Objective To investigate the effect of the timing of tracheostomy in patients who required prolonged mechanical ventilation using two methods: analysis of early versus late tracheostomy and landmark analysis. Study Design Retrospective cohort study. Methods Patients who were emergently intubated and admitted into the intensive care unit or high dependency unit between January 2011 and August 2016, with or without tracheostomy, were included. In the early and late tracheostomy analysis, all patients were divided into early (≤10 days, n = 88) and late (>10 days, n = 132) groups. In the landmark analysis, 198 patients requiring ventilation for more than 10 days were divided into early tracheostomy (≤10 days, n = 57) and nonearly tracheostomy (>10 days, n = 141) groups. We compared 60‐day ventilation withdrawal rate and 60‐day mortality. Results Early tracheostomy was a significant factor for early ventilation withdrawal, as shown by log‐rank test results (early and late tracheostomy: P = .001, landmark: P = .021). Multivariable analysis showed that the early group was also associated with a higher chance of ventilation withdrawal in each analysis (early and late tracheostomy: adjusted hazard ratio [aHR] = 1.69, 95% confidence interval [CI] = 1.20–2.39, P = .003; landmark: aHR = 1.61, 95% CI = 1.06–2.38, P = .027). Early tracheostomy, however, was not associated with improved 60‐day mortality (early and late tracheostomy: aHR = 0.88, 95% CI = 0.46–1.69, P = .71; landmark: aHR = 1.46; 95% CI = 0.58–3.66; P = .42). Conclusion For patients requiring ventilation, performing tracheostomy within 10 days of admission was independently associated with shortened duration of mechanical ventilation; 60‐day mortality was not associated with the timing of tracheostomy. Level of Evidence 2b

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression.

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Several epidemiological studies have suggested that Epstein–Barr virus (EBV) lytic infection is essential for the development of nasopharyngeal carcinoma (NPC), as the elevation of antibody titers against EBV lytic proteins is a common feature of NPC. Although ZEBRA protein is a key trigger for the initiation of lytic infection, whether its expression affects the prognosis and pathogenesis of NPC remains unclear. In this study, 64 NPC biopsy specimens were analyzed using immunohistochemistry. We found that ZEBRA was significantly associated with a worsening of progression‐free survival in NPC (adjusted hazard ratio, 3.58; 95% confidence interval, 1.08–11.87; p = 0.037). Moreover, ZEBRA expression positively correlated with key endocrinological proteins, estrogen receptor α, and aromatase. The transcriptional level of ZEBRA is activated by estrogen in an estrogen receptor α‐dependent manner, resulting in an increase in structural gene expression levels and extracellular virus DNA copy number in NPC cell lines, reminiscent of lytic infection. Interestingly, it did not suppress cellular proliferation or increase apoptosis, in contrast with cells treated with 12‐ O ‐tetradecanoylphorbol‐13‐acetate and sodium butyrate, indicating that viral production induced by estrogen is not a cell lytic phenomenon. Our results suggest that intratumoral estrogen overproduced by aromatase could induce ZEBRA expression and EBV reactivation, contributing to the progression of NPC.

Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC.