[Inverted papilloma of the nose and paranasal sinuses : Diagnosis, treatment, and malignant transformation]. / Invertiertes Papillom der Nase und Nasennebenhöhlen : Diagnostik, Therapie und maligne Transformation.

Inverted papilloma (IP) are benign tumors that show a locally aggressive behavior, a high rate of recurrence, and a potential for malignant transformation. Specific radiological signs such as hyperostosis at the origin of the IP and convoluted cerebriform patterns, as well as the typical endoscopic aspect, can lead to diagnosis and enable preoperative planning of surgical access and the extent of surgery. Endonasal endoscopic techniques are considered the gold standard and the introduction of extended surgical techniques such as the prelacrimal approach, frontal drillout, or orbital transposition facilitate complete subperiosteal resection with preservation of important physiological structures. There is a risk of synchronous and metachronous squamous cell carcinomas (IP-SCC). Research focuses on radiological criteria to differentiate benign IP from IP-SCC, genetic and epigenetic factors in the process of malignant transformation, and estimation of the risk of IP progressing to IP-SCC.

["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.

[Fundamentals and practice of the application of nasal packing in sinonasal surgery]. / Grundlagen und Praxis der Anwendung von Nasentamponaden in der endonasalen Chirurgie.

BACKGROUND AND OBJECTIVES: This paper presents an overview on nasal packing materials which are available in Germany. The current literature is analyzed whether there are robust criteria regarding use nasal packing after sinonasal surgery, whether there are fundamental and proven advantages or disadvantages of products, and what this means in clinical practice. MATERIALS AND METHODS: Selective literature analysis using the PubMed database (key words "nasal packing", "nasal tamponade", "nasal surgery", "sinonasal surgery", or "sinus surgery"), corresponding text books and resulting secondary literature. RESULTS AND CONCLUSIONS: Because of systematic methodological shortcomings, the literature does not help in the decision-making about which nasal packing should be used after which kind of sinonasal surgery. In fact, individual approaches for the many different clinical scenarios are recommended. In principle, nasal packing aims in hemostasis, should promote wound healing, and should not result in secondary morbidity. Nasal packing materials should be smooth (non-absorbable materials), inert (absorbable materials), and should not exert excessive pressure. Using non-absorbable packing entails the risk of potentially lethal aspiration and ingestion. For safety reasons inpatient control is recommended as long as this packing is in situ. With other, uncritical packing materials and in patients with special conditions, outpatient control could be justified.

[Sinunasal surgery as outpatient procedure with special consideration of nasal packing - Position paper of the German Society of Otorhinolaryngology, Head and Neck Surgery, the working group Rhinology / Rhinosurgery (ARHIN) of the German Society of Otorhinolaryngology, Head and Neck Surgery and German Professional Association of Otorhinolaryngologists]. / Ambulante Durchführung rhinochirurgischer Operationen unter Berücksichtigung des Einsatzes von Nasentamponaden Positionspapier der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie, der Arbeitsgemeinschaft Rhinologie/Rhinochirurgie (ARHIN) der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie und des Deutschen Berufsverbandes der HNO-Ärzte.

OBJECTIVE: Currently, there is an intensive discussion on advancing and expanding outpatient rhinosurgical procedures. Many questions about how to stratify into out- and inpatient procedures are still not sufficiently clarified. Particularly, the use of nasal packing materials is not adequately discussed. MATERIAL AND METHODS: Development of a checklist to stratify sinunasal procedures into in- or outpatient procedures with consideration of current scientific literature and risk factors. RESULTS AND CONCLUSIONS: After comprehensive assessment of the literature and analysis of specific risk factors, a list of sinunasal procedures is presented, which should be performed as inpatient procedures. We present a checklist for in- and outpatient sinunasal procedures, which considers social, medical and surgical factors as well as the use of nasal packing materials. Furthermore, a checklist is added to assess, whether patients are ready for discharge after a planned outpatient procedure.

[Survey on the use of nasal tamponades in sinunasal surgery]. / Umfrage zum Einsatz von Nasentamponaden in der sinunasalen Chirurgie.

OBJECTIVE: Currently, there is an intensive discussion about enhancing and expanding outpatient rhinosurgical procedures. Many questions about how to stratify into out- and inpatient procedures are still not sufficiently clarified. Particularly, the use of nasal packing materials is not adequately discussed. MATERIAL AND METHODS: We performed a Germany-wide survey among otorhinolaryngologists regarding the use of nasal packing materials in sinonasal surgery. Additionally, we asked for any complication in relation to nasal packing. RESULTS: In 85,6% nasal packing was used for septal and turbinate surgery at least occasionally, in 44,2% always. In sinus surgery these numbers are 94,1% and 49%, respectively. Non-resorbable nasal packing materials were predominantly used.Most frequent complications were bleeding with nasal packing in situ (> 50% of respondents) and posterior dislocation (24% of respondents), requiring emergency treatment. Death was listed in 5 patients. One patient suffered from permanent brain damage due to hypoxia. CONCLUSIONS: Application of non-resorbable nasal packing materials with occlusion of the nasal cavity carry a substantial risk of complications, which necessitate emergency treatment, thus requiring inpatient care.

Cross-cultural adaptation and validation of the 22-item sinonasal outcome test (SNOT-22) in German-speaking patients: a prospective, multicenter cohort study.

PURPOSE: Chronic rhinosinusitis (CRS) is a common condition associated with a significant reduction of the health-related quality of life. One of the most widely used assessment tools in CRS is the disease-specific, health-related questionnaire SNOT-22. The aim of this study was to translate and validate the SNOT-22 into the German language. METHODS: The questionnaire was translated using the forward-backward translation technique. After the translation its reliability, validity, and sensitivity were evaluated. For this purpose, the questionnaire was completed by patients diagnosed with CRS before, 3 months and 1 year after endoscopic sinus surgery and by healthy individuals as controls at three university hospitals in Germany. The individual scores of the questionnaire before surgery was correlated with the Lund-Mackay score as well as a global disease-specific question. RESULTS: A total of 139 CRS patients and 31 healthy individuals participated in the study. Internal consistency at all timepoints was very good, with Cronbach's alpha scores of 0.897, 0.941, and 0.945. The questionnaire was able to discriminate between CRS patients and control subjects (p < 0.0001) and scores improved significantly 3 month and 1 year after sinus surgery (p < 0.0001), indicating a good test-retest reliability, validity, and responsiveness. A significant correlation to the single global disease-specific question could be found (p < 0.0001), but no correlation with the Lund-Mackay score. CONCLUSION: The German Version of the SNOT-22 is a reliable, valid, and sensitive instrument for measuring health-related quality of life in patients with CRS. It can be recommended for clinical practice and outcome research for German-speaking patients.

Partial Maxillectomy for the Improvement of Nasal Obstruction Can Be Combined with Septorhinoplasty.

We describe the (anteromedial) partial maxillectomy technique which can be used to address impaired nasal breathing in cases of significant protrusion of the frontal process of the maxilla into the nasal cavity, narrowing the nasal pathway. It fits to nasal physiology avoiding mucosal resection. It can be combined with surgery of the inferior turbinate. The described technique can be used in all forms of rhinoplasty.

[Evaluation of a structured e-learning-based approach to CT anatomy of the paranasal sinuses for medical students : A pilot study]. / Evaluation eines strukturierten E­Learning-basierten Ansatzes zur Vermittlung der CT-Anatomie der Nasennebenhöhlen bei Medizinstudierenden : Eine Pilotstudie.

BACKGROUND: Computed tomography (CT) anatomy is not an integral part of undergraduate medical training in many countries. Radiology seems to be well suited for new online-based teaching methods. OBJECTIVE: The aim of this study was to evaluate whether e­learning is appropriate for introducing complex learning contents such as sinus CT anatomy to novices and to assess whether identification of relevant anatomical variants in sinus CT scans by medical students can be improved with a sinus CT checklist. MATERIALS AND METHODS: Medical students were asked to assess sinus CT scans for anatomical variants before and after implementation of the CLOSE mnemonic (cribriform plate, lamina papyracea, Onodi cell, sphenoid sinus pneumatization, and [anterior] ethmoidal artery). Sinus CT anatomy and the CLOSE mnemonic were introduced by e­learning. The rate of correctly identified variants and the results of the individual CLOSE items were recorded. A questionnaire was distributed for subjective evaluation of the usefulness of the checklist and e­learning. RESULTS: Ten students took part in this pilot study. The rate of correctly identified variants improved significantly, from 33.3 to 61.1%. The analysis of the individual CLOSE items showed a significant improvement for C, S, and E. The subjective evaluation of the CLOSE mnemonic and e­learning was very positive. CONCLUSION: E­learning was able to transfer complex learning contents in previously non-trained medical students and was evaluated as an appropriate introduction to the topics. Structured assessment of paranasal sinus CT scans using the CLOSE criteria can significantly improve the recognition of anatomical variants.

[Risk profile analysis of stationary epistaxis patients]. / Analyse des Risikoprofils stationärer Epistaxis-Patienten.

BACKGROUND: Epistaxis is a disease well known to general practitioners and ENT specialists in the outpatient sector as well as in hospitals. The aim of this study was to analyze data of patients that were treated as inpatients at the ENT university hospital Freiburg between 2014-2018. MATERIALS AND METHODS: This retrospective study analyzes data of admitted patients with epistaxis regarding age, medication, bleeding site, underlying health conditions, radiological imaging and treatment. Risk factors for longer inpatient length of stay and readmission were identified. RESULTS: Median length of stay was 3.5 days. 55 % of the patients suffered from posterior epistaxis. 72.3 % of patients were treated with anticoagulants at the time of admission. The most prevalent medical conditions were hypertension (66 %) and arrhythmia due to atrial fibrillation (36.1 %). 63.5 % of the patients were treated by nasal packing. 97 patients (14.6 %) had to be treated surgically. Surgical treatment, transfusion, posterior epistaxis and anticoagulant treatment were risk factors for longer length of inpatient stay. Preexisting hypertension, posterior bleeding and single anticoagulant treatment increased the risk of readmission. CONCLUSIONS: Determination and consideration of risk factors allow identification of patients at risk of longer inpatient length of stay and readmission. Adequate management accounting for risk profiles of patients could help reduce morbidity.

[Quality management in a postgraduate refresher course in otolaryngology]. / Qualitätssicherungssystem zur Bewertung eines HNO-Facharztrepetitoriums.

BACKGROUND: Residency training is often characterized by locally influenced training content and focus, which can lead to heterogeneous training outcomes. Refresher courses before the speciality certificate examinations can harmonize the situation. OBJECTIVE: The current publication aims to present a quality management system for evaluation of a postgraduate refresher course for otolaryngology residents. MATERIALS AND METHODS: The teaching sessions of a postgraduate course were evaluated using questionnaires. Descriptive statistics and multivariable binary logistic regression analysis were performed. To evaluate the factors leading to a negative perception of a teaching session, the focus was set on the worst 15% of all total ratings. An exemplary strength/weakness profile of a lecturer was created for individual feedback. RESULTS: Analysis of the evaluation results showed an overall average rating of 12.8 (±2.4) out of a maximum of 15 possible points. Multivariable regression determined the items "friendliness," "systematic structure," "own involvement," "prior knowledge," and "efficient teaching session" to be significant for a negative perception of a teaching session. Using the lecturer profile, the strengths and weaknesses of the individual lecturer can be shown in an objective manner. CONCLUSION: The developed questionnaire represents a good tool for quality management of a postgraduate refresher course for otolaryngology residents. This is achieved by regression analysis and creation of an individual lecturer profile, which provides an objective basis for improving the individual teaching session through detailed feedback to the lecturer.

Quality of Surgical Therapy of Chronic Inflammatory Diseases of the Paranasal Sinuses. / Qualität in der chirurgischen Therapie chronisch entzündlicher Erkrankungen der Nasennebenhöhlen.

Endonasal endoscopic surgery of the paranasal sinuses is the gold standard in surgical treatment of chronic inflammatory diseases of the paranasal sinuses. Improvement of subjective complaints and objective findings has been confirmed in numerous studies. Due to the discrepancy between objective and subjective results after paranasal sinus surgery, the assessment of patient reported outcomes has gained importance.Quality and efficiency in medicine became increasingly important during the last years. In many countries and transnationally, the association of experts, partly coordinated by different medical societies, led to initiatives focusing on improvement of the quality of surgical care.The present article represents an overview of quality-related factors in surgical treatment of chronic inflammatory diseases of the paranasal sinuses, summarizing the existing literature and focusing particularly on process and outcomes quality. Particular attention will be paid to the outcome quality individually assessed by the patients.

[Sinus surgery at German ENT departments - a regional survey]. / Nasennebenhöhlenchirurgie an deutschen HNO-Kliniken ­ eine Bestandsaufnahme.

OBJECTIVE: Sinus surgery has evolved dramatically over the last decades towards endonasal endoscopic techniques for the treatment of benign and malignant diseases of the paranasal sinuses. The aim of this survey was to capture the current state of sinus surgery in German ENT departments. MATERIAL AND METHODS: A questionnaire with questions regarding number of surgeries, surgical technique, interdisciplinary cooperation, postoperative care, CT-checklists, surgical training and quality of life was sent to all ENT departments in Germany. RESULTS: 79.5 % of questionnaires were answered and returned. 89.1 % of ENT departments state that they conduct 200-400 or more than 400 sinus surgeries per year for benign diseases of the paranasal sinuses. The number of sinus surgeries for malignancies of the paranasal sinuses is much smaller. Not all of the departments who take part in interdisciplinary tumor boards work in interdisciplinary surgical teams. Most of the departments declare that they use video endoscopy and surgical navigation systems for their surgeries. Surgical training for sinus surgery usually starts in year 2 to 4 and almost all trainees visit dissection courses during their training. In more than half of the departments CT checklists are used for preoperative analyses of CT scans. Quality of life before and after surgery is evaluated in only a few departments. CONCLUSION: Our investigation is a representative survey of current practice in sinus surgery in ENT departments in Germany.

Asymmetric hearing loss and the benefit of cochlear implantation regarding speech perception, tinnitus burden and psychological comorbidities: a prospective follow-up study.

OBJECTIVES: We determined the audiological outcome, the subjective and objective hearing quality in patients suffering from asymmetric hearing loss (AHL). Furthermore, we evaluated psychological comorbidities and tinnitus burden before and after cochlear implantation. STUDY DESIGN: Prospective cohort study. METHODS: 44 AHL patients were unilaterally implanted with a multichannel cochlear implant between 2011 and 2016. Speech discrimination (Freiburg Monosyllable Word Test, Oldenburg Sentence Test) was measured before, 6 and 12 months after implantation. Subjective hearing quality, health-related quality of life (HRQoL), tinnitus burden, anxiety, depressiveness, perceived stress level and coping abilities were evaluated before implantation, 6 and 12 months postoperative using specific validated questionnaires (Oldenburg Inventory, Nijmegen Cochlear Implantation Questionnaire, Tinnitus Questionnaire, General Anxiety Disorder-7, Depression Scale, Perceived Stress Questionnaire and Cope Inventory). RESULTS: Subjective and objective hearing quality, speech discrimination and health-related quality of life were significantly increased in AHL patients. Tinnitus burden significantly decreased over the 12 postoperative months. No significant alteration was observed for anxiety, depressiveness, coping abilities and stress level. CONCLUSIONS: This study demonstrates that cochlear implantation achieves hearing rehabilitation, increases HRQoL and decreases tinnitus burden in patients suffering from AHL. Subjective hearing quality increased, while tinnitus burden significantly decreased 6 and 12 months after implantation. HRQoL in AHL patients is an important factor to focus on and is significantly increased postoperatively. In contrast, general anxiety, depressiveness, coping abilities and perceived stress level remained unaffected.

The Diagnosis and Treatment of Chronic Rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous condition characterized by local chronic inflammation of the mucous membranes of the nose and paranasal sinuses. It affects approximately 5% of the population. METHODS: This review is based on relevant publications retrieved by a selective search of the literature, with particular attention to current national and international guidelines. RESULTS: CRS is defined by, and diagnosed on the basis of, a combination of symptoms and objective findings of nasal endoscopy and imaging studies. It markedly impairs quality of life and gives rise to both direct and indirect health care costs. In 20-45% of cases, CRS is associated with comorbid bronchial asthma and a significantly elevated risk of further diseases (e.g., COPD, OR 1.73; depression, HR 1.50; obstructive sleep apnea, OR 1.91; carcinoma, OR 1.14-5.30). CRS is primarily treated medically with topical steroids (standardized mean difference of nasal symptoms, -0.63 (95% confidence interval [-0.89; -0.37]; standardized mean difference of quality of life as measured by SNOT -22, -5.46 [-8.08; -2.84]), as well as with nasal lavage and, as an option, systemic steroids (and antibiotics where appropriate). If appropriate medical treatment fails to bring about adequate and sustained improvement, endoscopic surgery on the paranasal sinuses is indicated. This improves the individual symptoms, the overall symptom score, and patients' quality of life. Severe refractory CRS with nasal polyposis can be treated with biological agents. CONCLUSION: CRS calls for individually adapted medical and/or surgical treatment.

Is the Position of the Basal-Most Electrode Depending on Electrode Array Design and Influencing Postoperative Speech Perception? A Retrospective Analysis of 495 Ears.

OBJECTIVE: The objective of this study is to examine the influence of electrode array design on the position of the basal-most electrode in cochlear implant (CI) surgery and therefore the stimulability of the basal cochlea. Specifically, we evaluated the angular insertion depth of the basal-most electrode in perimodiolar and straight electrode arrays in relation to postoperative speech perception. MATERIALS AND METHODS: We conducted a retrospective analysis of 495 patients between 2013 and 2018 using the Cochlear™ Contour Advance® (CA), Cochlear™ Slim Straight® (SSA), or Cochlear™ Slim Modiolar® (SMA) electrode arrays, as well as the MED-EL Flex24 (F24), MED-EL Flex28 (F28), and MED-EL FlexSoft (F31.5) electrode arrays. Cochlear size and the position of the basal-most electrode were measured using rotational tomography or cone beam computed tomography, and the results were compared with postoperative speech perception in monosyllables and numbers. RESULTS: The straight electrode arrays, specifically the F31.5 (31.5 mm length) and the F28 (28 mm length), exhibited a significantly greater angular insertion depth of the basal-most electrode. No significant correlation was found between cochlear morphology measurements and the position of the basal-most electrode artifact. Cochleostomy-inserted electrode arrays showed a significantly higher insertion depth of the basal-most electrode. Nevertheless, the position of the basal-most electrode did not have a significant impact on postoperative speech perception. CONCLUSION: Straight electrode arrays with longer lengths achieved deeper angular insertion depths of the basal-most electrode. Cochlear morphology does not have a substantial influence on the position of basal-most electrode. The study confirms that the basal area of the cochlea, responsible for high-frequency range during acoustic stimulation, is not the primary region for speech understanding via electrical stimulation with CI.

Reliability of High-resolution Gadolinium-enhanced MR Cisternography and Gasket-seal Technique for Management of Anterior Skull Base Defects.

PURPOSE: Precise preoperative localization of anterior skull base defects is important to plan surgical access, increase the success rate and reduce complications. A stable closure of the defect is vital to prevent recurrence of cerebrospinal fluid (CSF) rhinorrhea. The purpose of this retrospective case series was to evaluate the reliability of a new high-resolution gadolinium-enhanced compressed-sensing SPACE technique (CS T1 SPACE) for magnetic resonance (MR) cisternography to detect cerebrospinal fluid leaks of the anterior skull base and to assess the long-term success rate of the gasket-seal technique for closure of skull base defects. METHOD: All patients with spontaneous or postoperative cerebrospinal fluid rhinorrhea and defects of the anterior skull base presenting to the Departments of Otorhinolaryngology and Neurosurgery between 2019 and 2020, receiving a computed tomography (CT) cisternography and MR cisternography (on a 3T whole-body MR scanner using a 64-channel head and neck coil) with CS T1 SPACE sequence and closure of the defect with the gasket-seal technique, were enrolled in the study. For the cisternography, iodinated contrast agent (15 ml Solutrast 250 M®), saline (4 mL) mixed with a 0.5 mL of gadoteridol was injected into the lumbar subarachnoid space. RESULTS: A total of four patients were included in the study and MR cisternography with CS T1 SPACE sequence was able to precisely localize CSF leaks in all patients. The imaging results correlated with intraoperative findings. All defects could be successfully closed with the gasket-seal technique. The mean follow-up was 35.25 months (range 33-37 months). CONCLUSION: MR cisternography with CS T1 SPACE sequence could be a promising technique for precise localization of CSF leaks and the gasket-seal technique resulted in good closure of the CSF fistula in this case series.

A Virtual Reality Anatomy Model of the Temporal Bone in ORL Residency Training-Gain or Gadget?

OBJECTIVES: Virtual reality (VR) appears to be a promising educational tool for otorhinolaryngology (ORL) residency training, as it allows for safe and effective practice immediate feedback and potential improvements in patient outcomes. Despite these advantages, VR has not yet been incorporated into residency training in ORL, which may be due to limited availability or validation and skepticism toward incorporation of new training methods. This study investigates whether a VR model of the temporal bone improves learning success for ORL residents in comparison to standard plastic models and whether it depends on surgeon's experience. We also included a subjective evaluation of the learning experience with both models. METHODS: ORL residents and specialists at 2 German university hospitals were tested on their knowledge of temporal bone anatomy after training with either VR or standard plastic models. In addition, we compared knowledge of the temporal bone anatomy before- and after-VR training. Lastly, a subjective survey on the benefits and limitations of VR was conducted to assess participants' views on this new technology. RESULTS: About 85% of the participants considered VR to be better than conventional models and agreed that VR was a useful tool for teaching complex anatomy. Objective evaluation showed significant improvement in knowledge after using VR (before/after comparison), especially in participants with a higher level of preexisting knowledge. Direct comparison to conventional plastic models showed no superiority of the VR model. CONCLUSION: VR models in ORL are not only appealing and motivating for residents, but also objectively improve their anatomical knowledge, especially in advanced residency. In addition, VR-in contrast to the plastic model-offers opportunities for further development and optimization.

Real Life Observational Study of Treatment Success of Monoclonal Antibodies for Refractory Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a mainly type-2-driven inflammatory disease that is often refractory to medical and surgical treatment and characterized by a high rate of recurrence. Monoclonal antibodies have been approved for severe refractory CRSwNP. Randomized controlled trials (RCT) have shown significant improvement in objective and subjective parameters. The results of these RCTs cannot necessarily be transferred to daily routine. The purpose of this retrospective study is to evaluate the treatment effects of biologics in patients with CRSwNP in a real-life setting. Patients treated with one of the approved biologics since July 2020 with at least 6 months follow-up were included in the study. Changes in SNOT-22 and nasal polyp score (NPS), as well as subjective change in sense of smell, number of sinus surgeries prior to and during treatment, comorbidities, discontinuation or change of monoclonal antibody and adverse events were evaluated. Thirty-three patients were included in this study. The mean SNOT-22 score and NPS improved significantly. The subjective assessment of sense of smell showed an improvement in 81.8% of patients. The monoclonal antibody had to be changed in seven patients. No severe adverse events occurred during the initiation of the treatment and follow-up. Biologics can be a treatment option in patients with severe refractory CRSwNP, showing significant improvements in quality of life, symptoms and polyp scores in randomized controlled trials and clinical routine with rare complications. Further research is needed to evaluate possible biomarkers, interdose interval prolongation and long-term safety.