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Outcome of patients with metastatic, papillary renal cell carcinoma
Get PDFBackground:
Targeted therapies such as VEGF-, mTOR- inhibitors and immune checkpoint inhibitors (ICIs) are established treatment strategies in metastatic clear cell renal cell carcinoma (RCC), however level 1 evidence is lacking in papillary RCC (papRCC). Evidence is derived from single-arm trials, expanded access schemes and subgroup analysis of larger RCC studies. Currently the most effective treatment approach for patients with papRCC represents an unmet therapeutic need.
Objective:
The aim of this dissertation was to analyse the outcome of patients with metastatic, papRCC who received treatment between 2005 – 2015, in the Department of Urology, University Hospital Munich Grosshadern, Ludwig-Maximilians University. We aimed to compare the effectiveness of different systemic therapies used and describe outcomes such as response to therapy, progression free survival (PFS), and overall survival (OS). We also analysed baseline clinical and pathological features which may influence patient outcomes. Furthermore, we aimed to review the relevant literature comparing the oncological outcomes of different systemic therapies in patients with metastatic papRCC in order to put this research into relevant context.
Results and limitations:
This is a retrospective, single centre audit with data collected over a period of 10 years. The median follow-up for this patient population was 71 months (95%CI, 24-118) which is the longest reported in the current literature. Baseline patient and tumour characteristics are similar to those previously described in the literature. The median disease-free survival (DFS) postsurgery was 14.9 months (95% CI, 2.5 – 27.3) and 43% of patients developed metastatic disease after initial surgery with curative intent. There was no statistical difference in OS in patients undergoing cytoreductive nephrectomy compared to those who didn’t (9.8 vs 7.7 months, p=0.777). All patients received front-line therapy, however only 48% received second line, 21% received third line and 5% received fourth line, subsequent therapies. The median OS was 10.5 months (95%CI, 5.4 – 15.7). The percentage of patients who were alive at 1 year, 2 years and 5 years were 41%, 31% and 5%, respectively. Sunitinib was the most frequently used first line therapy agent in 74% of patients. The overall response rate in these patients was 26% with 10% achieving complete response. Based on the results of the recent PAPMET trial (NCT02761057), cabozantinib is currently the recommended front-line therapy agent due to higher response rate (23% vs. 4%) and more favourable PFS (HR 0.60 [0.37–0.97], p = 0.019) compared to sunitinib. The combination of ICI and VEGF inhibitors have changed the therapy landscape of clear cell RCC, and it is likely that these agents will be adopted in papRCC as well. Limitations of this work include the retrospective nature of the data collection, and small number of patients. Furthermore, there were no cabozantinib treated patients as this therapy option was not approved at the time. The relatively long survival in some of the patients is attributed to the heavy selection bias.
Conclusions:
This retrospective, single centre cohort analysis showed that VEGF-inhibitors are effective and have superior outcomes with regards to response rate and survival when compared to mTOR inhibitors. Together with the robust summary of currently available data, this work contributes towards the establishment of evidence-based therapy of metastatic papRCC
Szenarienbasierte Selbsteinschätzung medienbezogener Kompetenzen von (angehenden) Lehrkräften
Get PDFAssessment of cytotoxicity against diffuse midline glioma and drug-induced neurotoxicity of novel chemotherapeutic agents
Get PDFCentral nervous system (CNS) tumors are the second most common pediatric malignancy in Germany after leukaemia and the leading cause of cancer-related death in childhood. Diffuse midline glioma (DMG) is a highly malignant glioma that accounts for only 15-20% of all CNS tumors in children, yet is responsible for the highest mortality rate in this patient population.
The poor prognosis of 9-15 months after diagnosis and the only marginal survival benefits of current treatment options highlight the need for new therapeutic approaches.
The aim of this thesis is to identify promising novel therapies against DMG using robust, preclinical, animal-free cell models to provide a basis for planning clinical trials.
A single-agent sensitivity drug screen against DMG and a neurotoxicity assessment of thirty novel chemotherapeutic agents identified HSP90 inhibitors HSP990 and SNX2112 and NAMPT inhibitor daporinad as promising anti-DMG candidates with a wide therapeutic window.
In this thesis, no animal-based experiments were conducted, as they are not only time-consuming, ethically controversial, and expensive, but also have limited translatability to humans. Five patient-derived DMG cell lines were used for sensitivity drug screening, whereas neurons for neurotoxicity screening were differentiated from human pluripotent cells. By using customized patient-specific tumor cells and iPSCs, it is possible to develop personalized therapies for patients using the same methods as in this work.
Our in vitro drug screening provides insights into neurotoxicity and efficacy against various DMG cell lines but does not account for other treatment challenges such as BBB penetration, drug resistance, and cell-environment interaction. Given the complexity of treating DMG, further, more in-depth drug validation experiments are needed.Tumore des zentralen Nervensystems (ZNS) sind nach Leukämien die zweithäufigste pädiatrische Tumorerkrankung in Deutschland und die führende Ursache für krebsbedingte Todesfälle im Kindesalter. Diffuse Mittelliniengliome (DMG) sind hochmaligne pädiatrische ZNS-Tumore, die zwar nur 15-20 % aller Hirntumoren im Kindesalter ausmachen aber für die höchste Mortalität in dieser Patientengruppe verantwortlich sind.
Die ungünstige Prognose der DMG mit einem Gesamtüberleben von 9 - 15 Monate nach Diagnosestellung und die bis dato nur marginalen Überlebensvorteile der bisherigen Behandlungsmöglichkeiten verdeutlichen den Bedarf an neuen therapeutischen Ansätzen.
Das Ziel dieser Arbeit ist es, durch den Einsatz robuster präklinischer tierfreier Zellmodelle neue therapeutische Optionen gegen DMG zu identifizieren und eine Grundlage für die Planung klinischer Studien zu bieten.
Durch ein in vitro Screening der zytotoxischen Wirkung von dreißig Chemotherapeutika gegen DMG-Tumorzellen und gesundes Nervengewebe konnten wir die HSP90-Inhibitoren HSP990 und SNX2112 sowie den NAMPT-Inhibitor Daporinad als vielversprechende Kandidaten mit einem breiten therapeutischen Fenster identifizieren.
In dieser Arbeit wurden keine tiergestützten Experimente durchgeführt, da sie nicht nur zeitaufwändig, ethisch umstritten und teuer sind, sondern die auch nur begrenzt auf den Menschen übertragbar sind. Für das Zytotoxizität-Screening gegen DMG-Tumorzellen wurden die Zellen von fünf DMG-Patienten gewonnen, während die Neuronen für das Neurotoxizitäts-Screening aus humanen pluripotenten Zellen differenziert wurden. Durch Verwendung von patientenspezifischen Tumorzellen und iPSCs ist es möglich mit denselben Methoden wie in dieser Arbeit personalisierte Therapien für Patienten zu entwickeln.
In Anbetracht der Herausforderungen bei der Behandlung von DMG, wie der Blut-Hirn-Schranke, der Entwicklung von Arzneimittelresistenzen oder der Mikroumgebung des Tumors, sind weitere, tiefergehende Experimente zur Arzneimittelvalidierung erforderlich
Regulation of cerebral cortex folding by controlling neuronal migration and progenitor expansion
Get PDFCerebral cortex folding represents a highly important evolutionary mechanism, one that remains, as yet, not fully understood. Present evidence suggests that cortex folding is caused by two cellular mechanisms: (1) expansion of progenitor cells, and (2) divergent radial migration of neurons. We previously generated a genetic deletion mouse model in which two cell adhesion molecules were ablated: Flrt1/Flrt3 double knockout mice. This model showed sulci-like cortex folding induced by divergent radial neuronal migration without expansion of progenitor cells. We used this ‘cell migration’ model to ask if the two folding mechanisms synergize, and whether the expansion of certain types of progenitors leads to qualitatively different cortical folds. In this thesis, I describe the generation and phenotypic analysis of two different triple knockout (TKO) mouse lines. I found that overproduction of intermediate progenitors by deletion of the centrosomal protein 83 (Cep83) in this ‘cell migration’ model (Cep83/Flrt1/Flrt3TKO mice, in short Cep83TKO mice) lead to cortical folding with an increased sulci-like appearance. In a separate mouse model, increasing the length of the early cortical stem cell expansion phase by deletion of fibroblast growth factor 10 (FGF10) in the ‘cell migration’ model (Fgf10/Flrt1/Flrt3TKO mice, in short Fgf10TKO mice) lead to cortical folding with a much increased penetrance and, interestingly, gyrus-like protrusions. These results indicate that expansion of progenitor cells and divergent radial migration of neurons synergize in vivo to induce cortical folding. They further suggest that expanding different types of progenitors leads to qualitatively different folding, raising the possibility that the formation of gyri and sulci requires the timely expansion of distinct progenitors
In-vivo Evaluation von Hauttumoren und inflammatorischen Dermatosen mittels nicht invasiver Bildgebung
Get PDFThis cumulative dissertation focusses on various applications of non-invasive imaging modalities in Dermatology. It aims to contribute to a better understanding of different non-invasive diagnostic methods and demonstrates their various applications. In addition to already established methods such as Dermoscopy, optical coherence tomography (OCT) and reflectance confocal microscopy (RCM), this work particularly addresses the new imaging method LC-OCT. This relatively unexplored technique has been applied in the early diagnosis of precancerous skin lesions and skin tumors with the intention of establishing diagnostic criteria. These were compared to correlates of already known OCT, RCM and histology criteria and tested for applicability in cases of dermatoscopically unclear lesions.
When suspicion of a skin disease arises after clinical inspection and Dermoscopy, a tissue sample is taken to confirm diagnosis. This approach is costly, time-consuming and not always conclusive, especially in larger or multilocular lesions. Conventional histology is the gold standard for diagnosing skin tumors and many other skin diseases. Efforts are being made to find methods that provide comparable diagnostic accuracy whilst being more cost-effective and timesaving than histological examination. In the context of this research project, images of skin tumors were taken using the LC-OCT technique and compared with corresponding H&E sections. Characteristic features for the respective skin diseases were identified and compared to already known features from OCT and RCM. LC-OCT showed higher diagnostic confidence in the diagnosis and subtyping of BCC compared to other techniques.
When considering lesions clinically not confidently classifiable as BCC but suspicious for BCC, very good diagnostic confidence and performance were achieved with LC- OCT to distinguish these lesions, compared to Dermoscopy and histology as the gold standard. Pitfalls, lesions misdiagnosed as BCC, occurred in 14 out of 182 lesions and consisted of sebaceous hyperplasia, molluscum contagiosum, pyogenic granuloma and actinic keratosis. Nevertheless, LC-OCT can assist clinicians in the diagnosis and subtyping of BCC and optimize both the diagnostic approach and the treatment procedure. In addition to avoiding unnecessary skin biopsies, this would have implications for therapy as well. While nodular and fibrosing BCCs should be treated surgically, conservative therapy options can be considered for superficial BCC.
Expanding the application spectrum of LC-OCT to other keratinocytic tumors, such as squamous cell carcinoma or its precursor actinic keratosis, showed new possibilities for the classification of field cancerization. By analyzing keratinocyte morphology and the architecture of the dermoepidermal junction, various stages of keratinocytic carcinomas can reliably be distinguished and correlated histologically.
Furthermore, LC-OCT was able to classify actinic keratoses based on the basal growth pattern of keratinocytes, providing the possibility to depict the PRO classification in vivo. The classification estimates the malignant transformation potential of AK by the displacement of keratinocytes into the papillary dermis, which could be achieved noninvasively with LC-OCT in the future.
Examining melanocytic lesions with LC-OCT showed no difference in performance in comparison to RCM, making LC-OCT a useful tool to discriminate between nevi and melanomas.
There has been a tremendous development in the field of non-invasive in vivo imaging in Dermatology. From early detection of skin cancer to staging or diagnosing skin diseases, non-invasive imaging methods support clinicians in their daily practice and decision making.
For the future an expansion of application to the inflammatory field of Dermatology is intended. In a prospective study we recently analyzed the applicability of non-invasive imaging tools in the diagnosis of onychomycosis. Further research in this field is necessary and potential new applications could entail inflammatory dermatoses like psoriasis and atopic dermatitis. Moreover, the influence of artificial intelligence in this fast-evolving research field could be further investigated. A first approach was made with artificial intelligence-based PRO score assessment in actinic keratosis. Whilst this was a first step towards a new chapter of non-invasive imaging, there will be numerous potential applications of artificial intelligence to be investigated in the future in this continuously advancing field of Dermatology
Antipsychotika und ihre Effekte auf die kognitive Funktion
Get PDFEinleitung Kognitive Defizite bilden eine unabhängige Symptomgruppe der Schizophrenie. Sie beeinflussen sowohl die Lebensqualität als auch die Funktionsfähigkeit der Betroffenen in ei-nem erheblichen Ausmaß. Antipsychotika gehören hierbei zu den Hauptbehandlungsmethoden, wobei es Hinweise darauf gibt, dass sich Antipsychotika in ihrer Wirkung auf die kognitive Symptomatik unterscheiden. Ziel dieser Arbeit ist es, eine evidenzbasierte Entscheidungsgrund-lage zu schaffen, die die Auswahl der besten Behandlungsmöglichkeit für die kognitive Symp-tomatik für den individuellen Patienten unterstützt.
Methoden Zur Untersuchung der Effekte von Antipsychotika auf die kognitive Funktion wurde eine systematische Übersichtsarbeit mit paarweisen Metaanalysen und Netzwerk-Metaanalysen erstellt. Hierbei wurden randomisiert-kontrollierte Studien eingeschlossen, die Patienten mit einer Schizophrenie untersuchten. Es wurden sowohl verblindete als auch offene Studien einge-schlossen. In den eingeschlossenen Studien wurden entweder verschiedene Antipsychotika miteinander oder mit Placebo verglichen und die Effekte auf die Kognition erhoben. Bei den Erhebungsinstrumenten zur Erfassung der kognitiven Symptomatik wurde sich vorzugsweise an den Empfehlungen der Initiative „Measurement and Treatment Research to Improve Cognition in Schizophrenia“ (MATRICS) orientiert oder Tests mit einer hohen Ähnlichkeit verwendet. Die Inter-ventionsphase betrug mindestens 3 Wochen. Die Suche nach passenden Studien erfolgte über das Cochrane Schizophrenia Trials Register. Als primäres Outcome gilt ein Gesamtscore, der aus den angegeben kognitiven Domänen gebildet wurde. Sekundäre Outcomes stellen die spe-zifischen kognitiven Domänen nach MATRICS, Lebensqualität und Funktionsfähigkeit dar.
Ergebnisse Es wurden 68 Studien mit insgesamt 9525 Patienten eingeschlossen. Ergebnisse der durchgeführten Netzwerk-Metaanalysen zeigen keine wesentlichen Effekte der untersuchten Antipsychotika im Vergleich zu Placebo auf den primären und die sekundären Outcomes. Er-gebnisse der Metaregressionen und Sensitivitätsanalysen zeigen Konsistenz zur primären Ana-lyse auf. Eine post-hoc Analyse, in der die Antipsychotika nach ihren Rezeptorprofilen vier Gruppen zugeordnet wurden, zeigt jedoch bessere Effekte aller Gruppen im Vergleich zu Pla-cebo auf.
Diskussion Nach aktuellem Kenntnisstand handelt es sich bei der vorliegenden Arbeit um die derzeit umfangreichste Netzwerk-Metaanalyse, die bisher zu den Effekten von Antipsychotika auf die kognitive Funktion im Rahmen einer Schizophrenie durchgeführt wurde. Es wurden alle bekannteren Antipsychotika miteinbezogen und sich am MATRICS-Goldstandard orientiert. Die Ergebnisse zeigen keine wesentlichen Überlegenheiten der einzelnen Antipsychotika im Ver-gleich zu Placebo, sowohl in Bezug auf den primären Outcome, als auch auf die sekundären Outcomes. Demnach kann auf Grundlade der aktuellen Evidenz keine eindeutige Empfehlung eines bestimmten Antipsychotikums für die Behandlung der kognitiven Symptomatik im Rah-men einer Schizophrenie ausgesprochen werden. Eine weitere Erkenntnis, die aus dieser Arbeit hervorgeht, ist, dass sich bisher kein Goldstandard zur Erhebung von Kognition durchsetzen konnte und demnach eine standardisierte Messung von Kognition im Rahmen einer Schizophre-nie dringend benötigt wird.Background Cognitive deficits form an independent symptom group of schizophrenia. They are a strong predictor of quality of life and functioning of affected people. Antipsychotics rep-resent a crucial treatment option but there is evidence that they differ in their effects on cogni-tive function. The objective of this work is to furnish an evidence-based foundation to enable the selection of the best treatment option for cognitive symptoms for each individual patient.
Methods A systematic review with paired meta-analysis and network meta-analysis was con-ducted to explore the effects of antipsychotics on cognitive function. Randomized controlled trials examining patients with schizophrenia were included. Both, (double-)blinded and open-label studies were included. Studies comparing antipsychotics with each other or placebo and which measured their effects on cognitive function were included. The measurement instru-ments for cognitive function were preferably based on the recommendations of the initiative „Measurement and Treatment Research to Improve Cognition in Schizophrenia“ (MATRICS) or showed a high similarity to the tests. The intervention phase was at least 3 weeks. The Cochrane Schizophrenia Trials Register has been screened for eligible studies. The primary outcome is an overall-score build by the given cognitive domains. Secondary outcomes are the specific cognitive domains by MATRICS, quality of life and functioning.
Results 68 studies were included with a total of 9525 patients. The results of the network meta-analyses showed no substantially better effects of the investigated antipsychotics compared to placebo for primary and secondary outcomes. Results of the meta-regressions and sensitivi-ty analyses showed consistency with the primary analysis. However, a post-hoc analysis cate-gorizing antipsychotics into four groups based on their receptor-binding profiles demonstrated better effects of all groups compared to placebo.
Discussion According to current knowledge, this is the largest network meta-analysis focusing on the effects of antipsychotics on cognitive function in schizophrenia. All known antipsychot-ics were included and the measurement of cognitive function followed the MATRICS-goldstandard. The results show no meaningfully better effects of a specific antipsychotic drug compared to placebo concerning the primary and secondary outcomes. Thus, based on the current evidence, no clear recommendation for a specific antipsychotic drug for the treatment of cognitive symptoms in schizophrenia can be made. A further finding emerging from this work is, that there is no established gold standard for assessing cognition in schizophrenia, so far. Therefore a standardized measurement of cognitive function in schizophrenia is of im-portant need
