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.

Symptom clusters after chemoradiotherapy in discharged nasopharyngeal carcinoma patients.

Objective: To investigate the incidence of complications and types of chemoradiotherepy induces symptom clusters in patients with nasopharyngeal carcinoma (NPC) who were first diagnosed after treatment and discharged from hospital. Methods: After their discharge home, 130 NPC patients who had been treated with chemoradiotherapy were asked to complete a modified Chinese version of the Quality of Life Questionnaire-Head and Neck Module developed by the European Organization for the Research and Treatment of Cancer in the Head and Neck. Symptom clusters in patients were identified through exploratory factor analysis. Results: The most serious symptoms for discharged NPC patients who had received chemoradiotherapy were dental problems, a sense of obstruction while swallowing, embarrassment in physical contact with family members and friends, difficulty in speaking with others, and embarrassment in public. The six symptom clusters identified through exploratory factor analysis were (1) painful eating, (2) social difficulties, (3) psychological disorders, (4) symptomatic shame, (5) teeth/throat injuries, and (6) sensory abnormalities. The total contribution rate of variance was 65.73%. Conclusion: NPC patients who are treated with chemoradiotherapy can experience adverse symptom clusters that continue after discharge. Nurses should evaluate the patients' symptoms before discharge and provide targeted health education services which would reduce the patients' complications and improve the quality of life at home. Besides, medical staff should evaluate the complications in a timely and comprehensive manner and provide individualized health education for the affected patients to help them manage chemoradiotherapy side effects.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309).

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3 weeks (Q3W), plus chemotherapy (Q3W for 4-6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p < 0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically "hot" tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment. VIDEO ABSTRACT.

[Diagnosis of nasopharyngeal carcinoma with convolutional neural network on narrowband imaging].

Objective:To evaluate the diagnostic accuracy of the convolutional neural network（CNN） in diagnosing nasopharyngeal carcinoma using endoscopic narrowband imaging. Methods:A total of 834 cases with nasopharyngeal lesions were collected from the People's Hospital of Guangxi Zhuang Autonomous Region between 2014 and 2016. We trained the DenseNet201 model to classify the endoscopic images, evaluated its performance using the test dataset, and compared the results with those of two independent endoscopic experts. Results:The area under the ROC curve of the CNN in diagnosing nasopharyngeal carcinoma was 0.98. The sensitivity and specificity of the CNN were 91.90% and 94.69%, respectively. The sensitivity of the two expert-based assessment was 92.08% and 91.06%, respectively, and the specificity was 95.58% and 92.79%, respectively. There was no significant difference between the diagnostic accuracy of CNN and the expert-based assessment （P=0.282, P=0.085）. Moreover, there was no significant difference in the accuracy in discriminating early-stage and late-stage nasopharyngeal carcinoma（P=0.382）. The CNN model could rapidly distinguish nasopharyngeal carcinoma from benign lesions, with an image recognition time of 0.1 s/piece. Conclusion:The CNN model can quickly distinguish nasopharyngeal carcinoma from benign nasopharyngeal lesions, which can aid endoscopists in diagnosing nasopharyngeal lesions and reduce the rate of nasopharyngeal biopsy.

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).

[Analysis of molecular genetics and clinical characteristics of 3 children with Waardenburg syndrome].

Objective:To analyze the molecular genetics and clinical characteristics of 3 children with syndromic deafness were analyzed to clarify their causative genes and genetic characteristics. Methods:The medical records of 3 children and their parents were collected and analyzed, including physical examination, hearing evaluation, temporal bone CT, and cranial MRI. Whole-exome sequencing（WES） was used to screen for pathogenic gene variants, and Sanger sequencing was used to verify the candidate positive variants in the probands and their parents. Results:All 3 patients were female with normal intelligence. Patient 1 and 3 had a family history of deafness, which conformed to the pattern of autosomal dominant inheritance. All three patients had bilateral profound sensorineural hearing impairment with bright-blue sclera. Other phenotypes included hypertelorism（patient 1）, multiple dyschromatosis（patient 2）, and yellowish hair（patient 2）, blepharoptosis（patient 3）. Patient 3 had bilateral vestibular enlargement, internal auditory canal enlargement, and bilateral inner ear malformations. Mother of patient 1 had only left mild hearing impairment; mother of patient 3 had bilateral hearing impairment with unilateral bright-blue sclera and yellowish hair. WES detected heterozygous variants, PAX3 c.811C>T, MITF c.632T>C, and SOX10 c.1359_1360 insGCCCCACA, in patient 1, 2, and 3, respectively. The variants in patient 1 and 3 were inherited from their mothers who had hearing impairment, and MITFvariant in patient 2 may be a spontaneous variation. The final diagnoses were that patient 1 with Waardenburg syndrome type 1（WS1）, and the mother of patient 1, patient 2, patient 3, and the mother of patient 3 with WS2. Conclusion:WS is a syndromic deafness, and the main clinical features include autosomal dominant inheritance and scleral pigment abnormalities. However, the findings of this study show that there is still phenotypic heterogeneity in WS even caused by the same gene variant, so it depends on genetic tests to confirm the diagnosis; The gene variant of patient 1 and 2 was never been reported in other patients, which expands the pathogenic variant spectrum of WS.

Blocking Notch signalling reverses miR-155-mediated inflammation in allergic rhinitis.

Although recent studies have shown that the Notch signalling pathway induces the production of Th2-related immune factors, the exact mechanism through which Notch signalling exacerbates allergic rhinitis (AR) remains unknown. To investigate the roles of Notch in AR, serum, nasal mucosa and spleen samples were isolated from BALB/c mice. Paraffin sections were stained with haematoxylin and eosin (H&E) or periodic acid-Schiff (PAS) to assess inflammation. Flow cytometry was performed to detect group 2 innate lymphoid cells (ILC2s) in the serum samples, and cytokine levels were measured by enzyme-linked immunosorbent assays (ELISAs). The mRNA expression levels of the Notch signalling pathway components and miR-155 were measured by quantitative real-time PCR (qRT-PCR). In addition, human nasal epithelial cells (HNEpCs) were cultured to investigate the functional consequences of Notch pathway inhibition. The findings demonstrated that symptomatology and pathology were substantially altered, and AR model mice were established. In vivo stimulation with ovalbumin (OVA) significantly increased the Th2-type immune responses and the expression of OVA-sIgE, IL-4, GATA3, NF-κB and miR-155. However, the Notch signalling pathway was significantly deteriorated in AR, and this effect was accompanied by reduced Notch1, Notch2, RBPj and Hes1 levels. These effects were abrogated by gamma-secretase inhibitor IX (DAPT) treatment, and DAPT inhibited the wound healing and proliferation of HNEpCs in a dose-dependent manner. Therefore, our results suggest that blocking the Notch pathway may alleviate miR-155-mediated inflammation via the regulation of immune homeostasis in AR.

Efficacy of concurrent chemoradiotherapy combined with nimotuzumab in the treatment of nasopharyngeal carcinoma with cervical lymph node metastasis.

OBJECTIVES: First, we retrospectively compared the clinical efficacy of concurrent chemoradiotherapy combined with nimotuzumab vs. chemoradiotherapy alone in patients with nasopharyngeal carcinoma (NPC) and cervical lymph node metastasis. Second, we analyzed the value of Ki-67 as a predictor of nimotuzumab efficacy. METHODS: From January 2012 to December 2019, 1250 patients with cervical lymph node metastasis eligible for enrollment were included, of whom 383 were treated with concurrent chemoradiotherapy combined with nimotuzumab (targeted therapy group), and 867 were treated with concurrent chemoradiotherapy (CRT group). A total of 381 pairs of patients were matched using 1:1 propensity score matching, and differences in clinical prognosis were compared between the two groups. RESULTS: Overall survival (OS) (P = 0.028), disease-free survival (DFS) (P = 0.040), and distant metastasis-free survival (DMFS) (P = 0.040) were better in the targeted therapy compared to the CRT group. Multivariate analysis revealed that clinical staging, chemotherapy, and nimotuzumab therapy were predictors of OS and DFS. In the targeted therapy group, patients with ≥ 50% Ki-67 positivity had better OS and DFS rates than those with < 50% Ki-67 positivity. CONCLUSIONS: In patients with stage N1-3 NPC and lymph node metastasis, the addition of nimotuzumab to concurrent chemoradiotherapy may provide additional survival benefits. Ki-67 is a potential biomarker with clinical predictive value for the efficacy of nimotuzumab combined with chemoradiotherapy.

Fluid dynamics of the upper airway in pediatric patients with severe laryngomalacia.

Laryngomalacia is the top cause of pediatric laryngeal wheeze. We used computational fluid dynamics to study the inspiratory airflow dynamics in severe pediatric laryngomalacia. Computed tomography was performed on the upper airways of two infants, one with severe laryngomalacia and one with normal airway, and 3D models were reconstructed. ANSYS CFD-POST software was used to simulate airflow in these models to compare the volumetric flow rate, flow velocity, pressure, wall shear, and vortex. The volume flow rate in the laryngomalacia model was significantly reduced compared with the control model. Under inspiratory pressures, the peak flow velocity, pressure, and shear force in the control model appeared at the soft palate stenosis, while that in the laryngomalacia model appeared at the supraglottis stenosis. In both models, the maximum flow velocity and shear force increased with decreasing inspiratory pressure, while the minimum pressure decreased with decreasing inspiratory pressure. In the control model, the airflow vortex appeared anteriorly below the posterior section of the soft palate. In the laryngomalacia model, the vortex appeared anteriorly below the posterior section of the soft palate and anteriorly below the vocal folds. Our methodology provides a new mechanistic understanding of pediatric laryngomalacia.

Epithelial-mesenchymal transition classification of circulating tumor cells predicts clinical outcomes in progressive nasopharyngeal carcinoma.

Background: Liquid biopsy facilitates the enrichment and isolation of circulating tumor cells (CTCs) in various human cancers, including nasopharyngeal carcinoma (NPC). Characterizing CTCs allows observation of the evolutionary process of single tumor cells undergoing blood-borne dissemination, such as epithelial-mesenchymal transition. However, the prognostic value of phenotypic classification of CTCs in predicting the clinical outcomes of NPC remains poorly understood. Patients and methods: A total of 92 patients who met the inclusion criteria were enrolled in the present study. The CanPatrol™ CTC technology platform was employed to isolate CTCs, and an RNA in situ hybridization-based system was used for phenotypic classification. Kaplan-Meier survival curves were used for univariate survival analysis, and the log-rank test was performed for between-group comparisons of the survival curves. Results: CTCs were detected in 88.0% (81/92) of the enrolled patients with NPC. The total CTC number did not vary between the T and N stages or between Epstein-Barr virus DNA-positive and -negative cases. The numbers of total CTCs and epithelial/mesenchymal (E/M) hybrid CTCs decreased significantly at 3 months post concurrent chemoradiotherapy (P=0.008 and P=0.023, respectively), whereas the numbers of epithelial or mesenchymal CTCs did not decrease. E/M hybrid-predominant cases had lower disease-free survival (P=0.043) and distant metastasis-free survival (P=0.046) rates than non-E/M hybrid-predominant cases. Conclusion: CTC classification enables a better understanding of the cellular phenotypic alterations responsible for locoregional invasion and distant metastasis in NPC. E/M hybrid-predominant CTC distribution predicts unfavorable clinical outcomes in patients with progressive NPC.

Awareness about laryngopharyngeal reflux disease among Chinese otolaryngologists: a nationwide survey.

OBJECTIVES: This study aimed to investigate the status of the current knowledge about laryngopharyngeal reflux disease (LPRD) among Chinese otolaryngologists. DESIGN: Multi-centre cross-sectional survey. SETTING: 220 medical centres in different regions of China. PARTICIPANTS: A total of 2254 otolaryngologists from 220 medical centres in China who were successfully on-site surveyed between November 2019 and December 2020. MAIN OUTCOME MEASURES: Awareness about LPRD included knowledge about risk factors, symptoms, laryngoscope signs, related diseases, current diagnostic methods and treatments. RESULTS: The percentage of participants who had heard of LPRD was 96.4%, with academic conferences as the most common source of information (73.3%). The most commonly known risk factor, symptom, laryngoscope sign, related disease, diagnostic method and treatment were alcohol consumption (44.0%), pharyngeal foreign body sensation (66.9%), hyperaemia (52.4%), pharyngolaryngitis (54.8%), pH monitoring (47.6%) and medication (82.1%), respectively. Only 28.3% of all participants knew that 24 h pH or multichannel intraluminal impedance pH monitoring was the most accurate diagnostic test. As many as 73.1% of all participants knew that proton pump inhibitors were the first-line treatment drugs. An analysis of the overall status of awareness using a scoring system suggested that otolaryngologists were better aware owing to more access, working at 3A hospitals, and postgraduate or above educational background (all p<0.05). CONCLUSION: Although the majority of Chinese otolaryngologists had heard of LPRD, their overall awareness about the disease was not encouraging. More efforts are needed to increase the knowledge about LPRD among this group of physicians. TRIAL REGISTRATION NUMBER: ChiCTR1900025581.

STAT3 regulates SRGN and promotes metastasis of nasopharyngeal carcinoma through the FoxO1-miR-148a-5p-CREB1 axis.

Nasopharyngeal carcinoma (NPC), which is marked by a distinct distribution, is a common subtype of epithelial carcinoma arising from the nasopharyngeal mucosal lining. SRGN acts as an important and poor prognostic factor of NPC through multiple different mechanisms. However, the biological role and mechanism of SRGN in NPC remain unknown. Expression levels of miR-148a-5p, CREB1, FoxO1, and SRGN in NPC tissues and cell lines were tested by qRT-PCR or/and Western blot. The impacts of miR-148a-5p, CREB1, FoxO1, and SRGN on NPC cell viability, proliferation, migration, and invasion were estimated in vitro by CCK-8, colony formation, wound healing and Transwell experiments, and in vivo by a xenograft tumor model. JASPAR analysis was used to predict the binding activity of Foxo1 (CREB1) with the miR-148a-5p (SRGN) promoter, and the interaction was validated by EMSA and ChIP assays. The miR-148a-5p-CREB1 interaction was validated by a dual-luciferase reporter and RIP assays. CREB1 and SRGN were increased while miR-148a-5p was decreased in NPC. Silencing of SRGN and CREB1, as well as miR-148a-5p overexpression, repressed NPC tumor progression in vitro and in vivo. CREB1 promoted SRGN expression in NPC by targeting the promoter area of SRGN. Silencing of FoxO1 facilitated NPC tumor progression, while silencing of STAT3 repressed NPC tumor progression. FoxO1 bound to and regulated miR-148a-5p in NPC, and miR-148a-5p targeted CREB1. Additionally, FoxO1 knockdown abolished the downregulation of CREB1 and SRGN induced by STAT3 silencing. Our results suggest that STAT3 regulates SRGN and promotes the growth and metastasis of NPC through the FoxO1-miR-148a-5p-CREB1 axis.

Prognostic value of hypothyroidism in patients undergoing intensity-modulated radiation therapy for nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to investigate the effect of hypothyroidism and thyroxine replacement therapy on the prognosis of nasopharyngeal carcinoma (NPC) patients. METHODS: The clinical data of 284 NPC patients, who received intensity-modulated radiation therapy (IMRT) between January 2011 and December 2016, were retrospectively analyzed. RESULTS: Hypothyroidism occurred in 38% of patients. Patients with hypothyroidism had significantly better disease-free survival (DFS) (p = 0.002) and relapse-free survival (RFS) (p = 0.008). Multivariate analysis showed that hypothyroidism was a positive independent prognostic factor (DFS and RFS). Among the patients with hypothyroidism, thyroxine replacement therapy did not yield inferior survival (DFS, RFS, all p > 0.05). CONCLUSIONS: The NPC patients with complete response are at risk of hypothyroidism, which is attributable to escalating dose. These patients experienced clinical hypothyroidism could be adequately treated with thyroid hormone replacement. Further investigation of the underlying biological mechanism and potential therapeutic implications are required.

Long intergenic non-protein coding RNA 02570 promotes nasopharyngeal carcinoma progression by adsorbing microRNA miR-4649-3p thereby upregulating both sterol regulatory element binding protein 1, and fatty acid synthase.

Our previous studies have elucidated a possible connection between long intergenic non-protein coding RNA 2570 (LINC02570) and nasopharyngeal carcinoma (NPC). However, the precise mechanism by which LINC02570 promotes NPC remains unknown. We used quantitative polymerase chain reaction (qPCR) to detect LINC02570 expression in nasopharyngeal cell lines, NPC tissues, and chronic rhinitis tissues. Subcellular LINC02570 localization was confirmed by fluorescence in situ hybridization (FISH). The effects of LINC02570 stable knockdown and overexpression on viabillity, proliferation, migration, and invasion were analyzed using 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl-2-H-Tetrazolium bromide (MTT), a colorimetric focus-formation assay, a wound healing assay, and transwell assays. RNA crosstalk analysis in silico predicted microRNA-4649-3p (miR-4649-3p) binding to LINC02570 or sterol regulatory element binding transcription factor 1 (SREBF1). A dual luciferase reporter assay was used to confirm potential interactions. Sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FASN) expression were detected by western blotting. The results suggest that LINC02570 is upregulated in late clinical stage NPC patients, and promotes NPC progression by adsorbing miR-4649-3p to up-regulate SREBP1 and FASN. This study elucidates a potential chemotherapeutic target involved in lipid metabolism in NPC.

Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial.

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36-0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364-0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.

Store-operated Ca2+ entry as a key oncogenic Ca2+ signaling driving tumor invasion-metastasis cascade and its translational potential.

Tumor metastasis is the primary cause of treatment failure and cancer-related deaths. Store-operated Ca2+ entry (SOCE), which is mediated by stromal interaction molecules (STIM) and ORAI proteins, has been implicated in the tumor invasion-metastasis cascade. Epithelial-mesenchymal transition (EMT) is a cellular program that enables tumor cells to acquire the capacities needed for migration and invasion and the formation of distal metastases. Tumor-associated angiogenesis contributes to metastasis because aberrantly developed vessels offer a path for tumor cell dissemination as well as supply sufficient nutrients for the metastatic colony to develop into metastasis. Recently, increasing evidence has indicated that SOCE alterations actively participate in the multi-step process of tumor metastasis. In addition, the dysregulated expression of STIM/ORAI has been reported to be a predictor of poor prognosis. Herein, we review the latest advances about the critical role of SOCE in the tumor metastasis cascade and the underlying regulatory mechanisms. We emphasize the contributions of SOCE to the EMT program, tumor cell migration and invasion, and angiogenesis. We further discuss the possibility of modulating SOCE or intervening in the downstream signaling pathways as a feasible targeting therapy for cancer treatment.

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.