No description available.

Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system caused by somatic mutations that accumulate in hematopoietic stem and progenitor cells. The cells are thereby transformed into leukemic stem cells (LSCs), which cannot be efficiently eliminated with the standard chemotherapy treatment. Thus, LSCs pose a risk of relapse for AML patients. There- fore, identification and characterization of LSCs is a major challenge in the field of AML research. Through next generation sequencing approaches the mutational spectrum of AML cells has been established and a continuous effort is being made to resolve the order of mutation acquisition and their functional consequences. In the subgroup of AML patients that bear a mutation in Nucleophosmin 1 (NPM1 ), a mutation in DNA-methyltransferase 3 A (DNMT3A) has been often found as a co-occurring event. Evidence suggests that this mutation arises early in leukemogene- sis and marks leukemic progenitors and stem cells. However, the functional consequences of this mutation are far from being understood. In this thesis work, I set out to unravel novel functional dependencies of the DNMT3A-mutant AML cells that can be exploited for therapeutic purposes. To nominate genes that are essential for the survival of primary AML cells, I performed a func- tional RNA interference-mediated drop out screen in 38 DNMT3A- and NPM1-mutant AML patient lines. The patients in this cohort were divided into two groups, based on the treatment outcome: an early relapse (ER) group and a long term remission (LTR) group. To nominate can- didate genes in each group, I have selected 12 screens with the highest data quality and performed a differential bioinformatic analysis. The analysis yielded 7 potential candidates, from which I initially validated three: Glucocorticoid modulatory element binding protein 1 (GMEB1), Mouse double minute 4 (MDM4) – both shared between the ER and the LTR groups – and Thioredoxin domain containing protein 9 (TXNDC9 ), which scored only in the ER group. Additional rounds of validation nominated MDM4 as the strongest candidate. To investigate the role of MDM4 in LSCs, I knocked it down in three patient samples and performed the long-term culture-initiating cell assay. However, the number of progenitor colonies that formed by the end of the assay was not enough for a statistical evaluation, probably due to the low frequency of long-term culture- initiating cells in the samples. Therefore, no conclusion regarding the functional dependency of LSCs on MDM4 could be made. However, a recent study suggested that loss of MDM4 causes cell cycle arrest and induces apoptosis in leukemic cell lines and primary cells, including progenitor populations, confirming the findings of this thesis. Nevertheless, the question about the role of MDM4 in NPM1 -mutant AML cells remains open. The NPM1 involvement in the p14Arf-MDM2- p53 pathway and the deregulation of this pathway caused by the NPM1 mutation indicate that MDM4 might poses special functions in NPM1 -mutant AML. Therefore, it should be investigated if MDM4 is a particularly suitable therapeutic target in AML with NPM1 mutation.

Wenn das eigene Kind an Krebs erkrankt, werden die Eltern mit massiven organisatorischen und psychosozialen Belastungen konfrontiert. Die Frage nach der Situation der Väter wurde in wissenschaftlichen Untersuchungen dabei bisher vernachlässigt, in aktuellen Fachdiskussionen zeigt sie aber mehr und mehr Präsenz. Ziel dieser Studie ist deshalb, zu erforschen, wie Väter die Krebserkrankung und die damit verbundenen – oft stark veränderten – Lebensumstände erleben. Gleichzeitig liegt der Fokus auf dem (männlichen) Bewältigungsverhalten, woraus schließlich auf mögliche psychosoziale Unterstützungsleistungen geschlossen werden soll. Die Studie stützt sich dabei auf theoretische Grundlagen aus den Themenfeldern „Krebs im Kindes- und Jugendalter“, „Lebenssituation betroffener Familien“, „Väterforschung“ sowie „Bewältigung kritischer Lebensereignisse“. Die Forschungsarbeit umfasst vier Interviews, welche mit der Methode des Problemzentrierten Interviews nach Witzel erhoben wurden. Darunter befinden sich ein Vater, dessen Kind erfolgreich therapiert wurde, zwei Väter, deren Kinder sich seit über zwei Jahren in Behandlung befinden, sowie ein Vater, dessen Kind an der Krebserkrankung verstorben ist. Die Interviews wurden nach der Methode des zirkulären Dekonstruierens von Jaeggi, Faas und Mruck einer Auswertung unterzogen. Die Ergebnisse eröffnen einen vielseitigen Einblick in das Erleben und das Bewältigungsverhalten der interviewten Väter. Neben dem „Kampf“ als zentraler Umgangsform werden verschiedenste Lebensbereiche der Väter deutlich, welche durch die Krebserkrankung des Kindes negativen, aber auch positiven Änderungen unterliegen. Zudem konnten vielfältige Formen (männlicher) Bewältigung erarbeitet werden. Auch Aspekte, die den Bewältigungsprozess fördern bzw. hindern, wurden ersichtlich. Aus den Ergebnissen lässt sich schließen, dass Väter oftmals einer Vielzahl organisatorischer und psychosozialer Belastungen ausgesetzt sind. Spezifische psychosoziale Angebote für Väter eröffnen dabei die Möglichkeit einer gezielten Unterstützung im Bewältigungsprozess. / When their child becomes ill with cancer, parents suddenly have to deal with great organizational and psychosocial burdens. The question of the situation of fathers has been neglected in scientific research for a long time, but present technical discussions give this specific issue more and more weight. The aim of this qualitative study is to research how fathers experience their child‟s cancer and the personal circumstances which are associated with the illness. In addition the focus of the study is on how fathers deal with this critical life event. As a result of the analysis possible methods of psychosocial support shall be worked out. The study is based on theoretical foundations of the topic areas “cancer at the age of childhood and youth”, “life situation of affected families”, “research on fathers” and “theories on how to overcome with critical life events”. The study comprises four interviews with fathers. These interviews were conducted based on the method of problem focused interview from Witzel. The sampling includes one father, whose child was successfully cured, two fathers, whose children are in therapy since more than two years and one father, whose child died of cancer. The interviews were analyzed with the method of circular deconstruction from Jaeggi, Faas and Mruck. The results give a complex insight into how the interviewed fathers experienced the cancer of their child and how they cope with this illness and the resulting personal circumstances. The different areas of life which were changed negatively as well as positively are shown. Furthermore it becomes clear that besides other (male) coping strategies the father`s central way of mastering their fate is by “fighting”. Moreover the results show aspects which promote or stop the coping process. According to the results of this study there are a lot of organizational and psychosocial burdens on fathers who have a child with cancer. Specific psychosocial offers for fathers open up possibilities of a targeted support in the coping process.

Background: The optimal extent of the prostate biopsy remains controversial. There is a need to avoid detection of insignificant cancer but not to miss significant and curable tumors. In alternative treatments of prostate cancer, repeated sextant biopsies are used to estimate the response. The aim of this study was to investigate the reliability of a repeated systematic sextant biopsy as the standard biopsy technique in patients with significant tumors which are being considered for curative treatment. Methods: Systematic sextant biopsy was performed in vitro in 92 radical prostatectomy specimens. Of these patients, 81 (88.0%) had palpable lesions. Results: Of the 92 investigated patients, 70 (76.1%) had potentially curable pT2-3pN0 prostate cancers. In these patients, the cancer was detected only in 72.9% of cases by a repeated in vitro biopsy. In the pT2 tumors, there was a detection rate of only 66.7%. Conclusions: This study underlines the fact that a considerable number of significant and potentially curable tumors remain undetected by the conventional sextant biopsy. A negative sextant biopsy does not rule out significant prostate cancer. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The subject of the diploma thesis is a project of Centre for Prevention and an extension of the Clinic of Radiational oncology on the edge of Masaryk Memorial Cancer Institute in Brno. The project completes pavilions composition. It responses to the future development designed in nearest surrounding. The project creates a new public space with a view towards Brno and the Pálava area. The project also proposes a sequential building – the Prevention centre at first and the Proton centre later.

No description available.

No description available.

No description available.

No description available.

Objective: Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress‐associated factors in these patients. - Methods: The PROSa‐study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross‐sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ‐4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models. - Results: Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9–15.0), and those with a disability pension (OR 3.1; 95% CI 1.9–5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2–2.7). Lowest distress was observed in patients 2 to <5 years and ≥5 years after diagnosis (comparison: <6 months) (OR 0.4; 95% CI 0.2–0.6) and (0.3; 95% CI 0.2–0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress(OR2.0;95%CI 1.1–3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1–2.8). - Conclusion: The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease.