Immunotherapeutics for head and neck squamous cell carcinoma stem cells.

Cancer stem cell (CSC)-related therapy resistance has become a new obstacle to the successful application of cancer treatment and head and neck squamous cell carcinoma (HNSCC) is no exception to this finding. Head and neck squamous cell carcinoma is highly immune-suppressive, and recently the immune suppression and invasion of HNSCC-CSCs have been characterized. These characteristics have received research and clinical attention because they would enable the stratification of patients into specific cancer subtypes and, consequently, the establishment of new therapeutic approaches with improved efficacy. This review discusses the feasibility of CSC-targeted strategies and their incorporation with nanotechnology to improve the efficacy of cancer immunotherapy.

[Comparison of piezoelectric and conventional osteotomy in rhinoplasty : A systematic review]. / Vergleich von piezoelektrisch assistierter und konventioneller Osteotomie bei der Rhinoplastik : Ein systematisches Review.

BACKGROUND: Postoperative periorbital edema and ecchymosis after rhinoplasty are mainly caused by the osteotomy with hammer and chisel. The introduction of piezoelectric surgery could lead to a better early postoperative outcome due to improved preservation of soft tissues. The aim of this systematic review was to evaluate the methods and results of studies comparing conventional osteotomy to piezoelectric osteotomy. METHODS: A systematic literature search was conducted in the PubMed/MEDLINE and Google Scholar databases. In the primary selection, all studies on the comparison of conventional and piezoelectric osteotomies with regard to postoperative periorbital edema and/or ecchymosis were identified. Secondary selection included only study designs with a control group. RESULTS: Primary selection resulted in 15 thematically relevant publications with a notable increase in annual publications between 2007 and 2017. Six studies with control groups were selected secondarily. Qualitatively and methodologically, the studies were very heterogeneous. The results of five of the six studies indicated a significant advantage of piezo technology compared to conventional osteotomy. Only in one study was no significant difference found in the investigated postoperative outcome. CONCLUSION: Piezoelectric osteotomy resulted in a reduced propensity for postoperative edema and ecchymosis compared to the conventional osteotomy technique with a chisel. At this time, the results should be regarded as a trend. A definite recommendation favoring piezoelectric osteotomy cannot be made until more studies with higher patient numbers become available.

Saddle nose deformity and septal perforation in granulomatosis with polyangiitis.

BACKGROUND: Patients who have granulomatosis with polyangiitis (GPA, syn. M. Wegener) often develop an external nose deformity which may have devastating psychological effects. Therefore, reconstruction of nasal deformities by rhinoplasty may become necessary to achieve a normal appearance. OBJECTIVE OF REVIEW: The aim of this systematic review was to investigate the efficacy and safety of surgical reconstruction in external nasal deformities and septal perforation in GPA patients. SEARCH STRATEGY: A systematic literature search with defined search terms was performed for scientific articles archived in the MEDLINE-Database up to 10 June 2016 (PubMed Advanced MEDLINE Search), describing management of cases or case series in GPA patients with saddle nose deformity and/or septal perforation. RESULTS: Eleven of 614 publications met the criteria for this analysis including 41 GPA patients undergoing external nasal reconstruction and/or septal reconstruction with a median follow-up of 2.6 years. Overall, saddle nose reconstruction in GPA patients is safe even if an increased rate of revision surgery has to be expected compared with individuals without GPA undergoing septorhinoplasty. Most implanted grafts were autografts of calvarial bone or costal cartilage. For septal perforation reconstruction, few studies were available. Therefore, based on the available data for surgical outcomes, it is impossible to make evidence-based recommendations. All included GPA patients had minimal or no local disease at the time of reconstructive surgery. Therefore, the relationship between disease activity and its impact on surgical outcomes remains unanswered. The potential impact of immune-modulating medications on increased complication rates and the impact of prophylactic antibiotics are unknown. CONCLUSIONS: This study systematically reviews the efficacy and safety of surgical reconstruction of external nasal deformities in GPA patients for the first time. Saddle nose reconstruction in GPA patients with minimal or no local disease is a safe procedure despite an increased rate of revision surgery. Further research is required regarding the impact of antibiotic prophylaxis, immune-modulating therapy, long-term outcomes and functional outcomes measured with subjective and objective parameters.

Otorhinolaryngology residency in Spain: training satisfaction, working environment and conditions.

Europe-wide efforts are being initiated to define quality standards and harmonize Otolaryngology, Head and Neck Surgery (ORL-HNS)-specialty-training by creating an European board examination. However, differences within and between countries remain and are underinvestigated making comparisons and further improvement more difficult. The study aimed at assessing quality of training, satisfaction and quality of life of residents and recent ORL-HNS specialists in Spain and to trace similarities and differences to France and Germany administering anonymous online-questionnaire to ORL-HNS-residents and recent specialists. 146 questionnaires were returned with answers of 75.6 % of residents, a mean age of 30 years and a female to male ratio of 1.46:1. The global satisfaction of training was high as 76 % would choose the same ENT training again, 86 % confirmed that responsibilities which were given to them were adapted to their level of training and 97 % felt well considered in their department. Ninety-two confirmed that helpful seniors contributed to a good work environment (75 %) and to a good organization within the department (69 %). The respondents spent on average 8.8 h per day at the hospital and covered on average 4.8 night duties or week-end shifts per month with mostly no post-day off (86 %). Seventy-four percent participated regularly at complementary training sessions. Research work was supported and guided in 59 %. This study is the first one, to our best of knowledge, to assess the ORL-HNS-training in Spain and to trace parallelisms and differences to other European countries, such as France and Germany. The satisfaction of training and supervision was high in Spain, but there are still efforts to make concerning resident's quality of life. Compared to France and Germany, satisfaction with ORL-HNS-training and the support and guidance provided by seniors was similar. Work conditions were comparable to those in France. Motivation, teaching and scientific output was higher in Spain, despite the salary being the lowest.

[Cancer stem cell phenotypes and miRNA: therapeutic targets in head and neck squamous cell carcinoma]. / Tumorstammzellphänotypen und miRNA : Therapietargets bei Kopf-Hals-Plattenepithelkarzinomen.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HNSCC is caused by persistent high-risk human papillomavirus (HR-HPV) infection or excessive consumption of alcohol or tobacco. The persistently low survival rates result from local recurrences and metastases, which are probably caused by so-called tumor stem cells (TSCs). The epithelial-mesenchymal transition (EMT) or transformation is a key event in metastasis initiation and is being increasingly associated with TSCs. OBJECTIVES: This review describes new therapeutic targets in HNSCC, focusing on the TSC hypothesis and EMT regulation. MATERIALS AND METHODS, RESULTS: TSCs and EMT are regulated directly and indirectly via transcription factors and microRNAs (miRNAs). These miRNAs regulate multiple cellular processes and may serve as new therapeutic targets, whose modulation could increase the effectiveness of HNSCC treatments. Post-transcriptionally, miRNAs regulate transcription factors associated with EMT (ZEB1/2, EZH2, Bmi-1), tumor suppressors (p53), TSC markers (ALDH, CD44, EpCAM, p63) and both epithelial (E-cadherin) and mesenchymal markers (vimentin). CONCLUSION: Alterations in HNSSC TSC miRNA expression before and after chemotherapy could potentially serve as a therapeutic control. In the long term, knowledge of a patient's individual protein expression pattern may permit application of specific chemotherapy. Such individualized therapy might prohibit the development of metastases and potentially unresectable recurrences with a high resistance to radiation and chemotherapy, thus improving the prognosis in HNSCC patients.

[Role of miRNA in malignoma of the head and neck]. / Die Rolle von miRNA bei Kopf-Hals-Malignomen.

Despite optimized therapeutic strategies, the long-term survival of head and neck squamous cell carcinomas (HNSCC) has improved in recent years only slightly. Most studies on the tumor cell genome focus on protein-coding genes (exons). Data on changes within the non-coding sequences (introns) are limited. miRNAs (microRNA, miR) are small non-coding single-stranded RNAs that control gene expression at the posttranscriptional level by interacting with the mRNA. miRNA functions include many biological processes and control up to 50 % of human genes. They can have oncogenic or tumor suppressive functions. Altered expression patterns of miRNAs are involved in carcinogenesis and tumor progression even in HNSCC, or those processes (increased resistance to radiation or chemotherapy) that could be responsible for the poor long-term prognosis by forming metastases and inoperable local recurrences. Therefore, we here present miRNA groups, which are involved in these processes and may serve as new potential therapeutic treatment targets. miRNAs may also serve as biomarkers for early diagnosis, evaluation and monitoring of treatment and tumor recurrence. Alterations in miRNA expression before and after chemotherapy are therefore of high interest. In the long run, this knowledge could lead to more effective therapies with improved therapeutic outcome of HNSCC.

[Jugular vein thrombosis caused by hypercoagulability following in-vitro fertilization-activated protein C resistance and immobilization]. / V.-jugularis-thrombose bei hyperkoagulabilität nach in-vitro-fertilisation.

Jugular vein thrombosis (JVT) is extremely difficult to diagnose clinically because of its rarity, the wide range of possible symptoms and the variety of differential diagnoses. A rapid diagnosis is important in order to avoid or prevent imminent life-threatening complications. This study reports a clinical case of extensive JVT due to increased thrombophilia in conjunction with ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization, increased APC resistance and immobilization. It also discusses the current literature that forms the basis for recommendations regarding the diagnosis, therapy and interdisciplinary management.

[Biology and relevance of stem cells in squamous head and neck cancer: latest insights and review of literature]. / Biologie und Bedeutung von Tumorstammzellen in der HNO: Neueste Erkenntnisse und Zusammenfassung der aktuellen Literatur.

The initiation, growth, recurrence and metastasis of head and neck squamous cell carcinomas (HNSCC) and other cancers have recently been related to the presence of cancer stem cells (CSC). Cancer stem cells have some characteristics in common with tissue stem cells like unlimited self renewal and the expression of stem cell factors. CSC express specific markers that vary considerably depending on tumor type or tissue of origin--the discovery of an universal marker has not yet been made. Compared to the bulk tumor mass, CSC are less sensitive to chemo- and radiotherapy and also have a lower immunogenicity. Another concept that explains the seeding of metastases is the epithelial-mesenchymal transition of CSC. CSC-targeted therapies may change the prognosis of patients with HNSCC in the future. Recent knowledge on the role of CSC in HNSCC is reviewed, and known CSC markers as well as possible therapeutic targets are described.

Role of caveolin-1 in the pathogenesis of tissue fibrosis by keloid-derived fibroblasts in vitro.

BACKGROUND: Recent studies have suggested that caveolin-1 (cav-1) plays an important role in the regulation of transforming growth factor (TGF)-ß1 signalling and participates in the pathogenesis of tissue fibrosis. However, its effects on dermal fibrosis keloids are unknown. OBJECTIVES: To investigate the effect of cav-1 in the pathogenesis of tissue fibrosis by keloid fibroblasts. METHODS: Keloid fibroblasts were cultured and exposed to different concentrations of cav-1 cell-permeable peptides (cav-1p) in the presence of TGF-ß1. Keloid fibroblast phenotypes and protein production were analysed by real-time reverse transcriptase-polymerase chain reaction, Western blot, and multiplex enzyme-linked immunosorbent assay techniques. The effect of cav-1p on cell viability was evaluated by MTT assay. RESULTS: Cav-1 was markedly decreased in the keloid-derived fibroblasts. Moreover, cav-1p significantly reduced TGF-ß receptor type I levels and Smad2/3 phosphorylation in response to added TGF-ß1. Additionally, TGF-ß1 decreased cav-1 expression in human skin fibroblasts. Cav-1 was able to suppress TGF-ß1-induced extracellular matrix production in cultured keloid fibroblasts through regulation of the mitogen-activated protein kinase pathway. CONCLUSIONS: Cav-1 appears to participate in the pathogenesis of tissue fibrosis in keloid. Restoration of cav-1 function by treatment with a cell-permeable peptide corresponding to the cav-1 scaffolding domain may be a novel therapeutic approach in keloid.

[Laser stapedotomy]. / Laserstapedotomie.

In addition to hearing aids, stapesplasty represents the standard treatment of otosclerosis-induced hearing loss. In this procedure, the stapes superstructure is replaced by a prosthesis that is attached to the long process of the incus and communicates through a perforation in the footplate with the perilymphatic space of the inner ear. The removal of the stapes superstructure and perforation of the footplate are the critical steps of this surgical procedure. With the introduction of laser-assisted perforation techniques, the surgical safety of this method has been improved compared to conventional techniques. KTP, argon, as well as diode, Er:YAG and CO(2) lasers are used for stapedotomy. By using the CO(2) laser in conjunction with a scanner system, the number of laser applications required for the perforation of the footplate has been markedly reduced. In contrast to other systems, a more reproducible perforation diameter of the stapes footplate is achieved with a CO(2) laser equipped with a scanner. Complications such as uncontrolled leakage of perilymph, irradiation of inner ear structures or the occurrence of pressure waves with subsequent damage to the inner ear can be reduced by using a CO(2) laser. In this review, the surgical technique of CO(2) laser stapedotomy, including clinically established variants and paying particular attention to the one-shot technique, are described and discussed in comparison to other laser systems.

T cell-tumor interaction directs the development of immunotherapies in head and neck cancer.

The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy.

In vitro chemosensitivity of head and neck cancer cell lines.

BACKGROUND: Systemic treatment of head and neck squamous cell carcinoma (HNSCC) includes a variety of antineoplastic drugs. However, drug-resistance interferes with the effectiveness of chemotherapy. Preclinical testing models are needed in order to develop approaches to overcome chemoresistance. - METHODS: Ten human cell lines were obtained from HNSCC, including one with experimentally-induced cisplatin resistance. Inhibition of cell growth by seven chemotherapeutic agents (cisplatin, carboplatin, 5- fluorouracil, methotrexate, bleomycin, vincristin, and paclitaxel) was measured using metabolic MTT-uptake assay and correlated to clinically-achievable plasma concentrations. - RESULTS: All drugs inhibited cell growth in a concentration-dependent manner with an IC50 comparable to that achievable in vivo. However, response curves for methotrexate were unsatisfactory and for paclitaxel, the solubilizer cremophor EL was toxic. Cross-resistance was observed between cisplatin and carboplatin. - CONCLUSION: Chemosensitivity of HNSCC cell lines can be determined using the MTT-uptake assay. For DNA-interfering cytostatics and vinca alkaloids this is a simple and reproducible procedure. Determined in vitro chemosensitivity serves as a baseline for further experimental approaches aiming to modulate chemoresistance in HNSCC with potential clinical significance.

[Jugular vein thrombosis caused by a neuroendocrine non-small cell lung cancer]. / V.-jugularis-Thrombose aufgrund eines neuroendokrinen nichtkleinzelligen Lungenkarzinoms.

A 65-year-old patient presented with extensive swelling of the lateral neck. B-mode ultrasound showed an oval, well defined, hypoechoic formation consisting of multiple circular layers extending from the base of the skull to the subclavian vein. On subsequent computed tomography the size of the lesion was confirmed and the cause, a mediastinal mass compressing the superior caval vein, was identified. Histological examination of the mass revealed a neuroendocrine active non-small-cell-cancer of the lung. Treatment with high-dose heparin and antibiotics was started immediately, combined with palliative chemotherapy.The differential diagnosis of neck masses includes congenital, infectious, neoplastic and secondary causes due to disease in other regions of the body. Etiologies for jugular vein thrombosis include prolonged central venous catheterization, trauma, obstruction, infection as well as hypercoagulation. In order to diagnose masses in the head and neck region, other parts of the body need to be successively included if no local cause can be identified.

[Simultaneous squamous cell carcinoma and follicular lymphoma of the tonsil]. / Simultanes Plattenepithelkarzinom und follikuläres Lymphom der Tonsille.

Squamous cell carcinoma of the head and neck is the most common neoplasia in the head and neck area followed by malignant lymphoma. Here we describe for the first time the synchronous manifestation of a squamous cell carcinoma and a follicular lymphoma of the palatine tonsil. Histomorphologic and etiopathogenetic characteristics are described and discussed on the basis of the current literature. The coincidence of a lymphoma and a squamous cell carcinoma in the head and neck area is an oncologic rarity as well as an interdisciplinary diagnostic and therapeutic challenge.

[Prophylactic and therapeutic vaccines against human papilloma virus]. / Prophylaktische und therapeutische Vakzinen gegen humane Papillomviren.

Infection with human papilloma virus (HPV) has been identified as the cause of recurrent papillomatosis and of a subgroup of squamous cell carcinomas of the head and neck. A change in prevalence of these lesions, especially for oropharyngeal carcinoma, can be expected as a consequence of the introduction of prophylactic HPV vaccines for young women, targeting the most frequent high- and low-risk HPV subtypes. Vaccination for the major low-risk HPV types has proven to be highly effective against genital warts and activity against papillomatosis can be expected. The possibilities of prophylactic HPV vaccination as well as new developments and the rationale for therapeutic vaccines are discussed on the basis of the current literature.

ORL residency in France: Satisfaction and training quality in 2013.

OBJECTIVES: To assess the quality of ORL training in France and hierarchical relationships, working conditions and quality of life, based on a questionnaire answered by ORL residents and fellows. MATERIAL AND METHODS: The anonymous questionnaire covered the following topics (106 questions): structure of training, supervision by superiors, involvement in teaching medical students, work for publication, working conditions, quality of life and practical and surgical skills. RESULTS: One hundred and seventeen questionnaires were included, with 56% female respondents and 78% resident respondents. A total of 80% of respondents would choose the same training again, with overall satisfaction of 70%. In total, 71% felt appreciated, with responsibilities matching their level of training (85%). Supervisors were supportive (85%) and showed good teaching ability (92%). Residents were mainly guided by fellows (70%), or consultants (60%). Providing good training was an important aim for the training structures (78%). Respondents worked 11 hours per day, with a median of 4 duties per month; the post-duty rest-day was fully respected in the case of 38% of respondents. Surgical procedures were taught and delegated step by step, shared fairly between residents, in a large majority of cases. Training progression was in line with seniority. CONCLUSIONS: Overall satisfaction, quality and supervision of ORL training were good in France. There remain geographical differences in terms of theoretical and surgical training.

Developments in therapeutic human papillomavirus vaccination.

Much progress has been made in the prevention and therapy of premalignant and malignant dysplasia caused by human papillomavirus by encouraging screening programs and recently by introducing preventive vaccines. To further reduce the worldwide burden of HPV-associated cancer supplementation of the established therapies with immunotherapeutic methods would have the potential for significant impact. Dysplastic epithelial lesions and cancer of the anogenital and the oropharyngeal region show strong association with HPV. Therefore cervical carcinoma and HPV-associated squamous cell carcinoma of the head and neck differ from most other malignancies in that they harbour HPV-derived antigens. Expression of the viral oncogenes is mandatory to maintain the cancerous phenotype. These antigens are unique to the tumour and attractive targets for "proof of concept" studies in the development of therapeutic vaccines showing the general applicability of tumour vaccination and prove the correlation of immune response and clinical response. To date numerous clinical trials have been performed with candidate vaccines predominantly testing the efficacy for cervical cancer and its precursors. Although a naturally induced anti-HPV T cell response in patients was shown, clinical success of therapeutic vaccines was sparse. This may be attributed to immunosuppression, immunoselection, and immunoediting by the tumour cells. Factors of the individual that led to the failure of autonomous clearance of the initial infection may also contribute. Overriding this failure, reversing immunosuppression and application of vaccines in early stages of the disease is the key task for the future. The aim of this article is to summarize recent developments of therapeutic vaccines and discuss obstacles that hinder their success.