Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
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- 277775 (2)
Background
Healthcare workers and medical students faced new challenges during the COVID-19 pandemic. Processes within many hospitals were completely disrupted. In addition, the face to face teaching of medical students was drastically reduced. Those at risk of developing mental health problems appear to be younger health care workers and women.
Objective
To investigate potential COVID-19 pandemic-related gender differences in psychological distress among medical students and physicians in their first years of practice.
Design and setting
An anonymous survey was carried out online between December 1, 2021, and March 31, 2022, at the Mannheim Medical Faculty and the Würzburg Medical Faculty, Germany, after obtaining informed consent. Primary outcome measures were changes in anxiety and depression symptoms using the Hospital Anxiety and Depression Scale (HADS), and changes in participants' current quality of life using the WHO Quality of Life BREF.
Results
The results show wave-like courses for perceived anxiety and burden overlapping with the course of the COVID-19 incidence. In comparison to men, women showed a significant higher increase in HADS (p = 0.005) and a reduced life quality (p = 0.007) after COVID-19. Both sexes showed different frequencies of the factors influencing quality of life, with the presence of a previous mental illness and mean anxiety having a significant higher negative impact in women.
Conclusion
Future and young female physicians reported a disproportionate higher burden during COVID-19 compared to their male colleges. These observations suggest an increased need for support and prevention efforts especially in this vulnerable population.
ICIs sind inzwischen integrales Therapiemittel vieler Tumoren, selbst in nicht metastasierten Stadien. Das Management von dabei eventuell entstehenden Nebenwirkungen bleibt wichtiger Bestandteil der Therapie vor allem im fortgeschrittenen Alter. Retrospektive Untersuchungen wie unsere tragen dazu bei, das in vielen klinischen Studien unterrepräsentierte Patientenkollektiv älterer Patienten in den klinischen Alltag sowie in Therapieentscheidungen und -planungen zu integrieren.
Der primäre Studienendpunkt unserer Arbeit unterstützt wichtige Erkenntnisse anderer Studien, dass irAEs insgesamt unter älteren Patienten nicht häufiger auftreten. Zwischen allen drei Altersklassen von ~55, ~70 und ~80 Jahren zeigten sich keine signifikanten Unterschiede im Auftreten von irAEs aller Grade, wobei irAEs Grad III/IV etwas häufiger bei ~80-Jährigen auftraten. In unserem Fall stellten wir fest, dass auftretende irAEs im Alter häufiger behandelt wurden, und dass die Immuntherapie häufiger pausiert oder abgebrochen wurde. Zudem war der Anteil an Therapieabbrüchen unter den älteren Patienten wegen bestimmter Ereignisse wie TRAEs und dem Einsatz von Glukokortikoiden höher als bei jüngeren Patienten.
Die Ergebnisse unserer Studie deuten außerdem darauf hin, dass selbst unter Polypharmazie und Multimorbidität irAEs nicht häufiger bei Älteren auftraten. Ebenso können wir die interessante Beobachtung verzeichnen, dass Patienten mit >5 Medikamenten und gleichzeitig >5 Erkrankungen signifikant mehr irAEs Grad III/IV aufwiesen oder mehr Patienten Glukokortikoide verabreicht bekommen haben. Auch der Anteil an Interventionsbedarf oder Therapieabbruch war hier in allen Altersklassen höher. Es stellt sich die Frage, inwiefern hohes Alter, Komorbidität und Polypharmazie Risikofaktoren für Interventionsbedarf oder Therapieabbruch in der Immuntherapie sind, und ob ihnen eher besondere Gewichtung als Risikofaktor zukommt als dem Alter selbst.
Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin — a transcription factor repressed by active glycogen synthase kinase 3 (GSK3) — is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC.
Severe and prolonged liver damage in pityriasis rubra pilaris treated with acitretin: a case report
(2022)
Acitretin is a systemic retinoid that is used in dermatology for treatment of various inflammatory and especially hyperkeratotic diseases. Elevation of liver enzymes may occur occasionally but normally resolves spontaneously, at the latest after termination of acitretin. However, it can very rarely develop into a life-threatening adverse event including drug-induced liver injury (DILI). A 45-year-old man with classical pityriasis rubra pilaris, a frequently severe, inflammatory skin disease, was started on acitretin. After a seemingly harmless elevation of transaminases, a few weeks after initiation of acitretin, the patient experienced a dramatic course of liver injury with hepatic jaundice though acitretin was stopped immediately. Eventually, laboratory values recovered upon high-dose oral prednisolone therapy. Prescribing physicians should keep in mind that acitretin might induce severe liver injury. Even after termination of acitretin laboratory values should be monitored for a while in order to recognize symptomless but harmful drug-induced liver injury in time.
The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors.
(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.
Forkhead box O transcription factors are a family of proteins involved in cellular processes downstream of the Insulin-PI3K-PKB pathway. In response to extra- or intracellular stresses, for example starvation or oxidative stress, FoxOs are required to direct cell cycle progression and apoptosis. In endothelial cells, they induce apoptosis, and their deregulation is linked to diseases involving the insulin pathway, such as diabetes. FoxOs also exhibit a complex role in tumour transformation: here their main function is to suppress tumorigenesis. In both physiological and cancer contexts, FoxO activation leads to the transcription of some general targets, such as p27kip1 or IGFBP1. The FoxOs can also induce tissue-specific genes, as ANGPT2 and BIM in the endothelium.
In endothelial cells, another pathway with a pivotal function is the MEK5/ERK5 MAPK signalling way. Its activation promotes cell survival and proliferation in stressful conditions, e.g., when blood vessels are exposed to the shear forces exerted by the blood stream. Furthermore, recent data described ERK5 as a kinase directing tumour resistance upon therapy-induced stress.
Comparing their reported roles in various tumours and in the endothelium, FoxO proteins and the MEK5/ERK5 MAPK cascade appear to exert opposite functions. First non-published data confirmed the hypothesis that FoxO factors are subject to a negative modulation by the MEK5/ERK5 pathway. Hence, one goal of this PhD project was to further characterise this crosstalk at molecular level. The major mechanism of FoxO regulation is the balance among several post translational modifications, such as phosphorylation, acetylation, and ubiquitination. Most importantly, the PKB dependent phosphorylation of FoxOs negatively controls their activity, and it is critical for their subcellular localization. Therefore, the regulation of FoxO localization as mechanism of ERK5 dependent suppression was studied, but the results presented in this thesis argue against this hypothesis. However, additional experiments are required to explore the impact of ERK5 activity on FoxO post-translational modifications.
FoxO activity can also be modulated by the interaction with other proteins, which in turn could explain general- and tissue-specific gene expression. Thus, another objective of this work was to investigate FoxO3-interactome in endothelial cells and the impact of MEK5/ERK5 activation on it. As published in (Fusi et al. 2022) and presented here, this analysis unveiled TRRAP as new FoxO bound protein in several cell types. Moreover, the interaction did not rely on the capacity of the FoxOs to bind their consensus DNA sequences at the promoter of target genes. Functional data demonstrated that TRRAP is required for FoxO-dependent gene transcription in endothelial and osteosarcoma cells. In addition, TRRAP expression in the endothelium is important for FoxO induced apoptosis. In summary, the interaction between FoxO factors and TRRAP revealed a new regulatory mechanism of FoxO-dependent gene transcription. It remains to be analysed whether the MEK5/ERK5 cascade may exert its suppressive effect on FoxO activity by interfering with their binding to TRRAP and whether such a mechanism may be relevant for tumorigenesis.
Blue nevus is a benign melanocytic lesion, typically asymptomatic and of unknown etiology. Several histologic and clinical variants have been distinguished, the most frequent being common blue nevus, cellular blue nevus, and combined blue nevus. Although melanocytic nevi with a satellite lesion are usually suggestive of locally advanced malignant melanoma, very few cases of blue nevi with satellite lesions have been reported. The diagnosis of common or cellular blue nevi is generally straightforward; however, the presence of structures such as irregular edges or satellitosis are highly suggestive for malignancy, and differential diagnoses such as locally advanced malignant melanoma and malignant blue nevus should be considered. Recurrent blue nevi can display atypical features not seen in the primary lesion, such as pleomorphism and mitotic activity. They usually tend to follow a benign course; however, in some cases, recurrence may indicate malignant transformation. We here report the unique case of a 64-year-old woman with a recurrent cellular blue nevus accompanied by satellite lesions. Such a biological behavior resulting in a clinical presentation as a melanoma-like lesion is a rarity in blue nevus and has not been described before.
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.