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Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a chronic disease, which predominantly affects the lung. Since sinonasal sarcoidosis is rare, little is known about the sarcoidosis manifestation at this site. Therefore, the aim of our study was to detect the prevalence of sinonasal sarcoidosis, its clinical occurrence, diagnosis, and therapy. Methods: The database of all patients having visited the otorhinolaryngology departments of the universities in Göttingen and in Bonn between 2003 and 2016 was searched for the diagnosis of sinonasal sarcoidosis. Results: Thirteen patients with a biopsy-proven sinonasal sarcoidosis were identified. Most patients presented non-specific clinical symptoms, which are also found in acute and chronic sinusitis. None of the patients was suspected to have sinonasal sarcoidosis by the ENT doctor before histological validation. The mean diagnostic delay was 262 (± 195) days. An additional pulmonary involvement was detected in four of six patients. Conclusions: Sinonasal sarcoidosis is presenting with heterogeneous clinical presentations. An early biopsy of granulomatous lesions is mandatory. A multidisciplinary approach is needed to exclude serious lung or heart manifestations, because even asymptomatic organ involvement is possible. A CT-scan may be useful even if unspecific. Local or systemic therapy has to be prepared individually using local and systemic corticosteroids, antimetabolites, or anti-TNF-alpha. [ABSTRACT FROM AUTHOR]

Amyloidosis in the upper aerodigestive tract is a very rare disease with mainly case reports documented so far. In the pathogenesis, amyloid protein fibers are deposited in organs and tissue. In the upper aerodigestive tract, mostly localized amyloidosis occurs with unspecific symptoms, e.g., dysphagia. We conducted a retrospective multicenter study with two study centers in Germany (tertiary referral hospitals), the University Hospital of Bonn and the University Hospital of Goettingen. For a period of the last 7 years, data were analyzed and patients were recruited consecutively. 14 cases were included to the study. The most common manifestation was in the larynx (n = 11); in one case each localized amyloidosis was found in the tongue, trachea and in the pharynx. Since the majority of our cases (n = 13; 92.6%) presented with unspecific symptoms, biopsy results confirmed the diagnosis of localized amyloidosis. Resection of the lesion was only performed in patients reporting of symptoms, in asymptomatic patients only a non-invasive biopsy was done. In two patients (14.2%), in addition to the focal lesion a systemic amyloidosis was found. Amyloidosis in the upper aerodigestive tract is a rare disease. Nonetheless, every otorhinolaryngologist should be aware of this disease. When detected it is a straight forward to treat illness. The appearance of a systemic amyloidosis needs to be ruled out; thus, there is a chance to develop a multiple myeloma. Given the slow progressive character of amyloidosis, a long-term follow-up up to 10 years is inevitable. [ABSTRACT FROM AUTHOR]

Background: Septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) methylation in circulating cell-free DNA (ccfDNA) are powerful biomarkers for colorectal cancer (CRC) screening, as well as head and neck squamous cell carcinoma staging and monitoring. In the present study, we investigated SEPT9 and SHOX2 ccfDNA methylation as auxiliary pre and post-therapeutic staging parameters in CRC patients.Methods: ccfDNA methylation was quantified in 184 prospectively enrolled patients prior to and 3-10 days after surgery, and biomarker levels were associated with clinico-pathological parameters.Results: Pre-therapeutic levels of SHOX2 and SEPT9 ccfDNA methylation were strongly associated with Union for International Cancer Control (UICC) stages, tumour (T), nodal (N), and metastasis (M) categories, and histological grade (all P ≤ 0.001), as well as lymphatic invasion and extracapsular lymph node extension (all P< 0.05). Post-therapeutic SHOX2 and SEPT9 ccfDNA methylation levels correlated with UICC stage (all P  <0.01). SEPT9 ccfDNA methylation further allowed for an accurate pre- and post-therapeutic detection of distant metastases (AUCpre-therapeutic = 0.79 (95%CI 0.69-0.89), AUCpost-therapeutic = 0.93 (95% CI 0.79-1.0)).Conclusions: DNA methylation analysis in plasma is a powerful pre and post-therapeutic diagnostic tool for CRC and may add valuable information to current TNM staging, thereby holding the potential to assist in the development of individually tailored treatment protocols. [ABSTRACT FROM AUTHOR]

Background: Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3).Aims: The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC.Methods: FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment.Results: Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398.Conclusions: Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity. [ABSTRACT FROM AUTHOR]

Clinical outcome of patients suffering from head neck squamous cell carcinomas is still poor due to recurrent disease and surgical limitations. There is still a demand for multimodality approaches and new therapeutic options. Hypericin is a promising phototoxic drug which was investigated for its effects on head neck squamous cell carcinoma cells in vitro. FaDu cells incubated with or without hypericin were illuminated (450-700 nm, 50,000 lx) for different time periods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide- and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to score metabolic and apoptotic activity. Even after the shortest illumination FaDu cells incubated with hypericin showed massive reduction of metabolism and excessive apoptosis. This was present even with the lowest hypericin concentration. Cells without hypericin or without illumination were not affected. These photosensitizing effects of hypericin could be suitable for clinical application and could lead to the development of an intraoperative photodynamic therapy of head neck squamous cell carcinomas. [ABSTRACT FROM AUTHOR]

Recently, the fibroblast growth factor receptor 1 (FGFR1) has been identified as the first actionable target in squamous cell lung cancer. Clinical trials testing specific FGFR inhibitors are in progress, and patients are selected based on their FGFR1 gene copy number status. Fluorescent in situ hybridization is the most commonly used method for detecting FGFR1 amplifications, but it has its limitations. In this paper, we describe a new non-fading and easy to assess assay for detecting FGFR1 amplification using a combination of chromogenic and silver in situ hybridization. We assessed 394 patients diagnosed with head and neck squamous cell carcinoma with the new assay and compared the results with those obtained by FGFR1 fluorescent in situ hybridization. We could assess copy number by the fluorescent in situ hybridization in 86.8 % (342/394) of cases, whereas with chromogenic and silver in situ hybridization, this was 79.4 % (313/394). By fluorescent in situ hybridization, a FGFR1 amplification was detected in 12.6 % (43/342) of cases, a low-level amplification (LLA) in 7.6 % (26/342) and a high-level amplification (HLA) in 5.0 % (17/342). By chromogenic and silver in situ hybridization, a FGFR1 amplification was found in 10.2 % (32/313) (5.7 % LLA, 4.5 % HLA). The two techniques showed highly concordant results (Pearson's correlation coefficient = 0.971, p < 0.01). [ABSTRACT FROM AUTHOR]

Management of life-threatening postsurgical bleeding is complex. If conservative or surgical therapy is demanding, an endovascular treatment can be considered. The goal of this study was to evaluate the outcome of endovascular approaches in the diagnosis and therapy of otherwise intractable postoperative haemorrhages with a study design of outcomes research. Charts of all patients with postsurgical bleedings receiving endovascular treatment were reviewed for clinical outcome, complications, and demographic data. 15 patients were identified. They had rhinosurgery (12/15), tonsillectomy (2/15) or transoral tumour debulking (1/15) prior to the endovascular procedure. In more than 70%, the source of bleeding was directly located angiographically and subsequently superselectively embolized. The remaining patients suffered from post-rhinosurgical epistaxis and underwent a bilateral embolization of the sphenopalatine artery. All bleedings were successfully controlled and no procedure-related complication was noted. In conclusion, endovascular treatment of life-threatening postsurgical haemorrhages should be considered if the source of bleeding is unknown or if surgery is difficult and may result in devastating postoperative complications. [ABSTRACT FROM AUTHOR]

The objective of this study was to describe and evaluate soft tissue and bone properties of nasal cavity and paranasal sinuses in ex vivo preparations for a safe robot-assisted endoscope movement during functional endoscopic sinus surgery (FESS). In a first experiment we measured forces exerted by the endoscope during FESS with a force/torque sensor. In a second experiment we used a purpose built device to exert forces on chosen tissue structures. The experiment was monitored by a custom software, which records force of the endoscope and the deformation and the breaking point of tissue. All tests were performed on five formalin fixed cadaver heads. In the first experiment we found that the average force during FESS is 2.21 N and the maximal force is 7.96 N. The force–way-ratio measurement shows highest elasticity for the ethmoidal bulla, followed by the lamina papyracea; however, they break at low forces (≥6 N). Furthermore the carotid canal seems to have the lowest elasticity but it can tolerate forces up to 30 N. Based on these measurements force thresholds can be defined for robot-assisted endoscope guidance. All thresholds have to be assigned to subregions of the nasal cavity and paranasal sinuses. [ABSTRACT FROM AUTHOR]

Manual segmentation is often used for evaluation of automatic or semi-automatic segmentation. The purpose of this paper is to describe the inter and intraindividual variability, the dubiety of manual segmentation as a gold standard and to find reasons for the discrepancy. We realized two experiments. In the first one ten ENT surgeons, ten medical students and one engineer outlined the right maxillary sinus and ethmoid sinuses manually on a standard CT dataset of a human head. In the second experiment two participants outlined maxillary sinus and ethmoid sinuses five times consecutively. Manual segmentation was accomplished with custom software using a line segmentation tool. The first experiment shows the interindividual variability of manual segmentation which is higher for ethmoidal sinuses than for maxillary sinuses. The variability can be caused by the level of experience, different interpretation of the CT data or different levels of accuracy. The second experiment shows intraindividual variability which is lower than interindividual variability. Most variances in both experiments appear during segmentation of ethmoidal sinuses and outlining hiatus semilunaris. Concerning the inter and intraindividual variances the segmentation result of one manual segmenter could not directly be used as gold standard for the evaluation of automatic segmentation algorithms. [ABSTRACT FROM AUTHOR]

Sudden sensorineural hearing loss is a symptom of cochlear injury. Potential aetiologies are vascular diseases, viral infections, allergic reactions, autoimmune disorders, and traumatic rupture of the intralabyrinthe membrane. Unlike in unilateral cases bilateral sensorineural hearing loss is often associated with specific disease entities. We report a case of sudden bilateral deafness after intravenous heroin abuse. The putative pathophysiological mechanisms are discussed. [ABSTRACT FROM AUTHOR]

The tumor-suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. In contrast to p53, p63 and p73 play an essential role in epithelial development, stem cell identity and cellular differentiation. Salivary gland tumors carry a wide spectrum of histopathological forms, which may share a common single-cell origin from the epithelial progenitor basal duct cells and have a different tendency of malignant progression. This study was performed to examine the expression of p53, p63, and p73 in benign salivary gland tumors. Expression and mutation of p53, p73, and p63 were examined by direct DNA sequencing, reverse transcription PCR using isoform-specific primers, and by immunohistochemistry in normal parotid tissue ( n=10), and various tumors of the salivary gland (42 pleomorphic adenomas, 12 myoepitheliomas, 8 basal cell adenomas, 5 oncocytomas, 5 canalicular adenomas, and 20 adenolymphomas). In normal parotid tissue the expression of p63 and p73 was restricted to few basal and myoepithelial cells. Ductal luminal and acinus cells were completely negative for the expression of all three family members. In contrast, in salivary gland tumors, strong nuclear staining for p63 and p73 was observed. Myoepithelial and basaloid cells and the basal epithelial layer of adenolyphomas and oncocytomas were positive for p63 and also, to a lesser extent, to p73. Mutations of p53 were detected in 4 of 42 (10%) pleomorphic adenomas, in 3 of 12 (25%) myoepitheliomas, and in 1 of 8 (13%) basal cell adenomas but not in other tumors. We failed to detect specific mutations of p63 and p73. Using isoform-specific PCR, we found that all isoforms of p63 were expressed in normal parotid tissue whereas the pleomorphic adenomas, myoepitehliomas, and basal cell adenomas dominantly expressed the transactivation-incompetent truncated isoforms. Our data indicate that p63 and p73 are upregulated in salivary gland tumors and may serve as a marker of epithelial and myoepithelial progenitor cells in salivary glands. The prevalence of p53 mutations and the observation of the expression of ΔNp63 isoforms only in pleomorphic adenomas, myoepitheliomas, and also basal cell adenomas may reflect their possible malignant potential. [ABSTRACT FROM AUTHOR]

Abstract Background. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, that play active roles in the p53 and Rb tumor suppressive pathways, respectively. We analyzed the alterations of p14ARF, p16INK4a and p53 to study the contribution of each pathway in tumorigenesis of 29 patients with primary and consecutive (second primary) squamous cell carcinoma of the head and neck (HNSCC), with a total of 68 carcinomas. Methods. After microdissection, the DNA of 29 primary and 39 consecutive squamous cell carcinomas was analyzed for INK4a-ARF inactivation and p53 mutation by means of DNA sequence analysis, methylation-specific polymerase chain reaction (MSP), restriction-enzyme-related polymerase chain reaction (RE-PCR), multiplex RT-PCR and immunohistochemistry. In addition, microdeletions of p14ARF and p16INK4a were assessed using differential PCR. Results. Altogether inactivation (methylation, loss of heterozygosity and mutation of exon 1β) of p14ARF was found in 29 of all 68 (43%) carcinomas, with a significant difference in primary [8 of 29 (28%)] relative to second primary carcinomas [21 of 39 (54%)]. Methylation of p16INK4a occurred in 22 of 68 (32%) carcinomas with an even distribution among primary and consecutive tumors. Only two (secondary) carcinomas showed simultaneous promoter methylation of p14ARF and p16 INK4a. Mutations of p53 were found in 32 of 68 HNSCCs (44%), evenly distributed among primary and recurrent carcinomas. p14ARF alterations showed no relationship to p53 mutations. Conclusions. Our data indicate that the INK4a-ARF-/p53 pathway was disrupted in 58 of 68 (84%) primary and recurrent tumors, either by p53 mutations or by INK4a-ARF inactivation. p14ARF methylation occurred independently of p16INK4a alterations and showed no correlation to p53 mutations. The significantly higher rate of p14ARF alterations in recurrent (respective second primary) carcinomas suggests a further acquired genetic aberration during the development of the recurrent carcinomas. [ABSTRACT FROM AUTHOR]

From April 1998 to May 2000, 14 patients with supraglottic cancer underwent transoral laser surgery (T-stage T1–2: 11 patients, T3: 3 patients). In three patients, an epiglottectomy or hemi-epiglottectomy was performed. In 11 patients, further structures (false cords, the valleculae and the base of the tongue and/or parts of the arytenoid cartilage) had to be resected. Thirteen patients had to undergo neck dissection and post-operative irradiation. Tracheostomy was carried out prophylactically in two cases. Every patient received a nasogastric tube peri-operatively. One week after surgery, an evaluation of dysphagia was performed by video endoscopy (VEED). Aspiration was the main problem; in no case did dysphagia occur. The aspiration was graded according to videolaryngoscopical classification. Four patients had an occasional and ten patients a permanent aspiration after surgery. According to this assessment, an individual deglutition therapy management was established. Ten patients with permanent aspiration received a temporary percutaneous endoscopic gastrostomy (PEG) and were integrated in a rehabilitation programme (stimulation of the swallowing reflex, training of compensatory swallowing manoeuvres, dietary regime). Due to this training programme, the PEG could be removed in eight patients after 2–9 months. No patient needed a laryngectomy or a tracheostomy due to aspiration. There were no cases of aspiration-associated pneumonia. To obtain satisfying functional results after transoral laser surgery of supraglottic cancers with resection of the epiglottis, post-operative deglutition management, consisting of video endoscopy, a training programme and often a PEG, is necessary. [ABSTRACT FROM AUTHOR]