| 1. |
- Roselli, Carolina, et al.
(author)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Journal article (peer-reviewed)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 2. |
- Tarpgaard, Line S., et al.
(author)
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Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab
- 2015
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:10, s. 2470-2477
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Journal article (peer-reviewed)abstract
- Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III) + (II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III) 1(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III) 1(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR51.30, 1.14-1.48, p=0.0001) and overall survival (OS) (HR51.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III) 1(II-III) was an independent biomarker of short OS (HR51.45, 1.20-1.75, p=0.0001). There were no significant interactions between plasma uPAR(I-III) 1(II-III) levels, KRAS mutational status and treatment either PFS (p=0.43) or OS (p=0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX+cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.
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| 3. |
- Tarpgaard, Line S., et al.
(author)
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TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells : A potential novel approach to the treatment of metastatic colorectal cancer
- 2016
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:37, s. 59441-59457
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Journal article (peer-reviewed)abstract
- It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP-1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.
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| 4. |
- Brændengen, Morten, et al.
(author)
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Health-related quality of life (HRQoL) after multimodal treatment for primarily non-resectable rectal cancer : Long-term results from a phase III study
- 2012
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 48:6, s. 813-819
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Journal article (peer-reviewed)abstract
- BACKGROUND: A randomised study in non-resectable rectal cancer showed that preoperative chemoradiotherapy (CRT) resulted in better local control and disease-specific survival, but not overall survival than radiotherapy alone. The present paper presents long-term (>4years) health-related quality of life (HRQoL) and a comparison between the results and reference values from the Norwegian general population. MATERIAL AND METHODS: A total of 207 patients with primarily non-resectable rectal cancer were randomised to preoperative CRT (2Gyx25+5FU/leucovorin) or RT (2Gyx25) before surgery. HRQoL was assessed using EORTC QLQ-C30, completed at baseline and sent to all patients alive in Norway and Sweden (n=105) after a minimum of 4years post treatment. A difference of ⩾5 points on the 0-100 scales was considered clinically significant. RESULTS: Seventy-six (72%) patients answered at follow-up. No statistically significant differences between the CRT and RT groups appeared at follow-up, although clinically significant differences in social functioning, dyspnoea and diarrhoea were found. Over time, a clinically significant reduction in physical functioning was found in both groups. Moreover, reduced social functioning and less diarrhoea in the CRT group and better role functioning and more diarrhoea in the RT group were found. Comparisons between the study group and age and gender matched reference values indicate impaired social functioning and more diarrhoea among the patients. CONCLUSION: There were no statistically significant differences in HRQoL between the randomisation groups. In general, despite having impaired social functioning and more diarrhoea, patients reported HRQoL comparable with the reference population several years after treatment.
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| 5. |
- Braendengen, Morten, et al.
(author)
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Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer
- 2008
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 26:22, s. 3687-3694
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Journal article (peer-reviewed)abstract
- PURPOSE: Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS: The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS: The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION: CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.
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| 6. |
- Dueland, Svein, et al.
(author)
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Chemotherapy or Liver Transplantation for Nonresectable Liver Metastases From Colorectal Cancer?
- 2015
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In: Annals of Surgery. - 0003-4932 .- 1528-1140. ; 261:5, s. 956-960
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Journal article (peer-reviewed)abstract
- Objective: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy. Background: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years. Methods: Patients with nonresectable liver-only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method. Results: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group. Conclusions: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases.
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| 7. |
- Hamfjord, Julian, et al.
(author)
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Survival Trends of Right- and Left-Sided Colon Cancer across Four Decades : A Norwegian Population-Based Study
- 2022
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 31:2, s. 342-351
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Journal article (peer-reviewed)abstract
- Background: Patients with right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ clinically and molecularly. The main objective was to investigate stage-stratified survival and recurrence of RCC and LCC across four 10-year periods. Methods: Patients diagnosed from 1977 to 2016 with colon adenocarcinoma were included from the Cancer Registry of Norway. Primary tumor location (PTL) was defined as RCC if proximal and LCC if distal to the splenic flexure. Multivariable regressions were used to estimate HRs for overall survival (OS), recurrence-free survival (RFS), survival after recurrence (SAR), and excess HRs (eHR) for relative survival (RS). Results: 72,224 patients were eligible for analyses [55.1% (n = 39,769/72,224) had RCC]. In 1977 to 1986, there was no difference between LCC and RCC in OS [HR, 1.01; 95% confidence interval (CI), 0.97-1.06; P = 0.581] or RS (eHR, 0.96; 95% CI, 0.90-1.02; P = 0.179). In 2007 to 2016, LCC had significantly better OS (HR, 0.84; 95% CI, 0.80-0.87; P < 0.001) and RS (eHR, 0.76; 95% CI, 0.72-0.81; P < 0.001) compared with RCC. The gradually diverging and significantly favorable prognosis for LCC was evident for distant disease across all time periods and for regional disease from 2007 onward. There was no difference in RFS between LCC and RCC in patients less than 75 years during 2007 to 2016 (HR, 0.99; 95% CI, 0.91-1.08; P = 0.819); however, SAR was significantly better for LCC (HR, 0.61; 95% CI, 0.53-0.71; P < 0.001). Conclusions: A gradually diverging and increasingly favorable prognosis was observed for patients with LCC with advanced disease over the past four decades. Impact Current PTL survival disparities stress the need for further exploring targetable molecular subgroups across and within different PTLs to further improve patient outcomes.
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| 8. |
- Kjersem, Janne B, et al.
(author)
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Let-7 miRNA-binding site polymorphism in the KRAS 3`UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/- cetuximab.
- 2012
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12:1, s. 534-
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Journal article (peer-reviewed)abstract
- 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 5-fluorouracil-oxaliplatin (Nordic FLOX) +/- 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 5-fluorouracil-oxaliplatin +/- cetuximab.
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