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- Hansson, Johan, 1964-
(författare)
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Loco-regional Treatment of Peritoneal Carcinomatosis: Survival, Morbidity and Quality of Life
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.
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- Nygren, Ingela, 1961-
(författare)
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ALS – a Clinical Thesis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of upper and lower motor neurons, resulting in muscle weakness and death from respiratory failure within 3-5 years after onset. The incidence is 1.5-2.7/100,000 inhabitants. 5-10% of all cases are hereditary. The aetiology of sporadic ALS is still unknown. The only neuroprotective drug approved for the treatment of ALS is riluzole, a glutamate-antagonist, which has shown to improve survival. We evaluated if riluzole sales statistics can be used as a method for estimating the prevalence of ALS/motor neuron disease in Sweden. We found that this method, which is less time consuming than conventional methods, could be used as a crude marker for the prevalence. In a longitudinal study of overall Quality of Life (QoL) in ALS we found that QoL changes only slightly over time despite disease progression. ALS does not necessarily result in a low QoL. Growth factors are important for the survival of neurons. In ALS we found increased or normal levels of GDNF mRNA and BDNF mRNA in muscle biopsies, VEGF in serum and spinal cord and FGF-2 in serum and cerebrospinal fluid. There is thus no deficit of these growth factors although there may be a relative lack because of high demands of the motor neurons. Polyamines are small aliphatic molecules that are important for the function of cells. The level of the polyamines spermidine and spermine were increased in red blood cells in both patients with ALS and patients with Parkinson’s disease, suggesting that polyamines may have a role for the neurodegenerative process. Polyamines in spinal cord were of the same level in the patients with ALS and in controls, indicating a maintained regulation of polyamines at the end-stage of the disease.
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| 6. |
- Rickardson, Linda, 1980-
(författare)
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New Methods to Screen for Cancer Drugs and to Evaluate their Mechanism of Action
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a common disease and due to problems with resistance against cancer drugs and the limited benefit from chemotherapy in many diagnoses, there is a need to develop new cancer drugs. In this thesis new methods to screen for cancer drugs and to evaluate their mechanism of action are discussed. In Paper I, it was found that by studying the gene expression of a cell line panel and combining the data with sensitivity data of a number of cytotoxic drugs, it was possible to cluster compounds according to mechanism of action as well as identifying genes associated with chemosensitivity. In Paper II, studies of compounds with selective activity in drug-resistant cell lines revealed the glucocorticoids as a group of interesting compounds. The glucocorticoid receptor was overexpressed in 8226/Dox40 and the difference in sensitivity was abolished when the cells were treated with a glucocorticoid receptor antagonist. In Paper III, an image-based screening method for new proteasome inhibitors was successfully developed and the compounds disulfiram, PDTC and NSC 95397 were identified as inhibitors of the proteasome. In Paper IV, disulfiram and PDTC were shown to induce cytotoxic activity, to inhibit the activation of the transcription factor NFkappaB and to inhibit the degradation of proteins normally degraded by the proteasome. In Paper V, NSC 95397 was shown to be cytotoxic to all cells in the resistance-based cell line panel as well as to patient samples from a variety of cancer diagnoses. Connectivity Map was successfully used as a tool to propose a new mechanism of action of NSC 95397. The gene expression induced by NSC 95397-treatment was similar to that induced by several proteasome inhibitors not present in the Connectivity Map.
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