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Träfflista för sökning "AMNE:(MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology) srt2:(2010-2014);srt2:(2010)"

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  • Bin Kaderi, Mohamed Arifin, 1978- (författare)
  • Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted<sup> </sup>the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the <em>GNAS1</em>, <em>BCL2</em> and <em>MDM2</em> genes and the RNA expression levels of the <em>LPL</em>, <em>ZAP70</em>, <em>TCL1, CLLU1 </em>and <em>MCL1</em> genes were suggested as novel prognostic markers in CLL.</p> <p>In papers I-III, we performed genotyping analyses of the <em>GNAS1</em> T393C, <em>BCL2</em> -938C&gt;A and <em>MDM2</em> SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.</p> <p>In paper IV, we measured the RNA expression levels of <em>LPL</em>, <em>ZAP70</em>, <em>TCL1,</em> <em>CLLU1</em> and <em>MCL1</em> in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except <em>MCL1</em>, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for <em>LPL</em> and <em>CLLU1</em> expression. Among the RNA-based markers, multivariate analysis revealed <em>LPL</em> expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with <em>LPL</em> expression status giving the most significant results.</p> <p>In summary, data from papers I-III could not verify the <em>GNAS1</em> T393C, <em>BCL2</em> -938C&gt;A and <em>MDM2 </em>SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that <em>LPL</em> expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize <em>LPL</em> quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.<em></em></p>
  • Johansson, Bengt, 1958- (författare)
  • Long-term outcome research on PDR brachytherapy with focus on breast, base of tongue and lip cancer
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Brachytherapy (BT) with continuous low dose rate (LDR) has been used for 100 years and is considered as the radiotherapy method able to deliver a dose in the shortest time with high efficacy and low risk of side effects. The drawbacks are need for patient isolation and radiation exposure of the staff during the treatment.</p> <p>Brenner and Hall published the radiobiology concept for pulsed dose rate (PDR) in 1991.  Short (10-20 minutes), hourly pulses of high dose rate (HDR) given to the same dose, with same overall treatment time will virtually simulate continuous LDR. At the same time new afterloading machine technology became available, where a single millimetre sized radiation <sup>192</sup>Iridium source sequentially moves through the applicator in small individually timed steps. The advantages are that the radiation dose can be optimized along the applicator and with no radiation exposure of the staff and no need for patient isolation more than during the pulse. This work deals with four different aspects of PDR BT</p> <p>An experimental comparison of measured absorbed doses outside a left sided breast target on a body equivalent Alderson phantom was made.  Five external beam radiotherapy (EBRT) whole breast treatments to 50 Gy versus five accelerated partial breast irradiations (APBI) by PDR BT to 50 Gy were studied. The absorbed doses were measured in 67 different positions inside the body phantom by thermoluminescence dosimeters. The result shows that dose points distant to the left breast will have 1-1.4 % of the prescribed dose with no difference between EBRT and PDR BT. Organs at risk in short distance (&lt;5 cm) to the target (such as parts of the left lung, heart muscle and the right breast) will have significantly less dose by PDR BT. In conclusion PDR BT has dosimetric advantages close to the target compared to EBRT and cannot do more damage to remote organs.</p> <p>PDR APBI as the adjuvant RT treatment to breast conserving surgery after early breast cancer was studied. Between 1994-2004 we treated 50 women and 51 breasts. The median age of the population was 53 (40-72) years. The cases were radically resected, unifocal T1-2N0-1M0 tumours. PDR BT was given to a dose of 50 Gy for 5 days directed to the operated sector of the breast. The median treated volume was 160 cm<sup>3</sup>, constituting in median 31 % of the breast volume. The treatment is called accelerated because total treatment time is 5 days compared to 5 weeks for EBRT. After a median follow-up of 130 months (&gt;10 years) we noted 5 (10 %) local recurrences in the treated breast. Four of these recurrences were outside the treated volume. Three women (6 %) developed cancers in the other breast. Early side effects were mild and less than with EBRT. As late side effects we found mild to moderate local fibroses in the treated volume. A cosmetic evaluation was done by both the patient and a nurse and was found to be lower than in other published data (56 % = good to excellent). The 10 years local failure rate is similar to the result from a large Swedish randomized study on whole breast radiotherapy to 50 Gy. The study indicates that PDR BT is highly effective.</p> <p>A combination of EBRT (40.8 Gy) and PDR boost (35 Gy) to T1-4N0-3M0, base of tongue (BOT) cancer, treated during 1994-2007 was analyzed. The study is the first with PDR and second largest with BT worldwide. A number of 83 patients with a median age of 60 (38-82) years were included. BT was given to a mean volume of 58 ccm 2 days after the neck dissection. Median follow-up was 54 months. At 5 years we found 89 % local tumour control, 95 % neck control, 80 % disease free survival and an overall survival of 65 %. Late side effects were 13 % minor transient soft tissue necrosis and 12 % long lasting or permanent soft tissue- or osteoradio-necrosis. The results are among the best published worldwide. An extensive quality of life analysis was done on 45 patients at last follow-up and showed limited, persistent xerostomia and dysphagia. The global quality of life was rated good in 75 % of the patients.</p> <p>The last study presented was PDR mono-brachytherapy (55-60 Gy) to cancer of the lip (T1-3N0M0). The study included 43 patients with a median age of 74 (37-92) years. The treatment time was 5.5-6 days and the mean treated volume was 15 ccm. The median follow-up time was 54 (1-158) months. Five year Kaplan-Meier data showed, local control 94 %, disease free survival 86 % and overall survival 59 %. An early side effect was a strong radiation mucositis and dermatitis, which healed in 1 month. Late side effects were uncommon and the cosmetic appearance and the lip function were found to be normal. Our data in total and per T-stage was compared to a European survey from 1993 on 2794 patients treated by LDR BT. The results are similar and are a strong indication of equal efficacy between PDR and LDR.</p>
  • Lövgren, Malin, et al. (författare)
  • Clock time and embodied time experienced by patients with inoperable lung cancer
  • 2010
  • Ingår i: Cancer Nursing. - Lippincott Williams & Wilkins. - 0162-220X .- 1538-9804. ; 33:1, s. 55-63
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>In this study, we explore how patients with inoperable lung cancer (LC) discuss their experiences of time, based on content analysis of open interviews with 35 patients 1 year after diagnosis, using Davies' distinction between "clock time" and "embodied time" as sensitizing concepts. Two interrelated themes were derived: (1) aspects related to the healthcare system, with 3 subthemes: waiting times in the healthcare system, limited time for patient-professional contact, and limited time for coordination of services, and (2) existential aspects, with subthemes: the future with LC and managing an uncertain and finite life with LC. Time could be experienced as problematic for these patients, when limited or lacking or through long periods of waiting, especially when these periods occurred without adequate preparation or information. This contributed to exacerbation of these patients' existing sense of uncertainty, their perception of care as impersonal and insecure, and their need to remain alert and act on their own behalf. Awareness of the seriousness of their disease and the prospect of a limited lifetime was described as increasing uncertainty about dying and fear of certain death. People also described efforts to constructively deal with their situation by reprioritizing their remaining time, having increased appreciation of some aspects of daily life, and living consciously in the present. This analysis suggests a collision between clock time, which steers the healthcare system, and embodied time, as experienced by individuals. Greater attention to psychosocial needs is suggested as one means of positively affecting patients' experiences of time and uncertainty.</p>
  • Nilsson, Lena Maria, 1965-, et al. (författare)
  • Consumption of filtered and boiled coffee and the risk of incident cancer : a prospective cohort study
  • 2010
  • Ingår i: Cancer Causes and Control. - Springer Netherlands. - 0957-5243 .- 1573-7225. ; 21:10, s. 1533-1544
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background  Despite potentially relevant chemical differences between filtered and boiled coffee, this study is the first to investigate consumption in relation to the risk of incident cancer.</p><p>Methods  Subjects were from the Västerbotten Intervention Project (64,603 participants, including 3,034 cases), with up to 15 years of follow-up. Hazard ratios (HR) were calculated by multivariate Cox regression.</p><p>Results  No associations were found for all cancer sites combined, or for prostate or colorectal cancer. For breast cancer, boiled coffee ≥4 versus &lt;1 occasions/day was associated with a reduced risk (HR = 0.52, CI = 0.30–0.88, <em>p</em> <sub>trend</sub> = 0.247). An increased risk of premenopausal and a reduced risk of postmenopausal breast cancer were found for both total (HR<sub>premenopausal</sub> = 1.69, CI = 0.96–2.98, <em>p</em> <sub>trend</sub> = 0.015, HR<sub>postmenopausal</sub> = 0.60, CI = 0.39–0.93, <em>p</em> <sub>trend</sub> = 0.006) and filtered coffee (HR<sub>premenopausal</sub> = 1.76, CI = 1.04–3.00, <em>p</em> <sub>trend</sub> = 0.045, HR<sub>postmenopausal</sub> = 0.52, CI = 0.30–0.88, <em>p</em> <sub>trend</sub> = 0.045). Boiled coffee was positively associated with the risk of respiratory tract cancer (HR = 1.81, CI = 1.06–3.08, <em>p</em> <sub>trend</sub> = 0.084), a finding limited to men. Main results for less common cancer types included total coffee in renal cell cancer (HR = 0.30, CI = 0.11–0.79, <em>p</em> <sub>trend</sub> = 0.009) and boiled coffee in pancreas cancer (HR = 2.51 CI = 1.15–5.50, <em>p</em> <sub>trend</sub> = 0.006).</p><p>Conclusion  These findings demonstrate, for the first time, the potential relevance of brewing method in investigations of coffee consumption and cancer risk, but they must be confirmed in future studies.</p>
  • Hemmingsson, Oskar, 1975-, et al. (författare)
  • ASNA-1 activity modulates sensitivity to cisplatin
  • 2010
  • Ingår i: Cancer Research. - American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:24, s. 10321-10328
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.</p>
  • Gustafson, Lars, et al. (författare)
  • A factor analytic approach to symptom patterns in dementia.
  • 2010
  • Ingår i: International Journal of Alzheimer's Disease. - Hindawi Publishing Corporation. - 2090-0252.
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.
  • Ahlgren, Sara, 1979- (författare)
  • Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules Preparation and Preclinical Evaluation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations <em>in vitro</em> and <em>in vivo</em> of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours.</p> <p>Papers I and II report the evaluation of the Affibody molecule Z<sub>HER2:2395</sub>-C, site-specifically labelled with the radiometals <sup>111</sup>In (for SPECT) and <sup>57</sup>Co (as a surrogate for <sup>55</sup>Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection.</p> <p>Papers III and IV report the development and optimization of a technique for site-specific labelling of Z<sub>HER2:2395</sub>-C with <sup>99m</sup>Tc using an N<sub>3</sub>S chelating peptide sequence. <sup>99m</sup>Tc-Z<sub>HER2:2395</sub>-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for <sup>99m</sup>Tc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of Z<sub>HER2:2395</sub>-C with <sup>99m</sup>Tc were contained in a single vial.</p> <p>Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of <sup>111</sup>In-ABY-025 was very similar to that of two variants of the parental molecule.</p> <p>It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.</p>
  • Wedenberg, Mina, et al. (författare)
  • Analytical description of the LET dependence of cell survival using the repairable-conditionally repairable damage model
  • 2010
  • Ingår i: Radiation Research. - 0033-7587 .- 1938-5404. ; 174:4, s. 517-525
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions.</p>
  • Sun, Aijun, 1973- (författare)
  • Radiolabeled acetate PET in oncology imaging studies on head and neck cancer, prostate cancer and normal distribution
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The use of positron emission tomography (PET) for imaging in oncology has grown rapidly in recent years. 2-[<sup>18</sup>F]-fluorodeoxyglucose (FDG) is the most common tracer of PET, although drawbacks exist. Radiolabeled 1-[<sup>11</sup>C]-acetate (C-AC) is a simple probe for evaluation of perfusion, anabolism (lipogenesis) and catabolism (oxidative metabolism) in all living tissues. This study explored the potential of AC PET in head and neck cancer, benign and malignant lymph nodes in prostate cancer and normal distribution. </p> <p>In head and neck cancer, C-AC PET detected more primaries and lymph node metastases than FDG PET. The mean primary tumor volumes delineated by C-AC was 51% larger than that of FDG before radiotherapy (RT). Both FDG and C-AC PET tumor volumes must be carefully validated before used in clinical routine. Baseline tumor clearance rate (k<sub>mono)</sub> was higher in complete responders (CR) than that in partial responders (PR). k<sub>mono</sub> tended to correlate inversely with FDG SUV at baseline. Radiosensitive tumors might rely predominantly on oxidative metabolism for their biogenetic needs. k<sub>mono</sub> increased in PR during RT. The potential reversibility of impaired k<sub>mono</sub> in radioresistant tumors imply that treatment targeting the intermediary metabolism might improve the outcome. Tumor relative perfusion index (rF) and k<sub>mono</sub> were coupled in CR throughout the RT, but not in PR. Dynamic C-AC PET provides a new non-invasive method to simultaneously evaluate the tumor oxidative metabolism and perfusion which link the RT response in patients by a single tracer injection.</p> <p>In prostate cancer, elevated C-AC accumulation is common in benign inguinal lymph nodes, probably due to increased lipogenesis rather than lymphatic drainage. CT Hounsfield unit of benign nodes was lower than that of metastases, suggesting that density measurement using CT might improve the specificity of nodal staging of prostate cancer.</p> <p>A novel tracer 2-[<sup>18</sup>F]-fluoroacetate (F-AC) was synthesized and used for dynamic PET-CT imaging in animals. Compared with C-AC PET-CT, F-AC showed prolonged blood retention, no detectable trapping in myocardium and salivary glands, rapid excretion from liver to bile and urine and de-fluorination resulting in intensive skeletal activity. F-AC does not mimic the normal physiologic path of C-AC and appears to be of little use for assessment of perfusion, intermediary metabolism or lipogenesis.</p>
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