Upfront surgery versus definitive radiotherapy: competing risk analyses for cancer-specific and noncancer mortality in oropharyngeal cancer.

PURPOSE: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT). METHODS: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts. RESULTS: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009). CONCLUSION: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings.

Predictors of Myelosuppression for Patients with Head and Neck Squamous Cell Carcinoma After Induction Chemotherapy.

Background: Induction chemotherapy (ICT) has become an initial treatment for head and neck squamous cell carcinoma (HNSCC). However, myelosuppression, an unavoidable side effect of ICT, significantly impacts follow-up treatment and prognosis. The main objective of this study is to identify the risk factors and predictors of myelosuppression and its different severity after ICT for ICT. Methods: We retrospectively reviewed medical records of 102 patients with hypopharyngeal cancer or oropharyngeal cancer who received initial ICT from 2013 to 2022. Univariate and multivariate logistic regression analyses were performed to identify risk factors for myelosuppression. Receiver-operating characteristic (ROC) curves were generated using the results of multiple logistic regression analysis to identify data with the highest sensitivity and lowest false-negative rate. Results: Pretreatment lymphocyte count (PLC) and the pretreatment platelet count (PPC) were identified as independent risk factors of myelosuppression (P < .05). Pretreatment hemoglobin count (PHC) was an independent risk factor for predicting myelosuppression in patients with grades III to IV disease. Patients with myelosuppression after ICT are more sensitive to chemotherapy. Conclusions: The PLC and PPC predicted myelosuppression in patients with HNSCC-administered ICT, and the PHC predicted grades III to IV myelosuppression. Myelosuppressed patients were more chemosensitive after ICT.

Socioeconomic status and asthma: A bidirectional Mendelian randomization study.

Background: Asthma is closely associated with lower socioeconomic status (SES), while the causal relationship between asthma and SES is undetermined. We aim to examine bidirectional relationships between asthma and SES using two-sample bidirectional Mendelian randomization (MR) for assessing potential causal inference. Methods: Education attainment (years of schooling), household income, and Townsend deprivation index (TDI) were 3 indicators of SES considered in our study. The genetic summary data for SES and asthma were retrieved from publicly available genome-wide association studies (GWASs) conducted in participants of European ancestry. The MR estimates from each genetic instrument were combined using random effects inverse variance weighted (IVW) meta-analysis, with alternate methods (eg, MR-Egger, weighted median). Horizontal pleiotropy was assessed by sensitivity analyses. Analyses were performed using the package TwoSampleMR in R. Results: The genetically instrumented years of schooling, household income, and TDI were not associated with the risk of asthma. However, according to the IVW method, 1.72 times increase in the odds ratio (OR) for asthma will lead to 0.024 standard deviation (SD) decrease in the years of schooling, 0.026 SD decrease in the household income, and 0.016 SD increase in the TDI. Although the substantial heterogeneity may undermine the reliability of results to some extent, sensitivity analyses further supported the causation of low household income by asthma. Conclusion: Our study indicated that genetically predicted asthma may play a causal role in lowering the household income. However, the causal role of lower SES in asthma development was not supported by our MR analyses. Considering the heterogeneity in the current study, additional MR studies are needed to validate the results in the future.

Upfront Surgery Versus Definitive Radiotherapy: Competing Risk Analyses in Early Stage Oropharyngeal Cancer.

OBJECTIVE: To compare the survival outcomes of early-stage oropharyngeal cancer (OPC) patients treated with upfront surgery versus definitive radiotherapy (RT). STUDY DESIGN: Retrospective observational study. SETTING: Publicly available database. METHODS: A total of 1877 patients with T1-2N0-1M0 OPC were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts. RESULTS: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 2.29; 95% confidence interval [CI], 1.42-3.68; p = .001) and noncancer mortality (adjusted SHR, 2.74; 95% CI, 1.50-5.02; p = .001). In the HPV-positive cohort, definitive RT and upfront surgery could achieve similar cancer-specific and noncancer survival outcomes. CONCLUSION: Upfront surgery is associated with lower cancer-specific and noncancer mortality in HPV-negative early-stage OPC patients. However, in the setting of HPV-positive early-stage OPC with better prognosis, the 2 treatment modalities have similar efficacy in terms of cancer-specific and noncancer survival outcomes. In the future, carefully designed prospective clinical trials are needed to confirm our findings.

Impact of prior cancer history on survival of patients with hypopharyngeal cancer.

BACKGROUND: The impact of prior cancer history on survival of hypopharyngeal cancer patients remains unknown. The present study assessed the impact of prior cancer history on survival of patients with hypopharyngeal cancer. METHODS: Patients with primary hypopharyngeal cancer diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. One-to-one PSM, Kaplan-Meier method, and log-rank test were performed for survival analysis. RESULTS: We included 5017 patients with hypopharyngeal cancer. Prior cancer history had no significant impact on overall survival of hypopharyngeal cancer patients in comparison with those without prior cancer history (p = 0.845, after PSM). Subgroup analysis showed that prior cancer history had no significant effect on overall survival of hypopharyngeal cancer patients. CONCLUSION: More hypopharyngeal cancer patients with prior cancer history should be considered for clinical trials. However, further prospective studies are needed.

CD69 and SBK1 as potential predictors of responses to PD-1/PD-L1 blockade cancer immunotherapy in lung cancer and melanoma.

Background: PD-1/PD-L1 blockade is a promising immunotherapeutic strategy with the potential to improve the outcomes of various cancers. However, there is a critically unmet need for effective biomarkers of response to PD-1/PD-L1 blockade. Materials and methods: Potential biomarkers of response to PD-1/PD-L1 blockade were obtained from the Cancer Treatment Response gene signature Database (CTR-DB). A comprehensive pan-cancer analysis was done on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Correlations between gene expression and infiltration by immune cells were assessed using TIMER, EPIC, MCPcounter, xCell, CIBERSORT, and quanTIseq. Immunophenoscore (IPS) was used to assess the potential application of the biomarkers to all TCGA tumors. Results: Analysis of CTR-DB data identified CD69 and SBK1 as potential biomarkers of response to PD-1/PD-L1 blockade. Correlation analysis revealed that in various TCGA cancer datasets, CD69 expression level correlated positively with most immune checkpoints and tumor-infiltrating immune cells, while SBK1 expression level correlated negatively with infiltrating immune cells. IPS analysis demonstrated the ability of CD69 and SBK1 to predict PD-1/PD-L1 blockade responses in various cancers. Conclusion: CD69 and SBK1 are potential predictors of response to cancer immunotherapy using PD-1/PD-L1 blockade. These biomarkers may guide treatment decisions, leading to precise treatment and minimizing the waste of medical resources.

Oncologic outcome of multimodality treatment for sinonasal malignancies: An 18-year experience.

Purpose: The aim of this study was to retrospectively evaluate the oncologic outcomes of sinonasal malignancies (SNMs) of various histologic subtypes and investigate the impact of multimodality treatment on prognosis of SNM. Methods: SNM patients treated with curative-intent surgery from 2000 to 2018 were included. The primary outcomes were overall survival (OS). Survival was then assessed through Cox proportional hazards models. Results: Three hundred and three patients were eligible for the analysis. The 5-year OS and event-free survival (EFS) were 61.0% (95% CI: 55.4%-67.1%) and 46.2% (95% CI: 40.4%-52.7%). The 5-year OS was the worst for malignant melanoma and the best for adenocarcinoma. Patients who received surgery had better OS than those who only received radiotherapy and/or chemotherapy. Endoscopic surgery had better OS than the open approach (p < 0.05). Microscopically margin-negative resection (R0 resection) significantly benefited OS and EFS (p < 0.001). No significant difference in OS was observed between patients who received macroscopic complete resection (R1 resection) followed by adjuvant therapy and patients who received R0 resection. Older age (HR = 1.02, p = 0.02), R1 resection (HR = 1.99, p = 0.02), sinonasal surgical history of more than 3 months before diagnosis (HR = 2.77, p = 0.007), and radiotherapy history (HR = 3, p = 0.006) are risk factors for worse EFS. Conclusions: Curative-intent surgery is irreplaceable in the treatment of SNM. The endoscopic approach is an effective alternative to the open approach. EFS is worse among patients with older age, R1 resection, sinonasal surgical history of more than 3 months before diagnosis, and radiotherapy history.

Effect of Bilateral Vocal Fold Microsuturing on Voice Quality Improvement in Patients With Anterior Glottic Webs: A Retrospective Observational Study.

PURPOSE: This study was performed to introduce a modified procedure involving a combination of bilateral vocal fold mucosal flaps and microsurgical sutures for the management of anterior glottic webs and to study its efficacy in decreasing the recurrence rate and improving voice quality. METHODS: We retrospectively reviewed 102 patients with anterior glottic webs who underwent surgical treatment by a carbon dioxide laser incision with or without microsurgical suturing in our hospital from May 2014 to April 2021. We focused on the reoperation rate and the voice outcomes based on the 30-item Voice Handicap Index. RESULTS: This study included 102 patients with anterior glottic webs, which were caused by papilloma excision and endoscopic laryngocarcinoma resection in 97 (95.1%) of the 102 patients; less common causes were infection and traumatic injury. All incisions were performed along the midline with a carbon dioxide laser under microscopy and a self-retaining laryngoscope; 37 (36.3%) patients underwent microsurgical suturing and 65 (63.7%) patients did not. The microsuture group had a lower reoperation rate (χ2= 7.069, P = 0.0078) and higher voice quality (t = 2.054, P = 0.0462) than the non-microsuture group. CONCLUSIONS: We introduced a modified procedure that can both decrease the recurrence rate and improve the voice quality in patients with anterior glottic webs. Hence, this combination therapy involving bilateral vocal fold mucosal flaps and microsurgical sutures is worthy of clinical application and promotion.

Comparison of Survival Outcomes of Different Treatment Options for cT1-2, N0 Glottic Carcinoma: A Propensity Score-Weighted Analysis.

Background: Treatments for cT1-2, N0 glottic squamous cell carcinoma (GLSCC) include endoscopic resection, open surgery, and radiotherapy. The purpose of this study was to compare the outcomes of three treatment modalities and provide reference data for treatment selection. Methods: In all, 4274 patients with cT1-2, N0 GLSCC underwent these three treatment modalities from 2004 to 2015 were identified from the Surveillance, Epidemiology, and End Results-18 database. Overall survival (OS) and disease-specific survival (DSS) of patients treated with the three modalities were compared. Results: In the entire cohort, there were no significant differences in 5-year OS and 5-year DSS among the three treatment groups. In subgroup analyses based on stage and age, endoscopic resection provided significantly better 5-year survival than radiotherapy for cT1, N0 patients aged <65 years, with an OS rate of 89.0% vs. 82.3% (p = 0.009) and a DSS rate of 95.6% vs. 88.2% (p = 0.021). For 5-year DSS, open surgery also had better outcomes than patients who received radiotherapy (5-year DSS: 98.5% vs. 88.2%, respectively; p = 0.046). Conclusions: To summarize, for cT1, N0 GLSCC patients younger than 65 years, surgical treatment (either endoscopic or open) appears to be superior to the radiotherapy, and endoscopic resection should probably be the first consideration.

Preservation of Internal Branch of Superior Laryngeal Nerve during Surgery for Hypopharyngeal Cancer.

OBJECTIVES: This study was performed to evaluate the significance of intraoperative preservation of the internal branch of the superior laryngeal nerve (ibSLN) during surgery for hypopharyngeal squamous cell carcinoma (HSCC). METHODS: Twelve patients with HSCC underwent surgery between January 2017 and December 2018. Sensation in the hypopharyngeal mucosa was tested using a flexible laryngeal endoscope on postoperative day 5. RESULTS: Surgeries were successfully performed in 10 patients with HSCC arising from the internal wall of the pyriform fossa and in 2 patients with HSCC arising from the posterior wall of the hypopharynx. The main trunk of the ibSLN was preserved in all patients. Testing of sensation in the hypopharyngeal mucosa revealed the presence of the cough reflex in all patients. All patients achieved a full normal oral diet at a median of 8.5 days (range, 6-11 days) and removal of the tracheal tube at a median of 10 days (range, 7-12 days). CONCLUSIONS: Our results showed that preservation of the ibSLN during surgery for HSCC is feasible and important in the recovery of sensation in the hypopharyngeal mucosa.

Type I IFNs repolarized a CD169+ macrophage population with anti-tumor potentials in hepatocellular carcinoma.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169+ macrophages exhibited significantly enhanced phagocytotic and CD8+ T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169+ macrophage population and enhancing CD8+ T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization.

Screening of Tumor Antigens and Construction of Immune Subtypes for mRNA Vaccine Development in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: A growing number of clinical studies have confirmed that mRNA vaccines are effective in the treatment of malignant tumors; however, their efficacy in head and neck squamous cell carcinoma (HNSCC) has not been determined. This study aimed to identify the potential antigens of HNSCC for mRNA vaccine development and further distinguish the immune subtypes of HNSCC to select suitable patients for vaccination. METHODS: We obtained gene expression profiles and corresponding clinical information of HNSCC from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). We visualized the genetic alterations of potential antitumor antigens using cBioPortal and obtained the immune gene set from Immport. The correlation between the expression of the identified antigens and the infiltration of antigen-presenting cells was visualized by Tumor Immune Estimation Resource (TIMER). We evaluated the potential biological functions of different samples and described the immune landscape. RESULTS: Increased expression of three potential tumor antigens, CCR4, TMCO1, and SPACA4, associated with superior prognoses and infiltration of antigen-presenting cells, was identified in HNSCC. Three immune subtypes (C1-C3) with different molecular, cellular, and clinical characteristics were defined. Patients with C3 tumor had a better prognosis, representing an immune "cold" phenotype, which may be more suitable for mRNA vaccination. In addition, different immune characteristics were observed among the three immune subtypes, including markers of immune cells, mutation burden, expression of immune checkpoints, and immune modulators. Finally, the immune landscape of HNSCC showed a high degree of heterogeneity between individual patients. CONCLUSION: CCR4, TMCO1, and SPACA4 may be potential antigens for developing mRNA vaccines against HNSCC, especially for patients with C3 tumor. This study could provide a theoretical basis for the development of an mRNA vaccine against HNSCC.

Ferroptosis Driver SOCS1 and Suppressor FTH1 Independently Correlate With M1 and M2 Macrophage Infiltration in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: To investigate the role of ferroptosis, an iron-dependent form of non-apoptotic cell death, in the head and neck squamous cell carcinoma (HNSCC) immune microenvironment. MATERIALS AND METHODS: A list of ferroptosis-related genes was obtained from the FerrDb database. Gene expression data were acquired from the cancer genome atlas (TCGA) and analyzed using the R language. Protein-protein interaction analysis was conducted using STRING and GeneMANIA. The correlations between gene expression levels and a patient's survival were analyzed using GEPIA, the Kaplan-Meier estimate, and a multivariate Cox proportional hazards model. The expression results were verified using Oncomine and Human Protein Atlas data. We used the TIMER, GEPIA2, GEPIA2021, and TIMER2 databases to investigate the relationships between gene expression and infiltrating immune cells. RESULTS: Analysis of differentially expressed genes (DEGs) identified nine each ferroptosis drivers and ferroptosis suppressors, among which four genes correlated with survival as follows: two drivers (SOCS1, CDKN2A) associated with better survival and two suppressors (FTH1, CAV1) associated with poorer survival. Multivariate Cox survival analysis identified SOCS1 and FTH1 as independent prognostic factors for HNSCC, and their higher expression levels were verified using Oncomine and HPA data. The results acquired using TIMER, GEPIA2, GEPIA2021, and TIMER2 data revealed that the driver SOCS1 and the suppressor FTH1 independently correlated with M1 and M2 macrophage infiltration. CONCLUSIONS: The ferroptosis driver SOCS1 and suppressor FTH1 are independent prognostic factors and that correlate with M1 and M2 macrophage infiltration in HNSCC. Targeting ferroptosis-immunomodulation may serve as a strategy to enhance the activity of immunotherapy.

Role of primary tumor resection in patients with metastatic medullary thyroid cancer who have unresectable distant metastases.

BACKGROUND: Whether patients with medullary thyroid carcinoma (MTC) who have unresectable synchronous distant metastases should undergo primary surgical resection (PTR) remains controversial. This study aimed to identify predictive factors associated with the survival of such patients. METHODS: We conducted a retrospective study of patients with MTC who were registered in the Surveillance, Epidemiology, and End Results registry. The overall and cancer-specific mortality rates were assessed using risk-adjusted Cox proportional hazards regression modeling and stratified propensity score matching. RESULTS: One hundred and eight matched patients were assessed. Patients in the PTR group had lower overall mortality than did those in the non-PTR group. The 1-, 3-, and 5-year overall and cancer-specific survival rates in the PTR group were significantly higher. CONCLUSIONS: PTR appears to be the most appropriate intervention for patients with good performance status. Such patients are likely to benefit from surgery and to experience long-term stable disease.

High S100A9+ cell density predicts a poor prognosis in hepatocellular carcinoma patients after curative resection.

S100A9 is differentially expressed in various cell types and is associated with the development, progression and metastasis of various cancers. However, the expression, distribution, and clinical significance of S100A9 in hepatocellular carcinoma (HCC) remain unclear. In the present study, The Cancer Genome Atlas (TCGA) database was used to examine S100A9 gene expression in HCC; we found that S100A9 expression was associated with HCC prognosis. In addition, S100A9 protein expression was assessed by immunohistochemistry analysis of tissues from 382 HCC patients. We found that the infiltration of S100A9+ cells in both tumor and nontumor tissues could predict poor overall survival (P = 0.0329, tumor; P = 0.0003, nontumor) and a high recurrence risk (P = 0.0387, tumor; P = 0.0015, nontumor) in our tissue microarray analysis. Furthermore, immunofluorescence double staining revealed that the primary S100A9-expressing cells in adjacent nontumoral tissue were CD15+ neutrophils, and both CD68+ macrophages and CD15+ neutrophils expressed S100A9 in HCC tumor tissues. Taken together, the results suggest that high S100A9+ cell density predicts a poor prognosis in HCC patients, and S100A9 expression could potentially serve as an independent prognostic marker for HCC.

Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors.

Ferritin is the most important iron storage form and is known to influence tumor immunity. We previously showed that expression of ferritin light chain (FTL) and ferritin heavy chain (FTH1) subunits is increased in head and neck squamous cell carcinoma (HNSC). Here, we analyzed solid tumor datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases to investigate correlations between FTL and FTH1 expressions and (i) patient survival, using univariate, multivariate, Kaplan-Meier and Receiver Operator Characteristic analysis; and (ii) tumor-infiltrating immune cell subsets, using the bioinformatics tools Estimation of Stomal and Immune cells in Malignant Tumor tissues, Microenvironment Cell Population-counter, Tumor Immune Estimation Resource, and Tumor Immunology Miner. We found that FTL and FTH1 are upregulated and downregulated, respectively, in most of the human cancers analyzed. Tumor FTL levels were associated with prognosis in patients with lower grade glioma (LGG), whereas FTH1 levels were associated with prognosis in patients with liver hepatocellular carcinoma, HNSC, LGG, and kidney renal papillary cell carcinoma. In many cancers, FTL and FTH1 levels was significantly positively correlated with tumor infiltration by tumor-associated macrophages and T regulatory cells. These results suggest an important role for FTL and FTH1 in regulating tumor immunity to solid cancers.

The interval between onset and admission predicts disease progression in COVID-19 patients.

BACKGROUND: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19). METHODS: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively. RESULTS: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients. CONCLUSIONS: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems.

Endoscopic surgery compared with intensity-modulated radiotherapy in resectable locally recurrent nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: The role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent nasopharyngeal carcinoma (NPC) who have previously received radiotherapy is a matter of debate. In this trial, we compared the efficacy and safety outcomes of salvage endoscopic surgery versus intensity-modulated radiotherapy (IMRT) in patients with resectable locally recurrent NPC. METHODS: This multicentre, open-label, randomised, controlled, phase 3 trial was done in three hospitals in southern China. We included patients aged 18-70 years with a Karnofsky Performance Status score of at least 70 who were histopathologically diagnosed with undifferentiated or differentiated, non-keratinising, locally recurrent NPC with tumours confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Eligible patients were randomly assigned (1:1) to receive either endoscopic nasopharyngectomy (ENPG group) or IMRT (IMRT group). Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre. Treatment group assignment was not masked. The primary endpoint was overall survival, compared between the groups at 3 years. Efficacy analyses were done by intention to treat. Safety analysis was done in patients who received treatment according to the treatment they actually received. This trial was prospectively registered at the Chinese Clinical Trial Registry, ChiCTR-TRC-11001573, and is currently in follow-up. FINDINGS: Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n=100) or IMRT (n=100). At a median follow-up of 56·0 months (IQR 42·0-69·0), 74 patients had died (29 [29%] of 100 patients in the ENPG group and 45 [45%] of 100 patients in the IMRT group). The 3-year overall survival was 85·8% (95% CI 78·9-92·7) in the ENPG group and 68·0% (58·6-77·4) in the IMRT group (hazard ratio 0·47, 95% CI 0·29-0·76; p=0·0015). The most common grade 3 or worse radiation-related late adverse event was pharyngeal mucositis (in five [5%] of 99 patients who underwent ENPG and 26 [26%] of 101 patients who underwent IMRT). Five [5%] of the 99 patients who underwent ENPG and 20 [20%] of the 101 patients who underwent IMRT died due to late toxic effects specific to radiotherapy; attribution to previous radiotherapy or trial radiotherapy is unclear due to the long-term nature of radiation-related toxicity. INTERPRETATION: Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy. FUNDING: Sun Yat-sen University Clinical Research 5010 Program.

Downregulation of MCM2 contributes to the reduced growth potential of epithelial progenitor cells in chronic nasal inflammation.

BACKGROUND: Recent studies have shown that human nasal epithelial progenitor cells (hNEPCs) are characterized by poor proliferation capacities during chronic nasal inflammation. OBJECTIVE: We sought to investigate the key molecular functions and candidates that contribute to the reduced growth potential of hNEPCs in chronically inflamed nasal mucosa. METHODS: Nasal biopsy specimens were obtained from 28 patients with nasal polyps (NPs) and 13 healthy controls. hNEPCs from nasal samples were cultured for 3 consecutive passages, and their molecular and functional profiles were analyzed by RNA sequencing. The minichromosome maintenance protein (MCM) family gene MCM2 was validated in hNEPCs and tissue samples from patients with NPs and control subjects by cell cycle, quantitative PCR, and Western blot analyses; small interfering RNA-mediated knockdown assay; and immunofluorescent staining. RESULTS: Compared with control hNEPCs, NP-derived hNEPCs showed (1) reduced growth kinetics, as evidenced by the colony-forming efficiency and doubling time; (2) inhibited cell cycle progression, as evidenced by gene ontology and/or pathway and cell cycle analyses; and (3) downregulated expression of MCM2, the key protein of the MCM complex, which is critical for DNA replication at the G1/S checkpoint. Moreover, hNEPCs with MCM2 knockdown showed a decreased proliferation rate, and the MCM2 protein level in basal cells was significantly lower in abnormally remodeled nasal epithelium than in normal epithelium. CONCLUSION: These results demonstrate inhibited cell cycle progression and MCM2 downregulation in basal or progenitor nasal epithelial cells from NP tissue, which may contribute to the decreased growth potential of hNEPCs in chronically inflamed upper airways.