| 1. |
- Nilsson, Johnny, et al.
(författare)
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Work-time profile, blood lactate concentration and rating of perceived exertion in the 1998 Greco-Roman Wrestling World Championship.
- 2002
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Ingår i: Journal of Sports Sciences. - : Informa UK Limited. - 0264-0414 .- 1466-447X. ; 20:11, s. 939-45
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine work-time profiles, blood lactate concentrations and perceived exertion among Greco-Roman wrestlers in the 1998 World Championship. Forty-two senior wrestlers from nine nations were studied in 94 matches. Each match was recorded with a video camera (Panasonic AG 455, film rate: 25 Hz) and analysed for duration of work (wrestling) and rest (interrupt) periods. Blood lactate concentration was determined with an electrochemical device (Analox P-LM5) and a rating of perceived exertion scale (Borg) was used to estimate general exertion and exertion in the extremity and trunk muscles. The mean duration of the matches was 427 s (range 324-535 s), with mean durations of work and rest of 317 and 110 s, respectively. The mean periods of work and rest were 37.2 and 13.8 s, respectively. Mean blood lactate concentration was 14.8 mmol x 1(-1) (range 6.9-20.6). The difference in mean blood lactate concentration between the first- and final-round matches was not significant (P > 0.05). Blood lactate concentration was significantly higher (P < 0.04) in matches of long duration than in those of short duration. The mean general rating of perceived exertion for all matches was 13.8 according to the scale used. Most of the wrestlers (53.3%) perceived exertion to be highest in the flexors of the forearm, followed by the deltoids (17.4%) and the biceps brachii muscles (12.0%). In addition to a relatively high rating of perceived exertion in the arm muscles, this indicates a high specific load on the flexor muscles of the forearm.
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| 2. |
- Braendengen, Morten, et al.
(författare)
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Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer
- 2008
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 26:22, s. 3687-3694
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Tidskriftsartikel (refereegranskat)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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| 3. |
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| 4. |
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| 5. |
- Dueland, Svein, et al.
(författare)
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Chemotherapy or Liver Transplantation for Nonresectable Liver Metastases From Colorectal Cancer?
- 2015
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Ingår i: Annals of Surgery. - 0003-4932 .- 1528-1140. ; 261:5, s. 956-960
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Tidskriftsartikel (refereegranskat)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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| 6. |
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| 7. |
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| 8. |
- Guren, Tormod Kyrre, et al.
(författare)
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Cetuximab in treatment of metastatic colorectal cancer : final survival analyses and extended RAS data from the NORDIC-VII study
- 2017
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Ingår i: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 116:10, s. 1271-1278
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Tidskriftsartikel (refereegranskat)abstract
- Background: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.Methods: A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.Results: Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.Conclusions: Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.
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| 9. |
- Hamfjord, Julian, et al.
(författare)
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Clinicopathological factors associated with tumour-specific mutation detection in plasma of patients with RAS-mutated or BRAF-mutated metastatic colorectal cancer
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:6, s. 1385-1397
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Tidskriftsartikel (refereegranskat)abstract
- Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.
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| 10. |
- Kjersem, Janne B, et al.
(författare)
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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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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12:1, s. 534-
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Tidskriftsartikel (refereegranskat)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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| 11. |
- Leon, Otilia, et al.
(författare)
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Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines
- 2014
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 113:3, s. 352-358
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Tidskriftsartikel (refereegranskat)abstract
- Objective:To evaluate treatment outcome in a large population-based cohort of patients with anal cancer treated according to Nordic guidelines.Material:Clinical data were collected on 1266 patients with anal squamous cell carcinoma diagnosed from 2000 to 2007 in Sweden, Norway and Denmark. 886 of the patients received radiotherapy 5464 Gy with or without chemotherapy (5-fluorouracil plus cisplatin or mitomycin). according to different protocols, stratified by tumor stage.Results:High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor performance status, and non-inclusion into a protocol were all independent factors associated with worse outcome. Among patients treated according to any of the protocols, the 3-year recurrence-free survival ranged from 63% to 76%, with locoregional recurrences in 17% and distant metastases in 11% of patients. The highest rate of inguinal recurrence (11%) was seen in patients with small primary tumors, treated without inguinal irradiation.Conclusions:Good treatment efficacy was obtained with Nordic, widely implemented, guidelines for treatment of anal cancer. Inguinal prophylactic irradiation should be recommended also for small primary tumors. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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| 12. |
- Mezheyeuski, Artur, et al.
(författare)
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Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:27, s. 41948-41958
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Tidskriftsartikel (refereegranskat)abstract
- Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown.Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC).Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-β or α-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-α and -β and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-α and -β remained independent factors for survival in multivariate analyses.Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-α and -β were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.
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| 13. |
- Nilsson, Johnny E, et al.
(författare)
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Effects of 20-s and 180-s double poling interval training in cross-country skiers
- 2004
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 92:1/2, s. 121-127
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the effect of upper body 20-s or 180-s interval training, using a double poling ergometer, on upper body power output and selected physiological and biomechanical parameters in cross-country skiers. Twenty (12 male, 8 female) well-trained cross-country skiers took part. Two intervention groups, a 20-s interval training group (IT20; n=6) and a 180-s interval training group (IT180; n=7), underwent training three times a week for 6 weeks on a double poling ergometer. A third group served as a control (CON; n=7) and followed the same training program as the IT20 and IT180 groups without the double poling ergometer interval training. The IT20 and IT180 groups significantly (P<0.05) increased both peak and mean power in a 30-s test and mean power in a 6-min test after double poling training. There was a significant improvement in work efficiency in both IT20 and IT180 (P<0.05) and, in IT180, a significant reduction (P<0.05) in blood lactate concentration at given sub-maximal workloads. VO(2peak) increased significantly during double poling in IT180 ( P<0.05) only. VO(2max) did not change significantly in either group. There were no significant changes in any of the test variables in CON. In conclusion, this study shows that 6 weeks of 20-s or 180-s double poling interval training, three times a week, significantly increases power output in both 30-s and 6-min tests, as well as in selected physiological and biomechanical parameters in well-trained cross-country skiers.
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| 14. |
- Nilsson, Johnny, et al.
(författare)
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Effects of speed on temporal patterns in classical style and freestyle cross-country skiing.
- 2004
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Ingår i: Sports biomechanics / International Society of Biomechanics in Sports. - : Informa UK Limited. - 1476-3141. ; 3:1, s. 85-107
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Tidskriftsartikel (refereegranskat)abstract
- The purpose was to study the adaptation to speed in the temporal patterns of the movement cycle and determine any differences in velocity, cycle rate and cycle length at the maximum speed level in the different classical style and freestyle cross-country skiing techniques. Eight skilled male cross-country skiers were filmed with a digital video camera in the sagittal plane while skiing on a flat cross-country ski track. The skiers performed three classical style techniques the diagonal stride, kick double poling and the double poling technique and four freestyle techniques paddle dance (gear 2), double dance (gear 3), single dance (gear 4) and combiskate (gear 5) at four different self-selected speed levels slow, medium, fast and their maximum. Cycle duration, cycle rate, cycle length, and relative and absolute cycle phase duration of the different techniques at the different speed levels were analysed by means of a video analysis system. The cycle rate in all tested classical and freestyle techniques was found to increase significantly (p < .01) with speed from slow to maximum. Simultaneously, there was a significant decrease in the absolute phase durations of all the investigated skiing techniques. A minor, not significant, change in cycle length, and the significant increase in cycle rate with speed showed that the classical and freestyle cross-country skiing styles are dependent, to a large extent, on an increase in cycle rate for speed adaptation. A striking finding was the constant relative phase duration with speed, which indicates a simplified neural control of the speed adaptation in both cross-country skiing styles. For the practitioner, the knowledge about the importance of increasing cycle frequency rather than cycle length in the speed adaptation can be used to optimise a rapid increase in speed. The knowledge about the decrease in absolute phase duration, especially the thrust phase duration, points to the need for strength and technique training to enable force production at a high cycle rate and skiing speed. The knowledge that the relative phase duration stays constant with speed may be used to simplify the learning of the different cross-country skiing techniques.
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| 15. |
- Nilsson, Johnny, et al.
(författare)
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Pole length and ground reaction forces during maximal double poling in skiing.
- 2003
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Ingår i: Sports biomechanics / International Society of Biomechanics in Sports. - : Informa UK Limited. - 1476-3141. ; 2:2, s. 227-36
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the investigation was to study the relationship between thrust phase duration, ground reaction force, velocity increase after pole thrust and pole angles versus pole length during double poling in roller skiing. Seven male regional elite cross-country skiers volunteered as subjects for the study. The subjects performed a maximal double pole thrust on roller skis with each of the three different pole lengths: 'short', self-selected (normal) and 'long'. The short and long poles were 7.5 cm shorter and 7.5 cm longer than the self-selected pole length. The subjects made seven maximal pole thrusts with each pole length, which were randomly selected during 21 trials. For each trial the subjects accelerated from a 1.2 m high downhill slope attaining a speed of 3.92 m.s-1 before making a maximal double pole thrust on a force plate placed at the bottom of the slope. The vertical (F2), anterior-posterior (Fy) and mediolateral (Fx) reaction forces of the left pole were measured by the force plate. The positions of the pole were recorded in 3-D by an opto-electronic system. Thrust phase duration, impulse, mean force, velocity increase after pole thrust and pole angles were calculated from the recorded data. Double poling with long poles produced a significantly larger propulsive anterior-posterior reaction force impulse and velocity increase than normal (p < .05) and short poles (p < .05). This was in spite of a larger mean anterior-posterior reaction force being produced with short poles. Thus, thrust phase duration was a primary factor in determining propulsive anterior-posterior impulse. For the practitioner, the results can be useful in the selection of pole length when the aim is to increase thrust phase duration, anterior-posterior force impulse and velocity.
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| 16. |
- Tarpgaard, Line S., et al.
(författare)
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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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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:10, s. 2470-2477
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Tidskriftsartikel (refereegranskat)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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| 17. |
- Tarpgaard, Line S., et al.
(författare)
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Plasma YKL-40 in Patients with Metastatic Colorectal Cancer Treated with First Line Oxaliplatin-Based Regimen with or without Cetuximab : RESULTS from the NORDIC VII Study
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2, s. e87746-
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab. Patients and Methods: A total of 566 patients in the NORDIC VII Study were randomized 1:1:1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P < 0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR) = 1.27 95% confidence interval (CI) 1.05-1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011). Conclusions: Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.
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| 18. |
- Tarpgaard, Line S., et al.
(författare)
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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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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:37, s. 59441-59457
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Tidskriftsartikel (refereegranskat)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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| 19. |
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| 20. |
- Thomsen, Maria, et al.
(författare)
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Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status
- 2017
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 81, s. 26-35
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers. Patient and methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, after every fourth cycle of chemotherapy, and at the end of treatment. HRQoL during 12 cycles of chemotherapy was evaluated over time, compared between treatment arms, and assessed for association with tumour mutation status and inflammatory markers. Results: QLQ-C30 was completed by 512 patients (90%) before start of treatment. HRQoL variables were well balanced across treatment arms at baseline, and no statistically significant differences during treatment were seen. Patients with BRAF-mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS-mutated or RAS/BRAF wild-type tumours. Patients with high serum interleukin-6 (IL-6) or C-reactive protein (CRP) had markedly impaired HRQoL compared to patients with normal levels. There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4. Conclusion: The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF-mutated tumours have both a worse prognosis and a poor HRQoL. The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment.
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| 21. |
- Thomsen, Maria, et al.
(författare)
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Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:46, s. 75013-75022
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: 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. Results: 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). Materials and Methods: 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. Conclusions: 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.
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| 22. |
- Thomsen, Maria, et al.
(författare)
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Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer : a BRAF-mutant subset with high CA 19-9 level and poor outcome
- 2018
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Ingår i: British Journal of Cancer. - : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 118:12, s. 1609-1616
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study.METHODS: CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2-4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 mu g/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status.RESULTS: For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS).CONCLUSIONS: High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.
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- Tveit, Kjell Magne, et al.
(författare)
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Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer : The NORDIC-VII Study
- 2012
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology: JCO. - 0732-183X .- 1527-7755. ; 30:15, s. 1755-1762
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. Patients and Methods: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. Results: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. Conclusion: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.
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