Kristiansand, Norway
Kristiansand, Norway

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Kjersem J.B.,University of Oslo | Ikdahl T.,University of Oslo | Guren T.,University of Oslo | Skovlund E.,Norwegian Institute of Public Health | And 9 more authors.
BMC Cancer | Year: 2012

Background: Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3′untranslated region (3′UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/- cetuximab.Methods: The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314).Results: LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16).Conclusions: The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/- cetuximab. © 2012 Kjersem et al.; licensee BioMed Central Ltd.


Kjersem J.B.,University of Oslo | Skovlund E.,Norwegian Institute of Public Health | Ikdahl T.,University of Oslo | Guren T.,University of Oslo | And 6 more authors.
BMC Cancer | Year: 2014

Background: Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314). Methods: 504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991). Results: The response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival.Conclusion: Patients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate. © 2014 Kjersem et al.; licensee BioMed Central Ltd.


PubMed | Copenhagen University, University of Oslo, University of Bergen, Akershus University Hospital and 4 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status.High levels of pretreatment serum IL-6 or CRP were associated with impaired outcome, in terms of reduced PFS and OS. Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months, respectively (P < 0.001). Stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months, (P < 0.001). IL-6 and CRP levels affected overall prognosis also in adjusted analyses. The effect of IL-6 was particularly pronounced in patients with BRAF mutation (interaction P = 0.004).IL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial, in which patients with mCRC received first line treatment. The effect of serum IL-6 and CRP on progression-free survival (PFS) and overall survival (OS) was estimated.High baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status.


Kersten C.,Southern Hospital Trust | Louhimo J.,University of Helsinki | Algars A.,University of Turku | Lahdesmaki A.,Porvoo Hospital | And 4 more authors.
Acta Oncologica | Year: 2013

Background. To characterize the stage-specific prognostic relevance of preoperative systemic inflammatory response, defined by C-reactive protein (CRP), in colon cancer (CC) patients. Material and methods. Data from CC patients operated on from 1998 to 2007 at three hospitals from three different Nordic countries were collected retrospectively from national registries, local databases and/or patient records. Patients with emergency surgery, infection or auto-immune disease were excluded. Associations between clinical or histopathological variables and CRP were assessed. Patients were followed from the date of surgery to death or end of follow-up. Disease-specific survival (DSS) was the main endpoint. Results. In total, 525 patients with age and stage distributions which were representative for CC patients were included. None of the patients was lost to follow-up. Age, TNM Stage, WHO differentiation grade and right-sided tumor location significantly associated with elevated CRP values, in contrast to postoperative morbidity, which did not. CRP levels were found to be a strong prognostic factor for DSS in CC. The risk of death due to CC was augmented with increasing levels of CRP in every stage of operated CC. Both short- and long-term DSS were impaired. The sub-hazard ratios for CRP-levels above 60 mg/L were 7.37 (CI 2.65-20.5) for stage I+ II, compared to 3.29 (CI 1.30-8.29) for stage III and 2.24 (CI 1.16-4.35) for stage IV. Conclusion. Increase of CRP concentrations correlate with clinically relevant poorer disease-specific survival in each stage of CC. © 2013 Informa Healthcare.


Kleist B.,Southern Hospital Trust | Poetsch M.,University of Duisburg - Essen
World Journal of Gastroenterology | Year: 2015

Neuroendocrine differentiation in sporadic colorectal cancer has been recognized since decades, but its clinical impact is still controversially discussed. Detailed parameter analyses hint at the possibility that probably not neuroendocrine differentiation itself, but its association with poor grade of tumor differentiation, lymph node metastases, distant metastases and other unfavorable features contribute to worse clinical outcome. However, other studies deny a relationship between neuroendocrine differentiation and prognosis of colorectal cancer. This review elucidates, whether new insights into the origin of neuroendocrine differentiation in the intestinal epithelium, its regulation by mTOR pathway components and its possible link to the intestinal stem cell compartment could determine a role of neuroendocrine cells as prognostic marker and putative therapeutic target in sporadic colorectal cancer. © 2015 Baishideng Publishing Group Inc. All rights reserved.


Kleist B.,Southern Hospital Trust | Xu L.,University of Texas M. D. Anderson Cancer Center | Kersten C.,Southern Hospital Trust | Seel V.,University of Duisburg - Essen | And 2 more authors.
American Journal of Translational Research | Year: 2012

Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5 genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein expression (p=0.0394), which mainly can be attributed to the negative influence of non-coding Lgr5 gene variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5 protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly prognostic importance, which has to be further evaluated by large cohort studies.


Kleist B.,Southern Hospital Trust | Kempa M.,University of Duisburg - Essen | Novy M.,ViennaLab Diagnostics GmbH | Oberkanins C.,ViennaLab Diagnostics GmbH | And 4 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2014

Neuroendocrine differentiation of tumor tissue has been recognized as an important prerequisite for new targeted therapies. To evaluate the suitability of colorectal cancer (CRC) tissue for these treatment approaches and to find a possible link to pretherapeutic conditions of other targeted strategies, we compared neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary and metastatic CRC. Immunohistochemical expression analysis of neuroendocrine markers chromogranin A and synaptophysin was performed on archival CRC tissue, comprising 116 primary tumors, 258 lymph node metastases and 72 distant metastases from 115 patients. All CRC samples but 30 distant metastases were subjected to mutation analysis of KRAS, NRAS, BRAF, PIK3CA, and TP53. Neuroendocrine marker expression was found significantly less frequently in lymph node metastases compared to primary tumors and distant metastases (20%, 31%, 28%, respectively, P = 0.044). KRAS mutation rates increased significantly from primary tumors to lymph node metastases and distant metastases within the neuroendocrine negative CRC group (44%, 53%, 64%, respectively, P = 0.042). Neuroendocrine differentiation was significantly less concordant than KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary tumor/lymph node metastases pairs (65% versus 88%-99%; P < 0.0001) and primary tumor/distant metastases pairs (64% versus 83%-100%; P = 0.027 and P < 0.0001, respectively). According to these data, therapeutic targeting of neuroendocrine tumor cells can be considered only for a subset of CRC patients and biopsies from the metastatic site should be used to guide therapy. A possible importance of lacking neuroendocrine differentiation for progression of KRAS mutant CRC should be further investigated.


PubMed | Southern Hospital Trust and University of Duisburg - Essen
Type: Journal Article | Journal: Journal of clinical pathology | Year: 2016

Failure and side effects of combined cytotoxic therapy are challenges in the treatment of metastatic colorectal cancer (CRC). DPYD gene variations can potentially predict toxicity to 5-fluorouracil (FU)-based therapy and KRAS-, NRAS-, BRAF-, PIK3CA-wild type status is a known prerequisite for epidermal growth factor receptor (EGFR) inhibitor therapy. This study was performed to search for a possible link between these therapeutic markers.The DPYD gene variations c.496A>G, c.1679T>G, c.2846A>T and KRAS/NRAS/BRAF/PIK3CA mutational status were determined in non-neoplastic, primary CRC and metastatic CRC tissue from 115 patients.The polymorphism c.496A>G was the DPYD gene variant with the highest detection rate (12.9%), occurred predominantly in females (86.7%, p=0.0044) and was exclusively seen in KRAS wild type primary CRC (15/65 (23.1%) vs 0/51 (0%) in KRAS-mutated primary CRC, respectively, p=0.0001).This genetic profile could define a patient group requiring alternative combined therapeutic approaches. Global testing of large patient cohorts is necessary to prove this concept.


PubMed | Southern Hospital Trust, University of Helsinki, Karolinska University Hospital and Umeå University
Type: Journal Article | Journal: Journal of surgical oncology | Year: 2016

Systemic inflammation has been associated with poor survival in several tumor types, but has been less extensively studied in resectable metastatic disease. The aim of the present study was to evaluate the prognostic role of CRP in colorectal cancer patients with liver metastases (CRLM) compared to conventional tumor- and patient-related clinicopathological features as well as other indicators of the systemic inflammatory response (SIR).A multinational retrospective study of 492 CRLM patients undergoing potentially curative resection of liver metastases between 1999 and 2009. Clinicopathological findings and the SIR markers CRP, hypoalbuminemia, and their combined Glasgow Prognostic Score (GPS) were analyzed.Multivariate analysis showed that preoperative CRP >10mg/L was a strong predictor of compromised survival (HR=1.72, 95%CI 1.84-2.50, P<0.01). Patients with CRP 10mg/L had a median survival of 4.27 years compared to only 47 days in patients with CRP 30mg/L (P<0.01). Similarly, increased GPS was independently predictive of poor survival (HR 1.67, 95%CI 1.22-2.27, P<0.01), but hypoalbuminemia alone did not have significant prognostic value.CRP alone is a strong prognostic factor, following curative resection of colorectal liver metastases and should be taken into consideration when selecting treatment strategies in CRLM patients. J. Surg. Oncol. 2016;114:895-899. 2016 2016 Wiley Periodicals, Inc.


PubMed | University of Agder and Southern Hospital Trust
Type: | Journal: BMC sports science, medicine and rehabilitation | Year: 2016

The short form of the International Physical Activity Questionnaire (IPAQ-sf) is a validated questionnaire used to assess physical activity (PA) in healthy adults and commonly used in both apparently healthy adults and cancer patients. However, the IPAQ-sf has not been previously validated in cancer patients undergoing oncologic treatment. The objective of the present study was to compare IPAQ-sf with objective measures of physical activity (PA) in cancer patients undergoing chemotherapy.The present study was part of a 12-month prospective individualized lifestyle intervention focusing on diet, PA, stress management and smoking cessation in 100 cancer patients undergoing chemotherapy. During the first two months of the lifestyle intervention, participants were wearing an activity monitor (SenseWear Armband (SWA)) for five consecutive days while receiving chemotherapy before completing the IPAQ-sf. From SWA, Moderate-to-Vigorous intensity PA (MVPA) in bouts 10min was compared with self-reported MVPA from the IPAQ-sf. Analyses both included and excluded walking in MVPA from the IPAQ-sf. Results were extrapolated to a wearing time of seven days.Sixty-six patients completed IPAQ-sf and wore the SWA over five days. Mean difference and limit of agreement between the IPAQ-sf and SWA including walking was 662 (1719) min(.)wk(-1). When analyzing time spent in the different intensity levels separately, IPAQ-sf reported significantly higher levels of moderate (602min(.)wk(-1), p=0.001) and vigorous (60min(.)wk(-1), p=0.001) PA compared to SWA.Cancer patients participating in a lifestyle intervention during chemotherapy reported 366% higher MVPA level from the past seven days using IPAQ-sf compared to objective measures. The IPAQ-sf appears insufficient when assessing PA level in cancer patients undergoing oncologic treatment. Activity monitors or other objective tools should alternatively be considered, when assessing PA in this population.

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