Bakgrund   Icke-maligna prostataförändringar är ett utbrett samhällsproblem och en vanlig anledning till att människor söker sjukvård. Prostatit och benign prostatahyperplasi är två icke-maligna förändringar som kan te sig på olika sätt och kan orsaka lidande hos de drabbade, ofta genom ”lower urinary tract symptoms” och smärta som är vanliga symtom. Att lindra lidande är vårdens uppgift och en sjuksköterskas ansvar.     Syfte Syftet med denna litteraturöversikt var att belysa hur det är att leva med en icke-malign prostataförändring.    Metod  Metoden som användes var icke-systematisk litteraturöversikt där 18 artiklar analyserades.    Resultat Resultatet efter att ha analyserat de inkluderad studierna visade att icke-maligna prostataförändringar kan ha inverkan på samliv och relationer, ge upphov till känslor av skam, rädsla och oro, att det finns faktorer som kan vara mer eller mindre gynnsamma vid dessa tillstånd samt att det finns rum för förbättring vid mötet med sjukvården.   Slutsats Resultatet i denna litteraturöversikt visar på att leva med icke-maligna prostataförändringar och symtomen de ger upphov till kan ha en tydlig inverkan på drabbade personers liv och livskvalitet i ett flertal aspekter / Background Non-malignant prostatic conditions are a prevalent problem in society and a common reason as to why people seek medical care. Prostatitis and benign prostatic hyperplasia are two examples of non-malignant conditions that can appear in different ways and that could cause the afflicted person suffering, oftentimes through symptoms like pain and lower urinary tract symptoms. Alleviating suffering is an undertaking of health-care professionals’ and a nurse’s responsibility.     Aim The aim of this literature review was to illuminate what it is like to live with a non-malignant prostatic condition.    Method Non-systematic literature review where 18 articles were analyzed.     Results The results of the included and analyzed studies show that non-malignant prostatic conditions can influence intimate relationships, cause feelings of shame, fear and worry, that there are factors that can be more or less favourable in relation to these conditions and that there is room for improvement in the meeting with healthcare professionals.    Conclusions The results in this non-systematic literature review show that living with non-malignant prostatic conditions, and the symptoms they cause, can have a significant influence on the affected persons’ lives and quality of life in several aspects.

No description available.

In the present investigation peripheral blood lymphocytes from patients with inflammatory bowel disease (IBD) and different cancer states were treated with various agents and compared with lymphocytes from healthy control individuals (HCI) treated in the same way and measured in the Comet assay. For inflammatory bowel disease, patient¿s responses in IBD patients treated with H2O2 were higher than in HCI and crohn¿s patients (CD) were found to have higher responses than Ulcerative colitis (UC) patients. The responses for all IBD and HCI were all reduced in the presence of chaga mushroom extract which behaved in an antioxidant manner. A second group of IBD patients were treated with the heterocyclic amine (food mutagen), IQ and H2O2 and responses were reduced in the presence of the flavonoids, quercetin and epicatechin and compared with HCI similarity treated. In all cells responses were reduced with flavonoids and again CD had higher responses than the UC patients and IBD patients higher than HCI. The responses with CD and UC were that confirmed in two independent studies with IBD, one with chaga mushroom extract and the other with flavonoids. Peripheral lymphocytes from malignant melanoma and suspected melanoma patients and colon cancer and polyposis patients were compared to the lymphocytes from HCI and treated with UVA. There were differential sensitivities when measured in the micronucleus and Comet assays. The cancer patients had higher responses than those in the precancerous states and they in turn were higher than responses in HCI. In all the studies, untreated baseline DNA damage values were also higher in IBD and cancer patients and pre-cancerous patients than HCIs. This would suggest that baseline frequencies of different diseases compared to controls could be an important biomarker in the diagnosis of pre-cancers and early stage cancers. Also peripheral lymphocytes are a useful surrogate for cancers and pre-cancerous disease states since, blood is present in all organs and tissues and DNA is basically the same in all cells.

No description available.

Objetivo: Identificar las características sociodemográficas y epidemiológicas del paciente con cáncer de piel diagnosticados en el servicio de anatomía patológica del Hospital Regional Lambayeque durante periodo enero del 2016 - diciembre del 2019. Métodos: La metodología empleada durante esta investigación estuvo basada en el diseño no experimental, descriptivo, de carácter retrospectivo, trasversal y observacional. Se incluyeron un total de 429 pacientes mayores de 18 años, diagnosticados con carcinoma cutáneo de tipo no melanoma (NPNM) y melanoma, mediante estudios anatomopatológicos de la lesión atendidos en Hospital Regional Lambayeque. La elección de la muestra fue mediante un muestreo no probabilístico de tipo censal, por la adaptabilidad al estudio. Resultados: De un total de 429 pacientes, 256(59,1%) tenían carcinoma basocelular (CBC), 146 (33,7%) carcinoma epidermoide (CsCC) y 31(7,2%) melanoma maligno cutáneo (MM). Siendo la edad promedio de aparición de 71 años en los NPNM y 62 años en el Melanoma Maligno Cutáneo, con predominio por el sexo femenino en el CBC y masculino en CsCC y MM. La ubicación anatómica más comprometida fue de la cabeza en los NPNM y miembros inferiores en MM, los cuales fueron identificadas mayormente por el servicio de Dermatología, seguido por Cirugía de Cabeza y Cuello del hospital. Los años con mayor número de carcinomas cutáneos fueron el 2019 para CBC y 2018 para los dos restantes. Conclusiones: La población general presenta más riesgo de presentar carcinomas no melanómico y en menor número el melanoma maligno, el cual predomina en áreas fotoexpuestas del cuerpo. / Objective: To identify the sociodemographic and epidemiological characteristics of the patient with skin cancer diagnosed in the pathological anatomy service of the Lambayeque Regional Hospital during the period January 2016 - December 2019. Methods: The methodology used during this investigation was based on the non-experimental design, descriptive, retrospective, cross-sectional and observational. A total of 429 patients over 18 years of age were included, diagnosed with non-melanoma skin carcinoma (NPNM) and melanoma, through anatomopathological studies of the lesion treated at Hospital Regional Lambayeque. The selection of the sample was by means of a non-probabilistic sampling of the census type, due to the adaptability to the study. Results: Of a total of 429 patients, 256 (59.1%) had basal cell carcinoma (BCC), 146 (33.7%) squamous cell carcinoma (SCC) and 31 (7.2%) cutaneous malignant melanoma (MM). Being the average age of appearance of 71 years in NPNM and 62 years in Cutaneous Malignant Melanoma, with a predominance of females in CBC and male in CsCC and MM. The most compromised anatomical location was the head in NPNM and lower limbs in MM, which were mostly identified by the Dermatology service, followed by Head and Neck Surgery at the hospital. The years with the highest number of skin carcinomas were 2019 for CBC and 2018 for the remaining two. Conclusions: The general population presents a higher risk of presenting non-melanoma carcinomas and a smaller number of malignant melanoma, which predominates in photo-exposed areas of the body.

Introduction: Malignant Melanoma (MM), caused by UV radiation-induced DNA damage, is the most invasive form of skin cancer and has an increasing incidence worldwide. The hallmarks of MM include the presence of reactive oxygen species (ROS) and excessive proliferation of tumour cells. Many treatments are available or under investigation as anticancer therapeutics such as cell therapy, immunotherapy, gene therapy and nanotechnology-based strategies but they all have severe complications and side effects that limit their wider use. Methods: The present in vitro study has evaluated the genotoxic and cytotoxic effects of Se and CBSC-derived exosomes, individually and in combination, on lymphocytes from MM patients and healthy controls, and on the CHL-1 melanoma cell line. The comet assay and cell counting kit-8 (CCK-8) assay were used to measure genotoxicity and cytotoxicity, respectively, in all cell types. Molecular mechanisms underlying the observed effects were explored using transcriptional and protein expression profiling of key cell cycle and apoptosis genes, by employing the RT qPCR and Western blotting techniques. Conclusion: Selenium displays antioxidant and genoprotective effects in human lymphocytes, especially in MM patients. Both Se (10 μM) and CBSC-derived exosomes (120 μL) are well tolerated in lymphocytes, but show significant genotoxicity and cytotoxicity towards the CHL-1 cell line, with combined administration exhibiting a synergistic effect.

Background: The accuracy of DNA image cytometry as an investigation method for potentially malignant disorders of the oral cavity is currently still a subject of controversy, due to inconsistently applied definitions of DNA aneuploidy, small cohorts and different application techniques of the method. The aim of this study was to examine the accuracy of the method as a supplementary diagnostic tool in addition to the cytological examination using internationally consented definitions for DNA aneuploidy. Methods: A total of 602 samples from 467 patients with various oral lesions were included in this prospective study. Brush biopsies from each patient were first cytologically examined and categorized by a pathologist, second evaluated using DNA image cytometry, and finally compared to either histological biopsy result or clinical outcome. Results: Using the standard definition of DNA aneuploidy, we achieved a sensitivity of 93.5%, a positive predictive value for the detection of malignant cells of 98.0%, and an area under the curve of 0.96 of DNA ploidy analysis for the detection of severe oral epithelial dysplasia, carcinoma in situ or oral squamous cell carcinoma. Importantly, using logistic regression and a two-step model, we were able to describe the increased association between DNA-ICM and the detection of malignant cells (OR = 201.6) as a secondary predictor in addition to cytology (OR = 11.90). Conclusion: In summary, this study has shown that DNA ploidy analysis based on conventional specimens of oral brush biopsies is a highly sensitive, non-invasive, patient-friendly method that should be considered as an additional diagnostic tool for detecting malignant changes in the oral cavity.

Glioblastoma (GBM) is the most common and deadliest of the malignant primary brain tumors in humans, with a reported 5-year survival rate of only 6.8% despite years of extensive research. Failure to improve local tumor control rates and overall patient outcome is attributed to GBM's inherent therapeutic resistance. Marked heterogeneity, extensive local invasion within the brain parenchyma, and profound immunosuppression within the tumor microenvironment (TME) are some of the unique features that drive GBM therapeutic resistance. Furthermore, tumor cells are sequestered behind the blood-brain barrier (BBB), limiting delivery of effective therapeutics and immune cell infiltration into the local tumor. Electroporation-based therapies, such as irreversible electroporation (IRE) and second generation, high-frequency IRE (H-FIRE) represent attractive alternative approaches to standard GBM therapy given their ability to induce transient BBB disruption (BBBD), achieve non-thermal tumor cell ablation and stimulate local and systemic anti-tumor immune responses without significant morbidity. The following work explores the use of H-FIRE to overcome GBM-induced therapeutic resistance and improve treatment success. Chapter 1 opens with an overview of GBM and known barriers to treatment success. Here, we emphasize the utility of spontaneous canine gliomas as an ideal translational model for investigations into novel treatment approaches. Chapter 2 introduces novel ablation methods (i.e. IRE/H-FIRE) capable of targeting treatment-resistant cancer stem cells. The focus of Chapter 3 is to highlight IRE applications in a variety of spontaneous tumor types. In Chapter 4, we investigate the feasibility and local immunologic response of percutaneous H-FIRE for treatment of primary liver tumors using a spontaneous canine hepatocellular carcinoma (HCC) model. In chapter 5, we characterize the mechanisms of H-FIRE-mediated BBBD in an in vivo healthy rodent model. In Chapter 6, we characterize the local and systemic immune responses to intracranial H-FIRE in rodent and canine glioma models to enhance the translational value of our work. Collectively, our work demonstrates the potential for H-FIRE to overcome therapeutic resistance in GBM, thereby supporting its use as a novel, alternative treatment approach to standard therapy. / Doctor of Philosophy / Glioblastoma (GBM) is the most common and deadliest form of primary brain cancer in humans, with only 6.8% of people surviving 5-years after their diagnosis. GBM is characterized by a number of unique features that make it resistant to standard treatments, such as surgery, radiation and chemotherapy. Examples include: (1) extensive invasion of tumor cells into the brain, making complete removal via surgery very difficult; (2) tumor cells are protected by a structure called the blood-brain barrier (BBB), which restricts the entry of most drugs (i.e. chemotherapy) and many immune cells, into the brain, thereby preventing them from reaching tumor cells; (3) tumor cells produce substances that block the immune system from being able to detect the tumor itself, which allows it to continue to grow undetected. High-frequency irreversible electroporation (H-FIRE) represents a new approach for the treatment of GBM. H-FIRE uses electric pulses to temporarily or permanently injure cell membranes without the use of heat, which allows for very precise treatment. The following work explores the ways in which H-FIRE can interfere with specific GBM features that drive its resistance to treatment. Here, we demonstrate that H-FIRE is capable of temporarily disrupting the BBB and characterize the mechanisms by which this occurs. This allows for drugs and immune cells within the blood to enter the brain and access the tumor cells, particularly those extending beyond the visible tumor mass and invading the brain. We also illustrate the potential for H-FIRE treatment within the brain to stimulate local and systemic immune responses by causing the release of proteins from injured cells. Similar to a vaccine, these proteins are recognized by the immune system, which becomes primed to help fight off cancer cells within the body. The end result is an anti-tumor immune response. Collectively, this work supports the use of H-FIRE as an alternative treatment approach to standard therapy for GBM given its potential to overcome certain causes of treatment resistance.

Das Multiple Myelom (MM) ist eine hämatologische Erkrankung, welche sich durch eine Akkumulation von malignen Plasmazellen im Knochenmark auszeichnet und eine gestörte Hämatopoiese und Osteolyse zur Folge hat. Komplexe molekulare Interaktionen zwischen MM-Zellen und der Mikroumgebung/Nische im Knochenmark (bone marrow microenvironment, BMM) führen zu einer Aktivierung von verschiedenen Wachstums-, Überlebens- und anti-apoptotischen Signalwegen, die zur Entstehung bzw. Wirkstoffresistenz von MM-Zellen beitragen. IL-6R/STAT3, Ras/MAPK und PI3K/Akt sind die drei wichtigsten Signalwege, die mit dem Wachstum und der Entwicklung des MM assoziiert sind. Auf der anderen Seite sind Myelomzellen insensitiv gegenüber einer Blockade des IL6R/STAT3-Signalweges bzw. des Ras/MAPK-Signalwegs in der Gegenwart von Knochenmarksstromazellen (bone marrow stroma cells, BMSCs), was die Entbehrlichkeit dieser beiden Signalwege unter Ko-Kultur-Bedingungen nahelegt. Interessanterweise aber induziert die gleichzeitige Unterbrechung der IL6R/STAT3 und Ras/MAPK Signalwege Apoptose in MM-Zellen. Ziel der Arbeit war die Identifizierung und Analyse von Zielgenen, die von beiden Signalwegen und nicht durch einen Signalweg alleine reguliert werden. Genexpressionsanalysen zeigten eine deutliche Herunterregulierung der Proteine Hsp90alpha und Hsp90beta nach einer gleichzeitigen Inhibition der IL6R/STAT3 und Ras/MAPK Signalwege. In Hinblick auf die zentrale Rolle von Hsp90 in der Tumorbiologie fokussiert sich die vorliegende Arbeit auf die Erforschung der Rolle von Hsp90 im Multiplen Myelom. Die siRNA-vermittelte Herunterregulation der Proteinexpression von Hsp90-Proteinen zeigte, daß das Ausschalten von HsP90alpha alleine nur zu einer moderaten Apoptoseinduktion in INA-6- und MM.1s-Zellen führte. Die gleichzeitige Herunterregulation von HsP90beta hingegen führte zu einer Verstärkung dieses Effektes und deutet darauf hin, daß beide Proteine miteinander kooperieren. Die pharmakologische Inhibition der Hsp90-Funktion mittels eines neuen Hsp90-Inhibitors (17-DMAG) führte zu einer Verringerung von phospho-ERK1/2, zur Degradation von STAT3 und zu einem verminderten Überleben von MM-Zellen. Die pro-apoptotischen Effekte der gestörten Hsp90-Funktion konnten weder durch BMSCs und Osteoklasten noch durch ECs (??) abgeschwächt werden, obwohl für ECs beschrieben wurde, daß sie zum Wachstum und Überleben von MM-Zellen beitragen können. Diese Beobachtungen deuten auf einen positiven Rückkopplungskreislauf zwischen HsP90alpha/beta und den wichtigsten Signalwegen hin, welcher das Überleben von MM-Zellen gewährleistet. Desweiteren zeigten immunhistologische Analysen, daß Hsp90-Proteine im Vergleich zu MGUS (??) bzw. normalen Plasmazellen in MM-Plasmazellen hochreguliert sind. Zusammengefasst zeigen die Ergebnisse der vorliegenden Arbeit die essentielle Rolle von Hsp90-Proteinen für die Überlebensfähigkeit von MM-Zellen. Ein neuer Mechanismus der Hsp90-Regulation durch das Zusammenwirken der Signalwege IL6R/STAT3 und Ras/MAPK in MM-Zellen konnte gezeigt werden. Darüber hinaus deuten die Ergebnisse darauf hin, daß ein positiver Rückkopplungskreislauf zwischen Hsp90-Proteinen und den wichtigsten Signalwegen existiert, welcher zum Wachstum und zur Entwicklung von MM-Zellen beiträgt. Die Inhibition der Hsp90-Funktion durch den pharmakologischen Inhibitor 17-DMAG führte zum Absterben von MM-Zellen und der pro-apoptotische Effekt der Hsp90-Depletion konnte nicht durch unterstützende BMM-Zellen aufgehoben werden. Diese Beobachtungen untermauern die multifunktionelle Rolle von Hsp90 in der MM-Biologie und zeigen die Wichtigkeit der Entwicklung neuer therapeutischer Wirkstoffe zur Inhibition der Hsp90-Funktion bei der Behandlung des MM. / Multiple myeloma (MM) is a haematological malignancy characterised by the accumulation of malignant plasma cells in the bone marrow leading to impaired haematopoiesis and osteolytic bone destruction. Intricate molecular interactions between MM cells and the BMM activate a diverse set of growth, survival and anti-apoptotic signaling cascades that mediate tumor progression and drug resistance. IL-6R/STAT3, Ras/MAPK and PI3K/Akt are the three major signal transduction pathways that are associated with MM growth and progression. However, myeloma cells have shown independence from IL-6R/STAT3 blockade or insensitivity towards Ras/MAPK pathway inhibition in the presence of BMSCs, indicating the dispensability of both in co-culture conditions. Interestingly, concomitant disruption of both IL-6R/STAT3 and Ras/MAPK pathways was successful to drive MM cells into significant apoptosis. This study aimed to identify and analyse the downstream target genes that are regulated by both pathways and not by either pathway alone. Gene expression profiling revealed prominent downregulation of Hsp90alpha and Hsp90beta proteins after combined inhibition of the IL-6R/STAT3 and Ras/MAPK pathways. Owing to the important role played by Hsp90 in cancer biology, this study was narrowed down to investigate the role of Hsp90 in MM. Specific siRNA-mediated knockdown of Hsp90 proteins showed that although knockdown of Hsp90beta was sufficient to induce moderate apoptosis in INA-6 and MM.1s cells, the effect was more pronounced when both Hsp90 proteins were targeted, indicating co-operation between them. Pharmacological inhibition of Hsp90 function by using a novel Hsp90 inhibitor (17-DMAG) down-regulated the levels of pERK1/2 and led to degradation of STAT3 and decreased viability of MM cells. The pro-apoptotic effects of compromised Hsp90 function could not be alleviated by either BMSCs, OCs or ECs, which are well-known to support myeloma growth and survival. These observations point to the existence of a positive feedback loop consisting of Hsp90alpha/beta and major signaling pathways supporting MM cell survival. Furthermore, immunohistochemical analysis unveiled the up-regulated status of Hsp90 proteins in MM PCs as compared to MGUS or normal PCs. Taken together, the results of this study explain the critical contribution of Hsp90 proteins to MM cell survival. A novel mechanism of Hsp90 regulation by co-operation between the IL-6R/STAT3 and Ras/MAPK pathways was discovered in myeloma cells. There is also strong evidence of the existence of a positive feedback loop between Hsp90alpha/beta proteins and major signaling pathways supporting MM growth and progression. Inhibition of Hsp90 function by using the Hsp90 inhibitory drug 17-DMAG proved to be lethal for myeloma cells and the pro-apoptotic effects of Hsp90 blockade could not be reversed by the presence of cells from the supportive BMM. These observations highlight a multi-functional role of Hsp90 in MM biology and strongly strengthen the notion that therapeutic strategies targeting Hsp90 may open new perspectives for anti-myeloma drug development.

Das maligne Melanom ist für 90 % der Sterbefälle bei Hautkrebs verantwortlich (Garbe et al., 2022). Verschiedene Mutationen wirken sich auf die Signalwege aus und fördern die Karzinogenese, was zu einem ständigen Wandel der Melanomtherapie führt. Zusätzlich zu der, in frühen Stadien kurativen, chirurgischen Therapie, erzielt die zielgerichtete Therapie mit BRAF- und MEK-Inhibitoren in den letzten Jahren durchschlagende Erfolge für das Gesamtüberleben der Patienten, bei nicht-resezierbaren Metastasen wird weiterhin die Chemotherapie empfohlen. Zunehmende Therapieresistenzen schränken die Melanomtherapie ein. Müller et al. (2020) weisen auf Wildtyp p53 exprimierende Tumorzellen hin, die mithilfe der Expression von nukleärer Caspase-8 den G2/M-Zellzyklusarrest umgehen und so die Proliferation und Expansion entarteter Tumorzellen fördern. Bei der Untersuchung von 16 Melanomzellproben, die sich in ihrem BRAF-/NRAS- und p53 Mutationsstatus, sowie in ihren klinischen Vortherapien unterscheiden, konnte die potenziell klinische Relevanz der nukleären Caspase-8 herausgearbeitet werden. Wir konnten bestätigen, dass nukleär lokalisierte Caspase-8 bei Wildtyp p53 exprimierenden Tumorzellen zu Chemoresistenz und auch in geringem Maß zur Resistenz gegenüber zielgerichteten Therapien führt. Zunächst wurde die subzelluläre Lokalisation von Caspase-8 in den vorhandenen 16 Melanomzellproben mithilfe immunzytochemischer Färbung bestimmt, wobei sich herausstellte, dass die Melanomzellproben mit nukleärer Caspase-8, alle von Metastasen stammen. Das hohe Metastasierungspotenzial dieser Zellproben wurde weiterhin dadurch betont, dass die Melanomzellproben mit nukleär lokalisierter Caspase-8 die stärkste Migration aufwiesen. Dem gegenüberstehend präsentierten sie die geringste Proliferation, was den direkten Zusammenhang zwischen migrativen und proliferativen Eigenschaften bei Tumorzellen unterstreicht. Ebenso zeigten BRAF-mutierte Zellproben die stärkste Migration und bekräftigen, dass Melanompatienten mit BRAF-Mutation früher Metastasen entwickeln. Das stärkste Wachstum zeigten hingegen die Zellproben mit diffus lokalisierter Caspase-8, was die protektive Relevanz der diffusen Caspase-8 für Tumorzellen verdeutlicht. Ein Einfluss des p53-Mutationsstatus auf die Proliferation und Migration konnte ebenfalls nachgewiesen werden. Die Zellproben mit Wildtyp p53 migrierten stärker, wohingegen die Zellprobe mit mutp53(E285K) stark proliferierte. Bei Korrelation der subzellulären Caspase-8-Lokalisation mit der Caspase-8- und p53-Expression der Melanomzellproben mithilfe Westernblotanalysen zeigte sich, dass metastatische Zellproben verstärkt Caspase-8 exprimieren. Dies betraf besonders die metastatischen Zellproben mit nukleär lokalisierter Caspase-8, die kein p53 oder wenig Wildtyp p53 exprimieren. Diese inverse Korrelation der Caspase-8- und p53 Expression konnte ebenfalls bei den unstimulierten Zellproben mit zytoplasmatischer Caspase-8 festgestellt werden. Zellprobe M31 mit mutp53(E285K) exprimiert konstant stark p53 und wies Chemoresistenz auf. Bei Untersuchung des Zelltods 24 h und 48 h nach Cisplatinstimulation, sowie 48 h nach Stimulation mit Dabrafenib, Trametinib und deren Kombination mithilfe des IncuCyte® Readers, wurde deutlich, dass die Zellproben mit nukleär lokalisierter Caspase-8 chemoresistenter sind als die restlichen Zellproben, wobei die Zellproben mit diffus lokalisierter Caspase-8 am resistentesten gegenüber den zielgerichteten Therapeutika sind. Die protektive Rolle der diffusen Caspase-8 für die Tumorzellen konnte unterstützend durch die Zunahme der Apoptose bei einigen Zellproben nach Herunterregulierung von Caspase-8 nachgewiesen werden. Hervorzuheben ist, dass die Zellproben mit zytoplasmatischer Caspase-8 am sensitivsten, sowohl auf zielgerichtete Therapeutika als auch auf Chemotherapie reagierten. Insgesamt induzierte Cisplatin deutlich mehr Zelltod als die zielgerichteten Therapien, weshalb die potenzielle Überlegenheit der Chemotherapie, besonders bei rezidivierten Melanomen bedacht werden muss. Es bestätigte sich ebenfalls die Relevanz des BRAF-/NRAS Mutationsstatus für die Therapiesensitivität, wobei BRAF-mutierte Zellproben die größte Chemosensitivität präsentierten und NRAS-mutierte Zellproben vor allem nach der Stimulation mit Trametinib und der Kombination Dabrafenib + Trametinib Zelltod aufwiesen. Überraschenderweise zeigten sich die Zellproben vortherapierter Melanompatienten sensitiver gegenüber Dabrafenib und Cisplatin als die Zellproben therapienaiver Melanompatienten, was die Bedeutung von Chemotherapie und Dabrafenib für vortherapierte, rezidivierte Tumore bzw. Metastasen hervorhebt. Weiterhin konnte der Impact des p53-Mutationsstatus herausgearbeitet werden. Die Zellproben mit mutiertem oder ohne p53 wiesen die größte Cisplatinresistenz auf, wohingegen die Zellproben mit Wildtyp p53 am meisten Zelltod zeigten, gefolgt von den Zellproben mit dem Einzelnukleotidpolymorphismus (wt(P72R)). Nach Herunterregulierung des mutierten p53 nahm die Apoptose nach Cisplatinstimulation hoch signifikant zu. Dahingegen zeigten besonders die Zellproben mit zytoplasmatischer Caspase-8 und Wildtyp p53 eine Hochregulierung von p53 nach Cisplatinstimulation im Westernblot. Wir konnten nachweisen, dass die Wildtyp p53 exprimierende Zellprobe M40 nukleär lokalisierte Caspase-8 aufweist und die stärkste Chemoresistenz zeigte, wohingegen die Zellproben mit diffus oder zytoplasmatisch lokalisierter Caspase-8, die Wildtyp p53 oder den Einzelnukleotidpolymorphismus (wt(P72R)) exprimieren, am chemosensitivsten waren. Die Therapieresponsivität von Melanomen wird durch eine Vielzahl an Faktoren beeinflusst, die für die optimale Behandlung der Patienten bei Beginn einer Therapie möglichst genau bestimmt werden sollten. Wir empfehlen für die Risikostratefizierung und Prognose des Krankheitsverlaufes, sowie für die Entscheidung des Therapiewegs, die Bestimmung der subzellulären Caspase-8-Lokalisation in Kombination mit dem p53-Mutationsstatus. Weiterhin weisen wir auf die Bedeutung des BRAF-/NRAS-Mutationsstatus sowie mögliche Vortherapien in Bezug auf Therapieresistenz hin und stellen die Bedeutung der Chemotherapie, besonders für rezidivierte, BRAF-mutierte Melanompatienten bei Resistenzentwicklung gegen BRAF- und/oder MEK-Inhibitoren heraus. / Malignant melanoma is responsible for 90 % of skin cancer deaths (Garbe et al., 2022). Various mutations affect the signaling pathways and promote carcinogenesis, which leads to a constant change in melanoma therapy. In addition to surgical therapy, which is curative in the early stages, targeted therapy with BRAF and MEK inhibitors has achieved resounding successes for the overall survival of patients in recent years while chemotherapy is still recommended for non-resectable metastases. Increasing therapy resistance limits melanoma therapy, with Müller et al. (2020) pointing to wild-type p53-expressing tumor cells that use the expression of nuclear caspase-8 to bypass the G2/M cell cycle arrest and thus promote the proliferation and expansion of degenerated tumor cells. By investigating 16 melanoma cell samples differing in their BRAF/NRAS and p53 mutation status, as well as in their prior clinical therapies, the potential clinical relevance of nuclear caspase-8 could be elaborated. We were able to confirm that nuclear localized caspase-8 in wild-type p53-expressing tumor cells leads to chemoresistance and, to a lesser extent, to resistance to targeted therapies. First, the subcellular localization of caspase-8 in the existing 16 melanoma cell samples was determined using immunocytochemical staining, which revealed that the melanoma cell samples with nuclear caspase-8 all originated from metastases. The high metastatic potential of these cell samples was further emphasized by the fact that the melanoma cell samples with nuclear localized caspase-8 showed the strongest migration. In contrast, they presented the lowest proliferation, underlining the direct correlation between migratory and proliferative properties in tumor cells. Likewise, BRAF-mutated cell samples showed the strongest migration and verified that melanoma patients with BRAF mutations develop metastases earlier. In contrast, the cell samples with diffusely localized caspase-8 showed the strongest growth, which illustrates the relevance of diffusely localized caspase-8 in its protective function in tumor cells. The impact of the p53 mutation status on proliferation and migration could also be demonstrated. The cell samples with wild-type p53 migrated stronger, whereas the cell samples with mutp53(E285K) showed stronger proliferation. Correlation of subcellular caspase-8 localization with caspase-8 and p53 expression of melanoma cell samples using western blot analysis showed that metastatic cell samples express more caspase-8. This was particularly true for the metastatic cell samples with nuclearly localized caspase-8, which express little wild-type p53 or no p53. This inverse correlation of caspase-8 and p53 expression was also observed in the unstimulated cell samples with cytoplasmically localized caspase-8, respectively. Cell sample M31 with mutp53(E285K) consistently expressed high levels of p53 and exhibited chemoresistance. When examining cell death 24 h and 48 h after cisplatin stimulation, as well as 48 h after stimulation with dabrafenib, trametinib and their combination using the IncuCyte® Reader, it became clear that the cell samples with nuclearly localized caspase-8 are the most chemoresistant, whereby the cell samples with diffusely localized caspase-8 are the most resistant to the targeted therapeutics. The protective role of diffusely localized caspase-8 for the tumor cells was supportively demonstrated by the increase in apoptosis in some cell samples after downregulation of caspase-8. It should be emphasized that the cell samples with cytoplasmically localized caspase-8 responded most sensitively to both targeted therapies and chemotherapy. Overall, cisplatin induced significantly more cell death than the targeted therapies, which is why the potential superiority of chemotherapy, especially in recurrent melanoma, must be considered. The relevance of BRAF/NRAS mutation status for therapy sensitivity was also confirmed, with BRAF-mutated cell samples presenting the greatest chemosensitivity and NRAS-mutated cell samples showing cell death particularly after stimulation with trametinib and the combination dabrafenib + trametinib. Surprisingly, the cell samples of pre-treated melanoma patients were more sensitive to dabrafenib and cisplatin than the cell samples of treatment-naive melanoma patients, which highlights the importance of chemotherapy and dabrafenib for pre-treated, recurrent tumors and metastases. Furthermore, the impact of the p53 mutation status could be worked out. The cell samples with mutated or no p53 showed the highest cisplatin resistance, whereas the cell samples with wild-type p53 showed the highest cell death, followed by the cell samples with the single nucleotide polymorphism (wt(P72R)). After downregulation of mutant p53, apoptosis increased highly significantly after cisplatin stimulation. In contrast, especially the cell samples with cytoplasmically localized caspase-8 and wild-type p53 showed an upregulation of p53 in the Western blot after cisplatin stimulation. We demonstrated that wild-type p53 and nuclear caspase-8 expressing cell sample M40 exhibited the strongest chemoresistance, whereas the cell samples with diffusely or cytoplasmically localized caspase-8 expressing wild-type p53 or the single nucleotide polymorphism (wt(P72R)) were the most chemosensitive. In summary, it is clear that the treatment response of melanoma is influenced by a variety of factors that should be determined as precisely as possible for the optimal treatment of patients at the start of therapy. We recommend the determination of subcellular caspase-8 localization in combination with the p53 mutation status for risk stratification and prognosis of disease progression, as well as for the optimal therapy. Furthermore, we point out the importance of BRAF/NRAS mutation status and possible prior therapies with regard to therapy resistance and emphasize the importance of chemotherapy, especially for relapsed, BRAF-mutated melanoma patients who developed resistance to BRAF and/or MEK inhibitors.