The value of biomarkers in the therapy of CRSwNP with biologicals-a long-term follow-up of dupilumab therapy.

PURPOSE: Since its release, Dupilumab has shown great results in treating severe uncontrolled CRSwNP. However, there is a lack of real-world data beyond 12 months of follow-up, and it is not clear to what extent biomarkers are appropriate for monitoring and predicting the Dupilumab therapy success. Hence, this study aims to analyze biomarkers for monitoring therapy, predicting therapy success and assess the effect of Dupilumab in real-world settings. METHODS: The follow-up was performed with 104 patients retrospectively up to 22 months, assessing SNOT-22, NPS, olfactometry, ACS, FEV-1, and blood biomarkers (total serum IgE, Eosinophils, ECP). Patients were divided into subgroups depending on their pretherapeutic biomarker levels and subsequent development was analyzed. RESULTS: There was substantially improvement in all clinical parameters up to 1 year and then continuously up to month 22. Patients with initially elevated baseline blood eosinophil counts (> 0.5 billion/L) had a trend of better SNOT-22 development after 1 year (- 12.19 points, p = 0.03). The course of total serum IgE showed moderate correlation with almost all clinical variables obtained. Therapy was well tolerated with only mild and transient adverse events. CONCLUSION: Dupilumab has considerably reduced symptoms and disease severity even beyond 1 year of treatment, supporting its role as targeted and effective treatment option for CRSwNP. Our data shows that total serum IgE is a promising biomarker for the monitoring during the treatment with Dupilumab. Elevated pre-therapeutic serum eosinophil counts may be a predictor of good subjective response to therapy. Larger cohorts and a long-term-follow-up over years are needed to further consolidate these findings.

[Endoscopic endonasal anterior skull base surgery : Presentation of a monocentric entity profile]. / Endonasal-endoskopische anteriore Schädelbasischirurgie : Darstellung eines monozentrischen Entitätenprofils.

BACKGROUND: Extended endoscopic endonasal surgery (EEES) is an essential part of treatment of various pathologies of the anterior skull base. In addition to significant improvements in the quality of life of affected patients and a lower complication profile compared to open skull base surgery, the therapeutic results are comparable if the indications are correct. MATERIALS AND METHODS: Data of all endoscopic endonasal skull base procedures performed at the University Skull Base Center Hamburg under the direction of the Department of Otorhinolaryngology between June 2018 and November 2022 were retrospectively collected. RESULTS: A total of 50 cases were identified. Of these, 56% (28/50) were malignant tumors, 24% (12/50) were benign pathologies with direct skull base involvement, and 20% (10/50) were anterior skull base defects with rhinoliquorrhea. In 96% (48/50) of cases, the preoperatively set goal of surgery (representative biopsy, complete resection, closure of the skull base defect) could be achieved. Complications grade III or higher according to Clavien-Dindo occurred in 4/50 cases. During the observation period, n = 5 olfactory neuroblastomas were diagnosed, all of which were exclusively and successfully operated on endoscopically. CONCLUSION: In recent years, the spectrum of endoscopically resectable pathologies of the anterior skull base has steadily expanded. In particular, midline-related tumors such as olfactory neuroblastoma or iatrogenic/idiopathic skull base defects with cerebrospinal fluid rhinorrhea are treated completely endoscopically with very good results. Nevertheless, there are also limitations to this technique. Due to high variance in the scope of frontobasal surgery, the extent, and the complex anatomy, as well as the overlapping responsibilities of the specialist disciplines, establishment of certified skull base centers and bundling of frontobasal surgery at these centers is highly relevant for quality assurance.

["Radical" versus "functional" surgery of the paranasal sinuses-A contradiction?] / "Radikale" vs. "funktionelle" Chirurgie der Nasennebenhöhlen ­ ein Widerspruch?

BACKGROUND AND OBJECTIVE: The terms "functional" and "radical" paranasal sinus surgery were often considered to be different operations which were mutually exclusive. This overview aims to look at the basics of these terms and surgical procedures and to work out the resulting surgical concepts for clinically relevant indications. MATERIAL AND METHODS: Selective literature analysis using the data base PubMed, corresponding textbooks and resulting secondary literature regarding functional and radical or extended paranasal sinus surgery. Similarly, the current literature regarding clinically relevant indications for sinus surgery were analyzed. RESULTS AND CONCLUSION: Modern pathophysiological knowledge, anatomically and pathophysiologically substantiated endoscopic surgical procedures and the usage of up to date technical possibilities have resulted in concepts which combine functional and so-called radical or extended surgery of the paranasal sinuses that complement each other and sometimes even overlap. The preoperative diagnosis and definition of underlying diseases are decisive and should be as precise as possible, as the extent and surgical details mainly depend on them: a sole creation of free drainage pathways, an additional creation of anatomical access for subsequent topical treatment or a complete (radical) removal of a pathological process.

[How much digitization do ENT curricula need? : Opportunities and limits from the perspective of students and teachers]. / Wieviel Digitalisierung braucht die HNO-Lehre? : Chancen und Grenzen aus Sicht von Studierenden und Lehrenden.

BACKGROUND: Digitalization has long been an integral part of students' everyday lives and increasingly also of their medical training. It seems to be an unwritten law that "digital natives" want as much digitalization as possible. This study aims to shed more light on how students in the clinical phase of medical studies perceive the increasing digitalization of teaching and what they need for good education. MATERIALS AND METHODS: This study analyzed two surveys that were conducted using an online questionnaire. On the one hand, students in the 5th-9th semesters of the medical faculty at the University of Hamburg (n = 282) were surveyed (survey 1). Another survey addressed all employees of ENT clinics in Germany (n = 175; survey 2). RESULTS: A total of 76 students took part in survey 1 and 123 lecturers in survey 2. The results show that both students and lecturers do not want face-to-face teaching to be completely replaced by digital formats. A total of 72.7% of students reject the possibility of teaching practical skills through digital formats. The majority of students surveyed stated that offline formats improve their concentration (61.1%), participation probability (63.9%), and motivation to learn (76.6%). In contrast, 40.2% of lecturers see digitalization as a way to reduce the workload without any relevant loss in teaching quality. CONCLUSION: Digital teaching formats have a negative impact on the medical education of the students surveyed. Interaction and physical presence are needed to increase the motivation to learn. This leads to the first conclusion that students are critical of the increasing digitalization of medical studies.

[Decision-making in the treatment of chronic rhinosinusitis with nasal polyps in the era of biologics]. / Entscheidungsfindung bei der Behandlung der chronischen Rhinosinusitis mit Nasenpolypen in der Ära der Biologika.

Chronic rhinosinusitis is one of the most common chronic diseases in the population. Chronic rhinosinusitis with nasal polyps (CRSwNP) in adults is predominantly characterized by a type 2 inflammatory endotype. If sufficient control cannot be achieved through primary drug therapy, surgical intervention is usually recommended as the next stage of treatment. Nowadays, various biologics are available that have been or will be approved for use in these patients. This review summarizes the presentations from the 29th Congress of the European Rhinologic Society in Sofia 2023 and the latest findings on decision-making in the treatment of CRSwNP. Standard therapy with medication and sinus surgery fails in some patients with CRSwNP. Biologics that act on the type 2 inflammatory pathway led to a reduction in the nasal polyp score (NPS), an improvement in nasal obstruction, and an improvement in quality of life without significant side effects. Biomarkers such as total IgE, serum eosinophils, and Osteoprotegerin (OPG) can provide indications of the success of the treatment. In summary, it can be said that for many patients with recurrent CRSwNP, a combination of paranasal sinus surgery and treatment with a biologic that is precisely tailored to the patient's endotype is the best option. However, the question of which surgical approach and which biologic at which time and for which patient is still ongoing and requires further studies.

Dupilumab (Dupixent®) tends to be an effective therapy for uncontrolled severe chronic rhinosinusitis with nasal polyps: real data of a single-centered, retrospective single-arm longitudinal study from a university hospital in Germany.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease, which is usually type 2-mediated in the western hemisphere, associated with severe therapeutic and socioeconomic challenges. The first targeted systemic treatment option for severe uncontrolled CRSwNP is a human monoclonal antibody against the interleukin-4 receptor α (IL-4Rα) subunit called dupilumab, which was approved for subcutaneous administration in Germany in October 2019. The purpose of this study is to investigate the efficacy of dupilumab in real life in patients treated with dupilumab in label according to license in our department in 2019-2021. MATERIALS AND METHODS: Since October 2019, we have investigated 40 patients (18 men, 22 women) treated with dupilumab in a single-center, retrospective single-arm longitudinal study. The following parameters were collected before treatment (baseline), at 1 month, 4 months, 7 months, 10 months, and 13 months: the Sino-Nasal Outcome Test-22 (SNOT-22), the forced expiratory pressure in 1 s (FEV-1), the olfactometry using Sniffin' Sticks-12 identification test (SSIT), a visual analog scale of the total complaints, the Nasal Polyp Score (NPS), histologic findings as well as total serum IgE, eosinophilic cationic protein in serum and blood eosinophils. RESULTS: The average age was 52.7 years (± 15.3). The follow-up period was 13 months. The SNOT-22 average was 60 points (± 22.2) at the first visit, 28.2 points (± 17.1) after 4 months and 20.8 points (± 17.7) after 13 months. The NPS was 4.3 points (± 1.5), after 4 months 2.1 points (± 1.3) and after 13 months 1.4 points (± 1.1). Olfactometry showed 3.2 points (± 3.7) at the baseline, 7.0 points (± 4.0) after 4 months and 7.8 points (± 3.5) after 13 months. The other parameters also improved. Most parameters showed linear dependence in the slopes under therapy (p < 0.001). Adverse side effects were mostly only mild, and no rescue therapy was needed. CONCLUSION: There is a clear improvement in the medical condition and symptoms in all categories mentioned under therapy with dupilumab, as well as a reduction in the need for systemic glucocorticoids and revision surgery as rescue treatment. Our results show that dupilumab tends to be an effective therapy alternative for severe CRSwNP.

Outcomes following oropharyngeal squamous cell carcinoma resection and bilateral neck dissection with or without contralateral postoperative radiotherapy of the pathologically node-negative neck.

PURPOSE: There are no consensus guidelines regarding the postoperative treatment of the contralateral pathologically node-negative neck in oropharyngeal squamous cell carcinoma. This study aimed to determine if omission of postoperative irradiation of the contralateral pathologically node-negative neck affects oncological outcomes. METHODS: We retrospectively identified 84 patients with primary surgical treatment including bilateral neck dissection and postoperative (chemo-)radiotherapy (PO(C)RT). Survival was analyzed using the log-rank test and the Kaplan-Meier method. RESULTS: Patients showed no decrease in tumor-free, cause-specific (CSS), or overall survival (OS) when PO(C)RT of the contralateral pathologically node-negative neck was omitted. Increased OS was found in patients with unilateral PO(C)RT and especially an increased OS and CSS was found in unilateral PO(C)RT and in tumors arising from lymphoepithelial tissue. CONCLUSIONS: Omitting the contralateral pathologically node-negative neck appears to be safe in terms of survival and our retrospective study advocates further prospective randomized control de-escalation trials.

Characteristics of smell and taste disorders depending on etiology: a retrospective study.

PURPOSE: This study investigates the impact of etiology on the epidemiologic profile, disease severity, type of treatment and therapy outcome in smell and taste disorders. METHODS: This is a retrospective analysis of 270 patients that presented with a smell or taste disorder in a specialized, tertiary care center. An established questionnaire was used to collect data from patients and physicians. Olfactometry was performed with the Sniffin' Sticks test kit, while gustometry was performed by taste strips. RESULTS: Post-traumatic etiology was associated with young age (median 46 years) and male sex, and showed the most severe degrees of smell loss compared to other etiologies (64.3% anosmia). Postinfectious causes occurred more frequently in females (77.3%) and correlated with a history of pharyngeal surgery, suggesting a vulnerability for virally mediated sensory dysfunction following adenoid/tonsil removal. Parosmia also correlated with both postinfectious etiology (62.5%) and female sex. In sinunasal etiology, the presence of nasal polyps worsened the overall olfactory test score by approximately 50%. In particular, smell threshold and discrimination were reduced, while smell identification was not significantly impacted by nasal polyp obstruction. Sinunasal dysfunction was the only etiology to show significant improvement after therapy (73.9% improved). Finally, we could establish good correlations between the subjective impairment and objective dysfunction for each sensory modality. CONCLUSION: Each etiology of chemosensory dysfunction shows particular distributions of variables like sex, age, comorbidities and operations, disease severity, sensory threshold, discrimination and identification. This paper offers a detailed account of the correlations between the cause and the characteristics of smell and taste loss.

Lipidome Analysis of Oropharyngeal Tumor Tissues Using Nanosecond Infrared Laser (NIRL) Tissue Sampling and Subsequent Mass Spectrometry.

Ultrashort pulse infrared lasers can simultaneously sample and homogenize biological tissue using desorption by impulsive vibrational excitation (DIVE). With growing attention on alterations in lipid metabolism in malignant disease, mass spectrometry (MS)-based lipidomic analysis has become an emerging topic in cancer research. In this pilot study, we investigated the feasibility of tissue sampling with a nanosecond infrared laser (NIRL) for the subsequent lipidomic analysis of oropharyngeal tissues, and its potential to discriminate oropharyngeal squamous cell carcinoma (OPSCC) from non-tumorous oropharyngeal tissue. Eleven fresh frozen oropharyngeal tissue samples were ablated. The produced aerosols were collected by a glass fiber filter, and the lipidomes were analyzed with mass spectrometry. Data was evaluated by principal component analysis and Welch's t-tests. Lipid profiles comprised 13 lipid classes and up to 755 lipid species. We found significant inter- and intrapatient alterations in lipid profiles for tumor and non-tumor samples (p-value < 0.05, two-fold difference). Thus, NIRL tissue sampling with consecutive MS lipidomic analysis is a feasible and promising approach for the differentiation of OPSCC and non-tumorous oropharyngeal tissue and may provide new insights into lipid composition alterations in OPSCC.

[Special tumor entities in the head and neck region: nasopharyngeal, salivary gland, and thyroid cancer]. / Spezielle Tumorentitäten im Kopf-Hals-Bereich: Nasopharynxkarzinom, Speicheldrüsenkarzinom und Schilddrüsenkarzinom.

BACKGROUND: At the meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) in 2022, studies were presented which suggest changes in the clinical routine of nasopharyngeal, salivary gland, and thyroid cancer. OBJECTIVE: Therapeutic innovations for special otorhinolaryngological tumor entities with potential clinical relevance were assessed after reviewing the studies presented at the ASCO 2022/ESMO 2022 meetings. MATERIALS AND METHODS: The presented clinical phase II and phase III studies were analyzed. Results were classified according to their potential clinical importance, taking into account current treatment standards. RESULTS: Three studies were presented that dealt with the topic of risk-adapted treatment stratification in advanced nasopharyngeal cancer. Dose-reduced radiotherapy (60 Gy) in low-risk patients resulted in a favorable toxicity profile with promising oncological results in a single-arm phase II study. In a phase III study, intensity-modulated radiotherapy alone showed comparable survival to combined radiochemotherapy with cisplatin in selected low-risk patients. In high-risk patients, addition of the EGFR antibody nimotuzumab to definitive radiochemotherapy showed an increased 5­year survival rate compared to placebo (phase III study). Although an immediate change in clinical practice in Europe based on these studies is questionable, the concept of risk-adapted therapy taking into account biological characteristics (Epstein-Barr virus [EBV] DNA level) is future orientated. Similar to previous years, the contributions on recurrent/metastatic salivary gland and thyroid cancer emphasized the importance of targeted therapies based on vulnerable molecular target lesions.

[Special tumor entities in the head and neck region : Nasopharyngeal carcinoma, salivary gland, and thyroid cancer]. / Spezielle Tumorentitäten im Kopf-Hals-Bereich : Nasopharynxkarzinom, Speicheldrüsenkarzinom und Schilddrüsenkarzinom.

BACKGROUND: In recent years the number of studies on special tumor entities in the head and neck region has increased. During the 2021 meetings of the American Society of Clinical Oncology (ASMO) and the European Society for Medical Oncology (ESMO), several studies were presented which predict changes in clinical treatment algorithms for nasopharyngeal carcinoma, salivary gland, and thyroid cancer. OBJECTIVE: Future treatment alterations in specific head and neck tumor entities were evaluated after screening clinical studies presented at the 2021 ASCO and ESMO meetings. MATERIALS AND METHODS: A systematic analysis of the phase II and III clinical trials for nasopharyngeal carcinoma, salivary gland, and thyroid cancer treatment presented at ASCO and ESMO 2021 was performed. Taking into account current treatment standards, the results are structured in terms of their potential clinical significance. RESULTS AND CONCLUSION: In curative treatment of advanced nasopharyngeal carcinoma, adjuvant therapy with capecitabine after primary chemoradiation should be discussed as a new standard. In the palliative treatment of nasopharyngeal carcinoma, an increasing role of immunotherapy can be predicted. Recurrent or metastatic salivary gland cancer can often be treated very effectively with targeted substances if molecular target lesions are present. Immunotherapies currently play a subordinate role; they only seem to be effective in a few patients with salivary gland cancer, who cannot currently be reliably identified using predictive markers. Patients with radioiodine-refractory differentiated thyroid cancer benefit from treatment with the multi-tyrosine kinase inhibitor cabozantinib after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy.

Analyzing tyrosine kinase activity in head and neck cancer by functional kinomics: Identification of hyperactivated Src family kinases as prognostic markers and potential targets.

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.

Endoscopic endonasal repair of complete bilateral choanal atresia in neonates.

Reported success rates of endoscopic choanal atresia (CA) surgery vary substantially due to a high heterogeneity in and between study groups. Comprehensive data on the unique patient cohort of newborns with bilateral CA are scarce. Our study aimed to close this gap by using narrow inclusion criteria and standardized surgical outcome parameters. A total of ten neonates who were diagnosed with bilateral complete CA and underwent endoscopic surgery at the Department of Otolaryngology, Head and Neck Surgery in the University Hospital of Munich between 2008 and 2017 were included. Preoperative findings, surgical procedures, outcome, and follow-up were analyzed. Standardized criteria were used to assess surgical outcome. Almost all patients (90%) required at least one revision procedure within the first 6 months after initial surgery because of symptomatic partial or complete restenosis. After that, all surviving patients remained asymptomatic until the end of the follow-up period.Conclusion: Endoscopic bilateral CA repair in neonates is a safe procedure with a high long-term success rate. However, compared to other patient groups with choanal obstruction, restenosis occurs frequently, and revision procedures are required in a large number of cases. This should be considered during preoperative planning and parent counseling. What is Known: • Bilateral complete choanal atresia (CA) is a neonatal emergency that requires surgical intervention. • Reported success rates of endoscopic choanal obstruction repair are highly variable and mostly derived from heterogenous study groups that do not reflect the situation in neonates adequately. What is New: • This study focuses exclusively on newborns with complete bilateral CA who underwent endoscopic surgery within the first 28 days of life and uses standardized criteria to assess outcome. • The long-term success rate of endoscopic bilateral CA repair in neonates is high; however, almost all patients require at least one revision procedure within the first 6 months.

Review of surgical techniques and guide for decision making in the treatment of benign parotid tumors.

PURPOSE: Surgical treatment of benign parotid tumors has developed in the direction of less invasive procedures in recent years and has raised great debate about the best surgical approach. Aim of this article is to analyse anatomical and other factors that are important in selection of the appropriate surgical technique in treatment of benign parotid tumors. Furthermore, to discuss the risk of complications and recurrent disease according to selected operation. Finally, to define patient selection criteria to facilitate decision making in parotid surgery and become a guide for younger surgeons. METHODS: Literature review and authors' personal opinions based on their surgical experience. RESULTS: All possible surgical techniques for benign parotid surgery with advantages and disadvantages are being described. An algorithm with anatomical and other criteria influencing decision making in benign parotid surgery is presented. CONCLUSION: Surgeons nowadays have many options to choose from for benign parotid surgery. ECD is one of the many surgical techniques available in parotid surgery and can achieve excellent results with proper training and if used for proper indications. PSP is mainly indicated in large tumors of the caudal part of the PG (ESGS level II). SP represents a universal solution in parotid surgery and should be the first technique young surgeons learn. TP has only few but important indications in benign parotid surgery. Surgeons need to carefully consider the patient and his/her preoperative imaging as well as her or his own special expertise to select the most appropriate surgical technique.

ENT Residents Benefit from a Structured Operation Planning Approach in the Training of Functional Endoscopic Sinus Surgery.

Background and Objectives: Preoperative planning utilizing computed tomographies (CT) is of utmost importance in functional endoscopic sinus surgery (FESS). Frequently, no uniform documentation and planning structures are available to residents in training. Consequently, overall completeness and quality of operation planning may vary greatly. The objective of the present study was to evaluate the impact of a structured operation planning (SOP) approach on the report quality and user convenience during a 4-day sinus surgery course. Materials and Methods: Fifteen participant were requested to plan a FESS procedure based on a CT scan of the paranasal sinuses that exhibited common pathological features, in a conventional manner, using a free text. Afterwards, the participants reevaluated the same scans by means of a specifically designed structured reporting template. Two experienced ENT surgeons assessed the collected conventional operation planning (COP) and SOP methods independently with regard to time requirements, overall quality, and legibility. User convenience data were collected by utilizing visual analogue scales. Results: A significantly greater time expenditure was associated with SOPs (183 s vs. 297 s, p = 0.0003). Yet, legibility (100% vs. 72%, p < 0.0001) and overall completeness (61.3% vs. 22.7%, p < 0.0001) of SOPs was significantly superior to COPs. Additionally, description of highly relevant variants in anatomy and pathologies were outlined in greater detail. User convenience data delineated a significant preference for SOPs (VAS 7.9 vs. 6.9, p = 0.0185). Conclusions: CT-based planning of FESS procedures by residents in training using a structured approach is more time-consuming while producing a superior report quality in terms of detailedness and readability. Consequently, SOP can be considered as a valuable tool in the process of preoperative evaluations, especially within residency.

Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (TopROC).

BACKGROUND: For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control. METHODS: TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program. DISCUSSION: This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine. TRIAL REGISTRATION: NCT03691441 Registered 1 October 2018 - Retrospectively registered.

Rationale and Design of the Hamburg City Health Study.

The Hamburg City Health Study (HCHS) is a large, prospective, long-term, population-based cohort study and a unique research platform and network to obtain substantial knowledge about several important risk and prognostic factors in major chronic diseases. A random sample of 45,000 participants between 45 and 74 years of age from the general population of Hamburg, Germany, are taking part in an extensive baseline assessment at one dedicated study center. Participants undergo 13 validated and 5 novel examinations primarily targeting major organ system function and structures including extensive imaging examinations. The protocol includes validate self-reports via questionnaires regarding lifestyle and environmental conditions, dietary habits, physical condition and activity, sexual dysfunction, professional life, psychosocial context and burden, quality of life, digital media use, occupational, medical and family history as well as healthcare utilization. The assessment is completed by genomic and proteomic characterization. Beyond the identification of classical risk factors for major chronic diseases and survivorship, the core intention is to gather valid prevalence and incidence, and to develop complex models predicting health outcomes based on a multitude of examination data, imaging, biomarker, psychosocial and behavioral assessments. Participants at risk for coronary artery disease, atrial fibrillation, heart failure, stroke and dementia are invited for a visit to conduct an additional MRI examination of either heart or brain. Endpoint assessment of the overall sample will be completed through repeated follow-up examinations and surveys as well as related individual routine data from involved health and pension insurances. The study is targeting the complex relationship between biologic and psychosocial risk and resilience factors, chronic disease, health care use, survivorship and health as well as favorable and bad prognosis within a unique, large-scale long-term assessment with the perspective of further examinations after 6 years in a representative European metropolitan population.

Implementation analysis of patient reported outcomes (PROs) in oncological routine care: an observational study protocol.

BACKGROUND: The successful implementation of patient-reported outcomes (PROs) in clinical routine faces many challenges, first and foremost the lack of consideration thereof in the patient care process. The aim of this study will be to first identify relevant barriers and facilitators and then design suitable implementation strategies which will be evaluated to improve the effectiveness of a PRO measure assessment in inpatient and outpatient cancer routine care. METHODS: During the preparation phase, interviews with oncological patients (N = 28) and medical staff (N = 4) as well as focus groups with medical staff (N = 18) across five different departments caring for cancer patients were conducted. On the basis of these, qualitative content analysis revealed relevant barriers and facilitators for implementation of PROs in cancer care. Subsequently, implementation strategies and a model of implementation were developed. In the study phase, implementation strategies will be evaluated based on nine different implementation outcomes in five different oncological clinics. Evaluation of the implementation process will take place during three months in each clinic and data will be conducted pre, while and post implementation of the PRO measure. Therefore a sample size of 60 participants of whom 30 staff members and 30 participants will be questioned using existing and newly developed implementation outcome evaluation instruments. DISCUSSION: Key to improving the effectiveness of PRO assessment in the time-critical clinical environment is the utilization of easy-to-use, electronic PRO questionnaires directly linked to patients' records thereby improving consideration of PROs in patient care. In order to validate the effectiveness of this implementation process further, an evaluation parallel to implementation following an observational study design with a mixed-methods approach will be conducted. This study could contribute to the development of adequate evaluation processes of implementation of PROs to foster sustainable integration of PRO measures into routine cancer care. TRIAL REGISTRATION: This study was registered at Open Science Framework (https://osf.io/y7xce/).

Phase III study of nivolumab alone or combined with ipilimumab as immunotherapy versus standard of care in resectable head and neck squamous cell carcinoma.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) often requires postoperative chemoradiation with high risk of toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining nivolumab (N), a PD-1-inhibitor and ipilimumab (I), a CTLA4- inhibitor, may improve DFS due to antitumor effects of immunotherapy. The IMSTAR-HN study compares neoadjuvant N and N ± I 6 months after adjuvant therapy versus standard therapy as first-line treatment for LA-HNSCC. Eligible patients have treatment-naive LA-HNSCC, Eastern cooperative oncology group performance score (PS) ≤1 and no distant metastasis. 276 patients will be randomized into two arms. Primary endpoint is DFS and secondary endpoint includes locoregional control (LRC) and overall survival (OS). This study is one of the first in HNSCCs implementing immunotherapy in first-line treatment in a curative setting. Clinical Trial Registration: NCT03700905 (ClinicalTrials.gov).

Fibroblast Growth Factor 23-Producing Phosphaturic Mesenchymal Tumor with Extraordinary Morphology Causing Oncogenic Osteomalacia.

A possible cause of hypophosphatemia is paraneoplastic secretion of fibroblast growth factor 23 (FGF-23). Tumors secreting FGF-23 are rare, mostly of mesenchymal origin, usually benign, and may be located anywhere in the body, including hands and feet, which are often not represented in conventional imaging. A 50-year-old woman presented with diffuse musculoskeletal pain and several fractures. Secondary causes of osteoporosis were excluded. Laboratory analysis revealed hypophosphatemia and elevated alkaline phosphatase, parathyroid hormone, and FGF-23. Thus, oncogenic osteomalacia due to neoplastic FGF-23 secretion was suspected. FDG-PET-CT and DOTATATE-PET-CT imaging demonstrated no tumor. Cranial MRI revealed a tumorous mass in the left cellulae ethmoidales. The tumor was resected and histopathological examination showed a cell-rich tumor with round to ovoid nuclei, sparse cytoplasm, and sparse matrix, resembling an olfactory neuroblastoma. Immunohistochemical analysis first led to diagnosis of olfactory neuroblastoma, which was later revised to phosphaturic mesenchymal tumor. Following the resection, FGF-23 and phosphate levels normalized. In conclusion, we here describe a patient with an FGF-23-secreting phosphaturic mesenchymal tumor with an unusual morphology. Furthermore, we emphasize diagnostic pitfalls when dealing with FGF-23-induced hypophosphatemia.