| 1. |
- Aasebö, Kristine Ö., et al.
(författare)
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Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors : A population-based cohort of metastatic colorectal cancer patients
- 2019
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Ingår i: Cancer Medicine. - : WILEY. - 2045-7634. ; 8:7, s. 3623-3635
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).
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| 2. |
- 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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| 3. |
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| 4. |
- Glimelius, Bengt, et al.
(författare)
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Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®) : a placebo-controlled randomised phase II study (PLIANT)
- 2018
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 57:3, s. 393-402
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).Patient and methods: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2, oxaliplatin 85 mg/m2 and 5-fluorouracil 2400 mg/m2 continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.Results: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1–8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.Conclusions: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.
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| 5. |
- 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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| 6. |
- Körber, R., et al.
(författare)
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SQUIDs in biomagnetism: A roadmap towards improved healthcare
- 2016
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Ingår i: Superconductors Science and Technology. - : IOP Publishing. - 0953-2048 .- 1361-6668. ; 29:11
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Tidskriftsartikel (refereegranskat)abstract
- Globally, the demand for improved health care delivery while managing escalating costs is a major challenge. Measuring the biomagnetic fields that emanate from the human brain already impacts the treatment of epilepsy, brain tumours and other brain disorders. This roadmap explores how superconducting technologies are poised to impact health care. Biomagnetism is the study of magnetic fields of biological origin. Biomagnetic fields are typically very weak, often in the femtotesla range, making their measurement challenging. The earliest in vivo human measurements were made with room-temperature coils. In 1963, Baule and McFee (1963 Am. Heart J. 55 95-6) reported the magnetic field produced by electric currents in the heart ('magnetocardiography'), and in 1968, Cohen (1968 Science 161 784-6) described the magnetic field generated by alpha-rhythm currents in the brain ('magnetoencephalography'). Subsequently, in 1970, Cohen et al (1970 Appl. Phys. Lett. 16 278-80) reported the recording of a magnetocardiogram using a Superconducting QUantum Interference Device (SQUID). Just two years later, in 1972, Cohen (1972 Science 175 664-6) described the use of a SQUID in magnetoencephalography. These last two papers set the scene for applications of SQUIDs in biomagnetism, the subject of this roadmap. The SQUID is a combination of two fundamental properties of superconductors. The first is flux quantization - the fact that the magnetic flux Φ in a closed superconducting loop is quantized in units of the magnetic flux quantum, Φ0 ≡ h/2e, ≈ 2.07 × 10-15 Tm2 (Deaver and Fairbank 1961 Phys. Rev. Lett. 7 43-6, Doll R and Nabauer M 1961 Phys. Rev. Lett. 7 51-2). Here, h is the Planck constant and e the elementary charge. The second property is the Josephson effect, predicted in 1962 by Josephson (1962 Phys. Lett. 1 251-3) and observed by Anderson and Rowell (1963 Phys. Rev. Lett. 10 230-2) in 1963. The Josephson junction consists of two weakly coupled superconductors separated by a tunnel barrier or other weak link. A tiny electric current is able to flow between the superconductors as a supercurrent, without developing a voltage across them. At currents above the 'critical current' (maximum supercurrent), however, a voltage is developed. In 1964, Jaklevic et al (1964 Phys. Rev. Lett. 12 159-60) observed quantum interference between two Josephson junctions connected in series on a superconducting loop, giving birth to the dc SQUID. The essential property of the SQUID is that a steady increase in the magnetic flux threading the loop causes the critical current to oscillate with a period of one flux quantum. In today's SQUIDs, using conventional semiconductor readout electronics, one can typically detect a change in Φ corresponding to 10-6 Φ0 in one second. Although early practical SQUIDs were usually made from bulk superconductors, for example, niobium or Pb-Sn solder blobs, today's devices are invariably made from thin superconducting films patterned with photolithography or even electron lithography. An extensive description of SQUIDs and their applications can be found in the SQUID Handbooks (Clarke and Braginski 2004 Fundamentals and Technology of SQUIDs and SQUID Systems vol I (Weinheim, Germany: Wiley-VCH), Clarke and Braginski 2006 Applications of SQUIDs and SQUID Systems vol II (Weinheim, Germany: Wiley-VCH)). The roadmap begins (chapter 1) with a brief review of the state-of-the-art of SQUID-based magnetometers and gradiometers for biomagnetic measurements. The magnetic field noise referred to the pick-up loop is typically a few fT Hz-1/2, often limited by noise in the metallized thermal insulation of the dewar rather than by intrinsic SQUID noise. The authors describe a pathway to achieve an intrinsic magnetic field noise as low as 0.1 fT Hz-1/2, approximately the Nyquist noise of the human body. They also descibe a technology to defeat dewar noise. Chapter 2 reviews the neuroscientific and clinical use of magnetoencephalography (MEG), by far the most widespread application of biomagnetism with systems containing ty ically 300 sensors cooled to liquid-helium temperature, 4.2 K. Two important clinical applications are presurgical mapping of focal epilepsy and of eloquent cortex in brain-tumor patients. Reducing the sensor-to-brain separation and the system noise level would both improve spatial resolution. The very recent commercial innovation that replaces the need for frequent manual transfer of liquid helium with an automated system that collects and liquefies the gas and transfers the liquid to the dewar will make MEG systems more accessible. A highly promising means of placing the sensors substantially closer to the scalp for MEG is to use high-transition-temperature (high-T c) SQUID sensors and flux transformers (chapter 3). Operation of these devices at liquid-nitrogen temperature, 77 K, enables one to minimize or even omit metallic thermal insulation between the sensors and the dewar. Noise levels of a few fT Hz-1/2 have already been achieved, and lower values are likely. The dewars can be made relatively flexible, and thus able to be placed close to the skull irrespective of the size of the head, potentially providing higher spatial resolution than liquid-helium based systems. The successful realization of a commercial high-T c MEG system would have a major commercial impact. Chapter 4 introduces the concept of SQUID-based ultra-low-field magnetic resonance imaging (ULF MRI) operating at typically several kHz, some four orders of magnitude lower than conventional, clinical MRI machines. Potential advantages of ULF MRI include higher image contrast than for conventional MRI, enabling methodologies not currently available. Examples include screening for cancer without a contrast agent, imaging traumatic brain injury (TBI) and degenerative diseases such as Alzheimer's, and determining the elapsed time since a stroke. The major current problem with ULF MRI is that its signal-to-noise ratio (SNR) is low compared with high-field MRI. Realistic solutions to this problem are proposed, including implementing sensors with a noise level of 0.1 fT Hz-1/2. A logical and exciting prospect (chapter 5) is to combine MEG and ULF MRI into a single system in which both signal sources are detected with the same array of SQUIDs. A prototype system is described. The combination of MEG and ULF MRI allows one to obtain structural images of the head concurrently with the recording of brain activity. Since all MEG images require an MRI to determine source locations underlying the MEG signal, the combined modality would give a precise registration of the two images; the combination of MEG with high-field MRI can produce registration errors as large as 5 mm. The use of multiple sensors for ULF MRI increases both the SNR and the field of view. Chapter 6 describes another potentially far-reaching application of ULF MRI, namely neuronal current imaging (NCI) of the brain. Currently available neuronal imaging techniques include MEG, which is fast but has relatively poor spatial resolution, perhaps 10 mm, and functional MRI (fMRI) which has a millimeter resolution but is slow, on the order of seconds, and furthermore does not directly measure neuronal signals. NCI combines the ability of direct measurement of MEG with the spatial precision of MRI. In essence, the magnetic fields generated by neural currents shift the frequency of the magnetic resonance signal at a location that is imaged by the three-dimensional magnetic field gradients that form the basis of MRI. The currently achieved sensitivity of NCI is not quite sufficient to realize its goal, but it is close. The realization of NCI would represent a revolution in functional brain imaging. Improved techniques for immunoassay are always being sought, and chapter 7 introduces an entirely new topic, magnetic nanoparticles for immunoassay. These particles are bio-funtionalized, for example with a specific antibody which binds to its corresponding antigen, if it is present. Any resulting changes in the properties of the nanoparticles are detected with a SQUID. For liquid-phase detection, there are three ba ic methods: AC susceptibility, magnetic relaxation and remanence measurement. These methods, which have been successfully implemented for both in vivo and ex vivo applications, are highly sensitive and, although further development is required, it appears highly likely that at least some of them will be commercialized. © 2016 IOP Publishing Ltd.
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| 7. |
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| 8. |
- 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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| 9. |
- Mezheyeuski, Artur, et al.
(författare)
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Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer
- 2018
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Ingår i: Virchows Archiv. - : SPRINGER. - 0945-6317 .- 1432-2307. ; 472:3, s. 395-405
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Tidskriftsartikel (refereegranskat)abstract
- Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU +/- irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.
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| 10. |
- Pfeiffer, Per, et al.
(författare)
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Maintenance Therapy With Cetuximab Every Second Week in the First-Line Treatment of Metastatic Colorectal Cancer : The NORDIC-7.5 Study by the Nordic Colorectal Cancer Biomodulation Group
- 2015
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Ingår i: Clinical colorectal cancer. - : Elsevier BV. - 1533-0028 .- 1938-0674. ; 14:3, s. 170-176
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Tidskriftsartikel (refereegranskat)abstract
- In the NORDIC-7.5 trial, cetuximab administered every 2 weeks in 152 patients with Kirsten rat sarcoma viral oncogene homolog wild type metastatic colorectal cancer was investigated. After 4 months of induction therapy with Nordic FLOX (oxaliplatin, bolus 5-fluorouracil, and bolus folinic acid) and cetuximab, patients continued with cetuximab monotherapy. Cetuximab might have added to a longer chemotherapy-free interval, but needs to be validated in clinical trials. Background: In the NORDIC-7.5 trial, how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected Kirsten rat sarcoma viral oncogene homolog wild type (KRASwt) metastatic colorectal cancer (mCRC) was investigated. Patients were treated in a multicenter phase II trial with cetuximab in combination with the Nordic bolus FLOX (oxaliplatin, 5-fluorouracil, and folinic acid) for 4 months followed by maintenance cetuximab. Patients and Methods: Patients had KRASwt, nonresectable mCRC, no previous chemotherapy, and Eastern Cooperative Group performance status of 0 to 2. Patients received 8 courses of Nordic FLOX (oxaliplatin 85 mg/m(2) over 1 hour on day 1, and 5-fluorouracil 500 mg/m(2) as a bolus injection, followed 30 minutes later with bolus folinic acid 60 mg/m(2) on days 1 and 2). Cetuximab was administered every 2 weeks at a dose of 500 mg/m(2) for 16 weeks followed by cetuximab as maintenance therapy until disease progression. Results: Between July 2008 and September 2010, 152 KRASwt patients were included. The response rate was 62% (95% confidence interval [CI], 54%-69%), median progression-free survival was 8.0 months (95% CI, 7.5-8.9) and median overall survival was 23.2 (95% CI, 18.1-27.4) months. Twenty-one patients (14%) had later R0-resection of metastasis. FLOX with cetuximab was reintroduced in 47 of 85 patients (55%). The most common Grade 3/4 nonhematologic adverse events were diarrhea in 14 patients (9%), skin rash in 13 patients (9%), infection without neutropenia in 11 patients (7%), and fatigue in 11 patients (7%). Conclusion: In a prospectively selected KRASwt population, biweekly cetuximab was safely integrated in an intermittent chemotherapy strategy and might have added to a longer chemotherapy-free interval. However, the combination of biweekly cetuximab with chemotherapy needs to be validated in trials using FOLFOX (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin).
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