Das Ovarialkarzinom ist eine maligne Entartung der Eierstöcke und die achthäufigste Krebserkrankung in Deutschland. Aufgrund einer initialen langen symptomfreien Zeit und einer raschen Dynamik wird die Erkrankung meist erst im fortgeschrittenen Stadium, d.h. im Stadium III oder IV diagnostiziert, welches mit einer geringen 5-Jahres-Überlebenswahrscheinlichkeit von ca. 43 % einhergeht. Aktuell beruht die Standard-therapie auf einer radikalen Operation mit dem Ziel der makroskopischen Komplettresektion gefolgt von einer Platin/Paclitaxel-basierten Chemotherapie, welche im fortgeschrittenen Stadium mit dem Antikörper Bevacizumab kombiniert wird. Doch bis zu 85 % der Patientinnen mit fortgeschrittenem Ovarialkarzinom erleiden ein Rezidiv, und dabei stellt vor allem die Platin-Resistenz ein großes Problem dar. Im Rahmen dieser Arbeit wurde die Wirkung des zugelassenen H1-Antihistaminikums Diphenhydramin (DIPH) auf die platin-basierte Chemotherapie in Ovarialkarzinomzellen in vitro und in vivo untersucht. Während frühere Arbeiten eher eine schützende Wirkung von DIPH vor den Nebenwirkungen (z.B. Nephrotoxizität, Ototoxizität) der Platin-Therapie berichtet haben, wird in dieser Arbeit gezeigt, dass DIPH außerdem überraschenderweise in platin-resistenten Ovarialkarzinomzellen als „Platin-Sensitizer“ fungieren kann, da in der Kombinationstherapie Cisplatin mit DIPH eine Erhöhung der intrazellulären DNA-Platinierung, sowie der Apoptoseinduktion beobachtet wurde. Nachfolgende Experimente belegen, dass DIPH, neben seiner bekannten Funktion als H1-Antagonist, die Transportkapazitäten der Effluxpumpen MRP2, MRP3 und MRP5 inhibiert, welche bereits mit der Platin-Resistenz im Ovarialkarzinom in Verbindung gebracht wurden. Diese Erkenntnis unterstützt die Hypothese, dass DIPH Tumorzellen für die Cisplatin-Behandlung sensitiviert, indem der MRP-vermittelte Cisplatin-Efflux inhibiert wird. Darüber hinaus wurde in dieser Arbeit erfolgreich ein intraperitoneales Mausmodell für das platin-resistente Ovarialkarzinom mit Hilfe von Biolumineszenzimaging etabliert, um den Effekt von DIPH als möglichen „Platin-Sensitizer“ auch in vivo zu untersuchen. Es zeigte sich, dass mit Cisplatin und DIPH behandelte Versuchstiere tendenziell ein geringeres intraperitoneales Tumorwachstum aufwiesen als die mit Cisplatin behandelten Versuchstiere, was für eine mögliche Rolle von DIPH als Platin-Sensitizer spricht. Jedoch konnte eine statistische Signifikanz dieses Effektes auf Grund einiger technischer Limitationen des etablierten Mausmodells bislang noch nicht gezeigt werden. Ziel der vorliegenden Arbeit ist es, den Effekt von DIPH auf die platin-basierte Chemotherapie in einem umfassenden experimentellen in vitro Ansatz zu erforschen. In diesem Kontext wurde eine pharmakologische Strategie zur DIPH-vermittelten Sensitivierung des platin-resistenten Ovarialkarzinoms entwickelt, die anschließend in einem in vivo System präliminär getestet wurde. Die Ergebnisse liefern insgesamt eine vielversprechende Basis für weiterführende präklinische in vivo Versuche mit DIPH im Rahmen eines „Drug repositioning“ Ansatzes. / Ovarian cancer is a malignancy of the ovaries and the eighth most common cancer in Germany. Due to an initial long symptom-free period and rapid dynamics, the disease is usually diagnosed only at an advanced stage, i.e. stage III or IV, which is associated with a low 5-year survival probability of about 43 %. Currently, standard therapy is based on radical surgery with the goal of complete macroscopic resection followed by platinum/paclitaxel-based chemotherapy, which is combined with the antibody bevacizumab in advanced stages. However, up to 85 % of patients with advanced ovarian cancer experience recurrence, and platinum resistance in particular is a major problem. In this dissertation, the effect of the approved H1 antihistamine diphenhydramine (DIPH) on platinum-based chemotherapy was investigated in ovarian cancer cells in vitro and in vivo. While previous work has tended to report a protective effect of DIPH against the side effects (e.g., nephrotoxicity, ototoxicity) of platinum therapy, this work demonstrates that DIPH can also, surprisingly, act as a 'platinum sensitizer' in platinum-resistant ovarian cancer cells, as an increase in intracellular DNA platinization, as well as apoptosis induction, was observed in combination therapy with cisplatin and DIPH. Subsequent experiments indicate that DIPH, in addition to its known function as an H1 antagonist, inhibits the transport capacities of the efflux pumps MRP2, MRP3, and MRP5, which have previously been associated to platinum resistance in ovarian cancer. This finding supports the hypothesis that DIPH sensitizes tumor cells to cisplatin treatment by inhibiting MRP-mediated cisplatin efflux. In addition, this work successfully established an intraperitoneal mouse model for platinum-resistant ovarian cancer using bioluminescence imaging to investigate the effect of DIPH as a potential 'platinum sensitizer' in vivo as well. It was found that experimental animals treated with cisplatin and DIPH tended to have lower intraperitoneal tumor growth than those treated with cisplatin, suggesting a possible role of DIPH as a platinum sensitizer. However, statistical significance of this effect has not yet been demonstrated due to some technical limitations of the established mouse model. The aim of the present work is to explore the effect of DIPH on platinum-based chemotherapy in a comprehensive experimental in vitro approach. In this context, a pharmacological strategy for DIPH-mediated sensitization of platinum-resistant ovarian cancer was developed and subsequently preliminarily tested in an in vivo system. Overall, the results provide a promising basis for further preclinical in vivo trials with DIPH in the context of a 'drug repositioning' approach.

Background: Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. Case presentation: A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. Conclusions: This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.

The term "teachable moment" (TM) has been used to describe a life transition or event which motivates an individual to change a behavior or presents an opportunity to intervene to prompt behavior change. We examined whether receipt of a false positive ovarian cancer (OC) screening result may represent a TM. 403 women participating in an OC screening program completed questionnaires assessing demographic, clinical, behavioral, and psychosocial information. The TM was operationalized as expressed interest in receiving health-related information. We hypothesized that among women receiving a false positive screening test result, those women who had experienced greater personal perceived risk for OC as well as distress would be more interested in receiving health-related information than women receiving a normal result. Analyses revealed that women receiving a false positive screening result were less interested in receiving health-related information than women receiving a normal screening result. For women receiving a false positive result, expressed interest in receipt of health-related information was only modestly related to distress and related even less to perceptions of OC risk. Our data do not support viewing a false positive OC screening result as a TM. Potential explanations for the current findings as well as recommendations for future research investigating the TM are discussed.

Ovarian cancer (OVCA) is the most lethal gynecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as targeted therapies and immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long term therapeutic success. Therefore, there is an urgent need to understand the cellular and molecular mechanisms of immune dysregulation in chemoresistant ovarian cancer in order to harness the host’s immune system to improve cancer survival. Early diagnosis and residual disease are key determinants of favorable survival in OVCA; however, CA125 which is the conventional marker is not reliable and has modest diagnostic accuracy. There is therefore an urgent need to discover reliable biomarkers to optimize individualized treatment and diagnostic recommendations. Plasma gelsolin (pGSN; an actin binding protein) is the secreted isoform of the gelsolin (GSN) gene implicated in inflammatory disorders, colon cancer and prostate cancer. Increased expression of total GSN is associated with poor survival of patients with gynecological cancers. As to whether this is due to pGSN is yet to be investigated. Increased expression of pGSN is significantly associated with the down-regulation of immune cell markers; however, the exact mechanism has not been explored. If and how pGSN is involved in the cellular and molecular mechanisms of OVCA remains to be determined. In our current research, we have demonstrated that pGSN is involved in the regulation of immune cells, early diagnosis, tumor recurrence and chemoresistance in OVCA, using standard in vitro techniques and human clinical samples (North America, Asia and public datasets). We have shown that pGSN is highly expressed and secreted in chemoresistant OVCA cells than their chemosensitive counterparts. pGSN, secreted and transported via exosomes, upregulated HIF1α–mediated pGSN expression in chemoresistant OVCA cells in an autocrine manner as well as conferred cisplatin resistance in otherwise chemosensitive OVCA cells. pGSN also induced the OVCA expression of the antioxidant and tumor growth promoter, glutathione (GSH), by activating Nuclear factor erythroid 2-related factor 2 (NRF2), a response that attenuated cisplatin (CDDP)-induced apoptosis. In human tumor tissues, increased pGSN mRNA and protein expressions were significantly associated with advanced tumor stage, suboptimal residual disease, tumor recurrence, chemoresistance and poor survival regardless of patients’ ethnic background and histologic subtypes. Increased Infiltration of CD8+ T cells was significantly associated with favorable patient survival; however, increased pGSN hindered the survival impact of these infiltrated CD8+ T cells. Further investigation revealed that pGSN induced CD8+ T cell death via caspase-3 activation, an action that resulted in decreased IFNγ levels. Increased epithelial pGSN expression was significantly associated with reduced survival benefits of infiltrated M1 macrophages, through caspase-3-dependent apoptosis as well as reduced production of TNFα and iNOS. The clinical application of circulatory pGSN as a biomarker for early detection and patients’ survival was investigated. Pre-operative circulating pGSN presented as a favorable and independent biomarker for early disease detection and residual disease prediction compared with CA125. The test accuracy of pGSN was significantly enhanced when combined with CA125 in multianalyte index assay. The findings suggest that pGSN is a potential target for chemoresistant OVCA and presents as a diagnostic marker for early stage disease and surgical outcomes, interventions that could maximize the therapeutic success of immunotherapies.

Promoters, neighboring regulatory regions and those extending further upstream of the 5’end of genes, are considered one of the main components affecting the expression status of genes in a specific phenotype. More recently research by Chen et al. (2006, 2012) and Mapendano et al. (2010) demonstrated that the 3’end regulatory regions of genes also influence gene expression. However, the association between the regulatory regions surrounding 3’end of genes and their over- or under-expression status in a particular phenotype has not been systematically studied. The aim of this study is to ascertain if regulatory regions surrounding the 3’end of genes contain sufficient regulatory information to correlate genes with their expression status in a particular phenotype. Over- and under-expressed ovarian cancer (OC) genes were used as a model. Exploratory analysis of the 3’end regions were performed by transforming the annotated regions using principal component analysis (PCA), followed by clustering the transformed data thereby achieving a clear separation of genes with different expression status. Additionally, several classification algorithms such as Naïve Bayes, Random Forest and Support Vector Machine (SVM) were tested with different parameter settings to analyze the discriminatory capacity of the 3’end regions of genes related to their gene expression status. The best performance was achieved using the SVM classification model with 10-fold cross-validation that yielded an accuracy of 98.4%, sensitivity of 99.5% and specificity of 92.5%. For gene expression status for newly available instances, based on information derived from the 3’end regions, an SVM predictive model was developed with 10-fold cross-validation that yielded an accuracy of 67.0%, sensitivity of 73.2% and specificity of 61.0%. Moreover, building an SVM with polynomial kernel model to PCA transformed data yielded an accuracy of 83.1%, sensitivity of 92.5% and specificity of 74.8% using 10-fold cross-validation for evaluation. These clustering and classification analyses strongly suggest that the regions surrounding the 3’end of genes contain sufficiently rich regulatory information to discriminate between over- and under-expressed genes; at least in the case of genes implicated in OC.

Le cancer ovarien comprend un groupe hétérogène de tumeurs pouvant affecter les cellules épithéliales, stromales ou germinales. Le traitement de ces tumeurs constitue un défi majeur car un taux important de patientes présentent une rechute suite à un traitement chimiothérapeutique. Il est donc important de comprendre les mécanismes de résistance à la chimiothérapie de ces tumeurs.Le facteur de croissance des fibroblastes 1 (FGF1) a été retrouvé surexprimé dans de nombreuses tumeurs dont les tumeurs ovariennes épithéliales de haut grade. Les études antérieures du laboratoire ont montré que le FGF1 exerce une activité anti-apoptotique via la modulation de la stabilité et des activités transcriptionnelles de p53. Le but de mon travail était donc de savoir si la surexpression du FGF1 était suffisante pour favoriser une résistance vis-à-vis de l’apoptose induite par des agents chimiothérapeutiques dans les tumeurs ovariennes et si le FGF1 pourrait réguler les activités de la protéine p53.À cet effet, nous avons utilisé trois lignées ovariennes ; la lignée de la granulosa ovarienne COV434, la lignée épithéliale A2780 et la lignée épithéliale résistante au cisplatine A2780cis qui surexprime le FGF1. L’invalidation du gène FGF1 par la technique CRISPR/Cas9 n’a pas permis de restaurer la sensibilité à la chimiothérapie dans les cellules A2780cis. D’autre part, nous avons montré que la surexpression du FGF1 confère une résistance à l’apoptose dans la lignée COV434, mais pas dans la lignée épithéliale A2780. Les mécanismes moléculaires de cette activité anti-apoptotique sont différents de ceux identifiés dans d’autres lignées. En effet, dans la lignée COV434 la surexpression du FGF1 a peu d’impact sur la stabilité de p53 et ne diminue pas son activité transcriptionnelle. De plus, nous montrons que la translocation mitochondriale de p53 joue un rôle important dans l’induction de l’apoptose par l’étoposide dans la lignée COV434. De plus, nous avons montré que, dans la lignée COV434, l’activité anti-apoptotique du FGF1 est exercée par une atténuation de la localisation mitochondriale de p53. Nos données préliminaires suggèrent la présence du FGF1 à la mitochondrie. En conclusion, l’ensemble de nos expériences permet de proposer un nouveau mode d’action pour le FGF1 qui n’a jamais été décrit auparavant. / Ovarian cancer is an heterogenous group of tumors, able to affect epithelial, stromal or germ cells. The treatment of these tumors is a major challenge as a high rate of relapse is observed in ovarian cancer patients following chemotherapy.Fibrobast growth factor 1 (FGF1) is overexpressed in numerous tumors such as high grade ovarian epithelial tumors. Previous work realized in our laboratory showed that FGF1 has an anti-apoptotic activity which is mediated by the regulation of p53 stability and transcriptional activities. The aim of my work was to understand whether FGF1 overexpression is sufficient to induce resistance to chemotherapy-induced apoptosis in ovarian tumors and if FGF1 could modulate the activities of p53 protein.For this purpose, we used three ovarian cell lines; the COV434 ovarian granulosa cell line, the ovarian epithelial A2780 cell line and its counterpart A2780cis cell line which is resistant to ciplatin and overexpresses FGF1.FGF1 knock out experiments in A2780cis cell line, using the CRISPR/Cas9 system, did not show any restoration of the sensibility of these cells to cisplatin. Moreover, we showed that FGF1 overexpression in COV434 cell line renders these cells resistant to apoptosis while no effect was observed in A2780 cells. The molecular mechanisms underlying this anti-apoptotic activity differed from those identified in other cell lines previously. Indeed, in COV434 cell line, FGF1 overexpression has only a small impact on p53 stability and it does not reduce its transcriptional activity. Furthermore, we show here that p53 mitochondrial translocation plays an important role in the induction of apoptosis by etoposide in COV434 cells. Moreover, we provide evidence that FGF1 anti-apoptotic activity in COV434 cells relies upon the attenuation of p53 mitochondrial localization. Our preliminary results suggest that FGF1 could be found at the mitochondria. In conclusion, our findings let us propose a novel mode of action for FGF1 which has never been described previously.

Indiana University-Purdue University Indianapolis (IUPUI) / Taxane-induced musculoskeletal pain (TIMP) is musculoskeletal pain that includes myalgia (i.e., diffuse muscle pain, usually accompanied by malaise) and/or arthralgia (i.e., joint pain) that occurs following treatment with taxane-based chemotherapy. TIMP is a symptom that is clinically reported as negatively affecting most cancer survivors receiving taxane-based chemotherapy; however, TIMP is not comprehensively understood. The purpose of this dissertation was to conduct a cross sectional, descriptive, correlational pilot study to describe TIMP in women with ovarian cancer who were being or had been treated with paclitaxel-containing regimens. Specific aims were to: (1) describe the TIMP symptom experience (intensity, distress, duration, location, quality, temporal pattern, aggravating and alleviating factors, and pain management); (2) describe the associations between TIMP (intensity, distress) and co occurring symptoms (pain [general], peripheral neuropathy, impaired sleep, fatigue, emotional distress, and/or hot flashes); and (3) identify associations between TIMP (intensity, distress) and patient-reported outcomes (interference with daily activities, physical functioning, and health-related quality of life). Primary data collection was performed on a convenience sample of 15 women with ovarian cancer. Participants were recruited from an outpatient cancer clinic, local cancer support communities, and a national cancer survivors’ research registry. Descriptive statistics and Spearman’s correlations were used. Findings showed TIMP is moderate to severe in intensity on average, constant, affecting a large area of the body, and aggravated by everyday walking. Greater TIMP intensity or distress was associated with greater intensity and interference of most co-occurring symptoms and was associated with greater interference with daily activities, worse physical functioning, and worse health-related quality of life. Nurses are encouraged to comprehensively assess TIMP using structured, validated tools for pain to better intervene on aggravating and alleviating factors and pain management regimens. Prospective, longitudinal studies with larger sample sizes are needed to further understand TIMP and its impact on cancer survivors.

Bakgrund: Äggstockscancer drabbar omkring 240 000 kvinnor världen över varje år och har den högsta dödligheten bland all gynekologisk cancer. Äggstockscancer påverkar kvinnor i olika aspekter. Syfte: Syftet med litteraturstudien var att beskriva kvinnors erfarenheter av att leva med äggstockscancer. Metod: Denna kvalitativa litteraturstudie är baserad på nio utvalda studier från databaserna CINAHL och PubMed. Analysen gjordes enligt Fribergs femstegsmodell. Resultat: Analysen resulterade i fyra kategorier och tolv subkategorier. Kategorierna var: Att genomgå hälsoförändringar, Att ställas inför störningar i det dagliga livet, Att bemästra sjukdomen samt Att leva med ständig oro för framtiden. Kategorierna tar tillsammans upp hur äggstockscancer påverkar kvinnorna i fysiska, psykiska, sociala samt existentiella aspekter. Lidandet är speciellt framträdande, men hopp och mening förekommer även. Konklusion: Äggstockscancer påverkar kvinnorna i många olika aspekter vilket gör det väsentligt att sjuksköterskan har ett personcentrerat förhållningssätt för att kunna identifiera behov. Att lyssna och ha de svåra samtalen gör att en bra kontakt mellan sjuksköterska och patient skapas och möjliggör bästa möjliga vård för kvinnorna att klara av sin situation. Ytterligare forskning behövs för att kunna ge bättre stöd och få mer kunskap kring äggstockscancer. / Background: Ovarian cancer affects 240 000 women globally every year and is the form of gynaecological cancer with the highest mortality. Ovarian cancer is affecting women in different aspects. Aim: The aim of this study was to describe women’s experiences of living with ovarian cancer. Methods: A literature study based on nine qualitative studies from the databases CINAHL and PubMed. The analysis was conducted according to Friberg’s five-stage model. Results: The analysis resulted in four categories and twelve subcategories. The categories were: To go through health changes, To face disruptions in everyday life, To master the disease and To live with constant worry of the future. The categories brings up how ovarian cancer affects the women in physical, psychological, social and existential aspects. Suffering was particularly prominent but hope and meaning also existed. Conclusion: Ovarian cancer affects women in many different aspects and it is essential that the nurse has a person-centered approach so needs can be identified. Listening and having difficult conversations leads to a good connection between nurse and patient which enables the best possible care for the women to handle their situation. Additional research needs to be conducted to give better support and to gain more knowledge about ovarian cancer.

Breast and ovarian cancers are the most serious cancers among women. Relatively high mortality at advanced stages of the disease is often associated with the development of resistance to the cytotoxic agents. Chemoresistance usually develops on the base of different adaptive mechanisms that significantly decrease therapy efficiency. Currently TRIP6, ABCC3 and CPS1 enzyme has been identified based on high-capacity expression profile monitoring in tumor cell and tissue profiles as one such candidate playing a role in taxane resistance. The main goal of this thesis was to clarify the role or possible association of the ABCC3, CPS1 and TRIP6 genes with the development of tumor cell resistance to taxanes in models of sensitive and paclitaxel-resistant ovarian cancer cells and in the cohorts of patients with ovarian and breast cancer. The in vitro part compares the efficacy of paclitaxel and taxane derivatives in the sensitive and resistant ovarian cancer cell lines and clarifies the association between the different structure of taxane derivatives and the change in CPS1 expression after their application. The study in patient's cohorts with ovarian cancer reveals a relationship between higher levels of the CPS1 gene and shorter progression-free survival. The achieved results may serve as a base for data...

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20662号 / 医博第4272号 / 新制||医||1024(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 松田 道行, 教授 原田 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM