| 21. |
- Johansson, Eva, et al.
(författare)
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Time, Symptom Burden, Androgen Deprivation, and Self-Assessed Quality of Life after Radical Prostatectomy or Watchful Waiting : The Randomized Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) Clinical Trial
- 2009
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 55:2, s. 422-432
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Quality-of-life outcomes are important in the choice of treatment strategy for men with localized prostate cancer.OBJECTIVE: To evaluate how follow-up time, number of physical symptoms, and presence of androgen deprivation affected quality of life among men randomized to radical prostatectomy or watchful waiting.DESIGN, SETTING, AND PARTICIPANTS: The study group was composed of all 376 living men included in the Swedish part of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) between January 1, 1989, and February 29, 1996. Quality-of-life data were collected after a mean follow-up time of 4.1 yr.INTERVENTION: All patients were randomly assigned to radical prostatectomy or watchful waiting. Forty-five men were androgen deprived.MEASUREMENTS: Data of specific symptoms, symptom-induced stress, sense of well-being, and self-assessed quality of life were obtained by means of a questionnaire. Psychological symptoms were assessed using seven-point visual digital scales.RESULTS AND LIMITATIONS: In analyses stratified on the basis of the numbers of physical symptoms, anxiety and depressed mood were less common, and sense of well-being and self-assessed quality of life were better throughout in the radical prostatectomy group than in the watchful waiting group. As the number of physical symptoms increased, all psychological variables became worse and more prominent in the watchful waiting group. After a follow-up time of 6-8 yr, a significant decrease in quality of life (p=0.03) was seen in the watchful waiting group. Twenty-four percent of androgen-deprived patients assigned to watchful waiting reported high self-assessed quality of life compared with 60% in the radical prostatectomy group. Eighty-eight percent of patients had clinically detected tumors.CONCLUSIONS: Androgen deprivation negatively affected self-assessed quality of life in men assigned to watchful waiting. The number of physical symptoms was associated with the level of quality of life. Quality of life was lower with longer follow-up time in both groups and was statistically significant in the watchful waiting group (p=0.03).
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| 22. |
- Mucci, Lorelei A., et al.
(författare)
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Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort
- 2008
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - Baltimore : Waverly Press. - 1055-9965 .- 1538-7755. ; 17:1, s. 249-251
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Tidskriftsartikel (refereegranskat)abstract
- Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer.
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| 23. |
- Setlur, Sunita R., et al.
(författare)
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Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer
- 2008
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:11, s. 815-825
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. METHODS: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. RESULTS: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). CONCLUSIONS: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
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| 24. |
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| 26. |
- Hemmingsson, Oskar, 1975-, et al.
(författare)
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ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite
- 2009
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer. - 0344-5704 .- 1432-0843. ; 63:3, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- Purpose ASNA1 is homologous to E. coli ArsA, a well characterized ATPase involved in efflux of arsenite and antimonite. Cells resistant to arsenite and antimonite are cross-resistant to the chemotherapeutic drug cisplatin. ASNA1 is also an essential ATPase for the insertion of tail-anchored proteins into ER membranes and a novel regulator of insulin secretion. The aim of this study was to determine if altered ASNA1 levels influenced growth and sensitivity to arsenite and cisplatin in human melanoma cells.Methods Cultured melanoma T289 cells were transfected with plasmids containing sense or antisense ASNA1. Cells were exposed to cisplatin, arsenite and zinc. Cell growth and chemosensitivity were evaluated by the MTT assay and apoptosis by a TUNEL assay.Results ASNA1 expression was necessary for growth. T289 clones with decreased ASNA1 expression exhibited 51 ± 5% longer doubling times than wildtype T289 (P = 0.0091). After exposure to cisplatin, ASNA1 downregulated cells displayed a significant increase in apoptosis. The cisplatin IC50 in ASNA1 underexpressing cells was 41.7 ± 1.8% compared to wildtype (P = 0.00097) and the arsenite IC50 was 59.9 ± 3.2% of wildtype IC50 (P = 0.0067).Conclusions Reduced ASNA1 expression is associated with significant inhibition of cell growth, increased apoptosis and increased sensitivity to cisplatin and arsenite.
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| 27. |
- Gruvberger, Sofia
(författare)
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Estrogen receptor alpha and beta in breast cancer - gene expression profiles and clinical implications
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignancy in women in the Western world with about 10% of women developing breast cancer during their lifetime, of which one third will eventually succumb to the metastatic form of the disease. Breast cancer arises from the epithelial cells of the breast mammary gland, but the mechanisms involved in tumor initiation, progression, and metastasis are still not fully understood. However, estrogen and its receptors are believed to play a crucial role in these events. Estrogen receptor alpha (ERalpha) has long been identified as a target for treatment and numerous studies have shown that patients expressing ERalpha are more likely to respond to endocrine therapy such as tamoxifen; however a significant fraction become resistant. Little is known of the role of the second estrogen receptor, estrogen receptor beta (ERbeta), in breast tumor biology and therapy response. This thesis is primarily concerned with investigating the global differences in gene expression between tumors that express and do not express ERalpha and/or ERbeta, and the relationship of such profiles to outcome in the setting of tamoxifen therapy. The present study shows that ERalpha status in primary breast tumor biopsies is associated with a very distinct gene expression profile, as determined by cDNA microarrays, involving a large number of genes (Papers I and III). Only a small fraction of these ERalpha-associated genes have previously been identified as estrogen-responsive in cell culture (Paper I). In addition, not only is the ERalpha status as a binary variable encoded in the gene expression profiles, but also the actual level of protein content can be predicted, as well as the percent cells in the DNA synthesis phase of the cell cycle and other prognostic markers (Paper III). However, predicting response to tamoxifen using gene expression profiles from primary breast tumors was not possible in a cohort of 44 patient with varying ERalpha status and clinical outcome (Paper II). Additionally, a previously published prognosis predictor did not have any prognostic significance in this data, suggesting that different data sets and various tumor/patient/treatment characteristics selected influence the success of an array-based predictor for prognosis (Paper II). Much less is known about the transactivating properties of ERbeta and its relationship to ERalpha and tamoxifen response. Herein, the ERbeta protein is shown to have prognostic value after adjuvant tamoxifen therapy in a large patient set (n=353; Paper IV). However, subgroup analysis shows the effect to be only significant in patients with tumors lacking ERalpha. From cDNA microarray analysis of a subset of these tumors, an ERbeta-associated gene expression profile could be generated from the ERalpha negative group of tumors but not for the ERalpha positive group, further corroborating the notion that ERbeta selectively influences the biological processes in tumors lacking ERalpha (Paper IV). These results suggest that the small subset of ERalpha negative tumors responding to tamoxifen may be explained by the presence of ERbeta, and that ERbeta is not a surrogate marker for ERalpha but is associated with its own biological processes and may respond to tamoxifen via different target genes. In conclusion, together these studies have added to our understanding of the importance of estrogen receptor status and their biological consequences in breast cancer.
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| 28. |
- Hardell, Lennart, et al.
(författare)
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Long-term use of cellular phones and brain tumours : increased risk associated with use for ≥10 years
- 2007
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Ingår i: Occupational and Environmental Medicine. - London : BMJ Publishing Group. - 1351-0711 .- 1470-7926. ; 64, s. 626-632
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To evaluate brain tumour risk among long-term users of cellular telephones. METHODS: Two cohort studies and 16 case-control studies on this topic were identified. Data were scrutinised for use of mobile phone for > or =10 years and ipsilateral exposure if presented. RESULTS: The cohort study was of limited value due to methodological shortcomings in the study. Of the 16 case-control studies, 11 gave results for > or =10 years' use or latency period. Most of these results were based on low numbers. An association with acoustic neuroma was found in four studies in the group with at least 10 years' use of a mobile phone. No risk was found in one study, but the tumour size was significantly larger among users. Six studies gave results for malignant brain tumours in that latency group. All gave increased odd ratios (OR), especially for ipsilateral exposure. In a meta-analysis, ipsilateral cell phone use for acoustic neuroma was OR = 2.4 (95% CI 1.1 to 5.3) and OR = 2.0, (1.2 to 3.4) for glioma using a tumour latency period of > or =10 years. CONCLUSIONS: Results from present studies on use of mobile phones for > or =10 years give a consistent pattern of increased risk for acoustic neuroma and glioma. The risk is highest for ipsilateral exposure.
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| 29. |
- Hardell, Lennart, et al.
(författare)
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Tumour risk associated with use of cellular telephones or cordless desktop telephones
- 2006
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Ingår i: World Journal of Surgical Oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 4:74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of cellular and cordless telephones has increased dramatically during the last decade. There is concern of health problems such as malignant diseases due to microwave exposure during the use of these devices. The brain is the main target organ. METHODS: Since the second part of the 1990's we have performed six case-control studies on this topic encompassing use of both cellular and cordless phones as well as other exposures. Three of the studies concerned brain tumours, one salivary gland tumours, one non-Hodgkin lymphoma (NHL) and one testicular cancer. Exposure was assessed by self-administered questionnaires. RESULTS: Regarding acoustic neuroma analogue cellular phones yielded odds ratio (OR) = 2.9, 95 % confidence interval (CI) = 2.0-4.3, digital cellular phones OR = 1.5, 95 % CI = 1.1-2.1 and cordless phones OR = 1.5, 95 % CI = 1.04-2.0. The corresponding results were for astrocytoma grade III-IV OR = 1.7, 95 % CI = 1.3-2.3; OR = 1.5, 95 % CI = 1.2-1.9 and OR = 1.5, 95 % CI = 1.1-1.9, respectively. The ORs increased with latency period with highest estimates using > 10 years time period from first use of these phone types. Lower ORs were calculated for astrocytoma grade I-II. No association was found with salivary gland tumours, NHL or testicular cancer although an association with NHL of T-cell type could not be ruled out. CONCLUSION: We found for all studied phone types an increased risk for brain tumours, mainly acoustic neuroma and malignant brain tumours. OR increased with latency period, especially for astrocytoma grade III-IV. No consistent pattern of an increased risk was found for salivary gland tumours, NHL, or testicular cancer.
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| 30. |
- Hedenus, Michael, 1945-
(författare)
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Clinical impact of epoetins in the treatment of anemia with special emphasis on patients with lymphoid malignancies. : dosing, iron supplementation and safety
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to determine the relevant dose of arbepoetin-alfa (DA) in patients with lymphoproliferative diseases (LPD) and chemotherapy induced anemia (CIA), to study the clinical impact of intravenous (IV) iron supplementation combined with epoetin beta treatment, to identify factors that might predict hemoglobin (Hb) response to treatment with epoetins and to investigate safety of DA.A dose-finding phase II study was able to assess a reasonable DA dose of 2.25 μg/kg once weekly for the treatment of CIA in patients with LPD. Dose-response trends were observed for the different dose cohorts although not statistically significant for any of the endpoints. However a significantly higher proportion of patients achieved Hb response (increase ≥2 g/dL) in the combined DA groups than in placebo (P<0.001).A larger pivotal phase II trial was performed in a similar setting o confirm that the dose 2.25μg/kg once weekly was appropriate and safe. The proportion of patients achieving Hb response was significantly higher in the DA group (60%) than in the placebo group (18%) (P<0,001) and resulted in higher mean changes in Hb than placebo from baseline, 2.66 g/dl versus 0.69 /dl. Also a significantly lower proportion of patients in the DA group (31%) received RBC tranfusions than in the placebo group (48%). The short-term safety of DA with the tested dose was confirmed. The efficacy of DA was consistent for all end points independent of malignancy type or baseline endogenous erythropoietin serum levels.The correction of moderate anemia in truly iron repleted patients with clinically stable LPD not receiving hemotherapy or RBC transfusions with epoetin beta treatment, with or without IV iron treatment was studied in an open label randomized trial. Also the impact on iron kinetics was assessed. The mean change in Hb concentration from baseline to end of treatment (EOT ) was 2.91 versus 1.50 g/dL respectively (P<0.0001). There was a significant (P<0.0001) difference in mean Hb at EOT between the iron and no-iron groups (13.0 g/dL versus 11.8 g/dL). Hb response was achieved by significantly more patients in the iron group (P=0.0012)than in the no-iron group (93% versus 53%) and the median time to achieve a Hb response was 6 weeks in the iron group compared with 12 weeks in the no-iron group. The mean weekly epoetin dose per patient was statistically significant lower in the iron group at week 13 (P =0.029) and at least 25% lower at EOT.To investigate the long-term safety of DA in cancer patients with CIA four previously published double blind, randomized placebo-controlled phase II -III studies were analysed (n = 1.129). Median durations of progression-free survival and overall survival was comparable between DA and placebo for lung cancer (median follow up 15.8 months), for LPD (median follow up 32.6 months) and in the pooled population (follow up 4 months).
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