Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

Whole-transcriptome sequencing reveals heightened inflammation and defective host defence responses in chronic rhinosinusitis with nasal polyps.

INTRODUCTION: The pathways underlying chronic rhinosinusitis with nasal polyps (CRSwNP) are unclear. We conducted genome-wide gene expression analysis to determine pathways and candidate gene sets associated with CRSwNP. METHODS: We performed whole-transcriptome RNA sequencing on 42 polyp (CRSwNP-NP) and 33 paired nonpolyp inferior turbinate (CRSwNP-IT) tissues from patients with CRSwNP and 28 inferior turbinate samples from non-CRS controls (CS-IT). We analysed the differentially expressed genes (DEGs) and the gene sets that were enriched in functional pathways. RESULTS: Principal component-informed analysis revealed cilium function and immune regulation as the two main Gene Ontology (GO) categories differentiating CRSwNP patients from controls. We detected 6182 and 1592 DEGs between CRSwNP-NP versus CS-IT and between CRSwNP-NP versus CRSwNP-IT tissues, respectively. Atopy status did not have a major impact on gene expression in various tissues. GO analysis on these DEGs implicated extracellular matrix (ECM) disassembly, O-glycan processing, angiogenesis and host viral response in CRSwNP pathogenesis. Ingenuity Pathway Analysis identified significant enrichment of type 1 interferon signalling and axonal guidance canonical pathways, angiogenesis, and collagen and fibrotic changes in CRSwNP (CRSwNP-NP and CRSwNP-IT) tissues compared with CS-IT. Finally, gene set enrichment analysis implicated sets of genes co-regulated in processes associated with inflammatory response and aberrant cell differentiation in polyp formation. CONCLUSIONS: Gene signatures involved in defective host defences (including cilia dysfunction and immune dysregulation), inflammation and abnormal metabolism of ECM are implicated in CRSwNP. Functional validation of these gene expression patterns will open opportunities for CRSwNP therapeutic interventions such as biologics and immunomodulators.

Mal-deficiency impairs the tolerogenicity of dendritic cell of patients with allergic rhinitis.

The tolerogenic dendritic cell dysfunction is associated with the pathogenesis of immune diseases. Microbial stimulus is required in the maintenance of immune functions. This study aims to elucidate the role of Mal signal in the maintenance of DEC205+ DC (decDC) immune tolerogenic function. In this study, peripheral DCs were collected from allergic rhinitis (AR) patients and healthy control (HC) subjects to assess the functional status of decDCs. An AR murine model was developed to test the role of Mal signals in the maintenance of decDCs' functions. We observed that AR decDCs (decDCs obtained from AR patients) were incompetent in the induction of type 1 regulatory T cells (Tr1 cells). AR decDCs expressed less IL-10 than that in HC decDCs. IL-10 mRNA decayed spontaneously in AR decDCs. Tat-activating regulatory DNA-binding protein-43 (TDP43) protected IL-10 mRNA from decay. AR decDCs expressed lower levels of Mal than that in HC decDCs. Mal depletion resulted in IL-10 mRNA decay in HC decDCs. Reconstitution of Mal in AR decDCs restored the capacity of inducing Tr1 cells and attenuated experimental AR in mice. In conclusion, Mal plays a critical role in the maintenance of decDC's immune tolerogenic function. The absence or insufficient Mal signal impairs decDC's tolerogenic property. Reconstitution of Mal in AR decDCs can restore the immune tolerogenic capacity, which may have translational potential in the treatment of AR and other allergic diseases.

Preoperative neutrophil-to-lymphocyte ratio is an independent prognostic marker in patients with laryngeal squamous cell carcinoma.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) has been shown to be associated with prognosis in various solid tumors. This study aimed to evaluate the prognostic role of NLR in patients with laryngeal squamous cell carcinoma (LSCC). METHODS: A total of 141 LSCC patients were retrospectively reviewed. Patients' demographics were analyzed along with clinical and pathologic data. The optimal cutoff value of NLR was determined using receiver operating characteristic (ROC) curve analysis. The impact of the NLR and other potential prognostic factors on disease-free survival (DFS) and overall survival (OS) was assessed using the Kaplan-Meier method and multivariate Cox regression analysis. RESULTS: The optimal cutoff value of the NLR was 2.17. In the NLR ≤ 2.17 group, the 1-, 3-, and 5-year DFS rates were 88.2, 73.9 and 69.1 %, respectively, while in the NLR > 2.17 group, the DFS rates were 83.0, 54.6 and 49.2 %, respectively. Correspondingly, the 1-, 3-, and 5-year OS rates were 98.9, 85.1 and 77.4 % in the NLR ≤ 2.17 group and 97.9, 63.8 and 53.3 % in the NLR > 2.17 group, respectively. The multivariate Cox proportional hazard model analysis showed that NLR > 2.17 was a prognostic factor for both DFS [hazard ratio (HR) = 1.869; 95 % confidence interval (CI) 1.078-3.243; P = 0.026] and OS (HR =2.177; 95 % CI 1.208-3.924; P = 0.010). CONCLUSION: Our results showed that elevated preoperative NLR was an independent predictor of poor prognosis for patients with LSCC after surgical resection.

Celecoxib enhances radiosensitivity via induction of G2-M phase arrest and apoptosis in nasopharyngeal carcinoma.

BACKGROUND: Previous work has proposed that celecoxib may be able to enhance the effects of radiotherapy. However, the underlying mechanism of this activity has not yet been determined. METHODS: The cell colony formation assay after the combination of celecoxib and radiation treatment was done on C666-1, CNE-1 and CNE-2 nasopharyngeal carcinoma cells, which expressed different COX-2 levels. Moreover, COX-2 knocked down or overexpressed cells were developed, and apoptosis and cell cycle analysis were performed. RESULTS: Celecoxib enhances radiation cytotoxicity in C666-1 and CNE-1 nasopharyngeal carcinoma cells that expressed high COX-2 but not in CNE-2 cells that expressed low COX-2. The radiosensitization of celecoxib in C666-1 cells disappeared after the COX-2 knocked down, while the CNE-2 cells were radiosensitized by celecoxib after the transfection of COX-2. Moreover, celecoxib enhanced radiation-induced G2-M phase arrest was observed in some of the tested cells. Furthermore, we found that the radiosensitivity of celecoxib in nasopharyngeal carcinoma was correlated with the apoptosis induction. Additionally, the combination of celecoxib (25 mg/kg) and radiation (6 Gy) treatment significantly reduced tumor volume in C666-1 and CNE-2 nasopharyngeal carcinoma xenograft models. CONCLUSION: These results indicate that the combination of celecoxib and radiation treatment has potential application in radiotherapy, and these effects may be attributable to the G2-M cell phase arrest and enhancement of cell apoptosis.

Intravoxel incoherent motion MRI: emerging applications for nasopharyngeal carcinoma at the primary site.

OBJECTIVES: We compared pure molecular diffusion (D), perfusion-related diffusion (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) based on intravoxel incoherent motion (IVIM) theory in patients with nasopharyngeal carcinoma (NPC). METHODS: Sixty-five consecutive patients (48 men) with suspected NPC were examined using a 3.0-T MR system. Diffusion-weighted imaging (DWI) was performed with 13 b values (range, 0-800 s/mm(2)). We regarded the result of endoscopy and biopsy as the gold standard for detection. D, D* and f were compared between patients with primary NPC and enlarged adenoids. RESULTS: IVIM DWI was successful in 37 of 40 NPC and 23 of 25 enlarged adenoids cases. D (P = 0.001) and f (P < 0.0001) were significantly lower in patients with NPC than in patients with enlarged adenoids, whereas D* was significantly higher (P < 0.0001). However, the ADC was not significantly different between the two groups (P > 0.05). The area under the ROC curve (AUC) for D was 0.849 and was significantly larger than that for ADC (P < 0.05). CONCLUSIONS: IVIM DWI is a feasible technique for investigating primary NPC. D was significantly decreased in primary NPC, and increased D* reflected increased blood vessel generation and parenchymal perfusion in primary NPC. KEY POINTS: • Intravoxel incoherent motion (IVIM) analysis permits separate quantification of diffusion and perfusion. • IVIM DWI is a feasible technique for investigating primary NPC. • IVIM suggests that primary NPC tissue voxels exhibit both perfusion and diffusion.

Initial experience of correlating parameters of intravoxel incoherent motion and dynamic contrast-enhanced magnetic resonance imaging at 3.0 T in nasopharyngeal carcinoma.

PURPOSE: To determine the correlation between intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters. METHODS: Thirty-eight newly diagnosed NPC patients were prospectively enrolled. Diffusion-weighted images (DWI) at 13 b-values were acquired using a 3.0-T MRI system. IVIM parameters including the pure molecular diffusion (D), perfusion-related diffusion (D*), perfusion fraction (f), DCE-MRI parameters including maximum slope of increase (MSI), enhancement amplitude (EA) and enhancement ratio (ER) were calculated by two investigators independently. Intra- and interobserver agreement were evaluated using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. Relationships between IVIM and DCE-MRI parameters were evaluated by calculation of Spearman's correlation coefficient. RESULTS: Intra- and interobserver reproducibility were excellent to relatively good (ICC = 0.887-0.997; narrow width of 95 % limits of agreement). The highest correlation was observed between f and EA (r = 0.633, P < 0.001), with a strong correlation between f and MSI (r = 0.598, P = 0.001). No correlation was observed between f and ER (r = -0.162; P = 0.421) or D* and DCE parameters (r = 0.125-0.307; P > 0.119). CONCLUSION: This study suggests IVIM perfusion imaging using 3.0-T MRI is feasible in NPC, and f correlates significantly with EA and MSI. KEY POINTS: Assessment of tumour perfusion is important in nasopharyngeal carcinoma. DCE-MRI provided perfusion information with the use of intravenous contrast media. Perfusion information could be provided by non-invasive IVIM MRI. IVIM parameter f correlated with DCE-MRI parameters.

International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma.

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.

Moderate Dose Irradiation Induces DNA Damage and Impairments of Barrier and Host Defense in Nasal Epithelial Cells in vitro.

Purpose: Radiotherapy (RT) is the mainstay treatment for head and neck cancers. However, chronic and recurrent upper respiratory tract infections and inflammation have been commonly reported in patients post-RT. The underlying mechanisms remain poorly understood. Method and Materials: We used a well-established model of human nasal epithelial cells (hNECs) that forms a pseudostratified layer in the air-liquid interface (ALI) and exposed it to single or repeated moderate dose γ-irradiation (1Gy). We assessed the DNA damage and evaluated the biological properties of hNECs at different time points post-RT. Further, we explored the host immunity alterations in irradiated hNECs with polyinosinic-polycytidylic acid sodium salt (poly [I:C]) and lipopolysaccharides (LPS). Results: IR induced DNA double strand breaks (DSBs) and triggered DNA damage response in hNECs. Repeated IR significantly reduced basal cell proliferation with low expression of p63/KRT5 and Ki67, induced cilia loss and inhibited mucus secretion. In addition, IR decreased ZO-1 expression and caused a significant decline in the transepithelial electrical resistance (TEER). Moreover, hyperreactive response against pathogen invasion and disrupted epithelial host defense can be observed in hNECs exposed to repeated IR. Conclusion: Our study suggests that IR induced prolonged structural and functional impairments of hNECs may contribute to patients post-RT with increased risk of developing chronic and recurrent upper respiratory tract infection and inflammation.

A genome-wide scan suggests a susceptibility locus on 5p 13 for nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) occurs with high frequency in Southeast Asian populations. The high prevalence and familial clustering of NPC in these populations suggest that genetic factors may contribute to the increased cancer risk by affecting susceptibility. The aim of the present study was to map chromosomal loci linked to susceptibility genes predisposing for NPC. We carried out a genome-wide scan by multipoint affected-only allele-sharing methods in 15 Chinese NPC families with two to six affected members per family. The families were from the Guangdong province in the south of China, where the highest risk of NPC is documented. These samples were genotyped using 800 microsatellite markers covering all autosomal chromosomes with an average marker distance of 5 cM. Using multipoint linkage analysis, four loci (2q, 5p, 12p, and 18p) showed LOD scores above 1.5. After genotyping additional markers in these four regions, only one locus on 5p13 showed an increased LOD of 2.1. In further haplotype analysis, affected individuals in six families shared three marker haplotypes between D5S674 and D5S418. In conclusion, a region on 5p13 may harbor a susceptibility gene for NPC.

Endoscopic surgery for primary sinonasal malignancies: Treatment outcomes and prognostic factors.

We retrospectively reviewed the cases of 85 patients with primary sinonasal malignancies who had undergone endoscopic surgery with curative intent achieved by "regional resection." Our goal was to assess the efficacy of endoscopic surgical treatment vis-à-vis traditional open surgery. Kaplan-Meier data analysis revealed that the 1-, 3-, and 5-year disease-specific survival rates were 82, 60, and 49%, respectively. Multivariate Cox model survival analysis revealed that male sex, certain pathologic types of cancer (i.e., undifferentiated carcinoma, olfactory neuroblastoma, and rhabdomyosarcoma), and T3/T4 category negatively impacted survival (adjusted hazard ratios: 3.601, 0.012, 0.287, 0.068, and 0.339, respectively; p < 0.05 for all). We also performed a separate analysis of 47 patients who had category T3 or T4 cancer to determine if the type of surgical approach is a prognostic factor. For this, we identified 20 new patients who had undergone open resection, and we compared them to 27 of our endoscopically treated patients who had similar clinical characteristics. We found that the type of surgical approach did not appear to be a prognostic factor (p > 0.10), although those patients who had undergone endoscopic resection had significantly shorter hospital stays (p < 0.001). We conclude that patients with primary sinonasal malignancies who are treated with endoscopic surgery have acceptable survival rates and therefore endoscopic surgery is justified in the hands of highly experienced surgeons in selected cases.

[Analysis of the efficacy and compliance of conventional immunotherapy and rush immunotherapy in patients with allergic rhinitis].

Objective:To analyze the efficacy and compliance of conventional immunotherapy(CIT)and rush immunotherapy(RIT)in patients with allergic rhinitis.Method:This trial was a prospective study involved 404 patients with persistent AR who were allergic to house dust mite.328 patients were assigned to the conventional immunotherapy reaching the maintenance dose within 14 weeks,and 76 patients were assigned to the rush immunotherapy reaching the maintenance dose within 1 week.The visual analog scale(VAS)score and the patients' compliance were recorded during treatment and follow-up.Result:After CIT and RIT,the VAS score were significantly reduced in each group,but the decrement of VAS score of RIT group was more evident than that of CIT in half ayear(P<0.05).After 5 years follow-up,the VAS score of two groups was also significantly reduced.The rate of treatment continuation of CIT group in 1 year,2 years and 3 years were 18.5%,39.0% and 57.3%,higher than RIT group(11.8%,26.3%,42.1%),respectively.Conclusion:Both CIT and RIT were beneficial for allergic rhinitis patients,and the clinical efficacy lasts for at least 5 years.But RIT has the superiority of faster onset and better compliance.

Endoscopic surgery for early-stage nasopharyngeal carcinoma: a justified initial option.

OBJECTIVES: To assess the prognosis of initial endoscopic surgery in T1N0M0 and T2N0M0 staged NPC patients. MATERIALS AND METHODS: Between 2002 and 2016, 10 previously untreated patients with T1N0M0 or T2N0M0 staged NPC volunteered to receive endoscopic surgery followed by four courses of TPF chemotherapy. EORTC QLQ-C30 and QLQ-H&N35 were used to evaluate the QOL after treatment. RESULTS: With the median follow-up of 30 months (range, 9 months to 128 months), the 24-month survival rate was 100% (6/6), 90% (9/10) patients were still alive and well, 20% (2/10) patients reported tumor recurrence. One died of the disease at 128 months with nasopharyngeal recurrence. Another patient who refused preoperative PET-CT had a cervical recurrence at nine months, accepted nasopharynx and neck radiation two months later and was still alive and well at 50 months. In the post-treatment questionnaires, several NPC-specific (pain, swallowing, speech, social eating, opening mouth, dry mouth, sticky saliva) QOL domains were better preserved compared with radiotherapy alone or combined chemoradiotherapy in other surveys. CONCLUSIONS: Initial endoscopic surgery combined with chemotherapy maybe justified in the hands of highly experienced surgeon in selected early-stage NPC cases and can improve their QOL. In addition, preoperative PET-CT should be included in case of possible minimal metastases.

Clinical survey and analysis of Chinese patients with family history of nasal polyposis.

CONCLUSION: Nasal polyposis (NP) is frequently found to run in families. Earlier onset of the condition strongly suggested the genetic basis for the development of NP and implied that it might be a genetic disease involving multiple genes. OBJECTIVE: The etiology and pathogenesis of NP remain largely unknown, although it is assumed to be associated with allergic reaction and infection. The reported familial cases suggested hereditary factors existing in NP. The purpose of this study was to determine whether a hereditary factor could be implicated in NP. METHODS: A total of 418 NP patients admitted to our department were questioned concerning the existence of familial history (parents, siblings or children) and other accompanying diseases. RESULTS: In all, 253 cases were successfully followed up. Among these, 44 cases (17.4%) were confirmed to have a familial history of NP, most (59.1%) of which had two immediate family members with a positive family history, with the distribution significantly greater among first-degree and second-degree relatives. Patients with familial NP reported an earlier onset (mean age = 27.7 years) than the sporadic group (mean age = 32.7 years, t = 2.133, p < 0.05). No statistical significance was found when both groups were associated with fungal and allergic diseases.

[Nasal endoscopic surgical treatment for chondrosarcoma of paranasal sinus and the skull base].

OBJECTIVE: To discuss the clinical characteristics and treatments for chondrosarcoma of paranasal sinus and the skull base. METHODS: The clinical characteristics of chondrosarcoma of paranasal sinus and skull base in 7 patients underwent endoscopic surgeries between 2001 and 2008 were analyzed. Of the patients, 4 men and 3 women. The patients' age ranged from 18 to 47 years, with a median of 31 years. CLINICAL SYMPTOMS: stuffy, nose bleeding, runny, headache, diplopia, eye outreach limited, blurred vision and even blindness. Surgery methods: under nasal endoscopy, after the attachment sites of the tumors to normal tissues were confirmed, the tumors were peeled off along the clear boundary between the tumors and normal tissues, and the potential residual tumor tissues on bones were cleared by a drill. RESULTS: The patients were followed up postoperatively for 24 to 108 months, with a median of 36 months. Five of 7 patients were no recurrence, 2 were alive with tumor. CONCLUSIONS: Chondrosarcoma of paranasal sinus and skull base can be treated by nasal endoscopic surgery, with good clinical outcome.