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Coming dissertations at MedFak

  • PET in Prostate Cancer – Detection, Tumour Biology and Prognosis Author: Naresh Kumar Regula Link: Publication date: 2020-04-16 14:18

    Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and the leading cause of cancer-related deaths in Sweden. Despite the major advances, the current diagnostic modalities fall short of standards, specifically, precise localization required for effective management of the PCa. positron emission tomography (PET) combined with computed tomography (CT) has evolved as a promising diagnostic imaging technique for PCa. The progression of the PCa is often associated with metabolic alterations and overexpression of several proteins. Increased de novo fatty acid synthesis and prostate-specific membrane antigen (PSMA) overexpression are some of the distinctive features linked with PCa growth and the potential targets for the development of PET radiotracers.       

    This thesis is based on four original articles and focuses on the utilization of some of several different PET tracers available to visualize PCa spread. The work can be divided into two distinctive parts: (1) evaluate the prognostic value of 11C-acetate PET/CT towards survival in the setting of biochemical relapse after surgery, investigate tumour biology using single-tissue compartment model derived parametric images of 11C-acetate dynamic PET/CT both at patient and cell level and (2) the comparison of 68Ga-PSMA-11 PET/CT with 11C-acetate PET/CT and 18F-NaF PET/CT in patients with PCa relapse depicting different aspects of PCa biology.

    We demonstrated that quantification of 11C-acetate accumulation in PCa lesions was a strong predictor of survival in patients with biochemical relapse. Furthermore, parametric images of 11C-acetate dynamic PET/CT enabled visualization of tumour biology exhibiting elevated extraction of 11C-acetate associated with cancer aggressiveness also confirmed in in-vitro studies. 68Ga-PSMA-11 PET/CT located more widespread disease and performed significantly better in locating lymph node and bone metastases compared to 11C-acetate PET/CT. Similarly, 68Ga-PSMA-11 PET/CT was able to detect most of the bone lesions detected with 18F-NaF PET/CT along with additional soft tissue lesions.

    In conclusion, we showed the role of 11C-acetate PET/CT in PCa prognosis with additional understanding of tumour biology. Further, we successfully showed better performance of 68Ga-PSMA-11 PET/CT in locating PCa relapse and established it as a promising option for PCa re-staging.

  • Identification and clinical implementation of biomarkers for cervical cancer Author: Malin Berggrund Link: Publication date: 2020-04-16 14:05

    Introduction of organised screening programs and prophylactic vaccination against human papilloma virus (HPV) have successfully reduced the incidence of cervical cancer globally. In Sweden, the incidence has been reduced by about 50 % since the introduction of the national screening programme in the late 1960’s. Despite these efforts, cervical cancer is still a major cause of cancer deaths globally.

    In order to reduce cervical cancer, the screening program should have a high participation rate and be based on a sensitive and specific screening test. About 20 % of women in Sweden do not participate in the organised screening program, and during the last years we have also seen a rise in cervical cancer cases in Sweden among women who participate in the screening program. Thus, there is a need to develop improved screening strategies that result in a higher participation rate, and are based on tests that more precisely identify women with high risk of developing cervical cancer. This includes searching for novel biological markers (biomarkers) that can be used to more accurately identify women with a high risk of developing cervical cancer.

    By offering women self-sampling for HPV analysis through direct mailing of sample kits with a chemically treated paper card, the FTA card, we were able to increase the participation rate in the screening program. We also found that the use of repeated self-sampling for women that were HPV positive in the primary screening sample increased the number of women detected with higher risk of cervical cancer (Paper II). Self-sampling was shown to be non-inferior to assisted sampling by midwife (Paper III). Using this sample collection device, we further investigated the association between increased risk of cervical cancer and HPV viral load (Paper V) as well as the vaginal microbiota (Paper VI). We also showed that proteins in the vaginal fluid can be studied using self-sampling and the FTA card (Paper I). Lastly, we identified plasma proteins that are associated with cervical cancer and could represent future biomarkers (Paper IV).

    This thesis has provided novel aspects on the present screening strategy, explored opportunities to increase the participation rate as well as examined possible future biomarkers for screening of cervical cancer.

  • The Human Vestibular Aqueduct, Endolymphatic Duct and Sac : A Morphological Study Using Micro-CT, Super Resolution Immunohistochemistry and Synchrotron Phase Contrast Imaging Author: Charlotta Kämpfe Nordström Link: Publication date: 2020-04-16 11:29

    The inner ear lies sheltered in the temporal bone and consists of basically three parts: the cochlea (the hearing organ), the vestibular (the balance organ), and the endolymphatic duct (ED) and endolymphatic sac (ES). The ES and ED are located in a bony canal, the vestibular aqueduct (VA), located on the medial side of the vestibule. While the functions of the cochlea and the vestibular part of the inner ear are rather well studied, our knowledge of the function/s of the ES and ED remains limited and has intrigued scientists for centuries. Earlier studies have supported several theories, such as being an immune mediator, an aid in pressure regulation, related to the absorption of endolymph, and the production of endolymph.

     Otologic disorders, which affect both hearing and balance, such as Meniere’s disease (MD) and large vestibular aqueduct syndrome (LVAS), have been linked to dysfunction of the ES/ED. Studies of the human inner ear are fairly sparse. Research on the ES and ED have mainly been performed on animals, although both the anatomy and function may differ among various species.

    This thesis aims to further investigate the anatomy and function of the human ES and ED with the two otologic disorders MD and LVAS in mind. To achieve this, we have used novel imaging techniques, such as super-resolution structured illumination microscopy (SR-SIM), micro-computerized tomography (micro-CT), and synchrotron radiation phase-contrast imaging (SR-PCI). The material used for imaging comes from different sources: human archival temporal bones from the Uppsala temporal bone collection; human fresh-frozen cadaveric bones from our collaborators at Western University, in London, Ontario, Canada; and fresh-frozen human ES harvested during vestibular schwannoma surgery after securing ethical permission.

    The results of these studies describe the micro-anatomy of the VA, ED and ES down to a nanoscopic level. The discussion is based on the findings, relating them to earlier research with clinical implications regarding MD and LVAS.