HPV-positive und -negative Plattenepithelkarzinome der Kopf-Hals-Region – Interaktionen in der Tumorstammzellnische am Beispiel der SDF-1α/CXCR4-Achse

Es wird diskutiert, dass Tumorstammzellen dafür verantwortlich sind, dass maligne Tumore nach initialem Therapieansprechen lokale Rezidive und Metastasen bilden. Diese Zellpopulation zeigt eine Resistenz gegenüber Chemotherapeutika und Bestrahlung. Ein möglicher Faktor für die Vermittlung dieser Resistenz stellt ihre Kommunikation mit ihrer Mikroumgebung, der Tumorstammzellnische, dar. Dabei gilt das Zytokin SDF-1α mit seinem Rezeptor CXCR4 als bedeutsamer Mediator. Patienten mit Humane-Papillomaviren (HPV)-positiven Plattenepithelkarzinomen der Kopf-Hals-Region (HNSCC) haben eine deutlich höhere Überlebensrate als solche mit HPV-negativen. In dieser Dissertation wurde der Einfluss von SDF-1α auf das Proliferations-, Migrations- und Morphologieverhalten einer HPV-positiven und zweier HPV-negativer Tumorzelllinien untersucht. Es wurde die Expression des Tumorstammzell-Markers CD44 und des SDF-1α-Rezeptors CXCR4 mittels Immunfluoreszenz und Immunhistologie in allen drei Zelllinien nachgewiesen. Unter dem Einfluss von SDF-1α wurden signifikant mehr Zellen der HPV-negativen Zelllinie UM-SCC 14C zur chemotaktischen Migration stimuliert, nicht jedoch in der HPV-positiven Zelllinie CERV196. SDF-1α stimulierte die Podienbildung der HPV-negativen Zelllinien in einer dosisabhängigen Korrelation. Im Gegensatz dazu war die Ausbildung von Podien in der HPV-positiven Zelllinie durch SDF-1α nicht signifikant stimulierbar. Die Proliferation war in keiner der Zelllinien durch SDF-1α beeinflussbar. Die HPV-negativen Zelllinien waren somit deutlich besser durch SDF-1α stimulierbar als die HPV-positive Zelllinie. Dies passt zu der klinisch überlegenen Prognose von HPV-positiven HNSCC, da die Podienbildung und die zielgerichtete Migration Voraussetzungen für lokale Invasion und Metastasierung darstellen. Zusätzlich dazu wäre der protektive Einfluss der Tumorstammzellnische auf die Tumorstammzellen eingeschränkt. Eine mögliche Erklärung hierfür bietet die formulierte Hypothese, dass Schlüsselproteine der SDF-1α/CXCR4-Achse durch virale Onkogene des HPV mutiert werden und ihre physiologische Funktion nicht mehr erfüllen können. Die hier gewonnenen Erkenntnisse tragen dazu bei, die Kommunikation in der Tumorstammzellnische besser zu verstehen. Ein verbessertes Verständnis derselben könnte neue therapeutische Strategien aufzeigen, welche gezielt die bestehenden Resistenzmechanismen angreifen könnten

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

IntroductionCheckpoint 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 methodsData 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.ResultsIrAE 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.DiscussionEven 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

Anosmia Testing as Early Detection of SARS-CoV-2 Positivity; A Prospective Study under Screening Conditions

Sudden onset of anosmia is a phenomenon often associated with developing COVID-19 disease and has even been described as an initial isolated symptom in individual cases. In this case-control study, we investigated the feasibility of this condition as a suitable screening test in a population at risk. We performed a prospective study with a total of 313 subjects with suspected SARS-CoV-2 infection. In parallel to routine PCR analysis, a modified commercial scent test was performed to objectify the presence of potential anosmia as a predictor of SARS-CoV-2 positivity. Furthermore, a structured interview assessment of the participants was conducted. A total of 12.1% of the study participants had molecular genetic detection of SARS-CoV-2 infection in the nasopharyngeal swab. It could be demonstrated that these subjects had a significantly weaker olfactory identification performance of the scents. Further analysis of the collected data from the scent test and medical history via random forest (Boruta) algorithm showed that no improvement of the prediction power was achieved by this design. The assay investigated in this study may be suitable for screening general olfactory function. For the screening of COVID-19, it seems to be affected by too many external and internal biases and requires too elaborate and selective pre-test screening

Post-COVID-19 Impairment of the Senses of Smell, Taste, Hearing, and Balance

Background: Various symptoms have been associated with COVID-19, but little is known about the impacts of COVID-19 on the sensory system, risk factors, and the duration of symptoms. This study assesses olfactory, gustatory, hearing, and vestibular systems after COVID-19. Methods: This cross-sectional, single-center study involved 50 patients one to six months after COVID-19 and reports their patient records and the extent, onset, and duration of olfactory, gustatory, hearing, and balance disorders using questionnaires during and after COVID-19. Sensory symptoms were objectively studied using the following clinical tests after COVID-19 Sniffin’ Sticks, taste tests, tone/speech audiometry, and video head impulse test. Results: Post-COVID-19-patients were suffering from olfactory and gustatory impairment for up to six months. According to the Dizziness Handicap Inventory, balance disorders were less noticed: Overall, about 40% of the patients during COVID-19 and nearly all patients recovered within six months. After COVID-19, clinical tests revealed that 75% were suffering from hyposomnia/anosmia, and 20% of all patients reported mild hypogeusia for up to six months. Vestibular disorders and hearing impairment rarely/did not occur. Females were significantly more affected by sensory impairments than males. Conclusions: COVID-19 particularly caused olfactory and gustatory impairment; balance disorders were present too; vestibular and auditory symptoms were negligible