Metabolic Signature of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma: Expression of Hypoxia-inducible Factor-1α and Several of Its Downstream Targets

Metabolic reprogramming mediated by hypoxia-inducible factors play a crucial role in many human cancers. HIF-1α is activated under hypoxic conditions and is considered a key regulator of oxygen homoeostasis during tumor proliferation under hypoxia. Aim of this research was to analyze the immunohistochemical expression of HIF-1α, VEGF-A, Glut-1, MCT4, and CAIX in atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). 21 paraffin-embedded AFX and 22 PDS were analysed by immunohistochemis-try, namely HIF-1α, VEGF-A (referred to as VEGF throughout the manuscript), Glut-1, MCT4, and CAIX. To quantify the protein expression, we considered the percentage of positive tumor cells (0: 0%, 1: up to 1%, 2: 2-10%, 3: 11-50%, 4: >50%) in relation to the staining intensity (0: negative, 1: low, 2: medium, 3: strong). HIF-1α expression (mean ± SD) in AFX (9.33±2.92) was significantly stronger than that in PDS (5.90±4.38; P= 0.007), whereas the expression of VEGF, Glut-1, MCT4, and CAIX did not show differences between AFX and PDS. When comparing all tumors without subgroup stratification, the expression of HIF-1α (P= 0.044) and MCT4 (P= 0.036) was significantly stronger in ulcerated tumors than in tumors without ulceration. Our findings provide the first evidence that HIF-1α-induced metabolic reprogramming may contribute to the pathogenesis of AFX and PDS. HIF-1α expression seems to be higher in AFX than in PDS, and ulcerated tumors show higher expression levels of HIF-1α and MCT4 irrespective of the diagnosis

S1-Guideline Cutaneous Angiosarcomas - Update 2021

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Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Hemato-Oncological Diseases as Risk Factor for Recurrence or Metastasis of Pleomorphic Dermal Sarcoma

BackgroundAtypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are increasingly common sarcomas of the skin with a genetic UV signature. Immunosuppression is a known risk factor for developing other UV-induced skin cancers such as cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma with increased mortality. In case reports or small case series of AFX/PDS patients, immunosuppression has been hypothesized as a risk factor for the development of distant metastases. The aim of the present study was to analyze immunosuppression as a risk factor for AFX/PDS in a large patient cohort. MethodsA cohort of 164 patients with AFX/PDS (47 AFX and 117 PDS) was collected between 2003 and 2021 and analyzed for clinicopathological data with a special focus on immunosuppression. ResultsOf all patients, 29.9% had any kind of immunosuppression; 6.4% of the AFX and 12.0% of the PDS patients had underlying hemato-oncological diseases. Patients with immunosuppression due to an underlying hemato-oncological disease had a significantly increased risk of progressing to (p = 0.010) and developing distant organ metastases (p = 0.000). ConclusionsImmunosuppression seems to be a risk factor for developing AFX/PDS with worse clinical outcomes. Therefore, immunosuppression, especially underlying hemato-oncological diseases, should be considered in the treatment and follow-up care of patients with AFX/PDS

Confession, Charity and Community in \u3cem\u3eThe Sun Also Rises\u3c/em\u3e

Reading the novel in the tradition of the Christian confession narrative, Helbig utilizes a three-part approach to the confession consisting of self-awareness, contrition, and sacrifice. Centers on the main characters’ loss of self and connection with others through selfishness and escapism and explores their path to healing through reconciliation with other lost souls in a Godless world. Helbig bookends her analysis by discussing the characters’ struggles with inclusive language, which is ultimately resolved at the end of the novel. References St. Augustine as a touchstone for salvation

Immune checkpoint inhibitors for unresectable or metastatic pleomorphic dermal sarcomas

Pleomorphic dermal sarcomas (PDS) are rare neoplasms of the skin that occur in UV-exposed sites in the elderly, but represent the most common cutaneous sarcomas. Although the majority of PDS can be surgically removed, local recurrences occur in up to 28%, usually occurring within the first two years after primary excision. Metastases are diagnosed in up to 20% of cases, mainly observed in the skin, lymph nodes and lungs, preferentially affecting patients with underlying hemato-oncologic diseases. Similar to other UV-induced tumors, PDS are inflammatory and immunogenic tumors (with a high number of CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and checkpoint molecule expression such as PD-L1, LAG-3, TIGIT) with a very high mutational burden. The most common genetic alterations include UV-induced TP53 loss of function mutations, followed by alterations in the CDKN2A/B gene. Rarely, targetable genetic alterations can be detected. Compelling experimental data and clinical reports about PD-1/PD-L1-blocking antibodies in patients with PDS suggest its use as first line treatment in unresectable or metastatic tumor stages. However, individual (off-line) patient management should be discussed in an interdisciplinary tumor board based on molecular genetic testing, mutational burden, PD-L1 expression, and evidence of tumor-infiltrating lymphocytes in addition to comorbities of the individual patient

Advanced Nursing Practice

Der demografische Wandel stellt insbesondere die Gesundheitsversorgung vor große Her- ausforderungen. Immer mehr ältere, chronisch erkrankte und häufig multimorbide Menschen stehen immer weniger jüngeren Menschen gegenüber, die sowohl als pflegende Angehörige als auch als Pflegefachpersonen, Ärzt_innen oder Angehörige anderer Gesundheitsberufe für die Sicherstellung der pflegerisch-medizinischen Versorgung zur Verfügung stehen. Das an der Hochschule Ludwigshafen am Rhein angesiedelte Teilprojekt „EB – Entwicklung durch Bildung – Pflege und Gesundheit“ fokussiert sowohl auf die Entwicklung eines hoch- schulischen Bildungsangebots für Pflegefachpersonen, als auch auf die Konzeption eines Modells erweiterter gemeindenaher Pflegepraxis für die Region Westpfalz

Bedarfsorientierte Gestaltung hochschulischer Bildungsangebote für eine erweiterte gemeindenahe Pflegepraxis

Zentrales Ziel des Teilprojekts „Pflege und Gesundheit“ des Verbundvorhabens „E-hoch-B“ ist es, ein hochschulisches Bildungsangebot zu entwickeln, das berufserfahrene Pflegefachpersonen dazu befähigt, Elemente einer vertieften und erweiterten Pflegepraxis im Sinne von Advanced Nursing Practice im ambulanten Bereich anbieten zu können. Darüber hinaus soll in der Region Westpfalz ein Modellprojekt konzipiert werden, in dessen Rahmen derart hochschulisch qualifizierte Pflegefachpersonen erweiterte Tätigkeiten auch in der Versorgungspraxis ausüben können

Bedarfsorientierte Gestaltung hochschulischer Bildungsangebote für eine erweiterte gemeindenahe Pflegepraxis

Zentrales Ziel des Teilprojekts „Pflege und Gesundheit“ des Verbundvorhabens „E-hoch-B“ ist es, ein hochschulisches Bildungsangebot zu entwickeln, das berufserfahrene Pflegefachpersonen dazu befähigt, Elemente einer vertieften und erweiterten Pflegepraxis im Sinne von Advanced Nursing Practice im ambulanten Bereich anbieten zu können. Darüber hinaus soll in der Region Westpfalz ein Modellprojekt konzipiert werden, in dessen Rahmen derart hochschulisch qualifizierte Pflegefachpersonen erweiterte Tätigkeiten auch in der Versorgungspraxis ausüben können