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- Bengtsson, Daniel, 1975-
(författare)
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Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD. Main conclusions of the thesis:Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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| 2. |
- Englund, Claire, 1954-
(författare)
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Teaching in an age of complexity : exploring academic change and development in higher education
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Higher education (HE) has expanded and diversified at an unprecedented rate over the last two decades in response to a rapidly changing educational and political climate. Change and development are omnipresent, a constant part of university teachers’ sociocultural and organisational practice at multiple levels; the micro-level, the meso-level and the macro-level Against this background, the aim of this thesis is to gain a deeper understanding of the factors that influence academic change. A further aim of the thesis is to provide insight into factors that may be relevant in the design of academic development activities to support teachers and managers in the enhancement of teaching and learning. A twelve-year longitudinal study of teachers on an online pharmacy programme forms the basis for the research, where a multilevel approach is used to investigate academic change and development in a teaching and learning environment supported by educational technology (Edtech). The approach captures the influence of factors such as conceptions and approaches to teaching at the micro-level of the individual teacher, as well as the influence of systemic factors such as the sociocultural context at the meso-level of the department or programme and the structural context at the macro-level of the institution.To explore and understand the complexity of change and development in academic practice at micro-, meso- and macro-level two theoretical frameworks are used: conceptions of and approaches to teaching (CAT), and Cultural-Historical Activity Theory (CHAT). An interventionist method based on the tenets of CHAT was also employed. Data analysed in the thesis includes interviews with teachers (n=57), observations (n=27 hours), student evaluation surveys (n=30) and document analysis (n=11) collected over a 12-year timespan (2004-2016). The analysis indicated that at the micro-level a critical factor in the choice and use of Edtech is the underlying conception of and approach to teaching and learning of the teacher. Opportunities for change and development were found to be facilitated by the sociocultural context at the meso-level of the department, where support from the community and mediating tools for communication were present, but could also be hindered when this was lacking. At macro-level, institutional policy and strategy documents were seen to impede change and development, where research is consistently prioritised over teaching. At the meso-level of the department or programme, the opportunity to work together as a team to collaboratively construct and develop practice was found to be of significance in the development of agency and academic practice.Taking into account a combined analysis of the five papers included, it can be concluded that if a deeper understanding of academic change and development is to be achieved, it is necessary to adopt a holistic approach, considering factors at micro-, meso- and macro-level and the interrelationships between these factors. This thesis discusses the consequences of the research for the facilitation of academic change and development. A multilevel, holistic approach is suggested, building on the principles of the Scholarship of Teaching and Learning (SoTL) model. SoTL initiatives at all levels should be aligned to promote academic change and development through: the development of teachers’ individual practice at micro-level, the collaborative development of scholarly practice at the meso-level of the department and a strategic institutional approach at macro-level linking SoTL to employment and promotion frameworks and the recognition of teaching quality.The main contribution of this thesis lies in the adoption of a holistic approach to understanding academic practice in higher education, taking into consideration factors at micro-, meso- and macro-level and the interrelationships between these factors.
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