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- Bjersand, Kathrine
(författare)
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Predictive and prognostic factors of epithelial ovarian cancer and pseudomyxoma peritonei
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of my thesis was to investigate potential prognostic and predictive factors associated with the tumor cells of epithelial ovarian cancer (EOC) and the gastrointestinal tumor pseudomyxoma peritonei (PMP) to improve and individualize cancer therapy. Both PMP and EOC can develop into peritoneal carcinomatosis (PC), which is characterized by widespread metastasis of cancer tumors in the peritoneal cavity. Major improvements in the management of PC, such as cytoreductive surgery in combination with chemotherapy, have dramatically changed the prognosis.To further optimize and tailor treatment, increased knowledge on tumor biology and pathogenesis is needed. Today’s choice of treatment is mainly based on clinical trials and standard protocols that have not taken individual differences in drug sensitivity into consideration. With ex vivo testing of tumor drug sensitivity, individuals at risk of side effects only (and no treatment benefit) could potentially be identified prior to treatment.Napsin A is an anti-apoptotic protein that promotes platinum resistance by degradation of the cell cycle regulator and tumor suppressor TP53. Immunohistochemical stainings of 131 early EOC tumors in study I showed that expression of Napsin A was associated with expression of the apoptosis regulators p21 and p53 and with histological subtype. Positivity of Napsin A in an epithelial ovarian tumor strengthens the morphological diagnosis of clear cell carcinoma and should be useful in diagnostics. In study II, the relevance of the proteins HRNPM and SLC1A5 as prognostic factors for recurrent disease, survival and impact on clinical or pathological features was evaluated in 123 patients with early EOC. Our results support concomitant positivity of HRMPM and PUMA/p21 in ovarian cancer and indicate that HRNPM may trigger activity in systems of cell cycle regulation and apoptosis. In subgroup analyses of tumors from patients with non-serous EOC histology, expression of SLC1A5 was shown to be a prognostic factor in terms of prolonged disease-free survival. In studies III and VI, we investigated the ex vivo drug sensitivity of tumor cells from EOC and PMP with the 72-h cell viability assay fluorometric microculture cytotoxicity assay (FMCA). The two studies confirm that drug sensitivity varies considerably between tumor samples from patients within the same diagnostic group. In ovarian cancer, ex vivo results show that type I tumors were generally less sensitive to cytotoxic agents than type II tumors. Samples from patients previously exposed to cytotoxic drugs generally tended to be more resistant to most drugs than samples from unexposed patients in both EOC and PMP. This observation is in line with clinical experience and findings supporting that exposure to cytotoxic treatments contribute to development of chemo-resistance mechanisms. In ovarian cancer, resistance to the kinase inhibitors after exposure varied but was less pronounced than that for standard cytotoxic drugs. In PMP patients, ex vivo drug sensitivity provided prognostic information for progression-free survival, and this is in line with earlier findings.
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| 2. |
- Dahm-Kähler, Pernilla, 1964
(författare)
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The Ovulatory Process. Studies in the human and the rabbit
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and general summary: Ovulation is the cascade of events ending with follicular rupture and oocyte extrusion. This ovulatory process is triggered by the LH surge, which induces biochemical and biophysical alterations within the preovulatory follicle. The ovulatory process is an inflammation-like process and also involves alterations in hemodynamics and pressure within the follicle. A model for investigations of the events of ovulation in vivo in the rabbit was developed. The expression and regulation of two macrophage specific chemokines in the human ovary were also explored. To enable studies of the intrafollicular pressure (IFP) in the human ovary a new method was developed. The aims of these studies were to develop methodologies for studies of ovulation and to more specifically study one component of the inflammation-like response at ovulation. Methods and results: An intravital microscopy method, permitting long-term observation of the rabbit ovary in vivo, was developed. During anaesthesia the ovary of an eCG/hCG primed rabbit was submerged into a specially designed organ chamber with a microscopy lens close to the ovary. Video recordings documented ovulations, which occurred around 12 h after hCG. The sequence of typical features of ovulation were; vascular shut down in the follicular apex, petechiae in the follicular wall, formation of a cone-shaped structure over the rupture site, bulky bleeding at the site of follicular rupture and a steady extrusion velocity of granulosa cells and the oocyte (Paper I). The presence and regulation of two macrophage specific chemokines, monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1£ (MIP-1£), were investigated in the human ovary during menstrual and IVF cycles. The levels of MCP-1 were markedly higher in follicular fluid as compared to blood plasma in both menstrual- and IVF-cycles. The follicular fluid to plasma difference in MCP-1 levels in menstrual cycles increased from the follicular phase to the late ovulatory phase. Theca cells from follicles of menstrual cycles secreted both MCP-1 and MIP-1 Ñ during basal conditions and the secretion increased by addition of IL-1. Granulosa-lutein cells secreted MCP-1 under basal condition and also MIP-1 Ñ after IL-1 (Paper II). MCP-1 expression and macrophage density were evaluated in the perifollicular stroma during precise phases of the ovulatory process in the human. Women, planned for laparoscopy, were monitored closely by transvaginal ultrasound and when the dominant follicle was 15-17mm in diameter 21 out of the 28 women received rhCG. Surgery was performed at four distinct ovulatory phases and the dominant follicle and its adjacent stroma was collected. The mRNA levels of MCP-1 in the perifollicular stroma increased from the preovulatory to late ovulatory phase and declined during post ovulatory phase. Immunoblot confirmed presence of macrophages and MCP-1 receptor CCR2 in the stroma. There was a tendency to higher macrophage density during the two earlier ovulatory phases (Paper III). A methodology for in vivo measurements of the IFP in the human ovary was developed. A pressure sensor was inserted into the follicular antrum, in ovaries of women undergoing laparotomy. The ovarian arteries and veins were dissected free to enable manipulation during pressure measurement. The baseline IFP was positive and stable. When the ovarian veins were blocked the IFP increased and then declined after clamping of the ovarian artery. The pressure inside ovarian non-follicular cysts was considerably lower and no alterations were seen during vascular manipulation (Paper IV).Taken together, the present studies present two new methodologies that enable in vivo examinations of the ovulatory process and do also show that the chemokine MCP-1 is expressed and under cytokine regulation during the ovulatory process of the human.
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