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  • Blom, Johannes, et al. (författare)
  • A 9-year follow-up study of participants and nonparticipants in sigmoidoscopy screening : importance of self-selection
  • 2008
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 17:5, s. 1163-1168
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>BACKGROUND: Self-selection may compromise cost-effectiveness of screening programs. We hypothesized that nonparticipants have generally higher morbidity and mortality than participants. METHODS: A Swedish population-based random sample of 1,986 subjects ages 59 to 61 years was invited to sigmoidoscopy screening and followed up for 9 years by means of multiple record linkages to health and population registers. Gender-adjusted cancer incidence rate ratio (IRR) and overall and disease group-specific and mortality rate ratio (MRR) with 95% confidence intervals (95% CI) were estimated for nonparticipants relative to participants. Cancer and mortality rates were also estimated relative to the age-matched, gender-matched, and calendar period-matched Swedish population using standardized incidence ratios and standardized mortality ratios. RESULTS: Thirty-nine percent participated. The incidence of colorectal cancer (IRR, 2.2; 95% CI, 0.8-5.9), other gastrointestinal cancer (IRR, 2.7; 95% CI, 0.6-12.8), lung cancer (IRR, 2.2; 95% CI, 0.8-5.9), and smoking-related cancer overall (IRR, 1.4; 95% CI, 0.7-2.5) tended to be increased among nonparticipants relative to participants. Standardized incidence ratios for most of the studied cancers tended to be &gt;1.0 among nonparticipants and &lt;1.0 among participants. Mortality from all causes (MRR, 2.4; 95% CI, 1.7-3.4), neoplastic diseases (MRR, 1.9; 95% CI, 1.1-3.5), gastrointestinal cancer (MRR, 4.7; 95% CI, 1.1-20.7), and circulatory diseases (MRR, 2.3; 95% CI, 1.2-4.2) was significantly higher among nonparticipants than among participants. Standardized mortality ratio for the studied outcomes tended to be increased among nonparticipants and was generally decreased among participants. CONCLUSION: Individuals who might benefit most from screening are overrepresented among nonparticipants. This self-selection may attenuate the cost-effectiveness of screening programs on a population level.</p>
  • Laurell, Helena, 1965- (författare)
  • Acute Abdominal Pain
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The aim was to identify diagnostic difficulties for acute abdominal pain at the emergency department and during hospital stay. A total of 3349 patients admitted to Mora Hospital with acute abdominal pain of up to seven days duration, were registered prospectively for history and clinical signs according to a structured schedule. The preliminary diagnosis from the attending physician at the emergency department, any investigations or surgery and final diagnosis were registered at a follow-up after at least one year.</p> <p>There were no differences in diagnostic performance between physicians with 0.5 to 5 years of medical experience. The information collected and a careful examination of the patient was more important than formal competence. The main differential diagnostic problem was non-specific abdominal pain; this was the same for diagnoses requiring surgery. Patients originally diagnosed as not needing surgery had a median delay before operation of 22 hours (mean 40 hours, with 95% confidence interval of 30-50 hours), compared to 8 hours (mean 15 hours, 95% confidence interval of 12-28 hours) for patients with the same final follow-up diagnosis as the preliminary diagnosis. Constipation was a diagnostic pitfall, as 9% of the patients considered constipated required surgery for potentially life threatening reasons and 8% were later found to have an abdominal malignancy. Both the preliminary diagnosis and the discharge diagnosis were less reliable for elderly patients than for younger patients. Elderly patients often had specific organ disease and arrived at the emergency department after a longer history of abdominal pain.</p> <p>This study confirms that assessment of suspected appendicitis can still be based on clinical judgements combined with laboratory tests. Classical clinical findings indicating localised inflammation, such as isolated pain in the right iliac fossa, rebound tenderness, right-sided rectal tenderness, pain migration to the right iliac fossa, local guarding and aggravation of pain when moving, were reliable for predicting acute appendicitis. A CT scan can be saved for the more equivocal cases of acute abdominal pain. A generous strategy regarding CT scan among elderly patients with acute abdominal pain, even in the absence of pronounced signs of an inflammatory intra-abdominal process, is recommended.</p>
  • Morris, Eva J. A., et al. (författare)
  • A population-based comparison of the survival of patients with colorectal cancer in England, Norway and Sweden between 1996 and 2004
  • 2011
  • Ingår i: Gut. - 0017-5749 .- 1468-3288. ; 60:8, s. 1087-1093
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Objective To examine differences in the relative survival and excess death rates of patients with colorectal cancer in Norway, Sweden and England. Methods All individuals diagnosed with colorectal cancer (ICD10 (International Classification of Diseases, 10th revision) C18-C20) between 1996 and 2004 in England, Norway and Sweden were included in this population-based study of patients with colorectal cancer. The main outcome measures were 5-year cumulative relative period of survival and excess death rates stratified by age and period of follow-up. Results The survival of English patients with colorectal cancer was significantly lower than was observed in both Norway and Sweden. Five-year age-standardised colon cancer relative survival was 51.1% (95% CI 50.1% to 52.0%) in England compared with 57.9% (95% CI 55.2% to 60.5%) in Norway and 59.9% (95% CI 57.7% to 62.0%) in Sweden. Five-year rectal cancer survival was 52.3% (95% CI 51.1% to 53.5%) in England compared with 60.7% (95% CI 57.0% to 64.2%) and 59.8% (95% CI 56.9% to 62.6%) in Norway and Sweden, respectively. The lower survival for colon cancer in England was primarily due to a high number of excess deaths among older patients in the first 3 months after diagnosis. In patients with rectal cancer, excess deaths remained elevated until 2 years of follow-up. If the lower excess death rate in Norway applied in the English population, then 890 (13.6%) and 654 (16.8%) of the excess deaths in the colon and rectal cancer populations, respectively, could have been prevented at 5 years follow-up. Most of these avoidable deaths occurred shortly after diagnosis. Conclusions There was significant variation in survival between the countries, with the English population experiencing a poorer outcome, primarily due to a relatively higher number of excess deaths in older patients in the short term after diagnosis. It seems likely, therefore, that in England a greater proportion of the population present with more rapidly fatal disease (especially in the older age groups) than in Norway or Sweden.</p>
  • Møller, Henrik, et al. (författare)
  • Colorectal cancer survival in socioeconomic groups in England : Variation is mainly in the short term after diagnosis
  • 2012
  • Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 48:1, s. 46-53
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The objective of this study was to examine differences in cancer survival between socioeconomic groups in England, with particular attention to survival in the short term of follow-up.</p> <p><strong>PATIENTS AND METHODS:</strong></p> <p>Individuals diagnosed with colorectal cancer between 1996 and 2004 in England were identified from cancer registry records. Five-year cumulative relative survival and excess death rates were computed.</p> <p><strong>RESULTS:</strong></p> <p>For colon cancer there was a very high excess death rate in the first month of follow-up, and the excess death rate was highest in the socioeconomically deprived groups. In subsequent periods, excess mortality rates were much lower and there was less socioeconomic variation. The pattern of variation in excess death rates was generally similar in rectal cancer but the socioeconomic difference in death rates persisted several years longer. If the excess death rates in the entire colorectal cancer patient population were the same as those observed in the most affluent socioeconomic quintile, the annual reduction would be 360 deaths in colon cancer and 336 deaths in rectal cancer patients. These deaths occurred almost entirely in the first month and the first year after diagnosis.</p> <p><strong>CONCLUSION:</strong></p> <p>Recent developments in the national cancer control agenda have included an increasing emphasis on outcome measures, with short-term cancer survival an operational measure of variation and progress in cancer control. In providing clues to the nature of the survival differences between socioeconomic groups, the results presented here give strong support for this strategy.</p>
  • Adam, René, et al. (författare)
  • Managing synchronous liver metastases from colorectal cancer A multidisciplinary international consensus
  • 2015
  • Ingår i: Cancer Treatment Reviews. - 0305-7372 .- 1532-1967. ; 41:9, s. 729-741
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and &gt;12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.</p>
  • Agarwal, Shruti, et al. (författare)
  • The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V.
  • 2015
  • Ingår i: Oncogene. - Nature Publishing Group. - 1476-5594. ; 34:35, s. 4581-4590
  • Tidskriftsartikel (refereegranskat)abstract
    • Oncogenic c-Kit mutations have been shown to display ligand-independent receptor activation and cell proliferation. A substitution of aspartate to valine at amino acid 816 (D816V) is one of the most commonly found oncogenic c-Kit mutations and is found in >90% of cases of mastocytosis and less commonly in germ-cell tumors, core-binding factor acute myeloid leukemia and mucosal melanomas. The mechanisms by which this mutation leads to constitutive activation and transformation are not fully understood. Previous studies have shown that the D816V mutation causes a structural change in the activation loop (A-loop), resulting in weaker binding of the A-loop to the juxtamembrane domain. In this paper, we have investigated the role of Y823, the only tyrosine residue in the A-loop, and its role in oncogenic transformation by c-Kit/D816V by introducing the Y823F mutation. Although dispensable for the kinase activity of c-Kit/D816V, the presence of Y823 was crucial for cell proliferation and survival. Furthermore, mutation of Y823 selectively downregulates the Ras/Erk and Akt pathways as well as the phosphorylation of STAT5 and reduces the transforming capacity of the D816V/c-Kit in vitro. We further show that mice injected with cells expressing c-Kit/D816V/Y823F display significantly reduced tumor size as well as tumor weight compared with controls. Finally, microarray analysis, comparing Y823F/D816V cells with cells expressing c-Kit/D816V, demonstrate that mutation of Y823 causes upregulation of proapoptotic genes, whereas genes of survival pathways are downregulated. Thus, phosphorylation of Y823 is not necessary for kinase activation, but essential for the transforming ability of the c-Kit/D816V mutant.Oncogene advance online publication, 1 December 2014; doi:10.1038/onc.2014.383.
  • Alam, Muhammad Wasi, et al. (författare)
  • HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.
  • 2016
  • Ingår i: Oncotarget. - Impact Journals, LLC. - 1949-2553. ; 7:10, s. 50-11238
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.
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