plants such as soybean, rice, and maize remain largely unknown. In this study, we cloned the GmTCP40 gene from soybean and investigated its expression pattern and function. Compared with wild-type (WT) plants, GmTCP40-overexpression plants flowered earlier under long-day (LD) conditions but not under SD conditions. Consistent with this, the overexpression lines showed upregulation of the flowering-related genes GmFT2a, GmFT2b, GmFT5a, GmFT6, GmAP1a, GmAP1b, GmAP1c, GmSOC1a, GmSOC1b, GmFULa, and GmAG under LD conditions. Further investigation revealed that GmTCP40 binds to the GmAP1a promoter and promotes its expression. Analysis of the GmTCP40 haplotypes and phenotypes of soybean accessions demonstrated that one GmTCP40 haplotype (Hap6) may contribute to delayed flowering at low latitudes. Taken together, our findings provide preliminary insights into the regulation of flowering time by GmTCP40 while laying a foundation for future research on other members of the GmTCP family and for efforts to enhance soybean adaptability.

Floral-promoting GmFT homologs trigger photoperiodic after-effects: An important mechanism for early-maturing soybean varieties to regulate reproductive development and adapt to high latitudes.

Soybean (Glycine max) is a typical short-day plant, but has been widely cultivated in high-latitude long-day (LD) regions because of the development of early-maturing genotypes which are photoperiod-insensitive. However, some early-maturing varieties exhibit significant responses to maturity under different daylengths but not for flowering, depicting an evident photoperiodic after-effect, a poorly understood mechanism. In this study, we investigated the postflowering responses of 11 early-maturing soybean varieties to various preflowering photoperiodic treatments. We confirmed that preflowering SD conditions greatly promoted maturity and other postflowering developmental stages. Soybean homologs of FLOWERING LOCUS T (FT), including GmFT2a, GmFT3a, GmFT3b and GmFT5a, were highly accumulated in leaves under preflowering SD treatment. More importantly, they maintained a high expression level after flowering even under LD conditions. E1 RNAi and GmFT2a overexpression lines showed extremely early maturity regardless of preflowering SD and LD treatments due to constitutively high levels of floral-promoting GmFT homolog expression throughout their life cycle. Collectively, our data indicate that high and stable expression of floral-promoting GmFT homologs play key roles in the maintenance of photoperiodic induction to promote postflowering reproductive development, which confers early-maturing varieties with appropriate vegetative growth and shortened reproductive growth periods for adaptation to high latitudes.

Real-world data of immunotherapy from China in recurrent or metastatic head and neck squamous cell carcinoma.

PURPOSE: Immune checkpoint inhibitors (ICIs) have become a standard therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC), however, there are still unanswered questions about immunotherapy. Furthermore, immunotherapy for R/MHNSCC of the mainland Chinese population are lacking. The aim of this study is to evaluate the efficacy and safety of ICIs in real-world settings in China. MATERIALS AND METHODS: We retrospectively reviewed 59 patients with R/MHNSCC who received immunotherapy between May 2019 and December 2021. We assessed demographics, efficacy, survival and safety. RESULTS: Fifty-nine patients were included in the study, all of whom had R/MHNSCC affecting the oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, paranasal sinuses and metastatic cancer in the neck with an unknown primary. The objective response rate (ORR) for all patients was found to be 40.6 %. Out of these patients, 11 patients achieved a complete response and 13 achieved a partial response. The median progression-free survival (PFS) was calculated to be 10.64 months (range: 1.15-29.24 months), while the median overall survival (OS) was 21.75 months (range 2.0-37.55 months). The addition of local radiotherapy resulted in higher ORR and PFS compared to previous reports. Notably, patients with R/MHNSCC in the paranasal sinuses and nasal cavity also showed benefits from immunotherapy. Additionally, patients who achieved stable disease (SD) had similar survival rates to those who achieved partial response (PR), indicating that SD is also an indicator of clinical benefit from immunotherapy. The overall incidence of immune-related adverse reactions in this study was low, with fatigue and rash being the most common side effects. CONCLUSION: These findings highlight the effectiveness and safety of immunotherapy for R/MHNSCC in a real-world setting in China. Further investigation is warranted to explore the potential benefits of incorporating local radiotherapy into the treatment of R/MHNSCC.

Characterization of immune microenvironment in patients with HPV-positive and negative head and neck cancer.

Human papillomavirus (HPV) status strongly predicts positive clinical outcomes in patients with head and neck squamous cell cancer (HNSCC); however, the potential reasons have not been fully elucidated. Here, we characterized the immune context in HPV+ and HPV- HNSCC by integrating scRNA-seq and bulk RNA-seq data. In scRNA-seq data, HPV + HNSCC displayed increased B cells, plasma cells, CD4+ effector T cells, and decreased macrophages and mast cells. This finding was validated using bulk-cell data. Plasma cells predicted improved survival, and macrophages were associated with survival disadvantage. 1403 upregulated and 1877 downregulated differential expressed genes (DEGs) were obtained. Gene Ontology and KEGG enrichment analysis showed these DEGs focused on cytokine-related activity. Transcriptional analysis of B and plasma cells revealed associations between B-cell surface marker FCER2 and improved survival. In vitro assays confirmed the ability of FCER2 to suppress cellular proliferation and migration of HPV + tumors. In conclusion, our analysis revealed a heterogeneous tumor immune environment (TME) for HPV+ and HPV- HNSCC. Further, FCER2+ B cells contribute to antitumor immunity.

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.

The quality of life in nasopharyngeal carcinoma radiotherapy: A longitudinal study.

Objective: This article aims to longitudinally compare nasopharyngeal carcinoma (NPC) patients' quality of life (QoL) during radiotherapy (RT) and identify QoL correlates. Methods: This study included 98 patients, with 85 completing full follow-up. Data were collected at baseline (T1), midpoint of RT (T2), and RT completion (T3), between October 2021 and November 2022. QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RIOM severity was evaluated by the toxicity criteria of Radiation Therapy Oncology Group (RTOG). The nutritional status was evaluated using the Nutritional Risk Screening 2002 (NRS 2002), body mass index (BMI), and the Patient-Generated Subjective Global Assessment (PG-SGA). The generalized estimating equation described the QoL evolution and correlated it with RIOM, nutritional status, and other influential factors. Results: Significant deterioration was observed in various subscales of EORTC QLQ-C30 during RT, including global health status (GHS), physical function, role function, emotional function, fatigue, nausea/vomiting, pain, insomnia, appetite loss, and constipation (all P â€‹< â€‹0.05). Substantial deterioration was also observed in RIOM, nutritional status, and part of hematological indexes (all P â€‹< â€‹0.05). The decline of QoL was associated with gender, age, education level, chemotherapy regimen, Karnofsky performance status (KPS) score, RIOM severity, NRS 2002 score, PG-SGA score, and lymphocyte level (all P â€‹< â€‹0.05). Conclusions: QoL declined during RT and were associated with certain factors. Healthcare professionals should focus on alleviating treatment-related complications and identifying individuals at high risk of malnutrition early to improve outcomes for patients with NPC.

Haplotype Analysis of GmSGF14 Gene Family Reveals Its Roles in Photoperiodic Flowering and Regional Adaptation of Soybean.

Flowering time and photoperiod sensitivity are fundamental traits that determine soybean adaptation to a given region or a wide range of geographic environments. The General Regulatory Factors (GRFs), also known as 14-3-3 family, are involved in protein-protein interactions in a phosphorylation-dependent manner, thus regulating ubiquitous biological processes, such as photoperiodic flowering, plant immunity and stress response. In this study, 20 soybean GmSGF14 genes were identified and divided into two categories according to phylogenetic relationships and structural characteristics. Real-time quantitative PCR analysis revealed that GmSGF14g, GmSGF14i, GmSGF14j, GmSGF14k, GmSGF14m and GmSGF14s were highly expressed in all tissues compared to other GmSGF14 genes. In addition, we found that the transcript levels of GmSGF14 family genes in leaves varied significantly under different photoperiodic conditions, indicating that their expression responds to photoperiod. To explore the role of GmSGF14 in the regulation of soybean flowering, the geographical distribution of major haplotypes and their association with flowering time in six environments among 207 soybean germplasms were studied. Haplotype analysis confirmed that the GmSGF14mH4 harboring a frameshift mutation in the 14-3-3 domain was associated with later flowering. Geographical distribution analysis demonstrated that the haplotypes related to early flowering were frequently found in high-latitude regions, while the haplotypes associated with late flowering were mostly distributed in low-latitude regions of China. Taken together, our results reveal that the GmSGF14 family genes play essential roles in photoperiodic flowering and geographical adaptation of soybean, providing theoretical support for further exploring the function of specific genes in this family and varietal improvement for wide adaptability.

Development and validation of a nomogram for prediction of recovery from moderate-severe xerostomia post-radiotherapy in nasopharyngeal carcinoma patients.

PURPOSE: Aim to create and validate a comprehensive nomogram capable of accurately predicting the transition from moderate-severe to normal-mild xerostomia post-radiotherapy (postRT) in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We constructed and internally verified a prediction model using a primary cohort comprising 223 patients who were pathologically diagnosed with NPC from February 2016 to December 2019. LASSO regression model was used to identify the clinical factors and relevant variables (the pre-radiotherapy (XQ-preRT) and immediate post-radiotherapy (XQ-postRT) xerostomia questionnaire scores, as well as the mean dose (Dmean) delivered to the parotid gland (PG), submandibular gland (SMG), sublingual gland (SLG), tubarial gland (TG), and oral cavity). Cox proportional hazards regression analysis was performed to develop the prediction model, which was presented as a nomogram. The models' performance with regard to calibration, discrimination, and clinical usefulness was evaluated. The external validation cohort comprised 78 patients. RESULTS: Due to better discrimination and calibration in the training cohort, age, gender, XQ-postRT, and Dmean of PG, SMG, and TG were included in the individualized prediction model (C-index of 0.741 (95% CI:0.717 to 0.765). Verification of the nomogram's performance in internal and external validation cohorts revealed good discrimination (C-index of 0.729 (0.692 to 0.766) and 0.736 (0.702 to 0.770), respectively) and calibration. Decision curve analysis revealed that the nomogram was clinically useful. The 12-month and 24-month moderate-severe xerostomia rate was statistically lower in the SMG-spared arm (28.4% (0.230 to 35.2) and 5.2% (0.029 to 0.093), respectively) than that in SMG-unspared arm (56.8% (0.474 to 0.672) and 12.5% (0.070 to 0.223), respectively), with an HR of 1.84 (95%CI: 1.412 to 2.397, p = 0.000). The difference in restricted mean survival time for remaining moderate-severe xerostomia between the two arms at 24 months was 5.757 months (95% CI, 3.863 to 7.651; p = 0.000). CONCLUSION: The developed nomogram, incorporating age, gender, XQ-postRT, and Dmean to PG, SMG, and TG, can be used for predicting recovery from moderate-severe xerostomia post-radiotherapy in NPC patients. Sparing SMG is highly important for the patient's recovery.

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).

Genomic Dissection and Diurnal Expression Analysis Reveal the Essential Roles of the PRR Gene Family in Geographical Adaptation of Soybean.

Pseudo-response regulator (PRR) family members serve as key components of the core clock of the circadian clock, and play important roles in photoperiodic flowering, stress tolerance, growth, and the development of plants. In this study, 14 soybean PRR genes were identified, and classified into three groups according to phylogenetic analysis and structural characteristics. Real-time quantitative PCR analysis revealed that 13 GmPRRs exhibited obvious rhythmic expression under long-day (LD) and short-day (SD) conditions, and the expression of 12 GmPRRs was higher under LD in leaves. To evaluate the effects of natural variations in GmPRR alleles on soybean adaptation, we examined the sequences of GmPRRs among 207 varieties collected across China and the US, investigated the flowering phenotypes in six environments, and analyzed the geographical distributions of the major haplotypes. The results showed that a majority of non-synonymous mutations in the coding region were associated with flowering time, and we found that the nonsense mutations resulting in deletion of the CCT domain were related to early flowering. Haplotype analysis demonstrated that the haplotypes associated with early flowering were mostly distributed in Northeast China, while the haplotypes associated with late flowering were mostly cultivated in the lower latitudes of China. Our study of PRR family genes in soybean provides not only an important guide for characterizing the circadian clock-controlled flowering pathway but also a theoretical basis and opportunities to breed varieties with adaptation to specific regions and farming systems.

The application and value of radiotherapy at the primary site in patients with high-risk neuroblastoma.

OBJECTIVE: To retrospectively analyze radiotherapy (RT) regimens for patients with high-risk neuroblastoma (HRNB) at the primary site after surgery, and to further analyze the characteristics of patients who would benefit more from RT. METHODS: 98 pediatric patients with HRNB were analyzed for local control (LC), RT dose, extent of excision and prognostic factors. Among them, 69 children received RT. RESULTS: The 3 year LC rates were 96.9 and 62.1% (p < 0.001) in the RT and non-RT groups, respectively. In the non-RT group, LC was better in patients with complete macroscopic resection (CME) than in those with incomplete macroscopic resection (IME) (p = 0.026), while in the RT group, no significant difference in LC was found (p = 0.985). Among patients with IME, the LC was 100% in patients with RT doses >= 36 Gy and 66.7% in patients with doses <36 Gy. CONCLUSION: RT is valuable, provides patients with excellent LC, and is safe in the short term. RT had a complementary therapeutic effect on incompletely resected tumors, thus bringing their LC to the level of patients with CME. For patients with IME, RT at a dose of not less than 36 Gy may improve LC. ADVANCES IN KNOWLEDGE: This study analysed the role of radiotherapy in HRNB, investigated the dose of RT depending on the degree of resection, and explored the characteristics of patients who would benefit more from RT.

The NF-κB-Regulated miR-221/222/Syndecan-1 Axis and Intestinal Mucosal Barrier Function in Radiation Enteritis.

PURPOSE: Radiation enteritis (RE) is the most common complication of pelvic radiation therapy, but proven therapies are lacking. Barrier function defects are closely associated with numerous inflammatory disorders. In this study, we investigated whether barrier dysfunction contributes to RE and whether syndecan-1 (Sdc1) protects intestinal barrier function in RE. The mechanism was also elucidated. METHODS AND MATERIALS: Blood, urine, and tissue samples were collected from 21 patients with cervical cancer who experienced RE during radiation therapy. The samples were used to detect inflammatory responses and barrier function. The role of Sdc1 in barrier function was examined in cultured fetal human colon (FHC) cells exposed to radiation and an induced mouse RE model. Barrier function was determined by zonula occludens (ZO)-1 and occludin expression, transepithelial electrical resistance (TEER), and fluorescein isothiocyanate-dextran (FD4) flux. The role of the nuclear factor (NF)-κB-P65 pathway was detected by Western blotting and chromatin immunoprecipitation. The role of miR-221/222 was assessed by real-time polymerase chain reaction and luciferase reporter assays. RESULTS: Patients with RE exhibited obvious pathologic and ultramicrostructural inflammatory injury and barrier disruption in the intestinal mucosa, as well as higher serum lipopolysaccharide (LPS), LPS-binding protein, and cytokine levels and a higher urine lactulose-to-mannitol ratio. Overexpression of Sdc1 in irradiated FHC cells reversed TEER suppression, repressed FD4 flux, and upregulated ZO-1 and occludin expression. Exogenous low-molecular-weight heparin supplementation in RE mice ameliorated the activity of enteritis and barrier defects. Mechanistically, irradiation-activated P65 increased the transcription of miR-221/222 via direct binding to the promoter regions, and miR-221/222 then posttranscriptionally suppressed the Sdc1 gene by binding to its 3'-untranslated region. CONCLUSIONS: The findings suggest that Sdc1 protects barrier function and controls inflammation during RE under transcriptional regulation by the NF-κB pathway and miR-221/222. The network including NF-κB, miR-221/222, and Sdc1 is important in the pathogenesis of RE, and Sdc1 might represent a therapeutic target for novel anti-RE strategies.

The Influence of Transcranial Magnetoacoustic Stimulation Parameters on the Basal Ganglia-Thalamus Neural Network in Parkinson's Disease.

Objective: Parkinson's disease (PD) is a degenerative disease of the nervous system that frequently occurs in the aged. Transcranial magnetoacoustic stimulation (TMAS) is a neuronal adjustment method that combines sound fields and magnetic fields. It has the characteristics of high spatial resolution and noninvasive deep brain focusing. Methods: This paper constructed a simulation model of TMAS based on volunteer's skull computer tomography, phased controlled transducer and permanent magnet. It simulates a transcranial focused sound pressure field with the Westervelt equation and builds a basal ganglia and thalamus neural network model in the PD state based on the Hodgkin-Huxley model. Results: A biased sinusoidal pulsed ultrasonic TMAS induced current with 0.3 T static magnetic field induction and 0.2 W⋅cm-2 sound intensity can effectively modulate PD states with RI ≥ 0.633. The magnitude of magnetic induction strength was changed to 0.2 and 0.4 T. The induced current was the same when the sound intensity was 0.4 and 0.1 W⋅cm-2. And the sound pressure level is in the range of -1 dB (the induced current difference is less than or equal to 0.019 µA⋅cm-2). TMAS with a duty cycle of approximately 50% can effectively modulates the error firings in the PD neural network with a relay reliability not less than 0.633. Conclusion: TMAS can modulates the state of PD.

The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence-based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow-up of NPC, which aim to improve the management of NPC.

Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial. METHODS: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing. FINDINGS: Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death). INTERPRETATION: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion. FUNDING: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Using arterial spin labeling blood flow and its histogram analysis to distinguish early-stage nasopharyngeal carcinoma from lymphoid hyperplasia.

ABSTRACT: To investigate the feasibility of arterial spin labeling (ASL) blood flow (BF) and its histogram analysis to distinguish early-stage nasopharyngeal carcinoma (NPC) from nasopharyngeal lymphoid hyperplasia (NPLH).Sixty-three stage T1 NPC patients and benign NPLH patients underwent ASL on a 3.0-T magnetic resonance imaging system. BF histogram parameters were derived automatically, including the mean, median, maximum, minimum, kurtosis, skewness, and variance. Absolute values were obtained for skewness and kurtosis (absolute value of skewness [AVS] and absolute value of kurtosis [AVK], respectively). The Mann-Whitney U test, receiver operating characteristic curve, and multiple logistic regression models were used for statistical analysis.The mean, maximum, and variance of ASL BF values were significantly higher in early-stage NPC than in NPLH (all P < 0.0001), while the median and AVK values of early-stage NPC were also significantly higher than those of NPLH (all P < 0.001). No significant difference was found between the minimum and AVS values in early-stage NPC compared with NPLH (P = 0.125 and P = 0.084, respectively). The area under the curve (AUC) of the maximum was significantly higher than those of the mean and median (P < 0.05). The AUC of variance was significantly higher than those of the other parameters (all P < 0.05). Multivariate analysis showed that variance was the only independent predictor of outcome (P < 0.05).ASL BF and its histogram analysis could distinguish early-stage NPC from NPLH, and the variance value was a unique independent predictor.

Combination of diffusion-weighted imaging and arterial spin labeling at 3.0 T for the clinical staging of nasopharyngeal carcinoma.

PURPOSE: To probe the utility of diffusion-weighted imaging (DWI) and 3D arterial spin labeling (ASL) in assessing the clinical stage of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: This prospective study included sixty-five newly diagnosed NPC patients who underwent DWI and 3D ASL scans on a 3.0-T magnetic resonance imaging (MRI) system. The apparent diffusion coefficient (ADC) and the tumor blood flow (TBF) of NPC were measured. Tumors were classified as low or high T, N and American Joint Committee on Cancer (AJCC) stages. Student's t-test was used to evaluate the differences between tumors with low and high clinical stages. Pearson correlation analyses were performed to determine the correlation between MRI parameters and clinical stages. Receiver operating characteristic (ROC) curves were then used to evaluate diagnostic capability. RESULTS: High T stage (T3/4) NPC showed significantly lower ADCmin (P = 0.000) and higher TBFmax (P = 0.003) and TBFmean (P = 0.008) values than low T stage (T1/2) NPC. High N stage (N2/3) NPC showed significantly lower ADCmin values (P = 0.023) than low N stage (N0/1) NPC. High AJCC stage (III/IV) NPC showed significantly lower ADCmin (P = 0.000) and higher TBFmax (P = 0.005) and TBFmean (P = 0.011) values than low AJCC stage (I/II) NPC. ADCmin values showed moderate negative correlations with T stage (r = -0.512, P = 0.000), N stage (r = -0.281, P = 0.023), and AJCC stage (r = -0.494, P = 0.000). TBFmax values showed moderate positive correlations with T stage (r = 0.369, P = 0.003) and AJCC stage (r = 0.346, P = 0.005). Compared with ADCmin and TBFmax alone, the combination of ADCmin and TBFmax improved the accuracy from 72.3% and 75.4% to 78.5%, respectively, for T staging, as well as from 72.3% and 69.2% to 83.1% for AJCC staging. CONCLUSIONS: ADCmin and TBFmax values in patients with NPC could help evaluate clinical stages. ADCmin and TBFmax values combined could clearly improve the accuracy in the assessment of AJCC stage.

Nasopharyngeal carcinoma perfusion MRI: Comparison of arterial spin labeling and dynamic contrast-enhanced MRI.

To investigate the feasibility of 3D arterial spin labeling (ASL) as an alternative to dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the qualitative and quantitative evaluation of nasopharyngeal carcinoma (NPC) perfusion.Fifty-two newly diagnosed NPC patients underwent 3D ASL and DCE-MRI scans on a 3.0-T MRI system. The visual qualitative evaluation of the NPC perfusion level was scored from 0 to 3 (0 = no contrast to normal peripheral soft tissue, 3 = pronounced contrast to normal peripheral soft tissue). The visual evaluation of the NPC outline was scored from 0 to 2 (0 = very vague outline, 2 = clear outline). Comparisons of the ASL-derived blood flow (BF) with the DCE-MRI-derived positive enhancement integral, maximum slope of increase, maximum slope of decrease, and time to peak (TTP) were conducted between NPC and non-NPC areas with independent samples t-tests. The diagnostic performance of these parameters was assessed by receiver operating characteristic curve analysis. The correlations between ASL BF and DCE parameters were assessed by Spearman correlation analysis.There was no difference in the visual scores of the NPC perfusion level between the 2 perfusion methods (P= .963). ASL had a lower visual score for describing the outline of NPC than DCE-MRI (P < .001). The ASL and DCE parameters of the NPC areas were significantly different from those of the non-NPC areas (P < .001). The ASL BF showed the largest area under the receiver operating characteristic curve (AUC) of 0.936 for identifying NPC. When all NPC and non-NPC areas were taken into account, significant correlations were observed between the ASL BF and the DCE parameters positive enhancement integral (r = 0.503, P < .001), maximum slope of increase (r = 0.616, P < .001), maximum slope of decrease (r = 0.380, P < .001), and TTP (r = -0.601, P < .001).3D ASL could reveal the hyperperfusion of NPC in a qualitative and quantitative manner without using contrast agent. Additionally, the ASL BF correlated significantly with the semiquantitative DCE-MRI parameters.

Safety and Effectiveness of De-escalated Radiation Dose in T1-3 Nasopharyngeal Carcinoma: A Propensity Matched Analysis.

Backgrounds: With the excellent local control in T1 to T3 nasopharyngeal carcinoma (NPC) treated with intensity modulated radiotherapy (IMRT), the importance of toxicities is increasingly being recognised. This retrospective propensity score analysis sought to assess whether moderate dose reduction compromised long-term outcome compared with standard dose in T1-3 NPCs. Materials and Methods: A total of 266 patients (67 female, 199 male) with a median age of 50 years between June 2011 and June 2015 were analysed. All were treated with IMRT, with or without systemic chemotherapy. The prescription radiation dose to gross tumor is 70Gy/2.12Gy/33F in our institution. Results: With a median follow-up time of 50 months, the 5-year loco-regional failure-free survival (LRFS) and overall survival (OS) were 93.5% and 81.8%, respectively. 32 patients received radiation dose less than prescription dose, with a median dose of 63.6Gy (53-67Gy). Another 234 patients received exactly the prescription dose of 70Gy. Propensity scores were computed (32 patients treated with de-escalated dose and 64 patients with standard dose), there was no significant difference in 5-year LRFS and 5-year OS between the two groups (92.5% and 91.7% with standard dose; 82.1% and 85.7% with de-escalation dose; p=0.863 for LRFS and 0.869 for OS). No independent prognostic factor was associated with loco-regional failure in univariate analysis. Conclusions: T1-3 nasopharyngeal carcinoma presenting with superior locoregional control, a moderately reduced dose (about 10%) delivered with IMRT resulted in comparable prognosis to those with prescription dose of 70Gy.

Ethyl pyruvate suppresses the growth, invasion and migration and induces the apoptosis of non­small cell lung cancer cells via the HMGB1/RAGE axis and the NF­κB/STAT3 pathway.

As an inhibitor of high mobility group protein B1 (HMGB1), ethyl pyruvate (EP) has been associated with various inflammatory diseases. Recent studies have investigated the relationship between EP and cancer. The present study aimed to determine the antitumor efficacy of EP in non­small cell lung cancer (NSCLC) cells and elucidate the underlying mechanism. A549, H520 and PC­9 cells were treated with EP in suitable concentrations. RT­qPCR and western blot analysis were performed to evaluate HMGB1 and RAGE expression levels. MTT and colony formation assays assessed the effect of EP on cell growth. A Transwell assay was used to evaluate invasion and migration potential and flow cytometry was performed to analyze cell apoptosis. Bcl­2 family proteins were identified by western blot analysis. The results demonstrated that an increased EP concentration effectively reduced HMGB1 and RAGE expression, thus inhibiting the HMGB1/RAGE axis. EP decreased level of PCNA and MMP­9 and increased P53 levels. Bcl­2 and Mcl­1 were also decreased, whereas Bax expression was increased. Furthermore, a high concentration of EP (30 mmol/l) significantly inhibited NF­κB and STAT3 activation. In summary, EP inhibited NSCLC cell growth, invasion and migration and induced apoptosis by suppressing the HMGB1/RAGE axis and the NF­κB/STAT3 pathway, thus suggesting that EP may be a valuable therapeutic agent for NSCLC.