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Background: Penicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model., Method: Twelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) μg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50 % T>MIC., Results: For both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50 % T>MIC) was achieved for both the low target (96 %) and high target (68 %) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70 %), but not the high target (35 %) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally., Conclusion: Intravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Background: HPV-positive head and neck squamous cell carcinoma of the oropharynx (OPSCC) are more sensitive towards radiation than HPV-negative OPSCC. Two main theories exist regarding the underlying mechanism. Stronger lymphocyte infiltration points to an enhanced immunogenicity, whereas data from HPV-positive HNSCC cell lines suggest an enhanced cellular radiosensitivity based on a defect in DNA double-strand break (DSB) repair. The critical limitation of the latter theory is that the evidence was largely derived from a small number of established HPV-positive HNSCC cell lines., Methods and Materials: Fresh patient-derived OPSCC samples were cut in 400 µm sections and cultured on cell culture inserts. Slice cultures were irradiated, in part combined with ATM inhibition, and fixed and frozen after 2 and 24 h. DSBs were analyzed by quantification of 53BP1 foci in nuclei co-stained with the SCC marker p63 via immunofluorescence microscopy., Results: Ex vivo OPSCC tumor slice cultures maintained stable oxygenation and proliferation characteristics for at least 3 days. Areas of p63-positivity in immunofluorescence microscopy matched histologically confirmed tumor cell areas in serial sections, indicating the suitability of p63 as a tumor cell marker. p63-positive nuclei in HPV-positive OPSCC tissues (n = 14) showed profoundly elevated numbers of residual radiation-induced DSBs as compared to those from HPV-negative OPSCC (n = 12) (3 Gy: on average 4.9 vs. 1.2 foci per nucleus; p < 0.0001). Within the HPV-positive subgroup, samples derived from patients with a smoking history of less than 10 pack years demonstrated higher residual DSBs as compared to those derived from patients with 10 or more pack years (3 Gy: on average 6.5 vs. 3.2 foci per nucleus; p = 0.0105). Additional ATM inhibition resulted in a substantial increase in residual foci in all 4 HPV-negative samples tested but strikingly only in 2 out of 11 HPV-positive samples., Conclusions: In summary, our data provide robust, cell line-independent experimental evidence for an intrinsic DSB repair deficiency in HPV-positive OPSCC, strongly suggesting a meaningful contribution to the enhanced clinical radiosensitivity. The reduced effectiveness of ATM inhibition indicates a defect in the ATM-orchestrated DNA damage response. Lower numbers of residual 53BP1 nuclear foci in the ex vivo assay may identify HPV-positive patients with effective DSB repair who should potentially be excluded from de-intensification approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study aimed to compare prognostic potential of Nanog expression analysed by three immunohistochemical scores in the group of 63 squamous cell carcinomas of oropharynx. Immunoreactivity of Nanog expression was analyzed by semiquantitative score, immunoreactive score and H-score. For all three scores, the cut-off points for Nanog overexpression and its lack, allowing for optimal separation of overall and disease free survival curves, were search by minimal p-value method. In semiquantitative score, the best separation of overall and disease free survival curves was obtain by cut-off point lack of staining vs. week/moderate/strong staining, although statistical significance was not reach (OS: HR = 1.016, p = 0.081, DFS: HR = 6.876, p = 0.061). The cut-off points for immunoreactive score and H-score were, respectively: 1 (OS: HR = 6.977, p = 0.014, DFS: HR = 6.002, p = 0.019) and 50 (OS: HR = 6.977, p = 0.014, DFS: HR = 6.002, p = 0.019). The cut-off points found for these two scores allow to identify the same subgroups of patients with lack of Nanog expression (11.1%) and its overexpression (88.9%). All patients with tumors characterized by lack of Nanog overexpression identifying by immunoreactive score and H-score survived 5 years without evidence of cancer progression. In multivariate analysis Nanog immunoreactivity analysed by QRS and IRS was independent prognostic factor for OS (HR = 10.195, p = 0.024). Immunohistochemical score using to distinguish Nanog overexpression or its lack has influence on prognostic potential of this biomarker.

Carriage of Neisseria meningitidis is an accepted endpoint in monitoring meningococcal vaccines effects. We have assessed N. meningitidis and vaccine-type genogroup carriage prevalence in college students at the time of MenACWY vaccine introduction in the Netherlands, and evaluated the feasibility of saliva sampling for the surveillance of carriage. For this, paired saliva and oropharyngeal samples collected from 299 students were cultured for meningococcus. The DNA extracted from all bacterial growth was subjected to qPCRs quantifying meningococcal and genogroup-specific genes presence. Samples negative by culture yet positive for qPCR were cultured again for meningococcus. Altogether 74 (25%) of students were identified as meningococcal carrier by any method. Sixty-one students (20%) were identified as carriers with qPCR. The difference between number of qPCR-positive oropharyngeal (n = 59) and saliva (n = 52) samples was not significant (McNemar's test, p = 0.07). Meningococci were cultured from 72 students (24%), with a significantly higher (p < 0.001) number of oropharyngeal (n = 70) compared with saliva (n = 54) samples. The prevalence of genogroups A, B, C, W, and Y was none, 9%, 1%, 1% and 6%, respectively, and 8% of students carried MenACWY vaccine-type genogroup meningococci. Saliva is easy to collect and when combined with qPCR detection can be considered for meningococcal carriage studies., (© 2021. The Author(s).)

Background: Oropharyngeal cancer is an important public health problem. The aim of our study was to correlatep16 immunohistochemistry in oropharynx squamous cell carcinomas(OPSCC) with clinical and epidemiological features., Material and Methods: We conducted across-sectional study on patients with OPSCC treated at a single institution from 2014 to 2019. Epidemiological and clinical-pathological data were collected from medical records and a questionnaire was applied to determine alcohol consumption, smoking, and sexual behavior. The HPV status was determined by p16 immunohistochemistry., Results: A total of 252 patients participated in the study, of these 221 (87.7%) were male. There were 81 (32.14%) p16 positive cases and 171 (67.85%) p16 negative cases. The p16positive group was significantly associated with younger patients (50-59 years), higher education level, lower clinical stage and patients who never drank or smoked. Through univariate logistic regression, we observed that female sex (OR, 3.47; 95% CI, 1.60-7.51) and higher education level (OR, 9.39; 95% CI, 2, 81-31,38) were significantly more likely to be p16 positive. Early clinical stage (AJCC8ed) was more associated with p16 positivity both in univariate (OR, 0.14; 95% CI, 0.07-0.26, p<0.001) and multivariate analysis (OR, 0.18; 95% CI, 0.06-0.49, p = 0.001)., Conclusion: This study showed that drinkers and current smokers were less likely to be p16+. Female sex, higher education level and younger age at diagnosis were associated with a higher probability of being p16+. Additionally, there was a higher proportion of patients with early clinical stage (I or II) in the p16 positive group when compared to the p16 negative group., Competing Interests: The authors have declared that no competing interests exist.

During oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects β-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and candidalysin during OPC. We found that EGFR and EphA2 constitutively associate with each other as part of a heteromeric physical complex and are mutually dependent for C. albicans-induced activation. Als3-mediated endocytosis of a C. albicans hypha leads to the formation of an endocytic vacuole where candidalysin accumulates at high concentration. Thus, Als3 potentiates targeting of candidalysin, and both Als3 and candidalysin are required for C. albicans to cause maximal damage to oral epithelial cells, sustain activation of EphA2 and EGFR, and stimulate pro-inflammatory cytokine and chemokine secretion. In the mouse model of OPC, C. albicans-induced production of CXCL1/KC and CCL20 is dependent on the presence of candidalysin and EGFR, but independent of Als3. The production of IL-1α and IL-17A also requires candidalysin but is independent of Als3 and EGFR. The production of TNFα requires Als1, Als3, and candidalysin. Collectively, these results delineate the complex interplay among host cell receptors EphA2 and EGFR and C. albicans virulence factors Als1, Als3 and candidalysin during the induction of OPC and the resulting oral inflammatory response., Competing Interests: The authors have declared that no competing interests exist.

Objective: The goal of this study was to evaluate the performance of p16 staining in cell-blocks vs tissue specimens as a surrogate marker for human papillomavirus (HPV) status in oropharyngeal squamous cell carcinomas., Methods: Head and neck squamous cell carcinoma cases presenting as a neck mass with a p16 result on cytology and corresponding tissue specimens (1 January 2014 to 30 June 1920) were included in the study. The following were assessed from cell-block material: number of tumour clusters, percentage of tumour cells with p16 staining, and presence of staining in clusters vs single cells. Results were compared to tissue p16 status. Results of any other ancillary HPV testing were also noted., Results: Forty-two head and neck squamous cell carcinoma neck metastases (35 oropharyngeal, five non-oropharyngeal, and 2 unknown primaries) were identified. The p16 staining pattern in cell-blocks was seen in single cells (27.6%), clusters (44.8%), or both (27.6%). The percentage of tumour cells staining for p16 in cell-blocks was much lower than in corresponding tissue specimens. There were four false negatives and one false positive (concurrent HPV DNA polymerase chain reaction testing was positive in cytology and surgical material)., Conclusions: Compared to tissue, the cut-off for p16 interpretation in cell-blocks is substantially lower and staining may be present in single cells or clusters. In 96.9% of cases, any p16 staining in cell-blocks correlated with positive p16 staining in surgical specimens. However, a negative or discrepant p16 result on cell-block should prompt confirmatory HPV studies, as false negative p16 staining in cell-blocks is high., (© 2020 John Wiley & Sons Ltd.)

Nonclinical studies are fundamental for the development of inhaled drugs, as for any drug product, and for successful translation to clinical practice. They include in silico, in vitro, ex vivo and in vivo studies and are intended to provide a comprehensive understanding of the inhaled drug beneficial and detrimental effects. To date, animal models cannot be circumvented during drug development programs, acting as surrogates of humans to predict inhaled drug response, fate and toxicity. Herein, we review the animal models used during the different development stages of inhaled pharmaceuticals and biopharmaceuticals, highlighting their strengths and limitations., Competing Interests: Declaration of Competing Interest NHV receives consulting fees from Cynbiose Respiratory, a CRO that develops and proposes animal models of respiratory diseases, including infectious pathologies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Conventional in vitro tests to assess the aerodynamic particle size distribution (APSD) from inhaler devices use simple right-angle inlets ("mouth-throats", MTs) to cascade impactors, and air is drawn through the system at a fixed flow for a fixed time. Since this arrangement differs substantially from both human oropharyngeal airway anatomy and the patterns of air flow when patients use inhalers, the ability of in vitro tests to predict in vivo deposition of pharmaceutical aerosols has been limited. MTs that mimic the human anatomy, coupled with simulated breathing patterns, have yielded estimates of lung dose from in vitro data that closely match those from in vivo gamma scintigraphic or pharmacokinetic studies. However, different models of MTs do not always yield identical data, and selection of an anatomical MT and representative inhalation profiles remains challenging. Improved in vitro - in vivo correlations (IVIVCs) for inhaled drug products could permit increased reliance on in vitro data when developing new inhaled drug products, and could ultimately result in accelerated drug product development, together with reduced research and development spending., Competing Interests: Declaration of Competing Interest Neither author has any conflicts of interest to report., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: No screening is available for human papillomavirus (HPV)-associated oropharyngeal cancers. The authors investigated whether cytology may be used as a screening tool and whether oral HPV infection is associated with cytologic abnormalities detected in oropharyngeal brushings and in oral rinse-and-gargle specimens from asymptomatic individuals at increased risk for oral HPV infection., Methods: Specimens were collected from men who have sex with men at 6-month intervals. Oropharyngeal samples and oral rinse-and-gargle specimens were collected using a cytobrush and mouthwash, respectively. Exfoliated cells were dispersed in PreservCyt. Liquid-based slides were stained with Papanicolaou. An HPV genotyping test using a linear array was used for HPV detection. Associations with abnormal cytology were investigated using logistic regression., Results: Overall, 631 brushings and 802 rinses collected from 310 individuals were evaluated; of these specimens, 2 brushings (0.3%) and 10 rinses (1.2%) were inadequate for morphologic evaluation. Of the adequate samples, 35 of 629 brushings (5.5%) and 19 of 792 rinses (2.4%) were abnormal. No associations of high-risk HPVs or HPV-16 infection with cytologic abnormalities were observed for oropharyngeal brushings (high-risk HPVs: odds ratio [OR], 1.19; 95% CI, 0.41-3.50; P = .75; HPV-16: OR, 0.76; 95% CI, 0.10-5.84; P = .79) or for oral rinses (high-risk HPVs: OR, 1.13; 95% CI, 0.26-4.98; P = .87; HPV-16: OR, 0.62; 95% CI, 0.04-10.60; P = .74). Concurrent moderate/heavy drinking and smoking significantly increased the risk of cytologic abnormalities in the brushings (hazard ratio, 4.84; 95% CI, 1.15-20.43; P = .03)., Conclusions: Oral HPV infection by high-risk HPVs and HPV-16 does not confer an increased risk of cytologic abnormalities in oropharyngeal brushings and oral rinses. Abnormal cytology seems to be associated with smoking and drinking habits., (© 2020 American Cancer Society.)

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4-hydroxy-2-nonenal (HNE), which is considered as a "second messenger of free radicals" that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately-differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer.

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts.

Head and neck squamous cell carcinomas (HNSCC) includes multiple subsites that exhibit differential treatment outcome, which is in turn reflective of tumor stage/histopathology and molecular profile. This study hypothesized that the molecular profile is an accurate prognostic adjunct in patients triaged based on clinico-pathological characteristics. Towards this effect, publically available micro-array datasets (n = 8), were downloaded, classified based on HPV association (n = 83) and site (tongue n = 88; laryngopharynx n = 53; oropharynx n = 51) and re-analyzed (Genespring; v13.1). The significant genes were validated in respective cohorts in The Cancer Genome Atlas (TCGA) for correlation with clinico-pathological parameters/survival. The gene entities (n = 3258) identified from HPV based analysis, when validated in TCGA identified the subset specifically altered in HPV+ HNSCC (n = 63), with three genes showing survival impact (RPP25, NUDCD2, NOVA1). Site-specific meta-analysis identified respective differentials (tongue: 3508, laryngopharynx: 4893, oropharynx: 2386); validation in TCGA revealed markers with high incidence (altered in >10% of patients) in tongue (n = 331), laryngopharynx (n = 701) and oropharynx (n = 404). Assessment of these genes in clinical sub-cohorts of TCGA indicated that early stage tongue (MTFR1, C8ORF33, OTUD6B) and laryngeal cancers (TWISTNB, KLHL13 and UBE2Q1) were defined by distinct prognosticators. Similarly, correlation with perineural/angiolymophatic invasion, identified discrete marker panels with survival impact (tongue: NUDCD1, PRKC1; laryngopharynx: SLC4A1AP, PIK3CA, AP2M1). Alterations in ANO1, NUDCD1, PIK3CA defined survival in tongue cancer patients with nodal metastasis (node+ECS-), while EPS8 is a significant differential in node+ECS- laryngopharyngeal cancers. In oropharynx, wherein HPV is a major etiological factor, distinct prognosticators were identified in HPV+ (ECHDC2, HERC5, GGT6) and HPV- (GRB10, EMILIN1, FNDC1). Meta-analysis in combination with TCGA validation carried out in this study emphasized on the molecular heterogeneity inherent within HNSCC; the feasibility of leveraging this information for improving prognostic efficacy is also established. Subject to large scale clinical validation, the marker panel identified in this study can prove to be valuable prognostic adjuncts., Competing Interests: The authors have declared that no competing interests exist.

Background: Oropharyngeal dysphagia (OD) is a prevalent disease with poor prognosis among older people and has no pharmacological treatment. Polymodal sensory receptors like the TRP or ASIC family receptors are potential targets to treat OD. TRPM8 agonists and acidic solutions can improve the swallow response in patients with OD, but little is known about the expression of TRPM8, ASIC1, and ASIC3 in the human oropharynx. The aim of this study was to assess the expression and localization of TRPM8, ASIC1, and ASIC3 in human samples of the oropharynx to lay the basis for new pharmacological treatments for OD., Methods: Pathology-free samples from oropharyngeal regions innervated by cranial nerves V, IX, and X were obtained during major ENT surgery and processed to obtain mRNA (20 patients) or to be used in immunohistochemical assays (12 patients). TRPM8, ASIC1, and ASIC3 expression and localization were studied with RT-qPCR and fluorescent immunohistochemistry., Key Results: ASIC3 was expressed in the 3 regions studied with similar levels and was localized on sensory fibers innervating the mucosa below the basal lamina of all studied regions. TRPM8 was also co-localized on the sensory fibers innervating the mucosa below the basal lamina of all studied regions. In contrast, ASIC1 was only found in the nerves innervating the tongue muscular fibers., Conclusions & Inferences: TRPM8 and ASIC3 are found on submucosal sensory nerves in the human oropharynx. Our study lays the basis to use oropharyngeal TRPM8 and ASIC3 receptors as therapeutic targets to develop new active pharmacological treatments for OD patients., (© 2018 John Wiley & Sons Ltd.)

The upper airway - which consists mainly of the naso- and oro-pharynx - is the first point of contact between the respiratory system and microbial organisms that are ubiquitous in the environment. It has evolved highly specialised functions to address these constant threats whilst facilitating seamless respiratory exchange with the lower respiratory tract. Dysregulation of its critical homeostatic and defence functions can lead to ingress of pathogens into the lower respiratory tract, potentially leading to serious illness. Systems-wide proteomic tools may facilitate a better understanding of mechanisms in the upper airways in health and disease. In this study, we aimed to develop a mass spectrometry based proteomics method for characterizing the upper airways proteome. Naso- and oropharyngeal swab samples used in all our experiments had been eluted in the Universal Transport Media (UTM) containing significantly high levels of bovine serum albumin. Our proteomic experiments tested the optimal approach to characterize airway proteome on swab samples eluted in UTM based on the number of proteins identified without BSA depletion (Total proteome: Protocol A) and with its depletion using a commercial kit; Allprep, Qiagen (cellular proteome: Protocol B, Ci, and Cii). Observations and lessons drawn from protocol A, fed into the design and implementation of protocol B, and from B to protocol Ci and finally Cii. Label free proteome quantification was used in Protocol A (n = 6) and B (n = 4) while commercial TMT 10plex reagents were used for protocols Ci and ii (n = 83). Protocols Ci and ii were carried out under similar conditions except for the elution gradient: 3 h and 6 h respectively. Swab samples tested in this study were from infants and children with and without upper respiratory tract infections from Kilifi County Hospital on the Kenyan Coast. Protocol A had the least number of proteins identified (215) while B produced the highest number of protein identifications (2396). When Protocol B was modified through sample multiplexing with TMT to enable higher throughput (Protocol Ci), the number of protein identified reduced to 1432. Modification of protocol Ci by increasing the peptide elution time generated Protocol Cii that substantially increased the number of proteins identified to 1875. The coefficient of variation among the TMT runs in Protocol Cii was <20%. There was substantial overlap in the identity of proteins using the four protocols. Our method was were able to identify marker proteins characteristically expressed in the upper airway. We found high expression levels of signature nasopharyngeal and oral proteins, including BPIFA1/2 and AMY1A, as well as a high abundance of proteins related to innate and adaptive immune function in the upper airway. We have developed a sensitive systems-level proteomic assay for the systematic quantification of naso-oro-pharyngeal proteins. The assay will advance mechanistic studies of respiratory pathology, by providing an untargeted and hypothesis-free approach of examining the airway proteome.

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Pepsin in saliva is a proposed biomarker for oropharyngeal reflux. Pepsin may be prevalent in saliva from subjects with gastro-esophageal reflux and may correlate with proximal reflux by intraluminal impedance/pH monitoring (MII/pH)., Methods: Patients (3 days to 17.6 years, n=90) undergoing 24-hour MII/pH monitoring and asymptomatic controls (2 months to 13.7 years, n=43) were included. Salivary pepsin was determined using a pepsin enzyme-linked immunosorbent assay. Eight saliva samples were collected from patients undergoing 24-hr MII/pH: (i) before catheter placement, (ii) before and 30 minutes after each of three meals, and (iii) upon awakening. One sample was collected from each control., Key Results: In MII/pH subjects, 85.6% (77/90) had at least one pepsin-positive sample compared with 9.3% (4/43) in controls. The range of pepsin observed in individual subjects varied widely over 24 hours. The average pepsin concentration in all samples obtained within 2 hours following the most recent reflux event was 30.7±135 ng/mL, decreasing to 16.5±39.1 ng/mL in samples collected more than 2 hours later. The frequency of pepsin-positive samples correlated significantly with symptom index (r S =0.332, P=.0014), proximal (r S =0.340, P=.0010), and distal (r S =0.272, P=.0095) MII events., Conclusions & Inferences: Concentration of salivary pepsin may not be an accurate measure of severity of reflux because of the wide range observed in individuals over 24 hours. Saliva samples must be obtained soon after a reflux event. Defining a regimen for optimal saliva collection may help to achieve the goal of using salivary pepsin as a biomarker for oropharyngeal reflux., Clinical Trial Registry: NCT01091805., (© 2016 John Wiley & Sons Ltd.)

Objective: The use of pneumoperitonium and the placement of patients in Trendelenburg position are commonly cited reasons for the potential development of intraoperative regurgitation of gastric contents and the need for an endotracheal tube in laparoscopic surgery. The main objective of the current investigation was to evaluate the presence of regurgitation of gastric contents in the oropharynx of patients having laparoscopic gynecological surgery with a laryngeal mask airway (LMA)., Design: Prospective, observational clinical investigation., Interventions: Not applicable., Measurements: Healthy subjects having a laparoscopic gynecological surgery under general anesthesia with a ProSeal LMA were included in the study. An insufflation pressure of 15 mm Hg was established as the maximum intra-abdominal pressure for the pneumoperitonium, and patients were placed in Trendelenburg position at a 15° angle. The pH of secretions extracted from subjects' hypopharynx was measured at multiple time points during the surgical procedure. A pH of oropharynx secretions ≤4.1 indicated the regurgitation of gastric contents., Main Results: Eighty subjects were recruited and completed the study. The median (range) of pH measurements at any time (T3-T9) was 6.5 (5.5-7.0). The median (range) for the lowest pH for each subject was 6.0 (5.5-7.0). The lowest detected pH in the hypopharynx was not correlated (Spearman ρ) with total surgical time (P = .9), total pneumopertitonium time (P = .17), or total Trendelenburg position time (P = .47)., Conclusions: Our current results suggest that the use of an LMA in healthy patients undergoing laparoscopic gynecological surgery may be safe. Future studies to confirm or refute our findings are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(™)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(™)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid., Methods: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients., Results: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA., Conclusions: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD).

We conducted a prospective, descriptive study of 27 individuals with known or suspected dysphagia to investigate the relationship between swallowing frequency, accumulated oropharyngeal secretion levels, and gustatory stimulation. Assessment of the secretion level was quantified with the use of a previously published 5-point rating scale using endoscopy. Overall, we found a moderate relationship between the baseline swallowing frequency at rest and the accumulated oropharyngeal secretion level (Pearson correlation 0.470; p = 0.01). The study sample was divided into two groups based on their secretion level. Group 1 (n = 19; mean age 59.7 ± 21.5 years) included patients whose accumulated oropharyngeal secretion level was rated as 1 (normal) or 2 (mild). Group 2 (n = 8; mean age 69.78 ± 8.35 years) included patients whose accumulated oropharyngeal secretion level was rated as 4 (severe) or 5 (profound). For Group 1, swallowing frequency increased from a baseline of 1.05 to 5.26 swallows over 2 minutes, following gustatory stimulation; for Group 2 it increased from a baseline of 0.125 swallows to 3.5 swallows. These results indicate that individuals with a lower baseline swallowing frequency at rest demonstrated a higher accumulated oropharyngeal secretion level as viewed by nasal endoscopy and that, regardless of secretion level, gustatory stimulation was effective at increasing swallowing frequency. Increasing swallowing frequency may be a functional dysphagia treatment objective in efforts to improve the efficiency of the swallow and may offer better management of accumulated oropharyngeal secretions.

Background: Previous studies have found that TRPV1 and TRPA1 receptor agonists improve swallow response in patients with oropharyngeal dysphagia (OD), but little is known about the expression of these receptors in the human oropharynx. The aim of this study was to assess the expression and localization of TRPV1 and TRPA1 in human samples from the oropharynx of healthy patients, to provide the basis for new pharmacological treatments for OD., Methods: Samples from oropharyngeal regions innervated by cranial nerves V, IX, and X (tongue, pharynx, and epiglottis) were obtained during ENT surgery and processed either for mRNA (21 patients) or for immunohistochemical assays (seven patients). The expression analysis was performed with RT-qPCR using ACTBh as reference gene. Hemotoxylin and eosin staining was used to study the histology; the immunohistochemical assay used (i) neuron-specific enolase to detect nerve fibers or (ii) fluorescent probes to locate TRPV1 and TRPA1., Results: TRPV1 was expressed in the three studied regions, with higher levels in CN V region (tongue) than in CN X region (epiglottis; p < 0.05), and was localized at epithelial cells and nociceptive fibers in all studied regions. TRPA1 was also expressed in all studied regions, but was always localized below the basal lamina. No immunoreactivity for TRPA1 was found on epithelial cells., Conclusions & Inferences: TRPV1 and TRPA1 are widely expressed in the human oropharynx with two distinct patterns. Our study further confirms that TRPV1/A1 receptors are promising therapeutic targets to develop active treatments for OD patients., (© 2015 John Wiley & Sons Ltd.)

Mechanical processes underlying pharyngeal closure have not been examined. We hypothesized that the pharyngeal mucosal surface would fold during closure, and lowering the upper airway lining liquid surface tension would unfold areas of mucosal apposition, i.e., folds. We compared baseline pharyngeal fold numbers and response to reduction in upper airway liquid surface tension in healthy and obstructive sleep apnea (OSA) subjects. Awake, gated magnetic resonance pharyngeal airway images of 10 healthy and 11 OSA subjects were acquired before and after exogenous surfactant administration (beractant). Upper airway liquid surface tension was measured at the beginning and end of image acquisition and averaged. Velopharyngeal and oropharyngeal images were segmented and analyzed separately for average cross-sectional area, circumference, and fold number. Compared with healthy subjects, at baseline, velopharynx for OSA subjects had a smaller cross-sectional area (98.3 ± 32.5 mm(2) healthy, 52.3 ± 23.6 mm(2) OSA) and circumference (46.5 ± 8.1 mm healthy, 30.8 ± 6.1 mm OSA; both P < 0.05, unpaired t-test), and fewer folds (4.9 ± 1.6 healthy, 3.1 ± 1.8 OSA, P < 0.03). There were no differences in oropharynx for cross-sectional area, circumference, or folds. Reduction in upper airway liquid surface tension from 61.3 ± 1.2 to 55.3 ± 1.5 mN/m (P < 0.0001) did not change cross-sectional area or circumference for velopharynx or oropharynx in either group; however, in OSA subjects, oropharyngeal folds fell from 6.8 ± 3.1 to 4.7 ± 1.2 (n = 8, P < 0.05), and velopharyngeal folds from 3.3 ± 1.9 to 2.3 ± 1.2 (P = 0.08), and were unchanged in healthy subjects. Subjects with OSA have fewer velopharyngeal wall folds, which decrease further when surface tension falls. We speculate that reduced pharyngeal wall folds contribute to an increase in pharyngeal collapsibility., (Copyright © 2015 the American Physiological Society.)

1. The aim of the present study is to describe, immunohistochemically, the expression and cell type localisation of growth factor receptors and some of their ligands in the oropharyngeal organs of the Chukar partridge. 2. The tissue samples from 10 healthy adult partridges were dissected under ether anaesthesia and then embedded in paraffin following routine histological procedures. The immunoreaction for receptors and ligands of the epidermal growth factor receptor (EGFR)/ligand system was localised in the cell membrane, nucleus and cytoplasm of the luminal and glandular epithelial cells, stromal and striated muscle cells, and vascular endothelial and smooth muscle cells. 3. Variations were observed in the avian oropharyngeal organs. The immunostaining for the erbB1/HER1 (human epidermal growth factor receptor 1) and the EGF (epidermal growth factor) and AREG (Amphiregulin) ligands in the luminal epithelial cells was higher than in the glandular epithelial, stromal and striated muscle cells. However, the immunostaining for erbB3/HER3 (human epidermal growth factor receptor 3) and erbB4/HER4 (human epidermal growth factor receptor 4) were similar in the luminal epithelium, stromal and striated muscle cells. 4. Growth factor receptors and some of their ligands were localised in different cell types in the oropharyngeal organs. We suggest that erbB/HERs (human epidermal growth factor receptors) and their ligands play an important role in proliferation, differentiation, growth, survival and migration of the cells.

Streptococcus pyogenes is responsible for a variety of infectious diseases and immunological complications. In this study, 91 isolates of S. pyogenes recovered from oropharynx secretions were submitted to antimicrobial susceptibility testing, emm typing and pulsed-field gel electrophoresis (PFGE) analysis. All isolates were susceptible to ceftriaxone, levofloxacin, penicillin G and vancomycin. Resistance to erythromycin and clindamycin was 15.4%, which is higher than previous reports from this area, while 20.9% of the isolates were not susceptible to tetracycline. The macrolide resistance phenotypes were cMLSB (10) and iMLSB (4). The ermB gene was predominant, followed by the ermA gene. Thirty-two emm types and subtypes were found, but five (emm1, emm4, emm12, emm22, emm81) were detected in 48% of the isolates. Three new emm subtypes were identified (emm1.74, emm58.14, emm76.7). There was a strong association between emm type and PFGE clustering. A variety of PFGE profiles as well as emm types were found among tetracycline and erythromycin-resistant isolates, demonstrating that antimicrobial resistant strains do not result from the expansion of one or a few clones. This study provides epidemiological data that contribute to the development of suitable strategies for the prevention and treatment of such infections in a poorly studied area.

Humans commonly carry pathogenic bacteria asymptomatically, but despite decades of study, the underlying molecular contributors remain poorly understood. Here, we show that a group A streptococcus carriage strain contains a frameshift mutation in the hasA gene resulting in loss of hyaluronic acid capsule biosynthesis. This mutation was repaired by allelic replacement, resulting in restoration of capsule production in the isogenic derivative strain. The "repaired" isogenic strain was significantly more virulent than the carriage strain in a mouse model of necrotizing fasciitis and had enhanced growth ex vivo in human blood. Importantly, the repaired isogenic strain colonized the mouse oropharynx with significantly greater bacterial burden and had significantly reduced ability to internalize into cultured epithelial cells than the acapsular carriage strain. We conducted full-genome sequencing of 81 strains cultured serially from 19 epidemiologically unrelated human subjects and discovered the common theme that mutations negatively affecting capsule biosynthesis arise in vivo in the has operon. The significantly decreased capsule production is a key factor contributing to the molecular détente between pathogen and host. Our discoveries suggest a general model for bacterial pathogens in which mutations that downregulate or ablate virulence factor production contribute to carriage., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. The frequent deletions and other alterations in these regions in multiple cancers has led to the discovery of a number of extremely large genes contained within these regions and several of the large CFS genes have already been demonstrated to function as tumor suppressors involved in the formation of many different cancers. To study the large CFS genes in oropharyngeal squamous cell carcinoma (OPSCC), we did RNA seq analysis from 11 head and neck cancer patients. This revealed that there are six large CFS genes which consistently had decreased expression in the tumor samples compared to their matched normal tissues. These six genes are PARK2, DLG2, NBEA, CTNNA3, DMD, and FHIT. PARK2 and FHIT are located within the two most frequently expressed CFSs and both have been demonstrated to function as tumor suppressors, while the other large genes are found to have frequent alterations in multiple cancers. Validation experiments using real time PCR indicated that over 60% of OPSCC tumors showed decreased expression for all six genes. Both HPV-positive and HPV-negative OPSCCs had similar proportions with loss of expression of these genes. Our results suggest that this selected group of large genes might serve as potential tumor suppressors involved in the development of OPSCCs. Further studies are needed to investigate whether the decreased expression observed is due to genomic instability within the CFS regions or the selection for alterations of specific large CFS genes., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Human papillomavirus-associated oropharyngeal carcinoma (HPV-OPC) is clinicopathologically distinct entity from the HPV-unassociated one (nHPV-OPC). This study aimed to determine the relationship between histological subtypes of OPC and HPV status for Japanese cases and to identify histological structures of HPV-OPC., Methods: 66 OPC cases were categorized into conventional squamous cell carcinoma (SCC) and the variants. Conventional SCC was subcategorized into keratinizing (KSCC), non-keratinizing (NKSCC), and hybrid SCC (HSCC). HPV status of all cases was determined using p16-immunohistochemistry and HPV-DNA ISH., Results: Two histological subtypes, NKSCC and HSCC, tended to be HPV-OPC and KSCC tended to be nHPV-OPC with statistical significance. Two histological structures, abrupt keratinization, defined in the text, and comedo-necrosis among non-maturing tumor island, were observed for 58.1% and 38.7% of HPV-OPC, and tended to exist for HPV-OPC with statistical significance., Conclusions: This study showed the association of NKSCC/HSCC with HPV-OPC in Japanese cases, and two histological structures, abrupt keratinization and comedo-necrosis among non-maturing island, were considered characteristic histological features of HPV-OPC., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1816432541113073.

Objective: Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE-/-) mice., Methods: ApoE-/- mice were fed a 'Western diet' (8 weeks) to induce 'complex' atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 μL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery., Results: Brachiocephalic atherosclerotic plaques were larger in ApoE-/- mice treated with DEP (59 ± 10%) than in controls (32 ± 7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4 ± 0.2 vs 1.8 ± 0.2; P = 0.048) and buried fibrous layers (1.2 ± 0.2 vs 0.4 ± 0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation., Conclusions: Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.

Purpose: The current study examined the effect of recombinant human deoxyribonuclease (rhDNase) on quality of life (QOL) measures, clinical improvement, and DNA content of thick oropharyngeal secretions (OPS) in patients with head-and-neck (H&N) cancers., Methods and Materials: Thirty-six patients with local-regional advanced H&N cancer receiving chemoradiationtherapy (CRT) were randomized to receive either placebo or rhDNase. Endpoints included MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) and Functional Assessment of Cancer Therapy-Head and Neck (FACT-NH) scores, along with clinical assessment and DNA concentration of OPS., Results: There were no statistically significant differences in patients' QOL outcomes over the study period. Both groups showed an increase in symptom and interference scores, although patients in the rhDNase group showed a greater decline in both scores during the 3 months posttreatment. Similarly, both groups showed a decline in physical and functional well being but recovered in the 3 months posttreatment follow-up, with the rhDNase group exhibiting speedier recovery. Patients in the rhDNase group exhibited significant clinical improvement in OPS, blindly assessed by a physician, compared with the placebo group (67% vs 27%, respectively; P=.046). The rhDNase group showed no change in OPS-DNA concentration, although the placebo group showed a significant increase in DNA concentration during the drug trial (P=.045). There was no differences in acute toxicities between the 2 groups., Conclusions: Our preliminary data suggest that rhDNase did not significantly improve study primary endpoints of QOL measures compared with the placebo group. However, there was a significant improvement in secondary endpoints of clinically assessed OPS and DNA concentration compared with placebo in H&N cancer patients treated with CRT. Further investigation in larger numbers of patients is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: There is no pharmacological treatment for oropharyngeal dysphagia (OD). The aim of this study was to compare the therapeutic effect of stimulation of oropharyngeal transient receptor potential vanilloid type 1 (TRPV1) with that of thickeners in older patients with OD., Design: A clinical videofluoroscopic non-randomised study was performed to assess the signs of safety and efficacy of swallow and the swallow response in (1) 33 patients with OD (75.94 ± 1.88 years) while swallowing 5, 10 and 20 ml of liquid (20.4 mPa.s), nectar (274.4 mPa.s), and pudding (3930 mPa.s) boluses; (2) 33 patients with OD (73.94 ± 2.23 years) while swallowing 5, 10 and 20 ml nectar boluses, and two series of nectar boluses with 150 μM capsaicinoids and (3) 8 older controls (76.88 ± 1.51 years) while swallowing 5, 10 and 20 ml nectar boluses., Results: Increasing bolus viscosity reduced the prevalence of laryngeal penetrations by 72.03% (p < 0.05), increased pharyngeal residue by 41.37% (p < 0.05), delayed the upper esophageal sphincter opening time and the larynx movement and did not affect the laryngeal vestibule closure time and maximal hyoid displacement. Treatment with capsaicinoids reduced both, penetrations by 50.% (p < 0.05) and pharyngeal residue by 50.% (p < 0.05), and shortened the time of laryngeal vestibule closure (p < 0.001), upper esophageal sphincter opening (p < 0.05) and maximal hyoid and laryngeal displacement., Conclusion: Stimulation of TRPV1 by capsaicinoids strongly improved safety and efficacy of swallow and shortened the swallow response in older patients with OD. Stimulation of TRPV1 might become a pharmacologic strategy to treat OD.

Background: Because reflux of gastric juice into the oropharynx must precede its aspiration into the lungs, it is reasonable to hypothesize that the detection of pepsin (the major gastric enzyme in gastric juice) in oral secretions may provide a relatively noninvasive method of predicting risk for aspiration., Objective: To describe the incidence of pepsin in oral and tracheal secretions collected concurrently from a sample of 50 gastric-fed patients undergoing mechanical ventilation., Methods: An exploratory descriptive design with a convenience sample from 4 medical and surgical intensive care units. An oral secretion and a tracheal secretion were collected concurrently from each patient (yielding a sample of 50 oral and 50 tracheal secretions). The tracheal secretions were obtained via the inline suction system with an attached sputum trap; oral secretions were obtained via a Yankauer suction tip with an attached sputum trap. All specimens were assayed for pepsin by the Western blot method., Results: Oral secretions from 10 patients (20%) and tracheal secretions from 2 patients (4%) were pepsin-positive. Both patients with pepsin-positive tracheal secretions also had pepsin-positive oral secretions. Pepsin was not found in the tracheal secretions from the remaining 8 patients with pepsin-positive oral secretions., Conclusions: Although reflux of gastric juice into the oropharynx must precede its aspiration into the lungs, individual reflux events do not necessarily lead to aspiration. Thus, it is reasonable that we found pepsin 5 times more often in oral secretions than in tracheal secretions.

After total thyroidectomy for papillary thyroid carcinoma, a 37-year-old woman underwent a 2-mCi (131)I whole-body scan which demonstrated focal uptake in the anterior neck and in the oropharynx. Preoperative contrast-enhanced neck computed tomography demonstrated a small enhancing nodule typical for ectopic thyroid at the tongue base. She was then treated with 150 mCi (131)I. Small asymptomatic lingual thyroid remnants typically do not affect high-dose (131)I therapy.

Background: Over the past 5 years, there has been a change in the clinical practice of pediatric anesthesiology with a transition to the use of cuffed instead of uncuffed endotracheal tubes (ETTs) in infants and children. As the trachea is sealed, one advantage is to eliminate the contamination of the oropharynx with oxygen which should be advantageous during adenotonsillectomy where there is a risk of airway fire. The current study prospectively assesses the oropharyngeal oxygen and volatile anesthetic agent concentration during adenotonsillectomy in infants and children., Methods: Following the induction of general anesthesia in patients scheduled for adenoidectomy, tonsillectomy or adenotonsillectomy, the trachea was intubated. The use of a cuffed or uncuffed ETT and the use of spontaneous (SV) or positive pressure ventilation (PPV) were at the discretion of the anesthesia team. The oxygen concentration was kept at 100% oxygen until the study was completed. Following placement of the mouth gag, the otolaryngolist placed into the oropharynx a small bore catheter, which was attached to a standard anesthesia gas monitoring device which sampled the gas at 150mL/min. The concentration of the oxygen and the concentration of the anesthetic agent in the oropharynx were measured for 5 breaths., Results: The cohort for the study included 200 patients ranging in age from 1 to 18 years. With the use of a cuffed ETT and either SV or PPV, the oxygen concentration in the oropharynx was 20-21% and the volatile agent concentration was 0% in all 118 patients. With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The mean oxygen concentration was 71% during PPV with an uncuffed ETT and 65% during SV with an uncuffed ETT. In these patients, the oropharyngeal oxygenation concentration exceeded 30% in 73 of the 82 patients (89%). The oropharyngeal oxygen and agent concentration was greater when the leak around the uncuffed ETT was ≥10cmH(2)O versus less than 10cmH(2)O and when the leak around the uncuffed ETT was ≥15cmH(2)O versus less than 15cmH(2)O., Conclusions: With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The oropharyngeal concentration of oxygen is high enough to support combustion in the majority of patients. The use of a cuffed ETT eliminates oropharyngeal contamination with oxygen during the administration of anesthesia and may be useful in limiting the incidence of an airway fire., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Narrow band imaging (NBI) with magnifying endoscopy (NBI-ME) allows the detection of abnormal micro-lesions smaller than 5 mm in diameter in the oro-hypopharynx that could not be visualized previously. The purpose of the present study was to clarify the clinicopathological characteristics of abnormal micro-lesions of the oro-hypopharynx detected by NBI-ME., Methods: Of the 62 lesions detected by NBI-ME, 40 abnormal micro-lesions in 37 patients were removed by endoscopic treatment and were pathologically evaluated. We reviewed the medical records of patients with these lesions and investigated the relationship between NBI-ME findings and pathological findings., Results: Pathological examination revealed the following: high-grade intraepithelial neoplasia (HGIN) in nine (23%) lesions, low-grade intraepithelial neoplasia (LGIN) in 22 (55%), pharyngitis in seven (18%) and papilloma in two (5%). Two NBI-ME findings, high microvascular density (MVD) and a brownish area (BA), were recognized more frequently as the grade of malignancy advanced. The likelihood ratio (confidential interval) for having HGIN in the patients with both MVD and BA was 13 (3.62-127)., Conclusions: The pathological diagnosis of abnormal micro-lesions ranged from pharyngitis to HGIN. High MVD and BA may be important findings for grading the malignancy of abnormal micro-lesions., (© 2011 The Authors. Digestive Endoscopy © 2011 Japan Gastroenterological Endoscopy Society.)

Objective: To evaluate the utility of fluorescence to assess penetration of quinolone ear drops (EDs) through tympanostomy tubes (TTs), the middle ear, eustachian tube, and into the oropharynx., Design: Before-and-after trial., Setting: Academic, tertiary care hospital., Patients: Young children undergoing TT placement for otitis media and adolescents or adults undergoing repair of tympanic membrane (TM) perforations were included., Interventions: Fluorescence of ofloxacin otic solution and serial dilutions was assessed with a Wood's lamp in vitro. Passage of ototopically administered ofloxacin into the pharynx was assessed in patients at the time of TT placement or TM repair. The oropharynx was visualized for fluorescence with a UV light for up to 2 hours after otic instillation., Main Outcome Measure: Oropharyngeal fluorescence., Results: Ofloxacin otic fluorescence was visible at up to a 1:4 dilution. Fluorescence was confirmed in vivo by placing 1 drop of ofloxacin into the posterior pharynx and visualizing it transorally. Fluorescence was not identified in any of 20 patients after TT placement and in any of 6 patients prior to tympanoplasty. Two patients undergoing tympanoplasty reported tasting the EDs., Conclusion: Fluorescence is not a satisfactory method of assessing quinolone ED penetration through TTs and TM perforations, the middle ear, and into the nasopharynx.

Background: Aspiration of secretions that accumulate above the cuff of the endotracheal tube is a risk factor for ventilator-associated pneumonia. Routine suctioning of oropharyngeal secretions may reduce this risk; the recommended frequency for suctioning is unknown., Objectives: To quantify the volume of secretions suctioned from the oropharynx of critically ill patients at 2 different intervals to assist in identifying a recommended frequency for oropharyngeal suctioning., Methods: A prospective, repeated measure, single-group design was used. Twenty-eight patients who were orally intubated and treated with mechanical ventilation were enrolled; 2 were extubated during data collection, yielding a sample of 26 patients. The patients were suctioned at baseline with a deep suction catheter, and the volume and weight of secretions were recorded. The procedure was repeated at 2-hour and 4-hour intervals., Results: Most of the patients were male (mean age, 49 years). Three suctioning passes were needed to clear secretions, with a mean time of 48.1 seconds. The mean volume of secretions at the 2-hour interval was 7.5 mL. Five patients required suctioning before the 4-hour interval. For the remaining 21 patients, the volume retrieved was 6.5 mL at the 2-hour interval and 7.5 mL at the 4-hour interval (P = .27). The 5 patients who required extra suctioning had significantly more secretions at the 2-hour interval (11.6 mL vs 6.5 mL; P = .05)., Conclusions: A minimum frequency of oropharyngeal suctioning every 4 hours is recommended. However, more frequent suctioning may be needed in a subset of patients.

Background and Objectives: To evaluate whether manual hyperinflation maneuvers can cause aspiration of oropharyngeal secretions in patients under mechanical ventilation., Methods: Adult patients under mechanical ventilation in whom a dye was injected in the oropharyngeal cavity and had their tracheal secretion aspirated after 30 minutes (min) participated in this study. In the event of dye slid, the patient was eliminated. The other patients were divided in Control Group: patients in whom tracheal secretions were aspirated after 30, 60, 120, and 180 min, and Experimental Group: after 30 min, manual hyperventilation maneuvers were performed and secretions were aspirated on the established intervals., Results: Forty-three patients were enrolled in this study. In 13, dye slippage was observed after 30 min, before allocating them into two groups. In the remaining 29 patients, 226 secretion samples were collected. In only two samples the presence of dye in the secretion was observed after manual hyperinflation maneuvers in the experimental group., Conclusion: Manual hyperinflation maneuvers did not cause aspiration of oropharyngeal secretions in patients under mechanical ventilation., (Copyright © 2011 Elsevier Editora Ltda. All rights reserved.)

Background: Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels., Methods: We used a nested case--control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression, we calculated the multivariate adjusted ORs and CIs comparing those with serum 25(OH)D adequate levels of 50 to <75 nmol/L to those <25.0., Results: We identified incident cancers of the oral cavity (n = 134), pharynx (n = 48), and larynx (n = 158). Median serum vitamin D was 31 nmol/L (interquartile range: 21-48), which is below the 50 nmol/L cutoff point was considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50 to <75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53-3.43, P(trend) = 0.65) for overall head and neck cancers. Stratification by cancer subsites of the oral cavity, pharynx, and larynx (P(trend) = 0.93, 0.78, 0.26, respectively) or by season of blood draw also showed no association., Conclusions: Our study showed no association between serum 25(OH)D and risk of head and neck cancers., Impact: This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers., (©2011 AACR.)

Background: Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction., Objective: We evaluated whether Cbl-D has a role in chronic, unexplained cough., Design: Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes ≥5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl-N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were ≤8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment., Results: Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 μm (95% CI: 95, 172 μm) compared with 230.8 μm (95% CI: 224, 237 μm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients., Conclusions: This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.

Objectives/hypothesis: To compare gene expression in oropharyngeal mucosa of children with (ex+) and without (ex-) secondhand smoke exposure., Study Design: Prospective case-control., Methods: Forty-one age- and gender-matched children (2-6 years old) undergoing tonsillectomy for sleep disordered breathing at a tertiary care children's hospital were assessed for secondhand smoke exposure. Parental response to a validated questionnaire relating to secondhand smoke exposure governed inclusion. Sixteen samples were selected for microarray analysis (7 ex+, 9 ex-). Following tonsillectomy, ex vivo brushing of the mucosa isolated total RNA. Genome-wide expression profiles were generated by comparing sample RNA to a reference of all samples, assessing 27,323 cDNA clones. Microarray clones were ranked according to their ability to distinguish between the two groups using a Student t test., Results: A total of 318 cDNA clones distinguished the two groups (P < .01); 180 genes were overexpressed and 138 underexpressed in ex+ samples relative to the ex- group. Independent analysis of these two groups sorted genes into disease processes and molecular functional groups, including cancer (34 genes in the overexpressed group, 29 underexpressed, P < .05), cell cycle (14 and 10), and cell growth and proliferation (7 and 11). Two of the upregulated genes, LCN2 and IQGAP1, have been previously linked to inflammation in smokers and response/repair to cellular injury in bronchial epithelium., Conclusions: Findings in this pilot study support the hypothesis that secondhand smoke exposure seems to induce gene expression changes in the oropharyngeal mucosa of exposed children, which may have significant implications for current and future disease processes.

Although tridermic species have two junctional regions of ectoderm and endoderm between their epidermis and digestive tract, we actually know little about these particular boundaries. Cytokeratins are the major intermediate filaments of epithelial cells and show a high degree of tissue specificity. Therefore, to characterize the epithelial cells in the junctional region of ectoderm and endoderm, we immunohistochemically examined the localization of cytokeratins 5, 7/17, 14, 18, Sox17, and alpha-fetoprotein (AFP) in the oropharyngeal and anorectal regions during the mouse gastrulation process. At embryonic day (E) 9.5, cytokeratins 5, 7/17, 14, and 18 were detected in all epithelial cells of the oropharyngeal region. At E12.5, cytokeratin 5-positive cells were not observed in the middle area of the oral cavity; however, the immunoreactivity was strong in the anterior and posterior areas. The immunoreaction of cytokeratins 18 was seen only in the middle and posterior areas of the oral mucosa. Cytokeratins 7/17 and 14 were localized in all areas of the oropharyngeal region. Sox17 and AFP, which are endodermal markers, were detected in the middle and posterior areas of the oral mucosa, but not in the anterior area. Moreover, this same localization pattern of cytokeratins also existed in the anorectal region of the E12.5 embryo, suggesting that the localization of cytokeratins and endodermal markers might give an implication for the boundary between ectoderm and endoderm. These results also suggest that these cytokeratins are useful molecules for monitoring the epithelial cell differentiation in the junctional region of the germ layers.

Background: The Staccato system employs a thermal vaporization technology to generate pure drug aerosols with a particle size optimized for alveolar deposition, leading to rapid absorption of the drug into the systemic circulation. Unlike most traditional aerosol-generation techniques, the particle size of the thermally generated aerosols is significantly affected by the airflow rate going through the device. The objective of this study was to determine the effects of flow rate and other operating conditions on predicted oropharyngeal and lung deposition when using the Staccato system., Methods: In vitro oropharyngeal deposition was measured at airflow rates of 15-80 L/min through the device. Oropharyngeal deposition was also measured for different inhalation profiles, different ambient temperatures and humidities, and device orientations. Deposition was measured using the Alberta geometry model, which was derived based on information available in the literature, CT scans of patients, and observations of living subjects., Results and Conclusions: Deposition in the oropharyngeal geometry was consistently approximately 11% of the emitted dose throughout the entire range of flow rates. Such consistency in deposition was due to the fact that mass median aerodynamic diameter (MMAD) varied inversely as the square root of the flow rate, resulting in an approximately constant value for the inertial deposition parameter. Thus, an increase in flow rate, which would increase the momentum of a fixed particle size and generally lead to higher oropharyngeal deposition, was almost exactly counterbalanced by the accompanying decrease in MMAD. Results also showed that deposition in the oropharyngeal region was unaffected by other potentially relevant factors such as different airflow ramp rates, inhalation time, ambient temperature and relative humidity, and device orientations.

A 58-year-old woman with dysphagia and hoarseness underwent 18F-FDG PET/CT to detect the original lesion and disease spread. Bilateral cervical lymphadenopathy and abnormal FDG uptakes in the right tonsil and pharyngeal wall were demonstrated. CT and MRI confirmed the bilateral cervical lymphadenopathy and mucosal thickening in the pharyngeal wall. On the basis of these findings, biopsy sites were selected. Pharyngeal tuberculosis was diagnosed based on culture of the biopsy specimens. 18F-FDG PET/CT contributed to clinical management in this case by detecting tuberculous lesions and showing the extent of these lesions in one examination.

There is a need for a simple and predictive model to identify the respiratory sensitization potential of (novel) proteins. The present study examined the use of a mouse draining lymph node assay (DLNA) approach, employing several routes of exposure, as a possible starting point for assessing protein sensitization potential. Consistent with the experimental procedure for the standard local lymph node assay (LLNA), female BALB/c mice were dosed dermally (topical), intranasally (IN) or by oropharyngeal aspiration (OP) on days 1, 2 and 3, and proliferation in the relevant draining lymph nodes was measured on day 6. For each route, the auricular, superficial cervical and tracheobronchial lymph nodes (TBLN) were evaluated following treatment with Subtilisin Carlsberg (SUB; a potent sensitizer/allergen), ovalbumin (OVA; a potent food allergen), beta-lactoglobulin (BLG; a moderate food allergen), and keyhole limpet hemocyanin (KLH; a strong immunogen with no reports of respiratory sensitization). Initial studies with OVA indicated that dermal administration did not stimulate lymph node proliferation. Responses in the tracheobronchial lymph node were most dramatic (stimulation indices up to 100) and reproducible for both the IN and OP routes. In a comparative experiment, all proteins induced lymph node proliferation with a rank order potency of SUB>KLH>OVA>BLG. The influence of the endotoxin content on lymph node proliferation was determined to be minimal, and did not impact the rank order potency. Molecular characterization of the TBLN at an equipotent proliferative dose was conducted for select gene transcripts based on research examining chemical sensitizers. Expression profiles differed among the four proteins, but the relevance of these responses was not clear and they did not further discriminate their allergic potential. These data illustrate both the opportunities and challenges associated with the examination of the draining lymph node proliferative response to assess the allergenic potential of proteins., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

We report a rare case of a child with epidermolysis bullosa simplex (EBS) with plectin deficiency but without muscular dystrophy, with severe lesions of the oral cavity, oropharyngeal, hypopharyngeal, laryngeal, tracheal and bronchial mucosa. Case report and a review of the world literature are used. The literature review revealed only five similar patients with EBS without muscular dystrophy complicated by respiratory involvement. This paper highlights the potentially serious complications of the EB in the form of breathing, swallowing and speech difficulties and describes the specific problems encountered in the treatment of this patient. Epidermolysis bullosa (EB) is a group of severe hereditary diseases, primarily of the skin, but which can also involve the respiratory and gastrointestinal tract mucosa. Respiratory tract involvement is usually only found in certain types of EB. The oral cavity and oropharynx are involved more frequently than the hypopharynx, larynx and trachea. Involvement of laryngeal and tracheal mucosa is generally associated with an increased morbidity and mortality, numerous complications and therapeutic difficulties, and is more common in junctional EB and dystrophic EB than in EBS. We present a rare case of a child with EBS and plectin deficiency with pronounced lesions of respiratory tract mucosa from the oral cavity to the bronchi and even extending into the trachea. Deciding on tracheotomy requires thorough consideration and should not be taken lightly., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: This study investigated the effect of oropharyngeal geometry on inhaled aerosol characteristics via pressurised metered dose inhalers (pMDIs), both with or without spacers., Methods: Seven adult oropharyngeal models with different centreline lengths, total volumes, and degrees of constriction were employed as induction ports for a laser diffraction particle size analyser and cascade impactor. Particle size change over time, mass median aerodynamic diameter (MMAD), average median volume diameter (D(V)50), inhaled doses, and oropharyngeal depositions (percentage of the nominal dose) for aerosols via suspension and ultrafine pMDIs with or without spacers at 30 l/min airflow were determined., Results: Variations in oropharyngeal geometry caused significant variations in inhaled particle size distributions, doses, oropharyngeal drug depositions, and particle size change over time when pMDIs were used without spacers. However, inhaled aerosol characteristics had marginal variations for the ultrafine pMDI plus large volume spacer (MMAD range: 0.69-0.78 microm, D(V)50 range: 1.27-1.36 microm, inhaled dose range: 46.46-52.92%). It was found that the amounts of inhaled aerosol particles with aerodynamic size of less than 0.83 microm via pMDIs plus large volume spacer were slightly affected by the oropharyngeal geometry., Conclusion: Inhaling ultrafine aerosols via spacers may reduce the effect of oropharyngeal geometry on inhaled aerosol properties.

Mice lacking the purinergic receptors, P2X2 and P2X3 (P2X2/P2X3(Dbl-/-)), exhibit essentially no tastant-evoked activity in the chorda tympani and glossopharyngeal nerves and substantial loss of tastant-evoked behavior as measured in long-term intake experiments. To assess whether the residual chemically driven behaviors in these P2X2/P2X3(Dbl-/-) mice were attributable to postingestive detection or oropharyngeal detection of the compounds, we used brief access lickometer tests to assess the behavioral capabilities of the P2X2/P2X3(Dbl-/-) animals. The P2X2/P2X3(Dbl-/-) mice showed avoidance to high levels (10 mM quinine and 10-30 mM denatonium benzoate) of classical "bitter"-tasting stimuli in 24-h, 2-bottle preference tests but minimal avoidance of these substances in the lickometer tests, suggesting that the strong avoidance in the intake tests was largely mediated by post-oral chemosensors. Similarly, increases in consumption of 1 M sucrose by P2X2/P2X3(Dbl-/-) mice in long-term intake tests were not mirrored by increases in consumption of sucrose in lickometer tests, suggesting that sucrose detection in these mice is mediated by postingestive consequences. In contrast, in brief access tests, P2X2/P2X3(Dbl-/-) mice avoided citric acid and hydrochloric acid at the same concentrations as their wild-type counterparts, indicating that these weak acids activate oropharyngeal chemoreceptors.

Olfaction and gustation are important sensory modalities for locating food and for determining which foodstuffs to ingest. It is becoming apparent that there is a strong link between olfaction, gustation and metabolic control. Because endocrine signaling in the naso-oropharynx is likely to influence food intake, satiety and general metabolic control, it is important to examine some of the major hormones that play an integral part in energy homeostasis. Here, we provide an overview of the main endocrine factors known to be present in the naso-oropharynx and discuss their functional roles in maintaining metabolic function. Gaining a greater appreciation of how flavor perception is linked to peripheral metabolism could lead to novel therapeutic strategies for obesity and lifestyle-related diseases.

The aim of this study was to explore the mechanism(s) by which oral cephalosporins penetrate into human oropharyngeal mucosa, and thus, the availability of sufficient concentrations at the site of infection. Two oral cephalosporin prototypes, cephalexin (first generation) and cefixime (third generation), were administered to five healthy subjects at two different visits with a 1-week washout period. Plasma and saliva samples were collected and drug concentrations were measured using an appropriate HPLC method. The maximum plasma concentrations (Cmax) of cefixime and cephalexin were 2.97+/-0.24 microg ml(-1) and 77.65+/-18.91 microg ml(-1), respectively. These concentrations were associated with a maximum salivary concentration (CSmax) of 0.56 microg ml(-1) for cefixime and 3.34 microg ml(-1) for cephalexin. Such levels exceed the reported minimal inhibitory concentration (MIC) for Streptococcus pyogenes and Streptococcus pneumoniae. The average concentration of cefixime in saliva corresponded to its plasma free fraction (saliva/plasma [S/P] ratio; 0.34). However, this observation was not true for cephalexin, for which antibiotic concentrations in the saliva did not appear to correspond to its plasma free fraction (0.8-0.85), with an S/P ratio of only 0.092. Our findings indicate that an active transport mechanism exists for cefixime excretion into human oropharyngeal mucosa, whereas cephalexin is passively diffused, although to a limited extent, as measured by its salivary concentrations.

Purpose of Review: The goals of this article are: to briefly review oropharyngeal anatomy; to provide a review of the epidemiology of oropharyngeal cancer in the Western Hemisphere; to review the literature on the association of human papilloma virus with oropharyngeal cancer; to review the recent literature on evolving diagnostic techniques for oropharyngeal cancer; and to summarize accepted management strategies for oropharyngeal cancer by subsite., Recent Findings: The incidence of oropharyngeal cancer may be increasing among younger age groups in the Western Hemisphere, and this may be related to an increased association with human papillomavirus 16. The implications of this viral association with regard to outcomes and management strategies remain under investigation. Screening with toluidine blue, autofluorescence, or both may be useful adjuncts to physical examination and panendoscopy in assessing potentially invasive or dysplastic lesions of the oropharynx. These techniques remain under study. MRI and PET scan are proving to be useful techniques for assessing local extension, regional metastases, and recurrences of squamous cell carcinoma (SCC) of the oropharynx in selected cases. However, serial computed tomography scanning remains the imaging modality of choice in the United States. Early SCCs of the oropharynx (T1-2), in general, may be managed effectively with either surgery or primary irradiation, though, with either technique, clinicians must have a management plan for the neck. Advanced SCCs of the oropharynx (T3-4, nodally aggressive, or both) require multimodal approaches consisting of either surgery along with adjuvant irradiation or concurrent chemoradiation along with salvage surgery (as necessary)., Summary: Management of SCC of the oropharynx is in a period of transition because of evolving changes in our understanding of the oncogenic process; evolving diagnostic techniques; and evolving combinations of therapies, both surgical and nonsurgical. For the time being, we propose using local subsite and disease stage to guide therapeutic decision-making.