| 1. |
- Carlsson, Christina, et al.
(author)
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Benefits from membership in cancer patient associations: relations to gender and involvement.
- 2006
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In: Acta oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 45:5, s. 559-563
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Journal article (peer-reviewed)abstract
- Cancer patient associations report a growing number of members and increasing possibilities to influence health care, but knowledge about the members' views on the benefit of involvement is scarce. We therefore investigated how members (n = 1742) of Swedish patient associations for breast cancer and prostate cancer rate the benefit of membership for their physical and psychological well-being and social adjustment to cancer. Using a scoring scale, 2/3 of the members reported that membership had benefit for psychological well-being, whereas half of the members reported benefit for physical well-being and social adjustment. Individuals who had been actively involved in board work and/or contact person activities within the associations reported significantly more benefit for all three parameters. Gender differences were observed with men, represented by individuals affected by prostate cancer, reporting greater benefit for all three parameters, although especially evident for psychological well-being. Individuals who obtained membership within two years of diagnosis reported greater benefit for psychological well-being and social adjustment compared to those who became members later. In conclusion, members in patient associations for cancer report benefit particularly for their psychological well-being and actively involved members and men affected by prostate cancer perceive the greatest benefit from membership.
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| 2. |
- Kronblad, Åsa
(author)
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Role of cyclin D1 as an estrogen receptor cofactor and the influence of hypoxia on estrogen receptor regulation, with focus on prognositic and treatment predictive features in breast cancer
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Estrogen receptor (ER) status can define breast cancer patients who would benefit from adjuvant tamoxifen therapy. However, resistance to tamoxifen is often observed and possible mechanisms may be loss or reduction of ER, dysfunctional ER- signaling and ligand independent activation of the receptor. Hypoxia and hypoxia inducible factor-1? (HIF-1) expression has been correlated to loss of ER in breast tumors. Cyclin D1, initially described as a cell cycle regulator, might also function as a cofactor to ER inducing ligand independent activation of the receptor. We therefore determined the relation between ER, cyclin D1 and HIF-1 expression in primary breast tumors and cell lines. Further, the prognostic and treatment predictive value of cyclin D1 and HIF-1 was analyzed in breast cancer patients receiving two years of tamoxifen versus no adjuvant treatment. The results indicated that ER heterogeneity in primary breast tumors was associated with cyclin D1 and HIF-1 expression. Further, breast cancer patients with cyclin D1 high tumors did not benefit from tamoxifen treatment. The survival for untreated patients with cyclin D1 high tumors was nevertheless slightly better than for patients with cyclin D1 low tumors. Hypoxia was also strongly linked to ER downregulation in DCIS and invasive breast cancer and caused ER downregulation in breast cancer cell lines. Interestingly, hypoxic cells were less differentiated, showing changes in morphology, proliferation and cytokeratin 19 expression. The hypoxia induced ER reduction was due to both proteasomal degradation and decreased transcription and active extracellular regulated kinase (ERK1/2)was involved in the transcriptional regulation of ER. Consequently, tamoxifen treatment did not affect proliferation as efficiently in hypoxia as in normoxia, but ERK1/2 inhibitors efficiently increased the tamoxifen effect in hypoxia. Unexpectedly, tumor specific HIF-1 expression was not a predictive marker for tamoxifen response in premenopausal breast cancer patients but associated with a worse recurrence free survival. These results suggest that cyclin D1 is a predictive marker for tamoxifen resistance and HIF 1 a marker of poor prognosis in breast cancer. Targeting cyclin D1 and/or ERK1/2 in conjunction with tamoxifen represent new treatment strategies for improving the tamoxifen response.
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| 3. |
- Olsson-Strömberg, Ulla, et al.
(author)
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Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase
- 2006
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 47:9, s. 1768-73
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Journal article (peer-reviewed)abstract
- The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.
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| 4. |
- Svensson Månsson, Sofie
(author)
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Invasion and Proliferation in Malignant Cells
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Two key events in the oncogenic process of tumor cells are to acquire uncontrolled proliferation and invasive properties. This allows the tumor to grow and invade beyond the tissue from which the tumor cells originate. We here specifically studied p16 and ERK1/2 with special focus on and the relation to proliferation and invasion in non-melanoma skin cancer and in breast cancer. In a model system of basal cell carcinoma, we observed that tumor cells changed phenotype from a highly proliferative type in the centre of the tumor to an invasive type with low proliferation and a marked upregulation of p16 at the invasive front. The expression of p16 was transcriptionally regulated and possible p16 activators such as ERK1/2 or Ets were not the sole contributors. Similar findings were observed in squamous cell carcinoma of the skin, despite a non functional Rb pathway, which might indicate a proliferation independent role for p16 in invasive behaviors. In primary breast cancer, a signaling cascade from VEGFR2 via ERK1/2 phosphorylation to Ets2 phosphorylation and cyclin D1, could be outlined and ERK1/2 phosphorylation was linked to small tumors with good prognosis. We also observed a Notch1 independent activation of Hes1 in breast cancer. Further, postmenopausal patients with ERK1/2 phosphorylated tumors had an impaired tamoxifen response, but ERK1/2 phosphorylation was not linked to tamoxifen resistance in premenopausal women. Taken together, our results implicate that there is a general inverse association between invasion and proliferation in some malignancies and this novel finding could be important when designing new treatment strategies for cancer patients.
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| 5. |
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| 6. |
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| 7. |
- Ekberg, Jenny
(author)
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Cyclin A1 Expression and Regulation in Hematopoietic and Leukemic Cells
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Increased expression of the cell cycle regulatory protein cyclin A1 has previously been detected in patients with acute myeloid leukemia (AML) and targeted overexpression of cyclin A1 in a transgenic mouse model initiated AML. The aim of this thesis was to further study the expression and regulation of cyclin A1 in hematopoietic cells. We started with evaluating the subcellular localization of cyclin A1 and found that the protein was localized to the nucleus of normal early hematopoietic cells while it had a cytoplasmic localization in leukemic bone marrow cells as well as in leukemic cell lines. We further found that treatment with all-trans retinoic acid (ATRA) resulted in nuclear localization of cyclin A1 in U-937 cells and in the formation of complex between cyclin A1, CDK1 and RAR?. Our results indicate that the cytoplasmic localization of cyclin A1 correlates with a leukemic phenotype. Next we continued with analyzing the clinical relevance of the increased cyclin A1 expression in 40 AML patients. We found that patients with high levels of cyclin A1 had a significantly worse overall survival and a significantly lower disease-free survival compared to patients with low levels of cyclin A1. We continued with analyzing the correlation between cyclin A1 and drug induced apoptosis. Induction of apoptosis using ATRA, staurosporine and TNF? resulted in significantly increased cyclin A1 protein levels in contrast to decreased levels of other cell cycle regulatory proteins. Interestingly, the increased protein levels did not result from increased protein synthesis but was rather a result from decreased ubiquitination and degradation. Further, upon overexpression of cyclin A1 a significant increased amount of apoptotic cells was found. Our results also suggest that there is an association between the post-translational modifications of cyclin A1 protein and the induction of apoptosis by therapeutic agents.
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| 8. |
- Nilsson, Kristina
(author)
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Proliferation, Invasion and p16 Localisation in Malignancies
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Uncontrolled proliferation and invasion are two characteristics in tumour development and progression. Previous studies have shown that invading tumour cells in colorectal cancer have low proliferation in parallel to upregulation of the tumour suppressor p16. We set out to detail the p16 expression and proliferation in basal cell carcinoma and squamous cell carcinoma of the skin, tumours that are locally infiltrative and aggressive. p16 was upregulated at the invasive margin compared to central parts in both tumours, and in basal cell carcinoma there was also a decreased proliferation in infiltrating p16 high tumour cells. In squamous cell carcinoma the Rb-pathway was non-functional, probably due to inactivation of Rb or a de-localisation of p16 to the cytoplasm, and p16 could consequently not inhibit proliferation in infiltrating cells. In contrast to the malignant skin tumours, p16 was commonly expressed in central parts of the tumour islands in cylindroma, and in this benign slow growing tumour p16 seemed important in restraining the proliferative activity of the tumour cells. Further, by subcellular fractionation we confirmed that p16 was expressed in both the nucleus and in the cytoplasm in tumour cell lines, and the protein could bind to cdk4/6 in both subcellular compartments, even if it seemed incapable of inhibiting proliferation. Investigating post-translational modifications of p16 revealed at least two forms of p16 in cell lines, as well as in skin tumours. We further investigated the relation between tumour cell proliferation and migration in a breast cancer cell line and observed that resting cells were more migratory than actively cycling cells. This was also confirmed in a cohort of primary breast tumours, where proliferation and infiltrative growth pattern were inversely correlated. However, the actively cycling breast tumour cells could be rendered more migratory upon exposure to macrophage like stimuli. Thus, in some tumour cells, proliferation and invasion/migration seem to be contrasting events. However, in other tumours, potentially with more severe aberrations in cell cycle regulatory pathways, the cells can proliferate and migrate concurrently.
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| 9. |
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| 10. |
- Gårdmark, Truls, et al.
(author)
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Analysis of clinical characteristics, management and survival of patients with Ta T1 bladder tumours in Sweden between 1997 and 2001
- 2006
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In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 40:4, s. 276-282
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Journal article (peer-reviewed)abstract
- Objective. To analyse the management and outcome of patients with Ta T1 urinary bladder cancer in a population-based national database. Material and methods. Between 1997 and 2001, 94% of all newly diagnosed cases of urinary bladder cancer were registered in the Swedish National Bladder Cancer Register. Data were analysed regarding gender, healthcare region, stage and grade for patients with Ta T1 tumours. The choice of initial treatment in different regions was reviewed. Survival was analysed by calculating relative survival. Results. Out of 9859 registered patients, there were 4442 Ta tumours and 2139 T1 tumours. The median age at diagnosis was 72 and 73 years for patients with Ta and T1 tumours, respectively. Seventy-six percent of the patients were men. The choice of treatment varied between different healthcare regions. A significant trend towards an increased use of intravesical therapy was seen over time. Significantly fewer older than younger patients received such therapy. There was also a tendency towards more intensive therapy in men. The bladder cancer relative 5-year survival rate was 93% for Ta and 75% for T1 tumours. Survival was similar for men and women. Conclusions. Our analysis revealed a regional variation in the treatment of bladder cancer. A large group of patients, even those at high risk, were still undertreated. However, the recent publication of guidelines may have contributed to an increased use of intravesical treatment. Urologists tended to treat TaG3 and T1G3 tumours more aggressively than T1G2 tumours. Therapeutic aggressiveness decreased as the age of the patients increased. The survival rate of patients with bladder cancer in Sweden seems to remain at the levels previously reported for the 1980s.
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