| 21. |
- Jin, Yuesheng, et al.
(författare)
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Clonal chromosome abnormalities in premalignant lesions of the skin.
- 2002
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 136:1, s. 48-52
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Tidskriftsartikel (refereegranskat)abstract
- Two lesions, actinic keratosis (AK) and squamous cell carcinoma in situ (CIS), are believed to be precursors of squamous cell carcinoma (SCC) of the skin. These lesions can serve as an excellent model system for studying genetic changes associated with the inception of skin SCC. In the present study, five such lesions of the skin, three AKs and two AK+CIS, from three patients were short-term cultured and analyzed cytogenetically. One of the patients (case 3) had also an SCC in addition to three premalignant lesions. All lesions, but one, showed clonal karyotypic abnormalities. The recurrent changes identified were numerical, that is, +7 and +20. The structural rearrangements found in three AK were different, but it could be noted that the distal part of the long arm of chromosome 4 was involved in two AK and the SCC of case 3A. It was also interesting that chromosome 1 participated in structural rearrangements in three AK with band 1p31 being involved in two tumors. The karyotypic profile of these lesions is compared with that of skin SCC; it turns out that the general patterns are different in the sense that the SCC more often have complex karyotypes and display unbalanced aberrations involving the centromeric regions. Some karyotypic similarities between the SCC and their precursors are revealed. The fact that the structural rearrangements involving chromosomal band 3p13 and the centromeric region of chromosome 3 in AK are common features for many types of malignant tumors, including skin SCC, indicates that these changes are early genetic events associated with malignant transformation.
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| 22. |
- Brun, Eva
(författare)
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Head and Neck Cancer: Studies on microvessel density, radiation response and FDG PET
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Treatment options of head and neck squamous cell carcinoma (HNSCC) usually include combinations of radiotherapy and surgery, and in some cases addition of chemotherapy. In locally advanced cases cure rates are low. Current prognostic factors cannot foresee the outcome for the individual patient. There is consequently a need for reliable prognostic and predictive factors. Through identification of such factors therapeutic interventions can be made early during therapy to increase tumour control and survival. In the present studies the association between microvessel density (MVD) in tumours and response to radiation has been explored. We have also studied the association between response to radiation and tumour metabolism, both prior to and during therapy (radical radiotherapy and in 10 cases also neoadjuvant chemotherapy). Metabolism was studied with a glucose analogue, FDG, and positron emission tomography, PET.The metabolic rate of FDG was compared to treatment outcome and survival and also to established tumour properties, as cell proliferation, tumourgrade and DNAcontent. Microvessel density showed a complex relation to radiation treatment response and outcome. Among patients with tumours manifesting complete response to radiotherapy MVD was above the lowest quartile of the MVDcounts according to computerised image analysis. In the subsequent study the relationship between higher MVD and response to radiotherapy could not be reproduced, when performed manually. High MVD within the epithelial tumour tissue, not in the tumour stroma, was then found to be an adverse prognostic factor, with a lower probability of local control and a higher rate of distant metastases.Tumour response evaluated histopathologically, after a preoperative radiation dose of 50 Gy was strongly correlated to outcome, regardless of the subsequent radical surgery.This implies that radiosensitivity per se is a strong prognostic marker. Tumour metabolism (FDG PET) was associated to therapy outcome. The pre treatment value was of limited prognostic value whereas the second PET, early during therapy, was associated to therapy outcome, in terms of complete response, local control and survival. When comparing the value of the metabolic rate (MR) to a simpler quantification, the standar-dised uptake value (SUV) of FDG, we found that MR was more strongly correlated to therapy outcome. Furthermore associations were found to be significant only for the primary tumours and not for node metastases. This implies a different pattern of response in node metastases compared to that of the corresponding primary tumour. There was no strong association between tumour metabolism and proliferation, DNA content or histologic grade. MR FDG reflects tumour aggressiveness. Repeated FDG studies during therapy are feasible and might justify therapeutic interventions in non-responders.
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| 23. |
- Edsjö, Anders
(författare)
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Neuroblastoma Cell Differentiation: The Role of Neurotrophin Receptor Signaling and N-myc Expression
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is a tumor of sympathetic nervous system derivation, mostly afflicting young children. This thesis is focused on a group of receptor proteins for neurotrophic factors, the Trk family, and on N-Myc, a transcription factor, all important in the formation of the sympathetic nervous system as well as in determining neuroblastoma patient outcome. Expression of trkA and trkC is linked to favorable prognosis, while amplification of the N-myc gene is strongly correlated to poor outcome. The role of trkA and trkC in neuroblastoma cell differentiation was studied using neuroblastoma cell lines constitutively expressing trkA or trkC. Stimulation of the trkA- and trkC-transfected cells with their cognate ligands resulted in differentiation of both cell clones, the differentiated trkC-transfected cells lacking important neuronal features present in the differentiated trkA-transfected cells. Signaling elicited by the two receptors was studied and differences described. The possible connection between expression of N-myc and trkB, another trk family member, was tested by examination of expression of these genes in a set of neuroblastomas and neuroblastoma cell lines. Results suggested high expression of N-myc per se to be insufficient to induce trkB expression. In other experiments, retinoic acid, an agent known to induce trkB expression was added to neuroblastoma cells in combination with the ligand of TrkB, brain-derived neurotrophic factor. Data from characterization of the resulting phenotype indicated that a sympathetic neuronal differentiation did not take place in these cells and alternative explanations were suggested. N-myc expression in the developing human sympathetic nervous system was studied using in situ hybridization and the role of N-myc in neuroblastoma cell was examined, utilizing non-N-myc-amplified neuroblastoma cells with constitutive N-myc overexpression as a model system. Overall, the capacity of these cells to differentitate morphologically in response to various differentiation protocols was retained, thus offering an explanation to the lack of correlation between N-myc expression and patient outcome in non-N-myc-amplified tumors.
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| 24. |
- Fernebro, Eva
(författare)
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Rectal Cancer - Tumor Biology and Prognostic Markers
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer is one of our most common malignancies and the second leading cause of cancer death worldwide. About 1/3 of the tumors are located in the rectum. Treatment advances such as the introduction of the standardized surgical technique total mesorectal excision (TME), pre-operative radiotherapy, and adjuvant chemotherapy have reduced the previously high local recurrence rates and improved survival in rectal cancer patients, but despite these advances about 40% of the patients still die from disseminated disease. Rectal cancer evolves through an accumulation of genetic alterations in the tumor cells, and although multiple such changes have been characterized, the molecular markers have not yet gained widespread clinical use. The prognostic markers currently available fail to identify patients at risk for tumor recurrencies, which implies a need for refined prognostic tools. This thesis focuses on analysis of different molecular events in rectal cancer with correlations to prognosis. Papers I-II evaluate the novel serological markers suPAR and TIMP-1 analyzed in pre-treatment plasma samples from patients with rectal cancer. High suPAR and TIMP-1 values were associated with shorter survival and these markers may thus be of potential prognostic use. In paper III, we evaluated the tissue microarray technique (TMA) for immunohistochemistry (IHC) using the markers p53 and Ki-67. Good quality staining was obtained and TMA could reproduce the results obtained from whole-tissue sections. Paper IV presents IHC tumor profiling using TMA in rectal cancer with correlations to prognosis using the markers Ki-67, p53, Bcl-2, EGFR, ß-catenin, E-cadherin, MLH1, and MSH2. The cell adhesion molecules ß-catenin and E-cadherin significantly correlated with metastatic disease, whereas the other markers did not. In paper V, we studied 30 cancers from patients younger than 50 years at diagnosis with respect to molecular alterations associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways for colorectal cancer development. We found that microsatellite stable (MSS), aneuploid tumors with increased expression of p53 and ß-catenin predominate also among young rectal cancer patients. Only 10% of the tumors displayed MSI, all of which showed loss of expression for MSH2, which suggests presence of a mutation associated with hereditary nonpolyposis colorectal cancer (HNPCC). In summary, this thesis presents confirmatory data on the plasma levels of suPAR and TIMP-1 as presumptive prognostic markers in rectal cancer. In addition, we have demonstrated that the TMA-technique allows high-throughput immunostaining in rectal cancer. A TMA-based molecular profiling demonstrated that aberrant expression patterns frequently occur, and that the expression of the cell-adhesion proteins ß-catenin and E-cadherin correlated with clinical outcome. Finally, the 5% of the rectal cancers that occur in young patients predominantly develop through the CIN pathway, whereas MSI is found in a small, HNPCC-related subset of the tumors. Hence, other mechanisms than defective MMR and HNPCC cause rectal cancer in the majority of young patients.
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| 25. |
- Hedström, Mariann, et al.
(författare)
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Distressing and positive experiences and important aspects of care for adolescents treated for cancer : adolescent and nurse perceptions
- 2004
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Ingår i: European Journal of Oncology Nursing. - : Elsevier BV. - 1462-3889 .- 1532-2122. ; 8:1, s. 6-17
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Tidskriftsartikel (refereegranskat)abstract
- Distressing and positive experiences for adolescents with cancer with regard to being told the diagnosis, receiving chemotherapy and being admitted to the ward, and important aspects of care for adolescents with cancer was investigated. Data were gathered through semi-structured interviews with 23 adolescents and 21 nurses, and analysed by content analysis. The findings indicate that cancer during adolescence is connected with a range of negative experiences such as fears of alienation, fears of altered appearance, fears of dying, and various physical concerns. Positive experiences include positive relations to staff and being well cared for. Important care for adolescents treated for cancer consists mainly of meeting nice, friendly, supportive, and competent staff, who provide them with age-appropriate information. The findings indicate that adolescents with cancer experience a range of negative and positive experiences related to disease and treatment and that good care for adolescents with cancer is a broad, complex, and multidimensional phenomenon.
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| 26. |
- Jönsson, Marzieh
(författare)
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Wnt-5a Signalling in Human Mammary Cells: Implications for the Development of Breast Cancer
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Wnt-5a gene encodes a secreted protein that regulates several normal processes in embryonic and adult tissues by as yet unknown mechanisms. Expression of Wnt-5a protein does not cause cell transformation, but it instead counteracts the effects induced by transforming Wnts. Inasmuch as Wnt-5a can activate the Wnt/beta-catenin signalling pathway, we performed experiments to determine whether molecules participating in this pathway were modified in breast tumours. Thirteen percent of the tumours we studied showed accumulation of beta-catenin protein but no mutations in the beta-catenin gene or defects in APC protein. Moreover, the human dishevelled gene (DVL-3) was rarely activated in the examined tumours. To elucidate the mechanisms of action of Wnt-5a, we studied the response of breast epithelial cells to overexpression or inhibition of this protein. Our results demonstrate that Wnt-5a is a co-factor that is needed to activate the collagen-binding discoidin domain receptor 1. In addition, the Wnt-5a protein exhibited activities involved in positive regulation of cell adhesion and negative regulation of cell migration. To determine whether the biological activities of Wnt-5a are linked to the development of breast cancer, we evaluated levels of this protein in invasive breast tumours. We found that expression of Wnt-5a had been lost in 44% of the studied carcinomas. This loss was significantly associated with higher histological grade and absence of estrogen and progesterone receptors, and proved to be an independent and powerful predictor of early relapse. Thus our data support the notion that Wnt-5a is a tumour suppressor, and that lack of this protein increases the risk of recurrent breast disease.
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| 27. |
- Kamp-Nielsen, Christian
(författare)
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Regulation and Function of the Human Leukotriene D4 Receptor CysLT1 in Epithelial Cells and Colon Cancer
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pro-inflammatory mediators leukotrienes have shown to be important players in the pathogenesis of diseases like asthma and inflammatory bowel disease (IBD). Patients suffering from IBD have been found to have an increased risk of developing colon cancer. Since leukotrienes have been shown in increased concentrations in stools of IBD patients we hypothesise that LTD4 can play a role in the development of colon cancer. In order to induce its effects on the intestinal epithelial cells, LTD4 binds to its receptor CysLT1R. We therefore chose to study CysLT1 in colon cancer specimens and in non-transformed and colon cancer cell lines. Our results show that CysLT1R can be found in increased levels in colon cancer enterocytes (50% of 84 patients) and that high expression of this receptor in Dukes`B staged tumours predicts a poor disease outcome. Furthermore, we observed that CysLT1R is located in the plasma membrane and in the outer nuclei membrane. We identified a putative nuclear localisation sequence in CysLT1R, which is crucial for the LTD4, induced internalisation of the receptor. Interestingly, stimulation of CysLT1R located in the nuclei induced the activation of ERK1/2, an enzyme which have been shown to mediate LTD4 induced proliferation. When studying the LTD4 induced signalling pathways we found that CysLT1R mediated stress fibre formation and a calcium response through two heterotrimeric G-proteins, Ga12 and Gai3, respectively and that the LTD4 induced calcium response is dependent on PKCe. Taken together we have shown that LTD4 might have an impact on tumour development through the regulation of CysLT1R and its downstream signalling pathways.
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| 28. |
- Rennstam, Karin
(författare)
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Molecular Cytogenetics in Sporadic Breast Cancer
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent time breast cancer has become the most common form of female cancer in the western world. It has been estimated that the lifetime risk of women falling ill from the disease is 10%. The number of patients diagnosed each year has been increasing steadily since the 1970s. In 2002 the number of Swedish women diagnosed with breast cancer was 6,600, constituting every third female cancer diagnosed.Little is known about the order of appearance of different types of genetic aberrations, how they relate to each other, what their role is in the defining the clinical outcome of the patient, and which aberrations underlie therapy resistance. A comparative study between cytogenetics and CGH was conducted in 29 invasive breast cancers (paper I). The differences seen in the comparison of cytogenetic and CGH karyotyping can best be explained by the difficulties of culturing breast carcinoma cells in vitro. The gains and losses found by CGH may represent the predominant (often aneuploid) clone, whereas the G-banding karyotypes represents minor abnormal, near-diploid cell clone(s), which, for unknown reasons, has a growth advantage in short term culture. To explore the order of appearance of genetic aberrations in a direct manner, tumor cells from 21 non-diploid breast carcinomas were sorted for their DNA content by flow cytometry, and then analyzed separately by FISH (paper II). Data from these uncultured interphase cells showed that oncogene amplification, which is biologically and prognostically a very important genetic defect in breast cancer, takes place already before aneuploidization. The simultaneous presence of diploid and non-diploid malignant cells is also a clear indication of heterogeneity in the genetic composition of breast carcinoma. In order to shed light on how copy number aberrations (CNA) patterns are composed, a CGH analysis of 305 breast cancer tumors was conducted (paper III). Two different statistical approaches were able to identify the exact same CNA pattern groups, indicating that the groups are true biological entities, rather than reflection of the statistical modeling technique used. These different groups were correlated to distinct clinicopathological features and patient prognosis, and could predict patient outcome just as well as the traditional prognostic factors. In paper IV, characterization of the new and intrinsically Herceptin® resistant cell line JIMT-1, revealed an aberration pattern characteristic for aggressive breast cancers. Molecular cytogenetic techniques revealed numerous regions of CNA. Many of the genes in the aberrant regions are implicated in cancer development and drug/hormone metabolizing. In conclusion, the results from the studies presented herein, indicate that the genetic aberrations of breast cancer are complex, and not detected by conventional cytogenetic techniques. Implementation of molecular cytogenetic techniques in a large breast cancer material, identified specific patterns of aberrations, and these patterns are linked to patient prognosis. Characterization of a Herceptin® resistant cell line by use of microarray techniques revealed amplification and upregulation of several genes that are linked to the promotion of breast cancer.
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| 29. |
- Von Essen, Louise, et al.
(författare)
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'Satisfaction with care' : associations with health-related quality of life and psychosocial function among Swedish patients with endocrine gastrointestinal tumours
- 2002
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Ingår i: European Journal of Cancer Care. - : Hindawi Limited. - 0961-5423 .- 1365-2354. ; 11:2, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to investigate ‘satisfaction with care’ and its possible relationships to hope, health-related quality of life, anxiety and depression. Eighty-five patients with endocrine gastrointestinal (GI) tumours responded to questionnaires a few days after a hospital visit. ‘Satisfaction with care’ was assessed by the Comprehensive Assessment of Satisfaction with Care (CASC), health-related quality of life by the EORTC QLQ C-30 and anxiety and depression by the Hospital Anxiety and Depression Scale (HADS). Patients’ highest satisfaction scores were obtained for ‘general satisfaction’ and ‘nurses’ and doctors’ technical skills’. The lowest satisfaction was expressed for ‘doctors’ interpersonal skills’, ‘nurses’ communication skills’ and ‘care organization’. Patients reporting a clinically relevant level of anxiety were less satisfied with several care aspects than those reporting less anxiety. Satisfaction with ‘nurses’ communication skills’ and ‘doctors’ interpersonal skills’ was associated with several aspects of health-related quality of life, whereas satisfaction with ‘doctors’ information’, ‘nurses’ technical skills’ and ‘general satisfaction’ was not. Satisfaction with psychosocial aspects of care is related to the psychosocial function of patients with endocrine GI tumours.
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| 30. |
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