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Coming dissertations at MedFak

  • Clinical and tumour biology studies of Diffuse Large B-cell Lymphoma : with emphasis on comorbidity, toxicity and outcome Author: Charlott Mörth Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-420746 Publication date: 2020-10-28 13:04

    Diffuse large B-cell lymphoma (DLBCL) is curable in around 70% when treated with standard immunochemotherapy R- CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Treatment related toxicity affecting survivors is a clinical problem as well as comorbidities influencing the possibility to give adequate treatment. The relevance of follow-up time and follow-up measures can be debated, follow-up time in Sweden has been reduced to two years due to studies showing an OS survival comparable to standard population among DLBCL achieving EFS24.The main objective of this thesis is to study known side-effects of treatment and comorbidities and explore outcome in DLBCL in order to improve clinical treatment and follow-up decisions. In Paper I we explored whether the omission of vincristine (VCR) due to neurotoxicity affect outcome (DFS,OS). In 541 patients omission of VCR was made in 95 (17.6%). There was no impact on outcome measures in the whole cohort irrespective of treatment cycle for the omission nor was there a difference in the elderly (≥70 years) group. In Paper II we studied the occurrence of different autoimmune disorders (AID) in 612 DLBCL and analysed whether AID affects treatment outcome. We found a high occurrence of AID among DLBCL patients (17.3%) compared to the general population (3-10%). AID did not affect EFS/LSS or OS in the whole cohort but women with B-cell response AID had a worse OS compared to other women (p=0.013). In Paper III we established event free survival at 24 months (EFS24) in a Swedish DLBCL cohort and analysed factors governing OS and compared OS with an age and gender matched standard population. 71.6% achieved EFS24 and OS was marginally lower than the standard population. Age was the only factor affecting OS in multivariate analysis and EFS24 patients<60 years had a comparable OS to the standard population. In older ages (>60years) there was a trend for worse OS driven by a significant difference in OS among those 60-69 years. Among DLBCL achieving EFS24, 22.4% died of cardiovascular disease and 16% from other malignancies. In Paper IV we explored whether advanced serum protein analysis can be used to measure doxorubicin (DXR) related cardiac/cardiovascular (CVD) disease in DLBCL patients. We found two proteins, SPON-1 associated with CVD at diagnosis and IL-1RT1 associated with emerging CVD after treatment. Compared to the general population and to a matched cohort DLBCL patients had a high occurrence of CVD at diagnosis, 33.4%. After treatment 22.6% developed CVD.

  • Studies of ulcerative colitis with concomitant primary sclerosing cholangitis : Beyond the clinical phenotype Author: Johan Vessby Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-419964 Publication date: 2020-10-14 14:47

    Inflammatory bowel disease (IBD) is a group of chronically relapsing immune-related disorders, engaging the gastrointestinal tract. Symptoms vary depending on inflammatory phenotype, but may include diarrhoea, bowel pain and weight loss. The two most common entities are Crohn's disease and ulcerative colitis (UC). A minority of IBD patients, particularly UC, is concomitantly affected by primary sclerosing cholangitis (PSC) – an inflammatory bile duct disease with dismal prognosis. IBD with associated PSC has distinct clinical features, and is regarded a unique IBD phenotype (PSC-IBD or PSC-UC). These features include higher rates of pancolitis, a milder clinical course, and an unexplained increased risk of colorectal neoplasia.

    This thesis aimed to compare immunological conditions in PSC-UC and UC, but also to search for molecular differences, potentially facilitating PSC-UC diagnosis.

    In paper I and II, we compared eosinophil and lymphocyte activation and regulation. PSC-UC had down-regulated mucosal eosinophil activity, during both flare and remission. Compared with UC, PSC-UC had a dampened, and less Th2 dominated mucosal immune response. This was evident by a low quote of CRTH2/CXCR3 CD4+ cells and a cytokine milieu with no upregulated Th2 cytokines. In contrast, PSC-UC had highly up-regulated cytokines in peripheral blood. Among these, sCD40 stood out as being most important for inter-group separation according to multivariate analysis.

    In paper III, we gave a detailed description of colonic tissue factor (TF) expression. We found discrepancies in TF depending on UC subtype and inflammatory status, where inflammation- associated TF up-regulation was detected in UC only. Also, we identified stromal TF deposition as a sensitive indicator of acute colitis.

    In paper IV, PSC-UC and UC intestinal proteomes were compared using LC-MS/MS. After detecting more than 7200 unique proteins in the discovery step, the top-five most distinctive findings were chosen for verification. Of these, AGPAT1 was verified, being significantly higher in PSC-UC. Despite phenotypical differences, the overall colonic proteome comparison showed high degree of concordance.

    In summary, this thesis demonstrates distinct immunological and molecular properties in PSC-UC, implying phenotypical features beyond clinical observations. Moreover, serum sCD40 and colonic AGPAT1 are suggested possible PSC-UC biomarkers.

     

  • Medical, cognitive and motor outcome after treatment of pilocytic astrocytoma in the posterior fossa in childhood Author: Ingela Kristiansen Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-418049 Publication date: 2020-10-02 10:59

    Introduction: Pilocytic astrocytoma is the most common brain tumour in childhood. The aim of the studies was to investigate late medical, cognitive and motor complications in patients treated in childhood for pilocytic astrocytoma in the posterior fossa. 

    Methods: We present a retrospective study including 193 children treated for CNS tumours 1995-2006 and, from the same cohort, 3 descriptive studies including 20 patients (out of 27 eligible patients) treated for pilocytic astrocytoma in the posterior fossa 1995-2011. The patients participated in an interview, a neurological investigation, screening tools for psychiatric symptoms, health-related quality of life (HRQoL), and tests of cognitive, language, academic and motor functions. 

    Results: Ten patients reported problems with motor skills, mainly from the upper limbs, and 8 reported learning difficulties. None had low results in screening for psychiatric symptoms or HRQoL. Intelligence tests showed average results, but 5 scored <-1 SD (70-84) and 3 low average (85-92) on full scale IQ. Patients scored average compared with norms in tests of executive function, except for significantly lower results in inhibition/switching (p= 0.004). In language and academic tests patients scored significantly lower results in naming ability (p=0.049), inference (p=0.046) and reading speed (p=0.024). Results in tests of motor function were normal, but in the Bruininks-Oseretsky Test of Motor Proficiency, patients had significantly lower results in manual dexterity (p=0.008). In the Mini-Balance Evaluation Systems Test, patients had significantly lower results compared with matched controls (p=0.036). Patients who reported learning difficulties had worse results in the performed tests.                           

    Conclusions: Although long-term functional outcome for patients treated for pilocytic astrocytoma was generally favourable, 40% of the patients display cognitive, learning and motor difficulties. Therefore, it is imperative to identify those in need of more thorough cognitive and motor follow-up programmes, including pedagogic interventions in school and training of motor functions. 

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