Abstract The presence of bile is not an uncommon finding in acidic oesophageal and extra‐oesophageal refluxate, possibly affecting the hypopharyngeal mucosa and leading to neoplastic events. We recently demonstrated that acidic bile ( pH ≤ 4.0) can induce NF ‐κB activation and oncogenic mRNA phenotype in normal hypopharyngeal cells and generate premalignant changes in treated hypopharyngeal mucosa. We hypothesize that curcumin, a dietary inhibitor of NF ‐κB, may effectively inhibit the acidic bile‐induced cancer‐related mRNA phenotype, in treated human hypopharyngeal primary cells ( HHPC ), supporting its potential preventive use in vivo. Luciferase assay, immunofluorescence, Western blot, qPCR and PCR microarray analysis were used to explore the effect of curcumin in HHPC exposed to bile (400 μmol/L) at acidic and neutral pH . Curcumin successfully inhibited the acidic bile‐induced NF ‐κB signalling pathway (25% of analysed genes), and overexpression of NF ‐κB transcriptional factors, c‐ REL , RELA (p65), anti‐apoptotic bcl‐2, oncogenic TNF ‐α, EGFR , STAT 3, WNT 5A, ΔNp63 and cancer‐related IL ‐6. Curcumin effectively reduced bile‐induced bcl‐2 overexpression at both acidic and neutral pH . Our novel findings suggest that, similar to pharmacologic NF ‐κB inhibitor, BAY 11‐7082, curcumin can suppress acidic bile‐induced oncogenic mRNA phenotype in hypopharyngeal cells, encouraging its future in vivo pre‐clinical and clinical explorations in prevention of bile reflux‐related pre‐neoplastic events mediated by NF‐κB.
To our knowledge, recurrent carotid blowout syndrome (rCBS) has not been well described. Our purpose was to review our institution's recent experience with patients who presented with multiple episodes of carotid blowout syndrome (CBS), and who were referred for emergent diagnostic angiography and endovascular therapy.We retrospectively reviewed the last 46 consecutive patients who had a clinical diagnosis of CBS. All patients were examined and treated prospectively according to a standardized protocol. Most patients (43 of 46) had undergone extensive primary and salvage radical surgery with intraoperative brachytherapy or external beam radiation or both. The remaining three patients had either traumatic or iatrogenic CBS.Twelve patients (26%) in our series had more than one episode of CBS in which a total of 32 (20 recurrent) events were observed (average 2.7, range 2-4). Intervals of rCBS ranged from 1 day to 6 years. Thirteen (65%) of 20 recurrent events were attributed to progressive disease (PD), and seven (35%) of 20 to treatment failures (TFs). In the PD group, seven (54%) of 13 had recurrent ipsilateral disease, and six (46%) of 13 had recurrent contralateral disease. Etiologies of rCBS were as follows: seven exposed carotids; seven carotid pseudoaneurysms; eight small-branch pseudoaneurysms; five tumor hemorrhages; three hyperemic/ulcerated wounds; and one aortic arch rupture. Twenty-seven of 32 events were treated with endovascular therapy, which included the following: nine carotid occlusions; 11 small-branch embolizations; three transarterial tumor embolizations; one carotid stent; and two direct-puncture embolizations. Four of six TFs were retreated successfully with endovascular therapy; the remaining two TFs were managed successfully by surgery. In the PD group, hemorrhagic complications of rCBS were managed successfully in all but one patient, who died. No permanent neurologic or ophthalmologic complications occurred.Recurrent CBS is a frequently encountered problem in which most cases are caused by PD resulting from both multifocal iatrogenic arteriopathy and occasional wound complications that are characteristic of aggressively managed head and neck surgical patients. Initial TFs are encountered often as well. Despite the diagnostic and therapeutic challenges of rCBS, most cases can be retreated effectively.
Background Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis. Methods Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis. Results There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS. Conclusions The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.
• Although spontaneous recovery of denervated facial muscles has been anecdotally recorded in the clinical setting, it has never been fully documented. The establishment of anastomoses between the terminal trigeminal and facial nerves provides a possible explanation of this phenomenon. Mechanisms of myoneurotization have also been described, by which regenerating branches of severed peripheral motor nerves directly reach motor end plates of denervated muscles, with variable recovery of function. A case demonstrating unequivocal clinical evidence of trigeminal-facial cross-innervation is presented, and the pertinent literature is reviewed as it applies to the mechanisms of this phenomenon. (Arch Otolaryngol Head Neck Surg. 1990;116:1079-1081)
Solitary fibrous tumors are relatively rare mesenchymal neoplasms that were originally described as pleural- or peritoneal-based lesions. Although they were considered a form of mesothelioma, subsequent investigation failed to reveal mesothelial differentiation. Characterization of their histologic and immunohistochemical features, as well as identification in a multitude of nonmesothelial-based locations has further served to distinguish these lesions from the more diffuse and aggressive mesothelioma. Reports of solitary fibrous tumor in the larynx are extremely rare. We report a case of solitary fibrous tumor of the larynx in a 38-year-old man.
• An investigation of laryngeal reflex maturation was undertaken in the dog to identify its period of most rapid postnatal differentiation. The canine model was selected because of its laryngeal reflex similarity to that of the human being. Observations in the dog indicate maximum differentiation to occur 1 to 1½ months postnatally, based on measurements of recurrent laryngeal nerve myelination and conduction velocity. Latency and threshold analyses of evoked laryngeal responses additionally confirm this viewpoint. The importance of these observations rests in an understanding of developmental upper respiratory tract mechanisms that may be chronologically related to causes of fatal ventilatory events producing unexplained infant death. Such a correlation, requiring further confirmation, is based on the assumption that a critical period of most rapid development allows a transient susceptibility to noxious influences that can cause a disruption in organ function and even death of that organism itself. (Arch Otolaryngol103:138-143, 1977)
6012 Background: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this therapeutic strategy. Engagement of programmed death-1 receptor (PD-1), expressed on activated T-cells, by its ligands, results in a negative regulatory effect, with inhibition of downstream cellular signaling events. Our aim was to investigate the expression and prognostic significance of immunoresistance molecule PDL-1 (the negative regulator programmed death-1-ligand 1) on an annotated HNSCC tissue microarray. Methods: A tissue array composed of 400 larynx cancers treated with surgery followed by radiotherapy was constructed. PDL-1 protein expression levels were assessed using automated quantitative protein analysis (AQUA). The objectives of this analysis were to determine the association of PDL-1 with efficacy outcomes ( overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) ). The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between PDL-1 and event-time distributions. Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Mean follow-up time for the entire cohort was 39.34 months. Two-hundred thirty eight of 400 cases had sufficient tissue for AQUA analysis. High tumor PDL-1 expression was associated with favorable outcome for OS (P=0.029) and trended towards improved DFS (P=0.06) at 5 years. In multivariable analysis, adjusting for well-characterized prognostic variables, PDL-1 expression status retained its prognostic significance for OS and there was again a trend for PFS (p=0.05). Conclusions: This paradoxical result is in accordance with reported studies in HPV-associated HNSCC where PD-1(+) T cells were associated with favorable clinical outcome. It is possible that PDL-1 detection may reflect a previous immune response against tumors. Further work will determine whether PD-1/PD-L1 blockade induces tumor regression in HNSCC.
We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content.We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs.Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (rho = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (rho = 0.30, P = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; rho = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01).These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.
We evaluated the efficacy of resorbable reconstruction plates (polylactic acid copolymer) for the open reduction and stabilization of displaced laryngeal fractures. Both MacroPore and Leibinger reconstruction plates were used with equal ease of application in 3 adult male patients. We found the plating system to be especially effective for the reduction of comminuted cricoid fractures. Adequate skeletal stabilization allowed early resumption of phonatory and respiratory function without long-term intraluminal stenting for skeletal support. No complications of hematoma, seroma, or infection were experienced. Resorbable plates appear to be relatively safe and useful for internal fixation of both cartilaginous and ossified parts of the larynx, allowing rapid rehabilitation and return of function.
