Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. METHODS: We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). RESULTS: The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041). CONCLUSIONS: These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC

Clinical outcomes of transoral videolaryngoscopic surgery for hypopharyngeal and supraglottic cancer

Abstract Background Transoral videolaryngoscopic surgery (TOVS) was developed as a new distinct surgical procedure for hypopharyngeal cancer (HPC) and supraglottic cancer (SGC) staged at up to T3. However, long-term treatment outcomes of TOVS remain to be validated. Methods Under a straight broad intraluminal view provided by combined use of a distending laryngoscope and a videolaryngoscope, we performed en bloc tumor resection via direct bimanual handling of the ready-made straight-form surgical instruments and devices. We retrospectively analyzed functional and oncologic outcomes of 72 patients with HPC (n = 58) or SGC (n = 14) whose minimum follow-up was 24 months or until death. Results The cohort comprised nine patients of Tis, 23 of T1, 33 of T2, and 7 of T3. Among 36 patients (50%) who underwent neck dissection simultaneously, all but one were pathologically node-positive. Twelve patients underwent postoperative concurrent chemoradiation (CCRT) as adjuvant treatment, and another four patients underwent radiation or CCRT for second or later primary cancer. The endotracheal tube was removed in an operation room in all but two patients who underwent temporary tracheostomy. Pharyngeal fistula was formed transiently in two patients. The median time until patients resumed oral intake and could take a soft meal was 2 and 5 days, respectively. Eventually, 69 patients (96%) took normal meals. The 5-year cause-specific survival (CSS), overall survival (OS), larynx-preserved CSS, and loco-regional controlled CSS were 87.3%, 77.9%, 86.0%, and 88.0%, respectively. Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis. Conclusions Considering its sound functional and oncological outcomes with various practical advantages, TOVS can be a dependable, less invasive, and cost-effective surgical option of an organ-function preservation strategy for HPC and SGC

The study protocol for PREDICT AF RECURRENCE: a PRospEctive cohort stuDy of surveIllanCe for perioperaTive Atrial Fibrillation RECURRENCE in major non-cardiac surgery for malignancy

Abstract Background A previous retrospective cohort study established the relationship between perioperative atrial fibrillation (POAF) and subsequent mortality and stroke. However, the details regarding the cause of death and etiology of stroke remain unclear. Methods The prospective cohort study of surveillance for perioperative atrial fibrillation recurrence in major non-cardiac surgery for malignancy (PREDICT AF RECURRENCE) registry is an ongoing prospective cohort study to elucidate the long-term recurrence rate and the clinical impact of new-onset POAF in the setting of head and neck, non-cardiac thoracic, and abdominal surgery for malignancy. In this study, cardiologists collaborate with a surgical team during the perioperative period, carefully observe the electrocardiogram (ECG) monitor, and treat arrhythmia as required. Furthermore, patients who develop new-onset POAF are followed up using a long-term Holter ECG monitor, SPIDER FLASH-t AFib®, to assess POAF recurrence. Discussion Even if patients with malignancy survive by overcoming the disease, they may die from any preventable cardiovascular diseases. In particular, those with POAF may develop cardiogenic stroke in the future. Because details of the natural history of patients with POAF remain unclear, investigating the need to continue anticoagulation therapy for such patients is necessary. This study will provide essential information on the recurrence rate of POAF and new insights into the prediction and treatment of POAF. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR): UMIN000016146; Data of Registration: January 7, 2015

Incidence and complications of perioperative atrial fibrillation after non-cardiac surgery for malignancy.

BackgroundPerioperative atrial fibrillation (POAF) is one of the common arrhythmias in the setting of non-cardiac surgeries for malignancy. As POAF may cause subsequent adverse events, it is important to confirm its characteristics and risk factors.Materials and methodsThe prospective cohort study of surveillance for perioperative atrial fibrillation recurrence (PREDICT AF RECURRENCE) is an ongoing prospective, single-center, observational study that aims to illustrate the clinical impact of POAF in major non-cardiac surgery for malignancy. Patients who planned to undergo non-cardiac surgery for definitive/suspected malignancy were registered. Those with a history of AF and atrial flutter were excluded. Any 30-day complications included acute myocardial infarction, congestive heart failure, bleeding, thrombosis, any infection, and acute kidney injury. The primary endpoint was an incidence of POAF.ResultsThe present study included 799 patients (age, 68 ± 11; male, 62%). Of these, 80 patients (10.0%) developed POAF. Notably, 66 patients (83%) had no symptoms. Any 30-day complications occurred in 180 patients (23%) (with POAF: 34 (43%); without POAF: 146 (20%); p ConclusionTen percent of patients who underwent non-cardiac surgery for malignancy developed POAF, which was strongly associated with perioperative complications. As a majority were asymptomatic, careful observation using electrocardiography monitoring is important to avoid oversights.Clinical trial registrationUMIN ID: UMIN000016146

Brain metastases in patients with salivary duct carcinoma: A retrospective study

Abstract Background Salivary duct carcinoma (SDC) is a high‐grade adenocarcinoma with a 5‐year survival rate of 40%. Although drug therapy has improved patients' prognosis, the impact of brain metastasis (BM) remains poorly understood. We aimed to retrospectively examine the incidence of BM in patients with SDC (n = 464) and develop a tool to estimate their prognoses. Methods We retrospectively examined 464 patients with SDC enrolled in a multicenter study. We investigated the incidence of BM, overall survival (OS) rates, and factors affecting prognosis in patients with BM. We also developed an SDC‐graded prognostic assessment (GPA) score for disease prognostication. Results Sixty‐five (14%) patients had BM. The median OS (mOS) was 13.1 months. On univariate and multivariate analyses, factors such as Eastern Cooperative Oncology Group Performance Status >1, human epidermal growth factor receptor 2‐negative status, and locoregional uncontrolled disease were associated with poor OS. SDC‐GPA scores according to the prognostic factors were 0, 1, 2, and 3 points, and mOS estimates were 50.5, 16.1, 3.9, and 1.2 months, respectively (p < 0.001). Conclusion The SDC‐GPA score emerged as a useful prognostication tool for patients with BM