J. A. Veit

Prefabrication of 3D Cartilage Contructs: Towards a Tissue Engineered Auricle – A Model Tested in Rabbits

The reconstruction of an auricle for congenital deformity or following trauma remains one of the greatest challenges in reconstructive surgery. Tissue-engineered (TE) three-dimensional (3D) cartilage constructs have proven to be a promising option, but problems remain with regard to cell vitality in large cell constructs. The supply of nutrients and oxygen is limited because cultured cartilage is not vascular integrated due to missing perichondrium. The consequence is necrosis and thus a loss of form stability. The micro-surgical implantation of an arteriovenous loop represents a reliable technology for neovascularization, and thus vascular integration, of three-dimensional (3D) cultivated cell constructs. Auricular cartilage biopsies were obtained from 15 rabbits and seeded in 3D scaffolds made from polycaprolactone-based polyurethane in the shape and size of a human auricle. These cartilage cell constructs were implanted subcutaneously into a skin flap (15×8 cm) and neovascularized by means of vascular loops implanted micro-surgically. They were then totally enhanced as 3D tissue and freely re-implanted in-situ through microsurgery. Neovascularization in the prefabricated flap and cultured cartilage construct was analyzed by microangiography. After explantation, the specimens were examined by histological and immunohistochemical methods. Cultivated 3D cartilage cell constructs with implanted vascular pedicle promoted the formation of engineered cartilaginous tissue within the scaffold in vivo. The auricles contained cartilage-specific extracellular matrix (ECM) components, such as GAGs and collagen even in the center oft the constructs. In contrast, in cultivated 3D cartilage cell constructs without vascular pedicle, ECM distribution was only detectable on the surface compared to constructs with vascular pedicle. We demonstrated, that the 3D flaps could be freely transplanted. On a microangiographic level it was evident that all the skin flaps and the implanted cultivated constructs were well neovascularized. The presented method is suggested as a promising alternative towards clinical application of engineered cartilaginous tissue for plastic and reconstructive surgery.

Prognostic Role of Circulating Tumor Cells during Induction Chemotherapy Followed by Curative Surgery Combined with Postoperative Radiotherapy in Patients with Locally Advanced Oral and Oropharyngeal Squamous Cell Cancer

Background The prognostic role of circulating tumor cells (CTCs) after induction chemotherapy using docetaxel, cisplatin and fluorouracil (TPF) prior to surgery and adjuvant (chemo)radiation in locally advanced oral squamous cell cancer (OSCC) was evaluated. Methods In this prospective study, peripheral blood samples from 40 patients of the phase II study TISOC-1 (NCT01108042) with OSCC before, during, and after treatment were taken. CTCs were quantified using laser scanning cytometry of anti– epithelial cell adhesion molecule–stained epithelial cells. Their detection was correlated with clinical risk factors, recurrence-free (RFS) and overall survival (OS). Results Before starting the treatment CTCs were detected in 32 of 40 patients (80%). The median number at baseline was 3295 CTCs/ml. The median maximal number of CTCs during treatment was 5005 CTCs/ml. There was a significant increase of CTCs before postoperative radiotherapy compared to baseline before 1st cycle of IC (p = 0.011), 2nd cycle of IC (p = 0.001), 3rd cycle of IC (p = 0.004), and before surgery (p = 0.002), but not compared to end of therapy (p = 0.118). CTCs at baseline >median was also associated to risk of recurrence (p = 0.014). Maximal CTCs during therapy >median was more frequently observed in tumors of the oral cavity (p=0.022) and related to higher risk of death during follow-up (p = 0.028). Patients with CTCs at baseline >median value had significant lower RFS than patients with CTCs at baseline <median value (p = 0.025). Patients with maximal CTCs values >median during the complete course of therapy had a significantly lower OS than patients with values <median (p = 0.049). Finally, the multivariate analysis revealed that OS was significantly lower in patients with maximal CTCs during treatment higher than the median value (HR=6.151; CI: 1.244-30.420). Conclusions Baseline CTCs and maximal CTCs during therapy both seem to be good prognostic markers for OSCC when treated by TPF induction chemotherapy, surgery, and postoperative (chemo)radiation.

Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck.

Mucosal melanoma of the head and neck is a rare and aggressive tumor entity with a poor prognosis. The standard treatment is radical tumor resection, with or without adjuvant radiation, where conventional chemotherapies in advanced stage or recurrent diseases have shown little benefit. Overexpression of the programmed cell death ligand 1 (PD-L1) is a common feature in human cancer. Although PD-L1 is an acknowledged prognostic biomarker for dismal prognosis in other tumors of the head and neck, expression and clinical relevance of PD-L1 in mucosal melanoma have not been addressed so far. We assessed PD-L1 expression using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma and correlated expression status with clinicopathological and outcome data. Tumors were derived from the nasal cavity (43.5%), nasal sinuses (43.5%), and the conjunctiva (13%). All patients had undergone surgery; 39% of all patients received adjuvant radiation and 13% were administered systemic interferon therapy. The probability of 1- and 5-year overall survival was 87 and 34.8%, respectively. The mean overall survival was 51 months and the mean recurrence-free survival was 23 months. Immunohistochemical staining showed PD-L1 expression in 13% (3/23) of mucosal melanoma. In contrast, prominent PD-L1 staining was detected in 100% of tissue sections from a control group of cutaneous melanoma (n=9). PD-L1 expression in mucosal melanoma was not correlated with age, sex, nor anatomical localization of the tumor. Interestingly, patients with PD-L1-positive mucosal melanoma had a significantly longer recurrence-free survival (P=0.026). In contrast to cutaneous melanoma and some other malignancies, a relevant PD-L1 overexpression in mucosal melanoma could not be confirmed.

Detection of paranasal ectopic adrenocorticotropic hormone-secreting pituitary adenoma by Ga-68-DOTANOC positron-emission tomography–computed tomography

Ectopic adrenocorticotropic hormone (ACTH)‐secreting tumors account for approximately 10% of Cushings syndrome (CS). We present an extremely rare case of a patient with CS caused by an ectopic ACTH‐secreting pituitary adenoma (EAPA) of the ethmoid sinus. The tumor was identified by positron‐emission tomography–computed tomography (PET/CT) using the somatostatin receptor analogue Ga‐68‐DOTANOC. Transnasal endoscopic resection was performed and the patient showed significant clinical improvement with normalization of the endocrine pituitary axis. Immunostaining showed a somatostatin receptor 2 and 5‐positive ACTH‐producing adenoma. In patients with ectopic ACTH secretion, Ga‐68‐DOTANOC‐PET/CT may play an important role in the localization of EAPA. Transnasal endoscopic resection is the therapy of choice.

The auricle's cavum conchae composite graft in nasal reconstruction.

Background Autologous transplants consisting of skin and cartilage, so-called composite grafts (CGs), are useful in nasal reconstruction of multilayered defects. A CG from the auricles cavum conchae serves both functional and esthetic demands. This article outlines the indications and the requirements of the CG, making special considerations to improve wound healing, and discusses our results in consideration with recent publications. Methods A retrospective case–control study assessing the functional and esthetic long-term results in the donor and recipient site is presented. Results Between 2005 and 2011, 91 patients received differently sized CGs of the auricle for nasal reconstruction. In 85/91 cases the donor site defect was closed using a retroauricular pedicled island flap. Six of 91 defects were closed primarily. Indications were multilayered defects of the nasal vestibule, the nasal floor, the inner nasal valve, and the lateral sidewall. The main indication for surgery was skin malignancies. One of 91 major and 14/91 minor complications were observed. Seventy-seven of 91 patients received a custom-made prosthesis to prevent stenotic scarring. The 2.5-year follow-up showed excellent results of stability and shape at the donor and recipient site. Conclusion The auricular inner lining CG is a versatile and reliable autologous transplant, which is ideal for multilayered nasal reconstruction because of easy harvesting, little donor site morbidity, and its convex shape. Septal splints and custom-made prosthesis secure healing and prevent stenotic scarring.

Three different turbinoplasty techniques combined with septoplasty: Prospective randomized trial.

Septal deviation and hypertrophic inferior turbinates are a frequent cause of nasal breathing disorders. The goal of this study was to prove the effectiveness and safety of three current turbinoplasty techniques.

Hybrid procedure for total laryngectomy with a flexible robot‐assisted surgical system

Total laryngectomy is a standard procedure in head‐and‐neck surgery for the treatment of cancer patients. Recent clinical experiences have indicated a clinical benefit for patients undergoing transoral robot‐assisted total laryngectomy (TORS‐TL) with commercially available systems. Here, a new hybrid procedure for total laryngectomy is presented.

Epithelial-to-Mesenchymal Transition in the Pathogenesis and Therapy of Head and Neck Cancer

Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior. EMT is mediated by a core set of key transcription factors, which are under the control of a large range of developmental signals and extracellular cues. Unraveling molecular principles that drive EMT provides new concepts to better understand tumor cell plasticity and response to established as well as new treatment modalities, and has the potential to identify new drug targets for a more effective, less toxic, and individualized therapy of HNC patients. Here, we review the most recent findings on the clinical relevance of a mesenchymal-like phenotype for HNC patients, including more rare cases of mucosal melanoma and adenoid cystic carcinoma.

[Persistent nasal obstruction following septoplasty: deviated nasal pyramid and perpendicular plate].

BACKGROUND Functional septorhinoplasty (SRP) is a surgical procedure for improvement of symptomatic deformity of the inner and outer nose. Due to inadequate preoperative analysis and consequently insufficient surgical indication, septoplasty (SPL) alone may be performed. A frequent cause for revision septorhinoplasty (rSRP) in our institution was found to be due to a deviated bony pyramid in compound with a contralateral high deviation of the perpendicular plate, ipsilateral reluxation of the cartilaginous septum and a resulting nasal valve stenosis. MATERIALS AND METHODS The medical records of all patients undergoing revision septorhinoplasty in our institution from 2005-2011 were evaluated retrospectively.398 patients underwent rSRP, in 57 patients (14%) a deviated bony nose after septoplasty was diagnosed. In all cases a deviated bony nose and contralateral deviation of the perpendicular plate was found and corrected by rSRP. The nasal breathing was improved in all cases. This was also shown in an increase of endonasal volume and nasal air flow in acoustic rhinometry and active anterior rhinomanometry. CONCLUSION A deviated nasal pyramid and perpendicular plate was found to be a common cause for persistent nasal obstruction after septoplasty. A careful preoperative analysis of the nose, the pathology of the bony and cartilaginous septum and the nasal valves is mandatory in order to recognize anatomical details and set up the right indication for rhinosurgical interventions.

[Immunotherapy of head and neck tumors: Highlights of the ASCO Meeting 2015].

BACKGROUND In recent years, new immunotherapeutic drugs have become available: the so-called immune checkpoint modulators. With these drugs, unprecedented treatment results have been achieved in different malignant diseases; primarily malignant melanoma, but also in various other malignomas. These achievements have revolutionized the oncologic treatment landscape. This quickly expanding research field, driven by revolutionary treatment results, has put immunotherapy in the focus of attention. OBJECTIVE Due to rapid developments in the field of immunotherapy, this article aims at introducing, illustrating, and summarizing the field of modern immunotherapy, based on recently presented clinical data from the Annual Meeting of the American Society of Clinical Oncology (ASCO) 2015. MATERIALS AND METHODS The most important ASCO Meeting 2015 immunotherapy trials for head and neck squamous cell carcinoma (HNSCC) were identified, summarized, and discussed with respect to the current state of research. RESULTS The oncologic landscape of clinical trials is currently dominated by the new immune checkpoint modulating drugs. Also for HNSCC, a variety of clinical trials and substances are under way. The current primary focus of these trials is targeting and inhibiting the programmed death 1 (PD-1) axis. Cancer immunotherapy with immune checkpoint modulating drugs seems to be independent of human papilloma virus (HPV) status. Robust predictive markers for patient selection are not yet available. CONCLUSION Current data from clinical trials with immune checkpoint modulators are promising. In the coming years, integration of these drugs into clinical routine can be expected. With regard to the public health economic burden and potential adverse events, the identification of predictive markers for patient selection is a major task for future trials.