Efficacy and biomarker analysis of second-line nab-paclitaxel plus sintilimab in patients with advanced biliary tract cancer.

Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second-line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second-line nab-paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first-line chemotherapy were enrolled. Subjects received nab-paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next-generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor-infiltrating lymphocytes were applied to explore potential biomarkers. Twenty-six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60-278 days). The median OS was 442 days (about 14.7 months, 95% CI 298-586 days). Grade 3 treatment-related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD-L1 and high proportions of CD8+ T-cell infiltration were correlated with improved clinical outcome. Nab-paclitaxel plus sintilimab is a potentially effective and tolerable second-line regimen for advanced BTC that deserves to be studied in large-scale trials. PD-L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction.

Viruses in deep-sea cold seep sediments harbor diverse survival mechanisms and remain genetically conserved within species.

Deep sea cold seep sediments have been discovered to harbor novel, abundant, and diverse bacterial and archaeal viruses. However, little is known about viral genetic features and evolutionary patterns in these environments. Here, we examined the evolutionary ecology of viruses across active and extinct seep stages in the area of Haima cold seeps in the South China Sea. A total of 338 viral operational taxonomic units are identified and linked to 36 bacterial and archaeal phyla. The dynamics of host-virus interactions are informed by diverse antiviral defense systems across 43 families found in 487 microbial genomes. Cold seep viruses are predicted to harbor diverse adaptive strategies to persist in this environment, including counter-defense systems, auxiliary metabolic genes, reverse transcriptases, and alternative genetic code assignments. Extremely low nucleotide diversity is observed in cold seep viral populations, being influenced by factors including microbial host, sediment depth, and cold seep stage. Most cold seep viral genes are under strong purifying selection with trajectories that differ depending on whether cold seeps are active or extinct. This work sheds light on the understanding of environmental adaptation mechanisms and evolutionary patterns of viruses in the sub-seafloor biosphere.

Relationship between Whole-Blood Magnesium and Cognitive Performance among Chinese Adults.

OBJECTIVE: To explore the association between magnesium levels and the odds of mild cognitive impairment (MCI). METHOD: In this cross-sectional study of 1006 participants (≥55 years) from China, whole-blood magnesium concentration was measured using inductively coupled plasma mass spectrometry. MCI was diagnosed according to Petersen criteria using self-reported cognitive decline and a neuropsychological test battery, including the trail-making test-part B (TMT-B), auditory verbal learning test (AVLT), digit symbol substitution test (DSST), and verbal fluency test (VFT), which measured the assessment of executive, memory, attention, and language functioning, respectively. A logistic regression was used to assess the relationship between magnesium levels and MCI, and linear regression analyses were performed for the association between magnesium and cognitive function score. RESULTS: The MCI group had a significantly lower concentration of magnesium compared to the Non-MCI group (34.7 ± 9.8 vs. 36.7 ± 9.7, p = 0.017). After adjusting for covariates, a negative association was observed between magnesium levels and MCI. Compared with the lowest quartile (median: 25.4 mg/L), the odds ratio for MCI was 0.53 (95%CI 0.32-0.90) for the highest quartile (median: 48.4 mg/L), and there was an inverse dose-response relationship (p for trend = 0.009). In addition, higher levels of magnesium were positively correlated with VFT scores (ß = 0.37, 95%CI = 0.11-0.62) and DSST scores (ß = 0.50, 95%CI = 0.01~0.98) and negatively correlated with TMT scores (ß = -1.73, 95%CI = -3.40--0.07) in the middle-aged and older adults. CONCLUSIONS: Whole-blood magnesium was inversely associated with the occurrence of MCI and positively associated with performance in neuropsychological tests assessing attention, executive, and language ability in middle-aged and older adults.

[Correlation between red meat intake and prevalence of adults diabetes in Hubei Province from 1997 to 2018].

OBJECTIVE: To explore the relationship between red meat intake and the prevalence of diabetes. METHODS: Using the data of the China Health and Nutrition Survey in 1997, 2000, 2004, 2006, 2009, 2011, 2015 and 2018, 1154 people aged 18-75 years were included, and age, gender, urban and rural, education, marital status, income, occupational physical activity, total energy intake, fat energy ratio, smoking, drinking, body mass index and hypertension were adjusted. The Cox proportional hazard regression analysis was used to calculate diabetes hazard ratio(HR) and corresponding 95%CI. RESULTS: In the study population, the per capita intake of red meat increased from 40.59 g/d in 1997 to 73.91 g/d in 2018, and the prevalence of diabetes rose from 6.14% in 2009 to 7.00% in 2018. In the early adjustment model, compared with the control group, the red meat intake HR of 1-39 g/d group was 0.92(95% CI 0.51-1.68), and the HR of 40-74 g/d group was 0.86(95% CI 0.47-1.58), and the HR of the group ≥75 g/d was 1.02(95% CI 0.62-1.68). In model 2, compared with the control group, the red meat intake HR of 1-39 g/d group was 0.71(95% CI 0.37-1.35), and the HR of 40-74 g/d group was 0.71(95% CI 0.38-1.35), the HR of ≥75 g/d group was 1.06(95% CI 0.69-1.87). In the fully adjusted model, compared with the control group, the red meat intake HR of 1-39 g/d group was 0.75(95% CI 0.61-1.55), the HR of 40-74 g/d group was 0.66(95% CI 0.57-1.43), and the HR of ≥75 g/d group was 1.27(95% CI 0.87-2.04). CONCLUSION: With the increase of red meat intake, the prevalence of diabetes was also increasing, but there was no statistically significant association.

Insight into the relationships between total suspended particles and mercury in meltwater in a typical glacierized basin in the inland Tibetan Plateau.

Mercury (Hg) released by melting glaciers is likely to bind to suspended particles in meltwater runoff, posing potential risks to downstream ecosystems. The rapidly receding glaciers on the Tibetan Plateau promote the export of total suspended particles (TSP), increasing the uncertainty of Hg export released by glacier melting. To investigate the relationships between TSP and Hg, a multimedia sampling campaign was conducted in July 2020 in the Kuoqionggangri glacier region of the Lhasa River Valley No. 1 glacierized basin located in the inland Tibetan Plateau. Samples from glacier snow/ice, supraglacial rivers, subglacial rivers, proglacial lakes, and meltwater runoff were obtained, and the relationships between TSP and Hg and their transport in glacier meltwater runoff in the context of glacier retreat were explored. The average TSP concentration of different environmental samples ranged from 9.51 mg/L to 399. 27 mg/L, showing significant differences. The average total Hg (THg) concentrations ranged from 0.52 ng/L to 58.81 ng/L and decreased in the order of snow/ice >runoff> subglacial river > proglacial lake > supraglacial river. Both TSP mass concentration and number concentration have an impact on the diurnal variation in meltwater runoff Hg, and the influence of TSP number concentration is stronger than that of concentration. Sites with high TSP concentrations and quantities tended to have higher Hg concentrations, while TSP particle size had no significant effect on Hg concentration or spatial distribution. Our study further divided the glacier recharge basin into the glacier cover zone, the periglacial zone, and the downstream zone and discussed the potential impact of TSP on Hg transport in each zone. Our analysis highlights that the periglacial zone will expand and activate the resuspension process of river sediments in the warming future, which may increase the export of TSP and Hg downstream.

Identifying the prognostic value of MRI-based tumor response and predicting the risk of radio-resistance in re-radiotherapy for locally recurrent nasopharyngeal carcinoma.

OBJECTIVE: To investigate the prognostic value of tumor response (TR) for locoregionally recurrent nasopharyngeal carcinoma (lrNPC) patients at the end of re-radiotherapy (re-RT) and develop a risk score model to predict patient's radiosensitivity to re-RT. MATERIALS AND METHODS: A total of 594 patients with lrNPC from 2010 to 2020 were retrospectively reviewed as the total cohort. Among these, 310 patients with complete first-line treatment data were reviewed as a secondary cohort. Overall survival (OS) was the primary endpoint. Locoregional control (LRC) was the secondary endpoint. Multivariate Cox analysis was performed to investigate the prognostic value of TR at the end of re-RT (rTR). A risk score model for predicting rTR was obtained by logistic regression analysis, and its effectiveness was compared using receiver operating characteristic (ROC) analysis. RESULTS: Patients with complete response (CR) to rTR had higher 5-year OS and LRC rate than non-CR patients in both the total and secondary cohort. rTR was an independent prognostic factor for OS (P = 0.002) and LRC (P = 0.008). We developed a risk score model including four significant risk factors (relapse T stage, relapse gross tumor volume, time to recurrence, and initial TR). The area under the curve of the risk score model was 0.73 (95% CI: 0.678 to 0.780), which was significantly higher than that of each variable alone. Patients with the highest risk scores may be insensitive to re-RT and had a residual tumor risk of 89.9% after rRT. CONCLUSION: rTR was an independent prognostic factor for OS and LRC in lrNPC patients. We developed a risk score model for predicting patients' sensitivity to re-RT to screen for radiosensitive patients. This can serve as a treatment decision-making tool for clinicians.

Characterization of the Complete Mitochondrial Genome of Agelas nakamurai from the South China Sea.

The Agelas genus sponges are widely distributed and provide shelter for organisms that inhabit reefs. However, there is a lack of research on the genetic diversity of the Agelas sponges. Additionally, only one Agelas mitochondrial genome has been documented, leaving the characteristics of the Agelas genus's mitogenome in need of further clarification. To address this research gap, we utilized Illumina HiSeq4000 sequencing and de novo assembly to ascertain the complete mitochondrial genome of Agelas sp. specimens, sourced from the South China Sea. Our analysis of the cox1 barcoding similarity and phylogenetic relationship reveals that taxonomically, the Agelas sp. corresponds to Agelas nakamurai. The mitogenome of Agelas nakamurai is 20,885 bp in length, encoding 14 protein-coding genes, 24 transfer RNA genes, and 2 ribosomal RNA genes. Through a comparison of the mitochondrial genes, we discovered that both Agelas nakamurai and Agelas schmidti have an identical gene arrangement. Furthermore, we observed a deletion in the trnD gene and duplication and remodeling of the trnL gene in the Agelas nakamurai's mitogenome. Our evolutionary analysis also identified lineage-specific positive selection sites in the nad3 and nad5 genes of the Agelas sponges' mitogenome. These findings shed light on the gene rearrangement events and positive selection sites in the mitogenome of Agelas nakamurai, providing valuable molecular insights into the evolutionary processes of this genus.

M1 stage subdivisions based on 18F-FDG PET-CT parameters to identify locoregional radiotherapy for metastatic nasopharyngeal carcinoma.

Purpose: To establish a risk classification of de novo metastatic nasopharyngeal carcinoma (mNPC) patients based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) radiomics parameters to identify suitable candidates for locoregional radiotherapy (LRRT). Methods: In all, 586 de novo mNPC patients who underwent 18F-FDG PET-CT prior to palliative chemotherapy (PCT) were involved. A Cox regression model was performed to identify prognostic factors for overall survival (OS). Candidate PET-CT parameters were incorporated into the PET-CT parameter score (PPS). Recursive partitioning analysis (RPA) was applied to construct a risk stratification system. Results: Multivariate Cox regression analyses revealed that total lesion glycolysis of locoregional lesions (LRL-TLG), the number of bone metastases (BMs), metabolic tumor volume of distant soft tissue metastases (DSTM-MTV), pretreatment Epstein-Barr virus DNA (EBV DNA), and liver involvement were independent prognosticators for OS. The number of BMs, LRL-TLG, and DSTM-MTV were incorporated as the PPS. Eligible patients were divided into three stages by the RPA-risk stratification model: M1a (low risk, PPSlow + no liver involvement), M1b (intermediate risk, PPSlow + liver involvement, PPShigh + low EBV DNA), and M1c (high risk, PPShigh + high EBV DNA). PCT followed by LRRT displayed favorable OS rates compared to PCT alone in M1a patients (p < 0.001). No significant survival difference was observed between PCT plus LRRT and PCT alone in M1b and M1c patients (p > 0.05). Conclusions: The PPS-based RPA stratification model could identify suitable candidates for LRRT. Patients with stage M1a disease could benefit from LRRT.

Contrast-enhanced ultrasound manifestations of synchronous combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma: A case report.

BACKGROUND: Synchronous combined hepatocellular-cholangiocarcinoma (CHC) and hepatocellular carcinoma (HCC) is very rare, with few literature reports and poor clinical outcomes associated with the disorder. Surgical resection is the main treatment, which makes the preoperative diagnosis very important. However, due to imaging manifestations overlapping with HCC, diagnosis of this type of synchronous cancer is challenging and it tends to be misdiagnosed as multiple HCC. Herein, we report the contrast-enhanced ultrasound (CEUS) manifestations of a case of synchronous CHC and HCC, aiming at adding to the understanding of this disease. CEUS displayed exquisite vascularity and tissue perfusion in real time with good spatial and temporal resolution and more accurately reflect tumor washin and washout times than contrast-enhanced computed tomography (CT) in this case. CASE SUMMARY: The patient was a 69-year-old female with a 20-year history of chronic hepatitis B. Due to months of epigastric pain and anorexia, she reffered to our hospital for treatment. Five days before hospitalization, abdominal magnetic resonance imaging performed at another hospital detected a space-occupying lesion in the liver. After her hospitalization, laboratory tests showed elevated alpha-fetoprotein and carbohydrate antigen 19-9 level. Two suspicious liver lesions located in S4 and S6, respectively, were identified in a cirrhotic background by abdominal contrast-enhanced CT (CECT). Furthermore, the lesion in S4 and S6 were detected by CEUS and assigned to CEUS LI-RADS 5 and M categories, respectively. The patient underwent tumor radical resections. Post-operative pathology confirmed the S4 and S6 lesions to be HCC and CHC, respectively. A newly-found suspicious liver nodule with potential malignancy was detected in liver S1 by both CEUS and CECT 7 mo after operation. CONCLUSION: The CEUS characteristics of CHC and HCC are different. CEUS features in combination with clinical information could help in effective diagnosis, clinical decision-making and better prognosis.

Association of mental health with clinical outcomes in hospitalized patients with moderate COVID-19.

OBJECTIVE: To assess the association of depression and anxiety with clinical outcomes and laboratory markers among hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: A prospective cohort study in Wuhan, China was conducted in 205 adult hospitalized patients with a diagnosis of moderate coronavirus disease from admission through discharge or death. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). The primary outcome was the incidence of severe or critical COVID-19, and the secondary outcomes were increased length of hospital stay and altered laboratory markers during follow up. RESULTS: Among the 205 hospitalized patients (mean age 58 years; 51.7% male), 25 (12.2%) developed severe or critical COVID-19. According to the HADS scores, 51 (24.9%) and 92 (44.9%) of participants presented with clinically significant anxiety and depression, respectively. Using multi-variable adjusted Cox regression analysis, the adjusted hazard ratio of developing severe or critical COVID-19 associated with anxiety and depression was 1.55 (95% CI: 0.63, 3.80) and 4.28 (95% CI: 1.20, 15.30), respectively. The risk of developing severe or critical COVID-19 with both anxiety and depression was more than four times higher than in patients without anxiety or depression (HR, 4.05; 95% CI: 1.02, 16.00). In addition, both the trends of depression and anxiety were positively associated with a prolonged duration of hospitalization, and immune response was significantly decreased in patients with depression than those without. CONCLUSIONS: In patients having coronavirus disease, depression was associated with worse clinical outcomes. These findings highlight the importance of prevention and management of mental health problems in confronting the COVID-19 pandemic.

Cost-Effectiveness analysis of combining plasma Epstein-Barr virus DNA testing and different surveillance imaging modalities for nasopharyngeal carcinoma patients in first remission.

BACKGROUND: To evaluate the cost-effectiveness of stage-based post-radiotherapy (PRT) nasopharyngeal carcinoma (NPC) surveillance strategies. METHODS: Four post-radiotherapy surveillance strategies were established by a Markov model based on data from 1664 patients: 1) clinical follow-up (CFP) with biannual Epstein-Barr virus (EBV) DNA (EBV DNA strategy); 2) CFP with biannual EBV DNA, annual head and neck magnetic resonance imaging (HNMRI), chest X-ray, abdominal ultrasonography, bone scan (only for the first two years) for five years (MCWU strategy); 3) CFP with biannual EBV DNA, annual HNMRI, chest, abdomen, pelvic computerized tomography (CT) and bone scan for the first two years, followed by annual MCWU strategy (without bone scans) for the last three years (CT strategy); 4) CFP with biannual EBV DNA, annual whole-body positron emission/computerized tomography (PET/CT) for the first two years and biannual EBV DNA for the last three years (PET/CT strategy). RESULTS: Compared with the EBV DNA strategy, the MCWU, CT, and PET/CT strategies gained 0.017, 0.047, and 0.082 quality-adjusted life years (QALY) for stage I-II patients. For stage III and IVa patients, the PET/CT strategy had a favorable incremental effectiveness (ICERs) of 0.277 and 0.385 QALY, respectively. The ICERs for the MCWU, CT, and PET/CT strategies were $74,037, $34,882, and $34,696 for stage III and $62,364, $27,981, and $28,340 for stage IVa, respectively. CONCLUSION: EBV DNA strategy was cost-effective for the long-term surveillance of stage I-II NPC patients with CR. PET/CT strategy was recommeded for patients having IVa NPC. As for stage III NPC, PET/CT strategy was still acceptable with the development of economy in China.

EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) was the first oncogenic virus identified in humans. It is primarily associated with multiple lymphoid and epithelial cancers, including nasopharyngeal carcinoma (NPC). However, its association with ferroptosis and its role in cancer therapy resistance have not been fully elucidated. Here, we show that EBV infection reduces the sensitivity of NPC cells to ferroptosis by activating the p62-Keap1-NRF2 signaling pathway in conjunction with upregulation of SLC7A11 and GPX4 expression. Knockdown of endogenous GPX4 or blockade of GPX4 using a specific inhibitor enhanced the chemosensitivity of EBV-infected NPC cells. Functional studies revealed that GPX4 knockdown suppresses the proliferation and colony formation of NPC cells. Mechanistically, GPX4 interacts with the TAK1-TAB1/TAB3 complex, regulates TAK1 kinase activity, and further activates downstream MAPK-JNK and NFκB pathways. High GPX4 expression is correlated with poor clinical outcomes in patients with NPC and other cancer types. Taken together, our findings suggest that EBV infection has important effects on redox homeostasis, revealing a previously unappreciated role for GPX4 in tumor progression. This novel mechanism provides a potential new target for the treatment of EBV-related tumors.

Development and validation of a transcriptomics-based gene signature to predict distant metastasis and guide induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

AIM: Metastasis is the primary cause of treatment failure in nasopharyngeal carcinoma (NPC); however, the current tumour-node-metastasis staging system has limitations in predicting distant metastasis and guiding induction chemotherapy (IC) application. Here, we established a transcriptomics-based gene signature to assess the risk of distant metastasis and guide IC in locoregionally advanced NPC. METHODS: Transcriptome sequencing was performed on NPC biopsy samples from 12 pairs of patients with different metastasis risks. Bioinformatics and qPCR were used to identify differentially expressed genes (DEGs), while univariate and multivariate analyses were used to select prognostic indicators for the gene signature. A signature-based nomogram was established in a training cohort (n = 191) and validated in an external cohort (n = 263). RESULTS: Eleven DEGs were identified between metastatic and non-metastatic NPC. Four of these (AK4, CPAMD8, DDAH1 and CRTR1) were used to create a gene signature that effectively categorised patients into low- and high-risk metastasis groups (training: 91.1 versus 70.4%, p < 0.0001, C-index = 0.752; validation: 88.4 versus 73.9%, p = 0.00057, C-index = 0.741). IC with concurrent chemoradiotherapy (CCRT) improved distant metastasis-free survival in low-risk patients (94.4 versus 85.0%, p = 0.043), whereas patients in the high-risk group did not benefit from IC (72.6 versus 74.9%, p = 0.946). CONCLUSIONS: Our transcriptomics-based gene signature was able to reliably predict metastasis in locoregionally advanced NPC and could be used to identify candidates that could benefit from IC + CCRT.

Comparison of new magnetic resonance imaging grading system with conventional endoscopy for the early detection of nasopharyngeal carcinoma.

BACKGROUND: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood. METHODS: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated. RESULTS: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; Pdifference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess. CONCLUSIONS: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.

Association of sleep quality before and after SARS-CoV-2 infection with clinical outcomes in hospitalized patients with COVID-19 in China.

Sleep is believed to benefit the host defense against pathogens. We aimed to investigate the association of sleep quality with clinical outcomes among hospitalized patients with COVID-19. We conducted a prospective cohort study in 205 adult hospitalized patients with diagnosed moderate COVID-19, with follow-up until hospital discharge or death. Pittsburgh Sleep Quality Index (PSQI) assessed sleep quality before and after infection. The primary outcome was the incidence of severe or critical pneumonia, and the secondary outcomes were duration of hospital stay and laboratory measurements during the follow up. Among the 205 included hospitalized patients, 185 (90.2 %) experienced poorer sleep quality after infection than before according to the PSQI score, and 25 (12.2 %) developed severe or critical pneumonia during follow-up. In Cox regression models, the adjusted hazard ratio of developing severe or critical pneumonia associated with each 1 score increment in the PSQI score before and after infection was 1.23 (95% CI: 1.09, 1.39) and 1.35 (95 % CI: 1.08, 1.67), respectively. Poorer sleep quality was also significantly associated with a prolonged hospital stay and more serious dysregulations in immune system indicated by several laboratory markers. Poorer sleep quality, either in the daily time or after infection with SARS-CoV-2, was associated with worse clinical outcomes. These findings highlight the importance of good sleep in confronting the emerging pandemic of COVID-19.

Establishment and validation of a prognostic nomogram to predict early metastasis in nasopharyngeal carcinoma patients within six months after radiotherapy and to guide intensive treatment.

PURPOSE: This study aimed to establish an effective prognostic nomogram to predict the risk of early metastasis (EM) in nasopharyngeal carcinoma (NPC) patients, as a guide for intensive treatment. MATERIALS AND METHODS: A total of 9021 patients with biopsy-confirmed NPC at our institute were enrolled in this study between December 2006 to December 2016. We randomized these patients using a proportion of 2/3 and 1/3 and selected 6044 and 2977 patients as the training and validation cohorts, respectively. All patients received radiotherapy with or without chemotherapy. Univariate and multivariate logistical regressions were used to identify independent risk factors. The nomogram's predictive value was evaluated by concordance indexes (C-indexes), calibration curves, probability density functions (PDFs), and clinical utility curves (CUCs). ROC analysis using Delong test was used to compare efficiency between the nomogram and other risk factors. RESULTS: In total, 174 (2.9%) and 81 (2.7%) patients in training and validation cohorts, respectively, had EM. Pretreatment plasma EBV DNA, N stage, LDH, ALP, BMI, and sex were independent predictive factors of EM. The C-indexes of nomogram were 0.756 (95% CI = 0.719-0.793) and 0.766 (95% CI = 0.720-0.813), in the training and validation cohorts, respectively. The C-index of the nomogram was significantly superior to any one of independent factors. According to the PDFs and CUCs and considering the balance of the true positive EM patients and true positive non-EM patients, we chose 5.0% as a threshold probability for clinical decision-making, which could distinguish about 85% and 48% of non-EM and EM patients, respectively. CONCLUSION: Our nomogram had good accuracy in predicting EM incidence, and a 5.0% threshold was appropriate for clinical decision-making.

Efficacy of Transnasal Endoscopic Fine-Needle Aspiration Biopsy in Diagnosing Submucosal Nasopharyngeal Carcinoma.

OBJECTIVES/HYPOTHESIS: The routine practices of examining submucosal lesions are not suitable for deep lesions. Therefore, we evaluated the efficacy of non-real-time image-guided transnasal endoscopic fine-needle aspiration biopsy (FNAB) in diagnosing nasopharyngeal carcinoma (NPC) with submucosal lesions. STUDY DESIGN: The effectiveness evaluation of diagnostic methods. METHODS: Fifty suspected NPC patients who failed in conventional biopsies were enrolled in this study. The efficacy, maneuverability, and safety of FNAB in diagnosing these intractable cases were evaluated. RESULTS: The definitive diagnostic results of these 50 patients were NPC (34/50, 68.0%), nasopharyngeal necrosis (1/50, 2.0%), nasopharyngeal mucositis (12/50, 24.0%), and other cancers (3/50, 6.0%), respectively. The results of the diagnostic efficacy of FNAB were sensitivity, 89.2%; specificity, 100.0%; positive predictive value, 100.0%; negative predictive value, 76.5%; and accuracy, 92.0%, respectively. The area under the receiver operating characteristic curves was 0.946 (95% confidence interval = 0.884-1.00, P < .001). No severe complications occurred after FNAB. CONCLUSIONS: FNAB can improve the diagnostic efficiency of NPC occurring in the submucosal space. It can be an additional option for routine nasopharyngeal biopsy and is worthy of clinical application. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1798-1804, 2021.

Nomogram Predicting the Benefits of Adding Concurrent Chemotherapy to Intensity-Modulated Radiotherapy After Induction Chemotherapy in Stages II-IVb Nasopharyngeal Carcinoma.

BACKGROUND: To compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: One thousand three hundred twenty four patients with newly-diagnosed NPC treated with IC+CCRT or IC+RT were enrolled. Progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), locoregional relapse-free survival (LRFS), and acute toxicities during radiotherapy were compared using propensity score matching (PSM). A nomogram was developed to predict the 3- and 5-year PFS with or without concurrent chemotherapy (CC). RESULTS: PSM assigned 387 patients to the IC+CCRT group and IC+RT group, respectively. After 3 years, no significant difference in PFS (84.7 vs. 87.5%, P = 0.080), OS (95.5 vs. 97.6%, P = 0.123), DMFS (89.7 vs. 92.8%, P = 0.134), or LRFS (94.0 vs. 94.1%, P = 0.557) was noted between the groups. Subgroup analysis indicated comparable survival outcomes in low-risk NPC patients (II-III with EBV DNA <4,000 copies/ml) between the groups, although IC+RT alone was associated with fewer acute toxicities. However, IC+CCRT was associated with significantly higher 3-year PFS, OS, DMFS, and LRFS rates, relative to IC+RT alone, in high-risk NPC patients (IVa-b or EBV DNA ≥4,000 copies/ml). Multivariate analysis showed that T category, N category, EBV DNA level, and treatment group were predictive of PFS, and were hence incorporated into the nomogram. The nomogram predicted that the magnitude of benefit from CC could vary significantly. CONCLUSIONS: IC+RT had similar efficacy as IC+CCRT in low-risk NPC patients, but was associated with fewer acute toxicities. However, in high-risk patients, IC+CCRT was superior to IC+RT.

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma.

BACKGROUND: The tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC). METHODS: Using multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients. RESULTS: Eight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed. CONCLUSIONS: The immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT.