Moritz F. Meyer

Prevalence and risk factors for oral human papillomavirus infection in 129 women screened for cervical HPV infection

BACKGROUND Oncogenic human papillomaviruses (HPV) are known to be associated with carcinomas of the uterine cervix. Furthermore, current studies have shown that HPV-infection is also associated with a subtype of oropharyngeal cancers. In general, a sexual transmission of the viruses has been shown by numerous studies in the genital lesions. However, there are unknown factors regarding the prevalence and transmission of HPV in the oropharynx. The aim of this study was to evaluate HPV prevalence in the oropharynx in female participants with and without genital HPV infection. In addition, we analyzed risk factors for an oropharyngeal colonization with HPV in their sexual partners, too. METHODS 129 Female participants were tested for presence of HPV-DNA by oral lavage, brush cytology of the tonsils and of the cervix. In addition, 15 male partners of these patients were included in the study. HPV-DNA was detected by PCR (polymerase chain reaction) amplification. For HPV-genotyping, PCR products were hybridized with type-specific digoxigenin-labeled oligonucleotide probes and discriminated into 14 high risk (HR) and 6 low risk (LR)-HPV types. The 129 female and 15 male participants were interviewed by a standardized questionnaire for socioeconomic details, drinking, smoking and sexual behaviours. RESULTS 59 (45.7%) Female participants were negative for a genital HPV-infection. Of these women, 3 (5.1%) showed a positive HPV-PCR result (HR and LR) in the oropharynx. 70 (54.3%) Female participants were positive for a genital HPV infection. In this group, 4 (5.7%) had a positive HPV-detection (HR and LR) in the oral cavity and oropharynx. Female participants with cervical HPV-infection had no higher risk for HPV-detection in the oropharynx (not significant). The analysis of sexual risk factors revealed no specific risk factor for an oral HPV-infection. CONCLUSION A correlation between cervical and oral colonization by HPV could not be demonstrated in our small cohort. Our limited data suggest that sexual transmission of HPV from the cervix uteri to the oropharynx is a rare and unlikely event.

Treatment of chronic recurrent juvenile parotitis using sialendoscopy

Abstract Conclusion: The combination of sialendoscopy and an intraductal application of corticosteroids can be recommended for children with chronic recurrent juvenile parotitis (CRJP) as there is growing evidence for a positive effect in the absence of side effects. Objective: CRJP is a disorder with painful, episodic swelling of the parotid gland in children. The majority of cases have a self-limiting character within 5–10 years, but the disease may also continue into adulthood. CRJP can occur on one or both sides and up to now the etiology has been unclear. The aim of this study was to analyze the therapeutic effect of a sialendoscopic application of corticosteroids on the clinical course of patients with CRJP. Methods: We retrospectively analyzed the clinical course of 9 children with 10 parotid glands affected by CRJP, who all underwent sialendoscopy and intraductal application of corticosteroids. In all cases the procedure was conducted under general anesthesia. The average follow-up period was 15 months. Results: There were no side effects associated with the sialendoscopy. All duct systems showed signs of chronic inflammation with an atrophic or thickened epithelium. At the follow-up visit, CRJP symptoms had completely resolved in eight children. One child still showed slight parotid swellings without the need for antibiotics. None of the parents reported that symptoms had continued at an equal level or worsened after sialendoscopy.

Comparison of TNM-based stage grouping versus UICC/AJCC stage grouping (7th edition) in malignant parotid gland tumors

BACKGROUND Although the UICC/AJCCs TNM staging of the 7th edition was improved in 2002, there are still shortcomings concerning the prognostic quality. Alternative TNM-based stage-groupings such as the T and N Integer Score (TANIS) where shown to have a better prognostic quality for various kinds of head and neck tumors in the past. The aim of the study was to compare the prognostic value of the 7th edition of the UICC/AJCC TNM-classification for carcinoma of the parotid gland with different TNM-based stage groupings. METHODS The retrospective analysis included 180 patients with carcinoma of the parotid gland diagnosed between 1986 and 2007. The stage grouping system of the 7th edition of the UICC/AJCC and TNM-based stage-groupings (TANIS-3, TANIS-8, Snyderman, Berg and Hart) were tested for their prognostic significance. Overall survival (OS) was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. RESULTS In univariate analysis all stage-groupings had a highly significant impact on overall survival (p<0.05), however in multivariate analysis, only the TANIS-8 scheme (p=0.008) and Snyderman scheme (p=0.047) predicted OS, while the UICC/AJCC-classification did not predict OS significantly (p=0.381). CONCLUSION In comparison to other TNM-based stage groupings the UICC/AJCC-classification did not provide significant prediction of OS, while alternative stage-groupings such as the TANIS-8 had a higher prognostic value.

Characterizing the active opening of the eustachian tube in a hypobaric/hyperbaric pressure chamber.

Objective Active and passive opening of the Eustachian tube (ET) enables direct aeration of the middle ear and a pressure balance between middle ear and the ambient pressure. The aim of this study was to characterize standard values for the opening pressure (ETOP), the opening frequency (ETOF), and the opening duration (ETOD) for active tubal openings (Valsalva maneuver, swallowing) in healthy participants. Design/Participants In a hypobaric/hyperbaric pressure chamber, 30 healthy participants (19 women, 11 men; mean age, 25.57 ± 3.33 years) were exposed to a standardized profile of compression and decompression. The pressure values were recorded via continuous impedance measurement during the Valsalva maneuver and swallowing. Based on the data, standard curves were identified and the ETOP, ETOD, and ETOF were determined. Results Recurring patterns of the pressure curve during active tube opening for the Valsalva maneuver and for active swallowing were characterized. The mean value for the Valsalva maneuver for ETOP was 41.21 ± 17.38 mbar; for the ETOD, it was 2.65 ± 1.87 seconds. In the active pressure compensation by swallowing, the mean value for the ETOP was 29.91 ± 13.07 mbar; and for the ETOD, it was 0.82 ± 0.53 seconds. Conclusion Standard values for the opening pressure of the tube and the tube opening duration for active tubal openings (Valsalva maneuver, swallowing) were described, and typical curve gradients for healthy subjects could be shown. This is another step toward analyzing the function of the tube in compression and decompression.

Impact of xylomethazoline on eustachian tube function in healthy participants.

Introduction The use of decongestants is common in otitis media eustachian tube (ET) dysfunction. However, the underlying mechanism and the type of action on the complex middle ear pressure equalization system are poorly understood. Here, by use of the pressure chamber, we investigated the impact of intranasal decongestive therapy (xylomethazoline) on ET function. Materials and Methods Thirty healthy participants (60 ears) were exposed to a predetermined profile of phases of compression and decompression in a hypobaric and hyperbaric pressure chamber. ET opening pressure, ET opening duration, ET opening frequency, and ET closing pressure were determined before and after intranasal application of xylomethazoline. Results A significantly higher number of ET openings (ET opening frequency) in passive equalization condition could be measured after application of decongestants than before. No significant difference could be found in the values of ET opening pressure, ET opening duration, and ET closing pressure parameters before in comparison with the values after application of xylomethazoline. Conclusion We conclude that xylomethazoline might only have a minor effect during active and passive middle ear pressure equalization. Larger cohorts and targeted application of decongestants should be tested to confirm these preliminary data and to find new evidence on the effects of decongestants.

MDM2 and CDK4 amplifications are rare events in salivary duct carcinomas

Salivary duct carcinoma (SDC) is an aggressive adenocarcinoma of the salivary glands associated with poor clinical outcome. SDCs are known to carry TP53 mutations in about 50%, however, only little is known about alternative pathogenic mechanisms within the p53 regulatory network. Particularly, data on alterations of the oncogenes MDM2 and CDK4 located in the chromosomal region 12q13-15 are limited in SDC, while genomic rearrangements of the adjacent HMGA2 gene locus are well documented in subsets of SDCs. We here analyzed the mutational status of the TP53 gene, genomic amplification of MDM2, CDK4 and HMGA2 rearrangement/amplification as well as protein expression of TP53 (p53), MDM2 and CDK4 in 51 de novo and ex pleomorphic adenoma SDCs. 25 of 51 cases were found to carry TP53 mutations, associated with extreme positive immunohistochemical p53 staining levels in 13 cases. Three out of 51 tumors had an MDM2 amplification, one of them coinciding with a CDK4 amplification and two with a HMGA2 rearrangement/amplification. Two of the MDM2 amplifications occurred in the setting of a TP53 mutation. Two out of 51 cases showed a CDK4 amplification, one synchronously being MDM2 amplified and the other one displaying concurrent low copy number increases of both, MDM2 and HMGA2. In summary, we here show that subgroups of SDCs display genomic amplifications of MDM2 and/or CDK4, partly in association with TP53 mutations and rearrangement/amplification of HMGA2. Further research is necessary to clarify the role of chromosomal region 12q13-15 alterations in SDC tumorigenesis and their potential prognostic and therapeutic relevance.

Valosin-containing protein (VCP/p97)-expression correlates with prognosis of HPV- negative oropharyngeal squamous cell carcinoma (OSCC).

Valosin-containing protein (VCP)/p97 has been shown to be associated with antiapoptotic function via activation of the nuclear factor-B (NFB) signaling pathway and with metastasizing of tumors in several studies. VCP is located on chromosome 9p13-p12, a region often deleted in oropharyngeal squamous cell carcinoma (OSCC). The clinical significance of VCP expression in OSCC however remains unclear. In this study, expression of VCP was determined in 106 patients (77 male (71.3%) and 31 female (28.7%); age-range: 34–79 years (mean age 57 years)) by immunohistochemistry and in a subset of 15 patients by quantitative PCR. HPV-DNA was detected by polymerase chain reaction and p16INK4a immunohistochemistry. The experimental findings were correlated with clinico-pathological data and survival parameters. 47.2% of all OSCC specimens were analyzed as negative or weak staining intensity for VCP. 52.8% of all specimens showed a high staining intensity for VCP. 73.1% of all patients were tested HPV-negative, 26.9% were HPV-positive. The 5-year disease-free and overall survival probabilities of all patients were 71.2% and 55.7%, respectively. No correlation could be found between HPV-status and VCP expression. VCP overexpression in HPV-negative patients was associated with significantly better 5-year disease-free survival (86.4% vs., 45.6%, p = 0.017). The level of VCP-intensity determined by immunohistochemistry could be an additional prognostic marker in HPV-negative OSCC. VCP expression seems not to correlate with the HPV-status.

Low SOX2 expression marks a distinct subset of adenoid cystic carcinoma of the head and neck and is associated with an advanced tumor stage

Introduction The transcription factor SOX2 has been identified as a lineage survival oncogene in squamous cell carcinoma and copy number gain is a common event in several human malignancies including head and neck cancer. However, the regulation and function of SOX2 during carcinogenesis as well as its prognostic value appears to be highly context dependent. As an example, high SOX2 expression in lung squamous cell carcinoma (SCC) is related to a favorable prognosis, while it is associated with poor outcome in lung adenocarcinoma. More recently, higher SOX2 levels and improved survival was also reported for head and neck SCC (HNSCC), and silencing of SOX2 expression in HNSCC cell lines revealed a mesenchymal-like phenotype with prominent vimentin expression. So far, SOX2 expression and its clinical relevance for other head and neck cancers, such as adenoid cystic carcinoma (HNACC) have not been sufficiently investigated. Material and methods SOX2, vimentin and E-cadherin expression was assessed by immunohistochemical staining on serial sections from formalin fixed and paraffin embedded tissue samples of a patient cohort (n = 45) with primary ACC and correlated with patient and tumor characteristics as well as survival. Results High SOX2 expression was found in 14 (31%) primary tumor specimens and was significantly correlated with a N0 lymph node status (p = 0.04), while low SOX2 expression was correlated with a solid growth pattern (p = 0.031). Of the 45 patients, 27 tumor samples resembled an EMT-like phenotype, as assessed by high vimentin and low E-cadherin levels. However, in HNACC SOX2 levels were neither correlated with vimentin nor with E-cadherin expression, further supporting a context dependent regulation and function of SOX2 in distinct tumor entities. Conclusion The absence of SOX2 was predominantly found in solid HNACC, which are characterized by a more aggressive phenotype in ACC. However, the underlying molecular mechanisms of SOX2 regulation and function in distinct HNACC subgroups remain to be fully elucidated.

Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum

Hypobaric hypoxia (HH) during airline travel induces several (patho-) physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min) in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE) and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF). Biological functions of regulated proteins were identified using functional network analysis (GeneMania®, STRING®, and Perseus® software). In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU) was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades “regulation of haemostasis” (four proteins), “metabolism” (five proteins), and “leukocyte mediated immune response” (five proteins). Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight), analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis

Reliability of Eustachian tube function measurements in a hypobaric and hyperbaric pressure chamber

Measurement of the Eustachian tube (ET) function is a challenge. The demand for a precise and meaningful diagnostic tool increases—especially because more and more operative therapies are being offered without objective evidence. The measurement of the ET function by continuous impedance recording in a pressure chamber is an established method, although the reliability of the measurements is still unclear.