[Cervical CUP Syndrome: Diagnosis and Therapy]. / Zervikales CUP-Syndrom: Diagnostik und Therapie.

In CUP syndrome (CUP = cancer of unknown primary) there are 1 or more metastases of a primary tumor that cannot be localized despite extensive diagnostics. CUP syndrome accounts for 5% of all human malignancies, making it one of the 10 most common forms of cancer. In addition to inflammatory lymph node enlargement and benign changes such as cervical cysts, lymph node metastases are among the most common cervical masses. Cervical CUP syndrome is a histologically confirmed cervical lymph node metastasis with an unknown primary tumor. In addition to anamnesis, clinical examination and histological confirmation, diagnostics include radiological imaging using PET-CT and panendoscopy with histological primary tumor search. Treatment options include surgical therapy with neck dissection and chemoradiotherapy.

Nivolumab as a Promising Treatment Option for Metastatic Salivary Duct Carcinoma.

Salivary duct carcinomas (SDC) of the parotid gland are rarely occurring highly malignant tumors. A 65-year-old man presented with a preauricular mass. After surgical treatment and histologic examination, the findings were interpreted as a squamous cell carcinoma (SCC) metastasis of the parotid gland deriving from a cancer of unknown primary DD primary SCC of the parotid gland. Adjuvant platinum-based radiochemotherapy was administered in domo. However, re-staging revealed multiple size-progressive pulmonary round lesions. After resection and histological examination of a pulmonary mass and in synopsis with the primary tumor, the initial diagnosis of SCC was revised to SDC of the parotid gland. With positive HER-2 status, off-label trastuzumab/docetaxel was initiated in an individual healing attempt, during which the pulmonary metastases showed clear progression. Consequently, the patient received immunotherapy with nivolumab according to his negative PD-L1 status. After 57 cycles of nivolumab, the patient presents with partial remission and in good condition. We report, for the first time, a robust response of metastatic SDC to checkpoint inhibition with nivolumab without additional radiotherapy.

Risk factors for immune-related adverse effects during CPI therapy in patients with head and neck malignancies - a single center study.

Introduction: Checkpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications. Material and methods: Data from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs. Results: IrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels. Discussion: Even though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out.

Artificial intelligence directed development of a digital twin to measure soft tissue shift during head and neck surgery.

Digital twins derived from 3D scanning data were developed to measure soft tissue deformation in head and neck surgery by an artificial intelligence approach. This framework was applied suggesting feasibility of soft tissue shift detection as a hitherto unsolved problem. In a pig head cadaver model 104 soft tissue resection had been performed. The surface of the removed soft tissue (RTP) and the corresponding resection cavity (RC) was scanned (N = 416) to train an artificial intelligence (AI) with two different 3D object detectors (HoloLens 2; ArtecEva). An artificial tissue shift (TS) was created by changing the tissue temperature from 7,91±4,1°C to 36,37±1,28°C. Digital twins of RTP and RC in cold and warm conditions had been generated and volumes were calculated based on 3D surface meshes. Significant differences in number of vertices created by the different 3D scanners (HoloLens2 51313 vs. ArtecEva 21694, p<0.0001) hence result in differences in volume measurement of the RTC (p = 0.0015). A significant TS could be induced by changing the temperature of the tissue of RC (p = 0.0027) and RTP (p = <0.0001). RC showed more correlation in TS by heating than RTP with a volume increase of 3.1 µl or 9.09% (p = 0.449). Cadaver models are suitable for training a machine learning model for deformable registration through creation of a digital twin. Despite different point cloud densities, HoloLens and ArtecEva provide only slightly different estimates of volume. This means that both devices can be used for the task.TS can be simulated and measured by temperature change, in which RC and RTP react differently. This corresponds to the clinical behaviour of tumour and resection cavity during surgeries, which could be used for frozen section management and a range of other clinical applications.

Modulation of PD­L1 expression by standard therapy in head and neck cancer cell lines and exosomes.

Although checkpoint inhibitors (CPI) have recently extended the treatment options and improved clinical response of advanced stage head and neck squamous cell carcinoma (HNSCC), treatment success remains unpredictable. Programmed cell death ligand­1 (PD­L1) is a key player in immunotherapy. Tumor cells, and exosomes derived therefrom, are carriers of PD­L1 and efficiently suppress immune responses. The aim of the present study was to analyze the influence of established therapies on PD­L1 expression of HNSCC cell lines and their exosomes. The HNSCC cell lines, UM­SCC­11B, UM­SCC­14C and UM­SCC­22C were treated with fractionated radiotherapy (RT; 5x2 Gy), cisplatin (CT) and cetuximab (Cetux) as monotherapy, or combined therapy, chemoradiotherapy (CRT; RT and CT) or radioimmunotherapy (RT and Cetux). The expression of PD­L1 and phosphorylated (p)ERK1/2 as a mediator of radioresistance were assessed using western blotting, immunohistochemistry and an ex vivo vital tissue culture model. Additionally, exosomes were isolated from concentrated supernatants of the (un­)treated HNSCC cell lines by size exclusion chromatography. Exosomal protein expression levels of PD­L1 were detected using western blotting and semi­quantitative levels were calculated. The functional impact of exosomes from the (un­)treated HNSCC cell lines on the proliferation (MTS assay) and apoptosis (Caspase 3/7 assay) of the untreated HNSCC cell lines were measured and compared. The HNSCC cell lines UM­SCC­11B and UM­SCC­22B showed strong expression of pERK1/2 and PD­L1, respectively. RT upregulated the PD­L1 expression in UM­SCC­11B and UM­SCC­14C and in exosomes from all three cell lines. CT alone induced PD­L1 expression in all cell lines. CRT induced the expression of PD­L1 in all HNSCC cell lines and exosomes from UM­SCC­14C and UM­SCC­22B. The data indicated a potential co­regulation of PD­L1 and activated ERK1/2, most evident in UM­SCC­14C. Exosomes from irradiated UM­SCC­14C cells protected the unirradiated cells from apoptosis by Caspase 3/7 downregulation. The present study suggested a tumor cell­mediated regulation of PD­L1 upon platinum­based CRT in HNSCC and in exosomes. A co­regulation of PD­L1 and MAPK signaling response was hypothesized.

Plasma-derived small extracellular vesicles unleash the angiogenic potential in head and neck cancer patients.

BACKGROUND: In Head and neck cancer (HNC) angiogenesis is essential for tumor progression and metastasis. Small extracellular vesicles (sEVs) from HNC cell lines alter endothelial cell (EC) functions towards a pro-angiogenic phenotype. However, the role of plasma sEVs retrieved from HNC patients in this process is not clear so far. METHODS: Plasma sEVs were isolated on size exclusion chromatography columns from 32 HNC patients (early-stage UICC I/II: 8, advanced-stage UICC III/IV: 24), 12 patients with no evident disease after therapy (NED) and 16 healthy donors (HD). Briefly, sEVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), BCA protein assays and Western blots. Levels of angiogenesis-associated proteins were determined using antibody arrays. The interaction of fluorescently-labeled sEVs with human umbilical vein ECs was visualized by confocal microscopy. The functional effect of sEVs on tubulogenesis, migration, proliferation and apoptosis of ECs was assessed. RESULTS: The internalization of sEVs by ECs was visualized using confocal microscopy. Based on antibody arrays, all plasma sEVs were enriched in anti-angiogenic proteins. HNC sEVs contained more pro-angiogenic MMP-9 and anti-angiogenic proteins (Serpin F1) than HD sEVs. Interestingly, a strong inhibition of EC function was observed for sEVs from early-stage HNC, NED and HD. In contrast, sEVs from advanced-stage HNC showed a significantly increased tubulogenesis, migration and proliferation and induced less apoptosis in ECs than sEVs from HD. CONCLUSIONS: In general, plasma sEVs carry a predominantly anti-angiogenic protein cargo and suppress the angiogenic properties of ECs, while sEVs from (advanced-stage) HNC patients induce angiogenesis compared to HD sEVs. Thus, tumor-derived sEVs within the plasma of HNC patients might shift the angiogenic switch towards angiogenesis.

Augmented reality during parotid surgery: real-life evaluation of voice control of a head mounted display.

PURPOSE: Augmented Reality can improve surgical planning and performance in parotid surgery. For easier application we implemented a voice control manual for our augmented reality system. The aim of the study was to evaluate the feasibility of the voice control in real-life situations. METHODS: We used the HoloLens 1® (Microsoft Corporation) with a special speech recognition software for parotid surgery. The evaluation took place in a audiometry cubicle and during real surgical procedures. Voice commands were used to display various 3D structures of the patient with the HoloLens 1®. Commands had different variations (male/female, 65 dB SPL)/louder, various structures). RESULTS: In silence, 100% of commands were recognized. If the volume of the operation room (OR) background noise exceeds 42 dB, the recognition rate decreases significantly, and it drops below 40% at > 60 dB SPL. With constant speech volume at 65 dB SPL male speakers had a significant better recognition rate than female speakers (p = 0.046). Higher speech volumes can compensate this effect. The recognition rate depends on the type of background noise. Mixed OR noise (52 dB(A)) reduced the detection rate significantly compared to single suction noise at 52 dB(A) (p ≤ 0.00001). The recognition rate was significantly better in the OR than in the audio cubicle (p = 0.00013 both genders, 0.0086 female, and 0.0036 male). CONCLUSIONS: The recognition rate of voice commands can be enhanced by increasing the speech volume and by singularizing ambient noises. The detection rate depends on the loudness of the OR noise. Male voices are understood significantly better than female voices.

Optimisation of Conditions for the Formation of Spheroids of Head and Neck Squamous Cell Carcinoma Cell Lines for Use as Animal Alternatives.

The use of in vitro 3-D cell culture models in cancer research has yielded substantial gains in knowledge on various aspects of tumour biology. Such cell culture models could be useful in the study of head and neck squamous cell carcinoma (HNSCC), where mimicking intratumoral and intertumoral heterogeneity is especially challenging. Our research aims to establish 3-D spheroid models for HNSCC that reproduce in vitro the connections between tumour cells and the surrounding microenvironment. The aims of this study were to determine the optimal conditions for the culture and use of spheroids from HNSCC cell lines and optimal timepoint for using the spheroids obtained, to evaluate the effects of coculture with tumour-specific fibroblasts on spheroid formation, and to investigate spheroid responses to cisplatin treatment. Four HNSCC cell lines (UMSCC-11A, UMSCC-11B, UMSCC-22B and UD-SCC-01) were seeded in flat or round bottom well ultra-low attachment spheroid plates, and spheroid formation was evaluated. The HNSCC cell lines were then cocultured with stromal cells of the tumour microenvironment, producing an accelerated formation of dense spheroids. The viability of cells within the spheroids was assessed during cell culture by using a fluorescent dye. Our results suggest that: three out of the four cell lines tested could form usable spheroids with acceptable viability; the addition of stromal cells did not improve the number of viable cells; and the use of round bottom well plates supported the formation of a single spheroid, whereas flat bottom well plates led to the formation of multiple spheroids of different sizes.

Targeted Treatment of HPV16-positive and -negative SCC Cells With Small Molecule Tyrosine Kinase Inhibitors and Everolimus Affects MMP2 and MMP14 Expression.

BACKGROUND/AIM: The rise of targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) has considerably widened the treatment range. Matrix metalloproteinases (MMPs) are key regulators of the tumor development of many cancer entities, which makes them a promising target for new treatment options. We examined the expression patterns of MMP2 and MMP14 in human papillomavirus (HPV)-positive and -negative SCC lines after treatment with small molecule tyrosine kinase inhibitors (TKIs) and a mechanistic target of rapamycin (mTOR) inhibitor in vitro. MATERIALS AND METHODS: Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 µmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of MMP2 and MMP14 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those of untreated SCC cells. RESULTS: MMP2 and MMP14 were expressed in all three tested cell lines; expression levels were highest in the UMSCC-14C cell line. The tested TKIs significantly (p<0.05) reduced MMP2 expression in the UMSCC-14C cell line. In the HPV-positive cell line, the drugs led to an increase in MMP2 and MMP14 expression. CONCLUSION: Dysregulations in MMP signaling are involved in tumorigenesis and metastasis of HNSCCs; MMP2 has been noted as a potential biomarker. The expression of MMP2 and MMP14 is influenced effectively by small molecule TKIs and everolimus. Based on our data, future research should concentrate on a better understanding of the interplay between tumor microenvironment and tumor cells in vitro and in vivo.

Conjoint analysis of OPRPN and SMR3A protein expression as potential predictive biomarkers for head and neck squamous cell carcinoma after radiotherapy.

Increased submaxillary gland androgen­regulated protein 3A (SMR3A) expression was previously shown to serve as an independent risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and as a surrogate biomarker for active estrogen receptor 2 signaling in radioresistant tumor cells. In the present study, it was aimed to unravel the expression and clinical significance of another member of the opiorphin family, opiorphin prepropeptide (OPRPN), in the radiotherapy for head and neck squamous cell carcinoma (HNSCC). Expression of SMR3A and OPRPN were analyzed for the prior and post fractionated irradiation (4x2 Gy) by double immunofluorescence staining in established HNSCC cell lines as well as by immunohistochemical (IHC) staining in ex vivo tumor tissues. Next, in a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n=96), who received definitive surgery and adjuvant radiotherapy were reviewed, and expression levels of OPRPN protein were detected by IHC. Immunoreactivity scores (IRS) were associated with pathological and clinical risk factors by Chi­square analysis. Survival analysis was performed by using the Kaplan­Meier plot, log­rank test and Cox regression analysis. The expression levels of OPRPN and SMR3A protein were both induced by fractionated irradiation in vitro and ex vivo. In primary tumor samples, IRS of OPRPN was significantly higher than scores of SMR3A expression and positively correlated with expression patterns of SMR3A. SMR3A was confirmed to serve as an unfavorable factor, while OPRPN protein had no significant association with the clinical outcome of patients with OPSCC. A combinational analysis revealed that the subgroup with SMR3AhighOPRPNlow staining pattern had the worst clinical outcome among the various subgroups. Multivariate Cox regression analyses indicated that high expression of SMR3A serves as an independent unfavorable biomarker, while increased expression of OPRPN appears to exert protective function. In summary, the present study indicated that SMR3A and OPRPN serve as potential prognostic markers for HNSCC after radiotherapy.

Biomarkers and 3D models predicting response to immune checkpoint blockade in head and neck cancer (Review).

Immunotherapy has evolved into a powerful tool in the fight against a number of types of cancer, including head and neck squamous cell carcinomas (HNSCC). Although checkpoint inhibition (CPI) has definitely enriched the treatment options for advanced stage HNSCC during the past decade, the percentage of patients responding to treatment is widely varying between 14­32% in second­line setting in recurrent or metastatic HNSCC with a sporadic durability. Clinical response and, consecutively, treatment success remain unpredictable in most of the cases. One potential factor is the expression of target molecules of the tumor allowing cancer cells to acquire therapy resistance mechanisms. Accordingly, analyzing and modeling the complexity of the tumor microenvironment (TME) is key to i) stratify subgroups of patients most likely to respond to CPI and ii) to define new combinatorial treatment regimens. Particularly in a heterogeneous disease such as HNSCC, thoroughly studying the interactions and crosstalking between tumor and TME cells is one of the biggest challenges. Sophisticated 3D models are therefore urgently needed to be able to validate such basic science hypotheses and to test novel immuno­oncologic treatment regimens in consideration of the individual biology of each tumor. The present review will first summarize recent findings on immunotherapy, predictive biomarkers, the role of the TME and signaling cascades eliciting during CPI. Second, it will highlight the significance of current promising approaches to establish HNSCC 3D models for new immunotherapies. The results are encouraging and indicate that data obtained from patient­specific tumors in a dish might be finally translated into personalized immuno­oncology.

Prognostic Factors for the Therapeutic Performance of Cisplatin in Head and Neck Malignancies.

Introduction: For squamous cell carcinoma of the head and neck (HNSCC), cisplatin is used as primary or adjuvant (radio)chemotherapy. In terms of dosage, two main regimens are used, weekly 40mg/m2 or 3-weekly 100mg/m2. For an optimal outcome, the highest possible cumulative total dose of cisplatin is aimed for. The selection of the scheme is patient-specific, but the factors for the selection of the optimal scheme have not yet been conclusively researched. The aim of this study was to find correlations between initial laboratory values and the cumulative total dose of cisplatin, as well as any correlations between early laboratory values or their dynamics and later laboratory values or their dynamics to provide support in the selection of the chemo regimen. Material and Methods: In this retrospective study, the clinical data and laboratory values, namely glomerular filtration rate (GFR), hemoglobin, albumin, leucocyte, erythrocyte and platelet count, over the course of time of 79 patients with HNSCC who had received chemotherapy with cisplatin in our clinic between 2018 and 2021 were evaluated. Results: Patients on 3-weekly regimens achieved a higher mean cumulative total dose of cisplatin than patients on weekly regimens (214.18 ± 65.95 vs 183.33 ± 65.2 mg/m2). Significant positive correlations were seen for total cumulative dose of cisplatin with initial GFR (p=0.001, Pearson's r=0.364), initial hemoglobin (p=0.035, r=0.237), initial erythrocyte (p=0.002, r=0.337), and initial albumin (p=0.002, r=0.337). There were no significant correlations for initial leucocyte or platelets. Regarding the dynamics of the laboratory values under the first chemo administration, no correlation was found with later laboratory values or dynamics. Discussion and Conclusion: As in other prospective studies, our retrospective analysis found a higher cumulative total dose in the 3-weekly regimen. As this seems to correlate positively with patient outcome, superiority of the 3-weekly regimen over the weekly regimen can be assumed. Functioning organ systems, especially of the bone marrow and kidneys, are associated with an increased cumulative total dose and can therefore be regarded as predictive factors. Regular monitoring of laboratory values is nevertheless essential throughout the entire course of chemotherapy.

3D cell culture alters signal transduction and drug response in head and neck squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) upregulation is a typical characteristic of head and neck squamous cell carcinoma (HNSCC). However, tyrosine kinase inhibitors have not yet been able to achieve enough therapeutic benefit in clinical trials to justify their use in standard therapy regimens. At present, little is known about the reasons for this treatment failure. In the present study, the HNSCC cell lines UM-SCC-11B and UM-SCC-22B were tested for their response to tyrosine kinase inhibitors (TKI) under 2D and 3D cell culture conditions. Absorption and luciferase-based viability assays were used for this, as well as optical evaluation via fluorescence microscopy. In addition, EGFR and HER3 expression as well as the downstream signalling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK were investigated using western blotting. Cell line UM-SCC-11B revealed a strong resistance to lapatinib under 3D cell culture conditions, while a good response to TKI therapy was observed under 2D cell culture conditions. An associated overexpression of phosphorylated HER3 under 3D cell culture conditions offered a plausible explanation for the altered treatment response. The results of the present study represent an idea of how signalling mechanisms of cancer cells can be changed using different cell culture methods. Overall, 3D cell culture could be an important component in the analysis of resistance mechanisms in cancer therapy.

[Time management in operating rooms-a cross-sectional study to evaluate estimated and objective durations of otorhinolaryngologic surgical procedures]. / Zeitmanagement im OP ­ eine Querschnittstudie zur Bewertung der subjektiven und objektiven Dauer chirurgischer Prozeduren im HNO-Bereich.

BACKGROUND: Accurate planning of operating times in surgical clinics is essential. Moreover, high-capacity utilization of operating rooms (ORs) is necessary for economic efficiency. OBJECTIVE: Most planning of operating times is performed by surgeons. Herein, surgeons' estimated times and the objective times for performing surgical procedures were compared to detect sources of error. MATERIALS AND METHODS: In a retrospective analysis, the durations of 1809 operations using general anesthesia (22 types of surgery) by 31 surgeons (12 specialists and 19 residents) were compared. Comparisons were analyzed by Mann-Whitney U­tests. RESULTS: The comparison of objective times of surgical action showed significant differences between specialists and residents in 6 of 15 types of surgeries. The post-processing times estimated by specialists deviated from the objective times in 2 out of 22 surgery types, while the post-processing times estimated by residents deviated in 7 of 15 types. Specialists misjudged the incision-to-suture times in 7 of 22 surgery types, and residents misjudged these times in 3 of 15 types. The preparation times estimated by specialists deviated from the objective times in 16 of 22 types of surgeries and in 7 of 15 types estimated by residents. CONCLUSION: A surgeon's routine must be carefully considered in order to estimate operating times. Specialists generally underestimated preparation and post-processing times and overestimated incision-to-suture times, whereas residents underestimated all three. Preparation and post-processing times must be considered in planning and, ideally, determined together with anesthesiologists and surgical assistants.

[Differential diagnosis of intraorbital masses - a narrative review]. / Differentialdiagnostik intraorbitaler Raumforderungen ­ eine Übersicht.

OBJECTIVE: Intraorbital masses represent a condition that is frequently threatening for the visual system. A rigorous differential diagnosis is essential to promptly initiate appropriate therapy and optimize prognosis. MATERIALS/METHODS: Narrative review of current literature and expert recommendations. For further illustration we describe the case of a 71-year-old male admitted to our department three months after sinus surgery. Postoperative intraorbital hematoma of the right orbit had been treated conservatively with antibiotics/corticosteroids, leading to a near-complete unilateral visual loss. The immediate surgical intervention aimed at decompression of the orbit and the optical nerve. Due to the delay, the intervention could not prevent formation of a lipogranuloma. Inflammatory phases associated with the lipogranuloma are successfully managed by conservative treatment based on multidisciplinary recommendations. RESULTS: In the case reported, delay of surgical therapy acted as a cause of intraorbital lipogranuloma formation. Literature supports our recommendation of immediate surgical intervention in case of acute retrobulbar hematoma. Besides acute conditions, intraorbital masses can be a sign of systemic disease. In every case, a multidisciplinary therapeutic approach is required for adequate management. CONCLUSIONS: Intraorbital masses can occur as a complication of trauma or e.g. sinus surgery. On the other hand they can be a sign of systemic disease. Timely diagnosis and treatment prevents from visual loss. That is why rigorous differential diagnosis is essential for every discipline managing intraorbital lesions.

Precision Medicine Gains Momentum: Novel 3D Models and Stem Cell-Based Approaches in Head and Neck Cancer.

Despite the current progress in the development of new concepts of precision medicine for head and neck squamous cell carcinoma (HNSCC), in particular targeted therapies and immune checkpoint inhibition (CPI), overall survival rates have not improved during the last decades. This is, on the one hand, caused by the fact that a significant number of patients presents with late stage disease at the time of diagnosis, on the other hand HNSCC frequently develop therapeutic resistance. Distinct intratumoral and intertumoral heterogeneity is one of the strongest features in HNSCC and has hindered both the identification of specific biomarkers and the establishment of targeted therapies for this disease so far. To date, there is a paucity of reliable preclinical models, particularly those that can predict responses to immune CPI, as these models require an intact tumor microenvironment (TME). The "ideal" preclinical cancer model is supposed to take both the TME as well as tumor heterogeneity into account. Although HNSCC patients are frequently studied in clinical trials, there is a lack of reliable prognostic biomarkers allowing a better stratification of individuals who might benefit from new concepts of targeted or immunotherapeutic strategies. Emerging evidence indicates that cancer stem cells (CSCs) are highly tumorigenic. Through the process of stemness, epithelial cells acquire an invasive phenotype contributing to metastasis and recurrence. Specific markers for CSC such as CD133 and CD44 expression and ALDH activity help to identify CSC in HNSCC. For the majority of patients, allocation of treatment regimens is simply based on histological diagnosis and on tumor location and disease staging (clinical risk assessments) rather than on specific or individual tumor biology. Hence there is an urgent need for tools to stratify HNSCC patients and pave the way for personalized therapeutic options. This work reviews the current literature on novel approaches in implementing three-dimensional (3D) HNSCC in vitro and in vivo tumor models in the clinical daily routine. Stem-cell based assays will be particularly discussed. Those models are highly anticipated to serve as a preclinical prediction platform for the evaluation of stable biomarkers and for therapeutic efficacy testing.

Augmented Reality with HoloLens® in Parotid Tumor Surgery: A Prospective Feasibility Study.

INTRODUCTION: Augmented reality can improve planning and execution of surgical procedures. Head-mounted devices such as the HoloLens® (Microsoft, Redmond, WA, USA) are particularly suitable to achieve these aims because they are controlled by hand gestures and enable contactless handling in a sterile environment. OBJECTIVES: So far, these systems have not yet found their way into the operating room for surgery of the parotid gland. This study explored the feasibility and accuracy of augmented reality-assisted parotid surgery. METHODS: 2D MRI holographic images were created, and 3D holograms were reconstructed from MRI DICOM files and made visible via the HoloLens. 2D MRI slices were scrolled through, 3D images were rotated, and 3D structures were shown and hidden only using hand gestures. The 3D model and the patient were aligned manually. RESULTS: The use of augmented reality with the HoloLens in parotic surgery was feasible. Gestures were recognized correctly. Mean accuracy of superimposition of the holographic model and patient's anatomy was 1.3 cm. Highly significant differences were seen in position error of registration between central and peripheral structures (p = 0.0059), with a least deviation of 10.9 mm (centrally) and highest deviation for the peripheral parts (19.6-mm deviation). CONCLUSION: This pilot study offers a first proof of concept of the clinical feasibility of the HoloLens for parotid tumor surgery. Workflow is not affected, but additional information is provided. The surgical performance could become safer through the navigation-like application of reality-fused 3D holograms, and it improves ergonomics without compromising sterility. Superimposition of the 3D holograms with the surgical field was possible, but further invention is necessary to improve the accuracy.

[Postoperative hypocalcemia - the most common complication of endocrine head and neck surgery: acute management]. / Postoperative Hypokalzämie ­ die häufigste Komplikation der endokrinen Chirurgie der Halsregion: Akutes Management.

BACKGROUND: In Germany, 8000 patients are affected by postoperative hypoparathyroidism per year following surgery of the thyroid gland, parathyroidal glands and the larynx. Patients do not only suffer from paresthesia in the acute phase of this complication, but are also adversely affected by the fear of loss of control following episodes of tetany even years after the first episode. OBJECTIVES: Discussion of a diagnostic pathway and presentation of a management pathway for postoperative hypocalcemia. METHODS: Narrative review, analysis and discussion of current literature and expert recommendations. RESULTS: Early determination of calcium and parathyroid hormone allows timely diagnosis and treatment of postoperative hypoparathyroidism. Active vitamin D is pivotal for the resorption of calcium. Only the combined treatment with active vitamin D and calcium can mitigate or prevent the postoperative drop of calcium levels. CONCLUSIONS: A standard operating procedure (SOP) for postoperative hypoparathyroidism should be implemented in every surgical department. An SOP for diagnosis and treatment of postoperative hypoparathyroidism is proposed for institutional individualization and implementation.

[The tumor stem cell niche of head and neck - point of intersection with therapeutic potential?] / Die Tumorstammzellnische im Kopf-Hals-Bereich ­ Knotenpunkt mit therapeutischem Potenzial?

An increasing amount of evidence suggests the existence of a stem cell-like population in head and neck squamous cell carcinoma (HNSCC). These cells have been termed cancer stem cells (CSC) due to the shared properties with somatic stem cells, such as the ability to self-renew and differentiate. Furthermore, the CSC are thought to be resistant to antineoplastic treatments and are therefore clinically relevant. As with somatic stem cells, CSC are thought to reside in a specialized supportive microenvironment, called the stem cell niche. One possible strategy to target the CSC could be through affecting functions of the stem cell niche.Stromal cell-derived factor-1 (SDF-1) is a multifunctional cytokine, which is secreted by e. g. stromal cells within the niche. SDF-1 is known to be the major regulator of stem cell trafficking between the niche and the peripheral vascular system. It elicits the chemotactic activity through interaction with a transmembrane receptor CXCR4, expressed by CSC. The SDF-1-CXCR4-axis is thought to play a crucial role in the interaction between CSC and their supportive cells in the tumor niche. A better understanding of these interactions could help in gaining further insight into the pathophysiology of progression/recurrence of malignant diseases and aid in finding new strategies for therapy.Specialized cell culture models are of advantage for deciphering the mechanisms of interaction between CSC and their niche. We anticipate that the recent technological advancements in bioprinting and the development of complex 3D cell culture model systems will contribute to our understanding of these mechanisms and to the establishment of individualized therapies.Here were provide an overview of the current knowledge on the CSC-tumor stem cell niche interactions in HNSCC with a focus on the SDF-1-CXCR4 axis.

Augmented reality with HoloLens in parotid surgery: how to assess and to improve accuracy.

PURPOSE: Augmented reality improves planning and execution of surgical procedures. The aim of this study was to evaluate the feasibility of a 3D augmented reality hologram in live parotic surgery. Another goal was to develop an accuracy measuring instrument and to determine the accuracy of the system. METHODS: We created a software to build and manually align 2D and 3D augmented reality models generated from MRI data onto the patient during surgery using the HoloLens® 1 (Microsoft Corporation, Redmond, USA). To assess the accuracy of the system, we developed a specific measuring tool applying a standard electromagnetic navigation device (Fiagon GmbH, Hennigsdorf, Germany). RESULTS: The accuracy of our system was measured during real surgical procedures. Training of the experimenters and the use of fiducial markers significantly reduced the accuracy of holographic system (p = 0.0166 and p = 0.0132). Precision of the developed measuring system was very high with a mean error of the basic system of 1.3 mm. Feedback evaluation demonstrated 86% of participants agreed or strongly agreed that the HoloLens will play a role in surgical education. Furthermore, 80% of participants agreed or strongly agreed that the HoloLens is feasible to be introduced in clinical routine and will play a role within surgery in the future. CONCLUSION: The use of fiducial markers and repeated training reduces the positional error between the hologram and the real structures. The developed measuring device under the use of the Fiagon navigation system is suitable to measure accuracies of holographic augmented reality images of the HoloLens.