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- Landerholm, Kalle, 1976-
(författare)
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Clinical and immunohistochemical studies of small bowel carcinoid tumours
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small bowel carcinoid tumours arising from enterochromaffin cells in the jejunum and ileum are neuroendocrine tumours (NETs) characterized by secretion of serotonin, tachykinins and other bioactive substances. These substances may lead to the typical carcinoid syndrome as well as pronounced fibrosis locally and in the heart. Although the most frequent histological subtype of malignancy in the small bowel, small bowel carcinoids are rare and therefore difficult to study. We found that previous studies either described selected patients at referral centres, or were based on limited data from large registries. The main objective of this thesis was to investigate small bowel carcinoid patients from a geographically defined cohort with no selection bias.PAPERS I AND IIThe aims of papers I and II were to investigate the incidence, histopathological characteristics, stage atdiagnosis, symptomatology, surgical treatment, prognostic factors and survival of small bowel carcinoid.All patients resident in Jönköping County when diagnosed with small bowel carcinoid between 1960 and2005 were eligible for inclusion. After thorough review of medical records and reexamination of availabletumour specimens, 145 patients were included.A higher incidence of small bowel carcinoid than previously described was found: 1.12 per 100,000 persons and year. The incidence increased during the study period. Symptoms were most often uncharacteristic: the carcinoid syndrome was seen in only 13% of symptomatic patients. Many small bowel carcinoid tumours presented as surgical emergencies without preceding symptoms, often as intestinal obstruction (35%) caused by mesenteric fibrosis. The majority of small bowel carcinoid tumours had metastasized to the mesentery or the liver at diagnosis. Disease-specific survival after 5 years was 75.0% and after 10 years 63.5%. Independent prognostic factors for worse disease-specific survival were higher age at diagnosis, more advanced disease stage at diagnosis and incomplete tumour resection. Completeness of resection was of particular importance in patients with regional metastases.PAPER IIIThere are previous case reports describing small bowel carcinoid in two first-degree relatives, but it is unknown whether this represents hereditary disease forms or chance. Paper III was the first article to describe metastasizing ileal carcinoid tumours in three consecutive generations − strongly suggestive of a hereditary disease form.PAPER IVWe recently demonstrated expression of cocaine- and amphetamine-regulated transcript (CART) in several types of NETs, including small bowel carcinoid. The aim of paper IV was to investigate whether content of CART in small bowel carcinoid tumours is associated with tumour characteristics, symptoms and survival. CART expression was examined in all available tumour specimens from the patients in Papers I and II − 97 patients were included.Presence of CART IR tumour cells was associated with histological grade, but not with stage or age. CART expression in small bowel carcinoid tumours was not associated with clinical symptoms. Increasing levels of CART IR in small bowel carcinoid tumour cells was associated with worse disease-specific survival. CART was also found to increase cell viability in an enteroendocrine cell line in vitro. The results suggest that CART could be used as a prognostic biomarker and that CART is a potential anti-tumour treatment target.
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| 2. |
- Meehan, Adrian, 1973-
(författare)
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Lithium-associated hyperparathyroidism : Prevalence, Pathophysiology, Management
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lithium has been used in the treatment of bipolar disorder, formerly called manic depression, for nearly seven decades. Lithium-associated hyperparathyroidism (LHPT) is an ill-defined and less well known possible side-effect of chronic lithium therapy and was first described in 1973. The condition has been considered to be rare, though there exists conflicting evidence as to its prevalence, its pathophysiological background, and, if and when identified, what the appropriate medical or surgical treatment should be. The principal aim of this thesis was to understand and more comprehensively characterise this condition through studying a large patient cohort, with regards its prevalence, development, and additionally by providing an evaluation of surgical management up until now.In Study I a population of 423 lithium-treated out-patients (251 women, 172 men) were recruited from Jönköping and Örebro County. We found that 18% met the criteria for hyperparathyroidism (HPT) and that a further 21% had intermittent episodes of hypercalcaemia. We then examined, in Study II, the effects of lithium only in patients with bipolar disorder and compared them, firstly, to patients with bipolar disorder without lithium and, secondly, to a control population. In total, 563 individuals participated in the study. Hypercalcaemia was found to be strongly associated to lithium therapy (adjusted OR 13.45; 95% CI 3.09, 58.55; p=0.001). Study III is a descriptive study of calcium homeostasis in 297 lithium-treated patients from Jönköping where three main groups could be discerned: 178 were normocalcaemic (60%), 102 hypercalcaemic (34%), and 17 hypocalcaemic (6%). Many patients demonstrate robust fluctuations in serum calcium intermittently. Of those with suspected LHPT, 31% had urinary calcium excretion values be-low 1.2 mmol/24hrs. Study IV analysed surgical results of 78 parathyroidectomies in 71 patients with concurrent lithium therapy. In strong contrast to surgical outcomes in those with primary HPT, the overall cure-rate was lower (58%) and the predominant histological diagnosis was hyperplasia (52%). Two patients had double adenomas.Factors which should be particularly taken into consideration while monitoring lithium-treated patients are age, gender and lithium-duration.
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| 3. |
- Hennings, Joakim, 1969-
(författare)
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Clinical Studies on Adrenocortical Tumours using [11C]-metomidate Positron Emission Tomography
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adrenal tumours, discovered en passant in patients undergoing radiological examinations for non-adrenal disease, so-called adrenal incidentalomas, have increased dramatically in the recent era of more sophisticated diagnostic modalities such as high resolution multidetector computed tomography (CT) and magnetic resonance imaging (MRI). Furthermore, primary aldosteronism (PA) has been documented in several screening studies as being far more common than previously believed among hypertensive patients. In this thesis, a long-term follow-up cohort of patients who had undergone surgery for PA revealed that there was an excellent effect on blood-pressure, reduction of anti-hypertensive medication and hypokalaemia after surgery, even though the majority of these patients still required some anti-hypertensive medication. This was also true, in the higher than expected number of dominant nodular hyperplasia (nIHA) found in the study, but was slightly less pronounced than in aldosterone producing adenomas (APA). Surgery was thus effective in lateralized PA. Metomidate positron emission tomography (MTO-PET) was explored in relation to histopathology in post-operative patients and found to be highly specific and sensitive in categorizing adrenocortical disease. Also, a higher standardized uptake value (SUV) ratio between tumours and normal adrenal cortex was found in hormonally hypersecreting adenomas as well as in adrenocortical cancer (ACC). The resolution limited the diagnosis of small tumours (<1-1.5 cm). MTO-PET was compared to standard radiological modalities (CT and MRI) in the diagnostic work-up of adrenal incidentalomas. All three modalities categorized and characterized the lesions well, with MTO-PET showing the highest sensitivity and specificity. However this method is currently recommended to be used as complementary to the others in unclear cases, due to high costs and less availability. The resolution of MTO-PET was improved with respect to less noise and better delineation of small tumours when applying masked volume-wise principal component analysis (MVW-PCA), which will possibly enable future detection of small tumours in PA patients. Dexamethasone suppression treatment prior to MTO-PET examinations in PA patients decreased SUV in normal adrenal cortex but could not be shown to increase the SUV ratio between adenoma and normal cortex enabling better detection of small tumours, even though all the tumours were readily categorized in the study. Heterogenic SUV reactions to dexamethasone treatment indicate a need for further studies and refinement of the suppression method. In conclusion, long-term results of surgery for lateralized PA are good. MTO-PET is a highly sensitive and specific method for categorizing adrenocortical disease. Modulation of the method, e.g. by using MVW-PCA and refined dexamethasone suppression treatment, may improve the resolution of the method in delineating small tumours in PA, thus making MTO-PET a non-invasive and non-operator dependent future alternative to the currently recommended adrenal venous sampling (AVS) for lateralization diagnosis prior to surgery for PA.
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