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BACKGROUND: SWI/SNF complex-deficient sinonasal carcinomas are rare, genetically distinct, and aggressive entities. METHODS: SMARCB1 and SMARCA4 immunohistochemistry was retrospectively performed on a cohort of undifferentiated, poorly differentiated, and poorly defined sinonasal carcinomas. Survival outcomes were compared between SMARCB1/SMARCA4 (SWI/SNF complex)-deficient and -retained groups. RESULTS: Eight SWI/SNF complex-deficient (six SMARCB1-deficient, two SMARCA4-deficient) cases were identified among 47 patients over 12 years. Triple-modality treatment was more frequently utilized in SWI/SNF complex-deficient carcinomas than in SWI/SNF complex-retained carcinomas (71.4% vs. 11.8%, p = 0.001). After a median follow-up of 21.3 (IQR 9.9-56.0) months, SWI/SNF complex-deficient sinonasal carcinomas showed comparable recurrence rates (57.1% vs. 52.9%, p = 0.839), time-to-recurrence (7.3 [IQR 6.6-8.3] vs. 9.1 [IQR 3.9-17.4] months, p = 0.531), and overall survival (17.7 [IQR 11.8-67.0] vs. 21.6 [IQR 8.9-56.0] months, p = 0.835) compared to SWI/SNF complex-retained sinonasal carcinomas. CONCLUSION: Triple-modality treatment may improve survival in SWI/SNF complex-deficient sinonasal carcinomas.
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Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr Virus infection (EBV). Despite ubiquitous EBV infection worldwide, NPC displays a unique geographical distribution in Southern China and Southeast Asia. This observed phenomenon can be attributed to the interplay of different strains of EBV infection with host genetics and environmental factors. Polymorphisms on the EBV BALF2 gene have been shown to influence risk of nasopharyngeal carcinoma (NPC). Notably, two non-synonymous EBV polymorphisms (162476T>C, 163364C>T) account for majority of NPC risk in endemic regions. These polymorphisms confer amino acid changes (I1613V, V317M) within the BALF2 protein. However, their impact on NPC tumor biology is unknown. We evaluated the distribution of BALF2 risk polymorphisms in five independent genomic datasets comprising 351 NPC clinical samples, confirming the high prevalence of high-risk EBV strains in NPC. Importantly, we observed two biologically distinct groups of tumors based on their gene expression profiles when grouped by their EBV risk strains. NPC tumors with the V317M substitution demonstrated increased proliferation processes including cell cycle (NES = 1.71, p = 5.64x10-24) and keratinization (NES = 2.42, p = 6.95x10-17). In contrast, NPC tumors without the V317M substitution demonstrated increased immune-related processes, including cell activation (NES = 1.85, p = 8.29x10-31), myeloid leukocyte activation (NES = 2.16, p = 6.51x10-24) and leukocyte mediated immunity (NES = 1.99, p = 1.05x10-23). These findings provide further insight on the influence of BALF2 variants on NPC tumor biology. EBV risk strains may have the potential to define biologically important groups in NPC.
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Infections à virus Epstein-Barr , Herpèsvirus humain de type 4 , Cancer du nasopharynx , Tumeurs du rhinopharynx , Humains , Cancer du nasopharynx/virologie , Cancer du nasopharynx/génétique , Herpèsvirus humain de type 4/génétique , Herpèsvirus humain de type 4/isolement et purification , Tumeurs du rhinopharynx/virologie , Tumeurs du rhinopharynx/génétique , Infections à virus Epstein-Barr/complications , Infections à virus Epstein-Barr/virologie , Protéines virales/génétique , Protéines virales/métabolisme , Mâle , Polymorphisme de nucléotide simple , Femelle , Régulation de l'expression des gènes tumorauxRÉSUMÉ
BACKGROUND: Epstein-Barr virus (EBV) IgA serology for viral capsid antigen (VCA) and early antigen (EA) aids early detection of nasopharyngeal cancer (NPC), resulting in improved survival. We evaluated the diagnostic performance of a prefabricated immunofluorescent assay (IFA) for NPC screening in high-risk individuals. METHODS: Sera from 96 biopsy-proven patients with NPC diagnosed at the outpatient clinic and 96 healthy family members were tested for EBV-VCA IgA and EBV-EA IgA using the prefabricated IFA from EUROIMMUN (EI) and the traditional immunofluorescence method. RESULTS: The AUC of EI EBV-VCA IgA and EBV-EA IgA was 0.907 (95% confidence interval [CI]: 0.894-0.965) and 0.898 (95% CI: 0.848-0.947), respectively. Combined testing with the prefabricated assay at a threshold of VCA ≥1:320 or EA ≥1:10 showed 92.7% sensitivity and 81.2% specificity. Overall, the traditional EBV-EA IgA assay demonstrated the best accuracy (sensitivity 91.7% and specificity 96.9%) at a threshold of ≥1:5. CONCLUSION: While the traditional IFA method was more accurate, the prefabricated IFA test kit can be a useful tool for NPC screening in high-risk populations.
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Dépistage précoce du cancer , Immunoglobuline A , Tumeurs du rhinopharynx , Humains , Tumeurs du rhinopharynx/diagnostic , Tumeurs du rhinopharynx/virologie , Mâle , Femelle , Adulte d'âge moyen , Dépistage précoce du cancer/méthodes , Adulte , Immunoglobuline A/sang , Antigènes viraux/immunologie , Infections à virus Epstein-Barr/diagnostic , Technique d'immunofluorescence , Sensibilité et spécificité , Sujet âgé , Herpèsvirus humain de type 4/immunologie , Herpèsvirus humain de type 4/isolement et purification , Anticorps antiviraux/sang , Protéines de capside/immunologieRÉSUMÉ
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) driven malignancy arising from the nasopharyngeal epithelium. Current treatment strategies depend on the clinical stage of the disease, including the extent of the primary tumour, the extent of nodal disease, and the presence of distant metastasis. With the close association of EBV infection with NPC development, EBV biomarkers have shown promise in predicting treatment outcomes. Among the omic technologies, RNA and miRNA signatures have been widely studied, showing promising results in the research setting to predict treatment response. The transformation of radiology images into measurable features has facilitated the use of radiomics to generate predictive models for better prognostication and treatment selection. Nonetheless, much of this work remains in the research realm, and challenges remain in clinical implementation.
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OBJECTIVES: To characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0-2 weeks) or delayed (8-12 weeks) EBV DNA result better predicts for disease-free survival (DFS). MATERIALS AND METHODS: Histologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0-2 and 8-12 weeks post-radiotherapy were included. RESULTS: We identified 302 patients with EBV DNA measured at 0-2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8-12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0-2 weeks experienced an inferior DFS (adjusted HR1-264 copies 1.72 [95 %CI: 1.05-2.83], P = 0.031; AHR≥265 copies 4.39 [95 %CI: 1.68-11.44], P = 0.002 relative to 0 copies/mL). At 8-12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0-2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8-12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8-12 weeks was strongly associated with relapse (73.3 % [11/15] for 1-264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725-0.909) for stage + EBV DNA8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA0-2w. CONCLUSION: EBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing.
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Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Humains , Cancer du nasopharynx/anatomopathologie , Herpèsvirus humain de type 4/génétique , Infections à virus Epstein-Barr/complications , Tumeurs du rhinopharynx/anatomopathologie , Pronostic , ADN viral , Récidive , Appréciation des risquesRÉSUMÉ
The objective of this study was to compare the outcomes of parent artery occlusion (PAO) versus stent-assisted reconstruction in radiated nasopharyngeal carcinoma (NPC) patients with internal carotid artery (ICA) blowouts. A retrospective review from our institution (2011-2021) and systematic review of Pubmed and Embase (1995-2022) was performed. Twenty-eight eligible studies were identified. Eighty-six PAOs and 37 stent-assisted reconstructions were analyzed, including 11 PAOs and 5 stents from our institution. Stents were associated with significantly higher incidence of overall re-bleeding (16.2% [95% CI 7.4-31.9] vs. 4.6% [95% CI 1.3-13.5], p = 0.047), delayed stroke (5.4% [95% CI 1.3-19.4] vs. 0%, p = 0.034) and reduced median survival (7.1 [95% CI 3.8-14.0] months vs. 29.0 [95% CI 9.4-63.4] months, p = 0.017) compared to PAO. There were no significant differences in terms of overall stroke, infection, extruded/migrated foreign body, and peri-procedure death. PAO is preferred over reconstructive treatment in patients with adequate collateral circulation.
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Procédures endovasculaires , Tumeurs du rhinopharynx , Accident vasculaire cérébral , Humains , Artère carotide interne/chirurgie , Procédures endovasculaires/méthodes , Cancer du nasopharynx/radiothérapie , Cancer du nasopharynx/complications , Tumeurs du rhinopharynx/radiothérapie , Tumeurs du rhinopharynx/chirurgie , Tumeurs du rhinopharynx/complications , Études rétrospectives , Endoprothèses , Accident vasculaire cérébral/étiologie , Résultat thérapeutiqueRÉSUMÉ
The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.
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COVID-19 , Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Humains , Pandémies/prévention et contrôle , Herpèsvirus humain de type 4 , SARS-CoV-2 , Cancer du nasopharynx/thérapie , ADN , Tumeurs du rhinopharynx/diagnostic , Tumeurs du rhinopharynx/thérapieRÉSUMÉ
The current understanding of genetic susceptibility factors for nasopharyngeal carcinoma (NPC) is still incomplete. To identify novel germline variants associated with NPC predisposition, we analysed whole-exome sequencing data from 119 NPC patients from Singapore with a family history of NPC and/or with early-onset NPC, together with 1337 Singaporean participants without NPC. Variants were prioritised and filtered by selecting variants with minor allele frequencies of <1% in both local control (n = 1337) and gnomAD non-cancer (EAS) (n = 9626) cohorts and a high pathogenicity prediction (CADD score > 20). Using single-variant testing, we identified 17 rare pathogenic variants in 17 genes that were associated with NPC. Consistent evidence of enrichment in NPC patients was observed for five of these variants (in JAK2, PRDM16, LRP1B, NIN, and NKX2-1) from an independent case-control comparison of 156 NPC patients and 9770 unaffected individuals. In a family with five siblings, a FANCE variant (p. P445S) was detected in two affected members, but not in three unaffected members. Gene-based burden testing recapitulated variants in NKX2-1 and FANCE as being associated with NPC risk. Using pathway analysis, endocytosis and immune-modulating pathways were found to be enriched for mutation burden. This study has identified NPC-predisposing variants and genes which could shed new insights into the genetic predisposition of NPC.
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OBJECTIVES: Evidence to support Epstein-Barr virus (EBV)-directed population nasopharyngeal carcinoma (NPC) screening has been growing. Familial aggregation is a well-recognized phenomenon in endemic regions. This systematic review summarizes the role of EBV-directed screening in individuals with a positive family history (FH+) of NPC. METHODS: We searched four electronic databases from their inception to October 2021. We included studies on individuals with FH+ of NPC who had undergone EBV-directed investigations, with no restriction in the testing methods or analytic techniques. The primary and secondary outcomes were EBV positivity rates and NPC incidence rates, respectively. Meta-analyses were performed using the random-effect model. RESULTS: Ten cross-sectional studies (n = 7436) and three cohort studies (n = 4306) were included. The pooled relative risk (RR) of EBV positivity between individuals with and without FH+ of NPC were 2.79 (95 % CI 1.37-5.68, p = 0.005) for viral capsid antigen (VCA) IgA, 3.09 (95 % CI 0.65-14.83, p = 0.16) for Epstein-Barr nuclear antigen (EBNA1) IgA, and 1.76 (95 % CI 1.04-2.96, p = 0.03) for combined EBNA1/VCA IgA. In the three cohort studies, the NPC incidence rates ranged from 90.2 to 266 per 100 000 person-years with high proportions of early-stage diseases. FH+ individuals who were EBV-positive had a 2.5 to 30.7-fold risk of NPC development compared to their EBV-negative counterparts. CONCLUSION: Family members of NPC patients had significantly higher EBV positivity rates than the general population. FH+ individuals who are EBV-positive had high risks of developing NPC. Familial screening using EBV serology may facilitate early NPC detection in endemic areas.
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Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Anticorps antiviraux , Études transversales , Infections à virus Epstein-Barr/complications , Herpèsvirus humain de type 4/génétique , Humains , Immunoglobuline A , Cancer du nasopharynx/complicationsRÉSUMÉ
PURPOSE: To review the effectiveness and safety of embolisation in managing haemorrhage from the external carotid artery (ECA) system in radiated nasopharyngeal carcinoma (NPC) patients. METHODS: Radiated NPC patients who presented with severe oronasal bleeding and underwent digital subtraction angiography that excluded blowouts from the internal carotid artery from 2011 to 2021 were reviewed. Those who subsequently underwent embolisation of the ECA system were analysed for technical success rate, post-embolisation re-bleeding rate and complications. RESULTS: Seventeen embolisations were performed in fifteen patients during the 10-year period. The technical success rate was 100%, however the early haemostatic rate (no re-bleed within 7 days of embolisation) was 70.6% (12/17) and the overall long-term haemostatic rate was 58.8% (10/17). The re-bleed rates of targeted and empiric embolisations were 33.3% (3/9) and 50.0% (4/8), respectively. The re-bleed rates with liquid agents, coils and particles were 0% (0/7), 33.3% (1/3) and 85.7% (6/7), respectively. Amongst the embolisations utilising liquid agents, 71.4% (5/7) were targeted, distal embolisations. All re-bleeds underwent surgical ligation or repeat embolisation; half of them further experienced recurrent bleeding. There were no significant complications with embolisation. CONCLUSION: Although embolisation of the ECA system in NPC has a high technical success rate and is safe, re-bleeding appears to be common. Targeted, distal embolisation with liquid embolics appear to have good haemostatic effect. Clinicians should be aware that patients may need repeated procedures to secure haemostasis.
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Embolisation thérapeutique , Hémostatiques , Tumeurs du rhinopharynx , Humains , Artère carotide externe/imagerie diagnostique , Cancer du nasopharynx/thérapie , Embolisation thérapeutique/effets indésirables , Embolisation thérapeutique/méthodes , Hémorragie/étiologie , Hémorragie/thérapie , Tumeurs du rhinopharynx/thérapie , Études rétrospectives , Résultat thérapeutiqueRÉSUMÉ
The detection of serum Epstein-Barr virus antibodies by immunofluorescence assay (IFA) is considered the gold standard screening test for nasopharyngeal cancer (NPC) in high-risk populations. Given the high survival rate after early detection in asymptomatic patients, compared to the poor prognosis in patients with late-stage NPC, screening using IFA has tremendous potential for saving lives in the general population. However, IFA requires visual interpretation of cellular staining patterns by trained pathology staff, making it labor intensive and hence nonscalable. In this study, an automated fuzzy inference (FI) system achieved high agreement with a human IFA expert in identifying cellular patterns associated with NPC (κ = 0.82). The integration of a deep learning module into FI further improved the performance of FI (κ = 0.90) and reduced the number of uncertain cases that required manual evaluation. The performance of the resulting hybrid model, termed deep learning FI (DeLFI), was then evaluated with a separate testing set of clinical samples. In this clinical validation, DeLFI outperformed human evaluation on the area under the curve (0.926 versus 0.821) and closely matched human performance on Youden J index (0.81 versus 0.80). Data from this study indicate that the combination of deep learning with FI in DeLFI has the potential to improve the scalability and accuracy of NPC detection.
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Apprentissage profond , Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Technique d'immunofluorescence indirecte , Herpèsvirus humain de type 4 , Humains , Cancer du nasopharynx , Tumeurs du rhinopharynx/diagnosticRÉSUMÉ
Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.
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Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Lignée cellulaire tumorale , Infections à virus Epstein-Barr/génétique , Infections à virus Epstein-Barr/anatomopathologie , Facteurs de croissance fibroblastique/métabolisme , Expression des gènes , Herpèsvirus humain de type 4/génétique , Herpèsvirus humain de type 4/métabolisme , Humains , Protéines et peptides de signalisation intracellulaire/génétique , Protéines membranaires/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Cancer du nasopharynx/génétique , Tumeurs du rhinopharynx/génétique , Tumeurs du rhinopharynx/métabolisme , Tumeurs du rhinopharynx/anatomopathologie , Transduction du signal , Microenvironnement tumoralRÉSUMÉ
Non-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles' heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.
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Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Récepteurs chimériques pour l'antigène , Ligand de 4-1BB , Animaux , Herpèsvirus humain de type 4 , Humains , Interleukine-6 , Interleukine-8 , Laminine , Souris , Cancer du nasopharynx , Récidive tumorale locale , Antigènes CD137RÉSUMÉ
BACKGROUND: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy. METHODS: Seven subjects (six patients) received cetuximab every 3 weeks (six doses maximum) in the pre-trial phase. Autologous NK cells, expanded by co-culture with irradiated K562-mb15-41BBL cells, were then infused on the day after administration of cetuximab. Primary and secondary objectives were to determine safety of this combination therapy and to assess tumor responses, respectively. RESULTS: Median NK cell expansion from peripheral blood mononucleated cells after 10 days of culture with K562-mb15-41BBL was 274-fold (range, 36-534, n = 10), and the median expression of CD16 was 98.4% (range, 67.8-99.7%). Skin rash, the commonest side effect of cetuximab in the pre-trial phase, was not exacerbated by NK cell infusion. No intolerable side effects were observed. Stable disease was observed in four subjects and progressive disease in three subjects. Three patients who received NK cells twice had time to disease progression of 12, 13, and 19 months. CONCLUSION: NK cells with high ADCC potential can be expanded from patients with heavily pre-treated NPC. The safety profile and encouraging clinical responses observed after combining these cells with cetuximab warrant further studies of this approach. (clinicalTrials.gov NCT02507154, 23/07/2015). PRECIS: Engaging NK cell-mediated ADCC using cetuximab plus autologous NK cells in EGFR-positive NPC was well tolerated among heavily pre-treated recurrent NPC. Promising results were observed with 3 out of 7 subjects demonstrating durable stable disease.
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Anticorps monoclonaux humanisés , Tumeurs du rhinopharynx , Anticorps monoclonaux humanisés/pharmacologie , Cytotoxicité à médiation cellulaire dépendante des anticorps , Lignée cellulaire tumorale , Cétuximab/pharmacologie , Cétuximab/usage thérapeutique , Humains , Cellules tueuses naturelles , Cancer du nasopharynx/traitement médicamenteux , Tumeurs du rhinopharynx/traitement médicamenteux , Récidive tumorale locale/traitement médicamenteux , Récidive tumorale locale/métabolismeRÉSUMÉ
INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.
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Infections à virus Epstein-Barr , Tumeurs du rhinopharynx , Ligand de 4-1BB/génétique , Cellules dendritiques , Herpèsvirus humain de type 4 , Humains , Cancer du nasopharynx/thérapie , Tumeurs du rhinopharynx/thérapieRÉSUMÉ
BACKGROUND: The primary objective is to identify clinical predictors of internal carotid artery (ICA) blowout in radiated nasopharyngeal carcinoma (NPC). METHODS: Seventeen ICA blowouts, 14 external carotid artery (ECA) bleeds, and 60 controls were identified from January 1, 2007 to July 31, 2020. Multinomial logistic regression was performed to identify features predictive of ICA blowouts. RESULTS: Headache was significantly more common among ICA blowouts than ECA bleeds and controls (58.8% vs. 7.1% vs. 6.7%, p < 0.001). The petrous skull base and sphenoid sinus lateral wall was eroded in all petrous and cavernous segment blowouts, respectively. Nasoendoscopy showing exposed clivus (OR 20.5, 95%CI 1.3-324.2) and computed tomography demonstrating skull base erosion (OR 17.8, 95%CI 1.0-311.0) were significantly associated with ICA blowouts compared to controls. CONCLUSIONS: Findings of headache and skull base erosion on nasoendoscopy or imaging during NPC surveillance warrants prophylactic intervention to avoid an ICA blowout.
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Artère carotide interne , Tumeurs du rhinopharynx , Artère carotide interne/imagerie diagnostique , Humains , Cancer du nasopharynx/radiothérapie , Tumeurs du rhinopharynx/radiothérapie , Base du crâne , TomodensitométrieRÉSUMÉ
We present a case of a 1.0 cm primary tumor of the left parotid gland that meets the histological criteria for the recently described entity sclerosing microcystic adenocarcinoma. The patient was a 73-year-old man with a concurrent tonsillar squamous cell carcinoma, and a history of nasopharyngeal carcinoma treated with radiotherapy 23 years prior. Fine needle aspiration cytology demonstrated low-grade biphasic basaloid neoplastic cells arranged in branching sheets and clusters with minimal nuclear pleomorphism. A biphasic appearance was apparent and some of the cell clusters were bordered by a layer of flattened cells with ovoid bland nuclei. On histology, the tumor comprised small bilayered infiltrative tubules, nests, cords, and microcysts. On immunohistochemistry, EMA, SOX-10, P63, and S-100 protein highlighted a dual cell population of luminal and abluminal cells. The cells were negative for CD117, and the Ki-67 proliferation index was low (<5%).
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Adénocarcinome/anatomopathologie , Noyau de la cellule/anatomopathologie , Kystes/anatomopathologie , Glande parotide/anatomopathologie , Adénocarcinome/diagnostic , Sujet âgé , Cytoponction/méthodes , Diagnostic différentiel , Humains , MâleRÉSUMÉ
Rapid diagnostics of adventitious agents in biopharmaceutical/cell manufacturing release testing and the fight against viral infection have become critical. Quantitative real-time PCR and CRISPR-based methods rapidly detect DNA/RNA in 1 h but suffer from inter-site variability. Absolute quantification of DNA/RNA by methods such as digital PCR reduce this variability but are currently too slow for wider application. Here, we report a RApid DIgital Crispr Approach (RADICA) for absolute quantification of nucleic acids in 40-60 min. Using SARS-CoV-2 as a proof-of-concept target, RADICA allows for absolute quantification with a linear dynamic range of 0.6-2027 copies/µL (R2 value > 0.99), high accuracy and low variability, no cross-reactivity to similar targets, and high tolerance to human background DNA. RADICA's versatility is validated against other targets such as Epstein-Barr virus (EBV) from human B cells and patients' serum. RADICA can accurately detect and absolutely quantify EBV DNA with similar dynamic range of 0.5-2100 copies/µL (R2 value > 0.98) in 1 h without thermal cycling, providing a 4-fold faster alternative to digital PCR-based detection. RADICA therefore enables rapid and sensitive absolute quantification of nucleic acids which can be widely applied across clinical, research, and biomanufacturing areas.
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COVID-19 , Infections à virus Epstein-Barr , Acides nucléiques , Clustered regularly interspaced short palindromic repeats , Herpèsvirus humain de type 4/génétique , Humains , SARS-CoV-2 , Sensibilité et spécificitéRÉSUMÉ
Epstein-Barr virus (EBV)-the prototypical human tumor virus-is responsible for 1-2% of the global cancer burden, but divergent strains seem to exist in different geographical regions with distinct predilections for causing lymphoid or epithelial malignancies. Here we report the establishment and characterization of Yu103, an Asia Pacific EBV strain with a highly remarkable provenance of being derived from nasopharyngeal carcinoma biopsy but subsequently propagated in human B-lymphoma cells and xenograft models. Unlike previously characterized EBV strains which are either predominantly B-lymphotropic or epitheliotropic, Yu103 evinces an uncanny capacity to infect and transform both B-lymphocytes and nasopharyngeal epithelial cells. Genomic and phylogenetic analyses indicated that Yu103 EBV lies midway along the spectrum of EBV strains known to drive lymphomagenesis or carcinogenesis, and harbors molecular features which likely account for its unusual properties. To our knowledge, Yu103 EBV is currently the only EBV isolate shown to drive human nasopharyngeal carcinoma and B-lymphoma, and should therefore provide a powerful novel platform for research on EBV-driven hematological and epithelial malignancies.
RÉSUMÉ
BACKGROUND: We examined whether existing licensed pharmacotherapies could reduce the spread of coronavirus disease 2019 (COVID-19). METHODS: An open-label parallel randomized controlled trial was performed among healthy migrant workers quarantined in a large multi-storey dormitory in Singapore. Forty clusters (each defined as individual floors of the dormitory) were randomly assigned to receive a 42-day prophylaxis regimen of either oral hydroxychloroquine (400 mg once, followed by 200 mg/day), oral ivermectin (12 mg once), povidone-iodine throat spray (3 times/day, 270 µg/day), oral zinc (80 mg/day)/vitamin C (500 mg/day) combination, or oral vitamin C, 500 mg/day. The primary outcome was laboratory evidence of SARS-CoV-2 infection as shown by either: (1) a positive serologic test for SARS-CoV-2 antibody on day 42, or (2) a positive PCR test for SARS-CoV-2 at any time between baseline and day 42. RESULTS: A total of 3037 asymptomatic participants (mean age, 33.0 years; all men) who were seronegative to SARS-CoV-2 at baseline were included in the primary analysis. Follow-up was nearly complete (99.6%). Compared with vitamin C, significant absolute risk reductions (%, 98.75% confidence interval) were observed for oral hydroxychloroquine (21%, 2-42%) and povidone-iodine throat spray (24%, 7-39%). No statistically significant differences were observed with oral zinc/vitamin C combination (23%, -5 to +41%) and ivermectin (5%, -10 to +22%). Interruptions due to side effects were highest among participants who received zinc/vitamin C combination (6.9%), followed by vitamin C (4.7%), povidone-iodine (2.0%), and hydroxychloroquine (0.7%). CONCLUSIONS: Chemoprophylaxis with either oral hydroxychloroquine or povidone-iodine throat spray was superior to oral vitamin C in reducing SARS-CoV-2 infection in young and healthy men.