Institute of Clinical Sciences / Institutionen för kliniska vetenskaper
https://hdl.handle.net/2077/284
2024-03-28T18:54:47ZPerinatal brain damage-phagoptosis and neuroprotection
https://hdl.handle.net/2077/79705
Perinatal brain damage-phagoptosis and neuroprotection
Jonsdotter, Andrea
Background: Neonatal encephalopathy is a serious outcome in term infants affecting 1-2/1000 live births and is often caused by perinatal hypoxia-ischemia (HI). However, brain injury is multifactorial and infection in the mother during pregnancy could cause or aggravate brain damage. Cerebral palsy (CP) is a known complication due to brain damage and occurs in both term and preterm infants. In preterm infants the risk of CP is inversely proportional to gestational age.
Aim: To better understand mechanisms of brain damage in preterm and term infants and thereby develop new strategies for neuroprotection.
Material and methods: Paper I, III and IV are animal experiments on mice and rats. Paper I focuses on the neuroprotective effect of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 after term HI in neonatal mice, with or without therapeutic hypothermia. In Paper IV the neuroprotective effect of exendin-4 in a preterm model of cerebral GMH is addressed in rats. Paper III aims to evaluate the neuronal cell death in a mouse model of HI after gene deletion of the phagocytic receptor Mer-tyrokine kinase (Mer-TK). Paper II presents a clinical study where a bolus dose of magnesium sulfate (MgSO4) is administered to pregnant women with imminent risk of preterm delivery to determine the concentration of serum magnesium (s-Mg) in both the mothers and the umbilical cords of the infants.
Results: Paper I: Exendin-4 treatment alone showed significant neuroprotection and it enhanced the cerebroprotective effect of hypothermia (p <0.0001). Tissue infarction was significantly reduced after only one dose of exendin-4 injection (saline: 50% 6.9%) and (exendin-4: 17% 8.6%) (p=0.03) and adding the dose regime every 12 h over a 48h period reduced brain injury further to 2% 1.8% (p=0.02). Paper IV: This study shows that exendin-4 reduced brain injury after GMH. The neuroprotective effect was detected as early as 48 h after GMH (p=0.05 in striatum and p=0.04 in hippocampus) and was sustained until adulthood (P40, p <0.0001). Exendin-4 improved motor skills significantly in different behavioral tests including rotarod (P20, p=0.003; P40, p <0.0001), eye opening (P14, p=0.05) and negative geotaxis (P8, p=0.05). Paper III: Genes related to phagoptosis including MerTK and Gas-6 were upregulated at 6-72h after HI in the brain. Brain injury was reduced by 48% in gray matter (p=0.002) in MerTK knock-out (KO) vs wild-type (WT) animals and in white matter by 32% (p=0.04). Immunostaining of neurons and microglia indicated less neuronal phagocytosis by microglia in MerTK KO vs WT animals, (p= 0.03). Paper II: A bolus dose of 6 g of MgSO4 seems to be well tolerated by the women and no extra surveillance is needed. The target concentration of s-Mg was reached in the blood of most of the women and the concentrations were low (0.87 to 1.4 mmol/l) in the umbilical cord at birth unlikely to adversely affect the newborn infants.
Conclusion: This thesis shows that: 1. the GLP-1 receptor agonist exendin-4 provides strong neuroprotection in rodent neonatal models of HI and GMH, and has, suggestedly, potential for clinical implementation; 2. gene deletion of the microglial MerTK receptor reduces both microglial phagocytosis of neurons and brain injury implicating involvement of phagoptosis in HI; 3. a 6 g bolus of MgSO4 is well tolerated in pregnant women and is not likely to adversely affect the newborn preterm infant. This regimen is now established and implemented in all Swedish hospitals that provide care for deliveries up to 32 weeks of gestation.
2024-03-27T00:00:00ZLong-term Bowel and Stoma Function Following Colorectal Cancer Surgery
https://hdl.handle.net/2077/79702
Long-term Bowel and Stoma Function Following Colorectal Cancer Surgery
Sandberg, Sofia
Aim: The aim of this thesis was to explore bowel and stoma function following colorectal cancer surgery, to investigate associated distress and identify possible risk factors. Methods: Papers I, II, and IV were based on two prospective, observational cohort studies focusing on rectal cancer (I, II) and colon cancer (IV). Paper I included patients who had an anastomosis, while paper II included patients with a permanent stoma. Paper III was a registry-based cross-sectional study. Results: Paper I found that more than half of the patients experienced significant bowel dysfunction, identifying a defunctioning stoma as a risk factor. Distress was common, decreasing over time. In paper II, most patients reported high stoma functionality and acceptance, only one-fifth experienced distress. Paper III demonstrated that the anastomotic configuration had equal impact on bowel dysfunction. Paper IV showed that most patients maintained intact bowel function after colon resection. After right-sided resections loose stools were common and associated with distress, as was incontinence. Conclusion: Providing preoperative information, managing expectations, and ensuring early detection and treatment of symptoms are important to achieve optimal function and minimise distress. For patients with minimal or no impairment, extensive follow-up may be unnecessary.
2024-03-25T00:00:00ZOn incidence, diagnostic algorithms and in-depth characterisation of thyroid cancer
https://hdl.handle.net/2077/79700
On incidence, diagnostic algorithms and in-depth characterisation of thyroid cancer
Dahlberg, Jakob
Background: Thyroid cancer (TC) incidence has increased dramatically. Overzealous detection of subclinical disease is the most common explanation. However, whether the higher rate of diagnosis of subclinical disease might conceal a true TC increase is unknown. EU-TIRADS has been developed to guide further management of nodules. Real-world data as well as controlled trials on effect and safety are largely missing. Although overall prognosis of TC is excellent, a subgroup of patients has limited treatment options and new ones need to be developed.
Aims: The objectives of Paper I were to investigate which tumor stages of TC were increasing and the modes of detection. Paper II and III aimed at assessing the impact and safety of EU-TIRADS on nodule management. Paper IV aimed to establish PDX model of TC development and drug testing.
Methods: Paper I was a population-based study. Paper II was a single center retrospective cohort study and Paper III was a regional randomized controlled trial. Paper IV was a prospective trial collecting tumor tissues from patients with advanced TC, subsequently transplanted to immunodeficient mice.
Results: TC increased threefold during 2001-2014 in Western Sweden. The increase comprised stages T1a-T3 and the most common mode of detection was clinical symptoms, mainly a palpable tumor. Imaging did not contribute to increased TC incidence. EU-TIRADS reduced cytology by 7% without missing TC diagnosis. Comparing selective and non-selective FNA revealed that EU-TIRADS significantly reduced the frequency of unnecessary FNA. Among fresh tumor tissue samples obtained from advanced TC only squamous cell carcinoma (SCC) was successfully transplanted to immunodeficient mice. Targeted therapy based on mutation profile inhibited PDX growth.
Conclusion: Increased TC incidence in Western Sweden was due to other factors than unnecessary imaging. A true increase cannot be ruled out. EU-TIRADS does not miss TC diagnosis but has limited impact on the clinical management of thyroid nodules. A thyroid origin of SCC was documented. Novel therapeutic options were suggested arguing for global mutation analysis of all patients with anaplastic TC.
2024-03-20T00:00:00ZQuality of life and long-term side effects after anal cancer treatment
https://hdl.handle.net/2077/79333
Quality of life and long-term side effects after anal cancer treatment
Axelsson, Anna
Anal cancer is a rare type of cancer with approximately two hundred new cases in Sweden per year. Treatment usually consists of a combination of radiotherapy and chemotherapy. Overall prognosis is good but about 10% of patients require pelvic surgery to be cured. This is referred to as “salvage surgery”. In this thesis we wanted to investigate patient reported quality of life (QoL) and long-term side effects after anal cancer treatment. Two hundred and five patients with anal cancer, diagnosed between 2011 and 2013 in Sweden, answered a comprehensive questionnaire at three and six years after diagnosis. One hundred and ninety-five patients returned the questionnaire at three years and one hundred and fifty-five patients at six years.
We found QoL to be good in 40% of the patients and low in 60% at both three and six years. Patients with bother from one or more functions had a higher risk of impaired QoL. Major bother was more prevalent in patients that reported low QoL. Impaired bowel function was common and remained stable between three and six years. The combination of chemotherapy and radiotherapy was associated with a higher risk of bowel side effects than radiotherapy alone. Both urinary and sexual function deteriorated between three and six years. Chemotherapy was not associated with a higher risk of urinary incontinence.
With a qualitative approach we explored patients’ experiences of bodily functions and QoL after salvage surgery. Eighteen in-depth interviews were performed. Inductive content analysis resulted in 8 categories and 1 theme describing the acceptance and reorientation to a new life despite several long-term bodily changes and functional side-effects.
There are significant long-term side effects after treatment for anal cancer, and there is a clear relationship between symptom burden, bother and QoL. Although bodily functions deteriorate over time QoL does not, indicating an adaptation process between three and six years.
2024-02-28T00:00:00Z