The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Δep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.

Over the past 60 years, hyaluronidase has been successfully utilized in ophthalmic surgery and is now being implemented in dermatosurgery as well as in other surgical disciplines. The enzyme is considered a “spreading factor” as it decomplexes hyaluronic acid (also called hyaluronan, HA), an essential component of the extracellular matrix (ECM). When applied as an adjuvant, hyaluronidase enhances the diffusion capacity and bioavailability of injected drugs. Therefore, the enzyme has been used as a local adjuvant to increase the diffusion capacity of local anesthetics, increasing the analgesic efficacy, and the anesthetized area particularly in the first minutes following injection, resulting in diminished intra- and postoperative pain. In aesthetic medicine, the off-label use of hyaluronidase is considered the gold standard for the management of HA-filler-associated complications. Here, we review the clinical use, underlying biological mechanisms, and future directions for the application of hyaluronidase in surgical and aesthetic medicine.

Background: The German government has made it mandatory to wear respiratory masks covering mouth and nose (MNC) as an effective strategy to fight SARS-CoV-2 infections. In many countries, this directive has been extended on shopping malls or public transportation. The aim of this paper is to critically analyze the statutory regulation to wear protective masks during the COVID-19 crisis from a medical standpoint. Methods: We performed an extensive query of the most recent publications addressing the prevention of viral infections including the use of face masks in the community as a method to prevent the spread of the infection. We addressed the issues of practicability, professional use, and acceptability based on the community and the environment where the user resided. Results: Upon our critical review of the available literature, we found only weak evidence for wearing a face mask as an efficient hygienic tool to prevent the spread of a viral infection. However, the use of MNC seems to be linked to relevant protection during close contact scenarios by limiting pathogen-containing aerosol and liquid droplet dissemination. Importantly, we found evidence for significant respiratory compromise in patients with severe obstructive pulmonary disease, secondary to the development of hypercapnia. This could also happen in patients with lung infections, with or without SARS-CoV-2. Conclusion: Epidemiologists currently emphasize that wearing MNC will effectively interrupt airborne infections in the community. The government and the politicians have followed these recommendations and used them to both advise and, in some cases, mandate the general population to wear MNC in public locations. Overall, the results seem to suggest that there are some clinically relevant scenarios where the use of MNC necessitates more defined recommendations. Our critical evaluation of the literature both highlights the protective effects of certain types of face masks in defined risk groups, and emphasizes their potential risks.

IntroductionPrimary brain and CNS tumor incidence is approximately 19 per 100,000 individuals per year in the United States compared with seven per 100,000 individuals worldwide. 1,2 Worldwide this accounts for 2% of all primary tumors and 7% of years of life lost from cancer before the age of 70 years. 1,2 Glioblastoma multiforme (GBM) is also the most aggressive brain tumor with poor prognosis; patients with GBM have a median survival time of about 14 months. [3][4][5][6][7][8][9][10] GBM metastases outside the CNS are rare, so therapeutic experience with these types of tumors is limited. 11-15 Normally the brain is immunologically and anatomically separated from the body by the blood brain barrier. Herein, we present the cases of three patients with GBM with extra-CNS metastasis. The variety of metastasis locations demonstrated in these cases helps to illustrate the various mechanism and corresponding risk factors that allow GBM to escape the CNS. Case ReportsPatient 1. A 51-year-old man presented with a general seizure. Magnetic resonance imaging (MRI) revealed a lesion in the left parieto-occipital lobe (Figs 1A and 1B). Coronal T1-weighted postcontrast ( Fig 1A) and axial T2-weighted cranial MRI (Fig 1B) demonstrated an enhancing left parietal mass involving small venules from the superior sagittal sinus (Figs 1A and 1B, arrows). The patient was diagnosed with a mixed diffuse glioma and underwent subtotal resection of the tumor and postoperative radiochemotherapy. The tumor progressed, and 5 years after diagnosis, the patient underwent contrast-enhanced fluorescence imaging-guided tumor reresection with a subsequent diagnosis of GBM. Two years later, follow-up MRI revealed recurrent tumor. After completing radiochemotherapy, the patient was hospitalized for progressive dyspnea. Chest X-ray revealed a pleural effusion requiring thoracic drainage. Axial contrastenhanced computed tomography demonstrated an ill-defined 4-cm mass in the left lower lung lobe (Fig 1C, arrow) and pleural metastases (Figs 1C and 1E, arrowheads) with infiltration of the chest wall and destruction of a ventrolateral left rib (Fig 1E, asterisks).The pleural lesion was biopsied, and histologic examination of the biopsy sample (Fig 1D, hematoxylin and eosin staining, ϫ200 original magnification) revealed a malignant astrocytic glioma.The patient underwent additional radiochemotherapy with concomitant temozolomide. He completed radiotherapy but died 4 weeks later.Patient 2. A 24-year-old man who had undergone resection of a left temporal GBM involving the greater wing of the sphenoid bone with invasion of the middle cranial fossa at an outside facility presented with anxiety and headaches. Postoperative MRI revealed on axial T1w postcontrast images a dural thickening and extraconal or-

Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses.

Dendritic cells (DCs) can release hundreds of membrane vesicles, called exovesicles, which are able to activate resting DCs and distribute antigen. Here, we examined the role of mature DC-derived exovesicles in innate and adaptive immunity, in particular their capacity to activate epithelial cells. Our analysis of exovesicle contents showed that exovesicles contain major histocompatibility complex-II, CD40, and CD83 molecules in addition to tumor necrosis factor (TNF) receptors, TNFRI and TNFRII, and are important carriers of TNF-␣. These exovesicles are rapidly internalized by epithelial cells, inducing the release of cytokines and chemokines, but do not transfer an alloantigen-presenting capacity to epithelial cells. Part of this activation appears to involve the TNF-␣-mediated pathway, highlighting the key role of DCderived exovesicles, not only in adaptive immunity, but also in innate immunity by triggering innate immune responses and activating neighboring epithelial cells to release cytokines and chemokines , thereby amplifying the magnitude of the innate immune response.

BackgroundAdjuvant radiotherapy (RT) of regional lymph nodes (LN) in early breast cancer is still a matter of debate. RT increases the Overall survival (OS) rate of breast cancer patients after breast conserving surgery and after mastectomy in patients with involved LN. The contribution of RT to regional LN to this improvement was poorly identified. Recently, the results of three large randomized trials addressing this question were published as full papers.Material and methodsPublished data of the MA.20 (n = 1832), the EORTC22922–10925 (EORTC) (n = 4004) trial and the French trial (n = 1334) were the foundation of this meta-analysis. Major eligibility criteria were positive i) axillary LN (all trials), ii) LN negative disease with high risk for recurrence (MA.20), and iii) medial/central tumor location (French, EORTC). The MA.20 and the EORTC trial analyzed the effect of additional regional RT to the internal mammary (IM) LN and medial supraclavicular (MS) LN, whereas in the French trial all patients received RT to the MS-LN and solely RT to the IM-LN was randomized. Primary endpoint was OS. Secondary endpoints were disease-free survival (DFS) and distant metastasis free survival (DMFS).ResultsRegional RT of MS-LN and IM-LN (MA.20 and EORTC) resulted in a significant improvement of OS [Hazard Ratio (HR) 0.88 (95 % CL 0.78 - 0.99)]. Adding results of the French trial and using a random effects model to respect the different design of the French trial, the effect on OS of regional RT remained significant [HR 0.90 (95 % CL 0.82 - 0.99)]. The absolute benefits in OS were 1 % in the MA.20 trial at 10 years, 1.6 % in the EORTC trial at 10 years, and 3.3 % in the French trial at 10 years (not significant in single trials). Regional RT of MS-LN and IM-LN (MA.20 and EORTC) yielded to a significant improvement of DFS [HR 0.86 (95 % CL 0.78 - 0.95)] and DMFS [HR 0.84 (95 % CL 0.75 - 0.94)].ConclusionAdditional regional RT to the internal mammary and medial supraclavicular LN statistically significantly improved DFS, DMFS, and OS in stage I-III breast cancer.

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