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Shirdel, M., Anderson, F., Myte, R., Axelsson, J., Rutegård, M., Blomqvist, L., . . . Gylling, B. (2020). Body composition measured by computed tomography is associated with colorectal cancer survival, also in early-stage disease. Acta Oncologica
Open this publication in new window or tab >>Body composition measured by computed tomography is associated with colorectal cancer survival, also in early-stage disease
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2020 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Cachexia and sarcopenia are associated with poor survival after colorectal cancer (CRC) diagnosis. Computed tomography (CT) can be used to measure aspects of cachexia including sarcopenia, myosteatosis and the amount of subcutaneous and visceral adipose tissue. The aim of this study was to relate CT-based body composition variables with survival outcomes in CRC. Material and methods: In this population-based, retrospective cohort study, CT scans of 974 patients with pathological stages I-IV CRCs, collected at or very near diagnosis (years 2000-2016), were used to measure cross-sectional fat and muscle tissue areas. Body composition variables based on these measurements were assessed in relation to tumor stage and site and cancer-specific survival in stages I-III CRC (n = 728) using Cox proportional hazards models and Kaplan-Meier estimators. Results: Sarcopenia was associated with decreased cancer-specific survival, especially in patients with stages I-II tumors. The hazard ratio (HR) for the lowest versus highest tertile of skeletal muscle index (SMI) was 1.67; 95% confidence interval (CI), 1.08-2.58 for all stages, and HR 2.22; 95% CI 1.06-4.68, for stages I-II. Myosteatosis was also associated with decreased cancer-specific survival [(HR 2.03; 95% CI 1.20-3.34 for the lowest versus the highest tertile of skeletal muscle radiodensity (SMR)]. SMI and SMR were lower in patients with right-sided CRC, independent of age and sex. No adipose tissue measurement was significantly associated with cancer-specific survival. Conclusion: In concordance with previous studies, sarcopenia and myosteatosis were associated with decreased cancer-specific survival. The strong association between sarcopenia and poor cancer-specific survival in early-stage disease could have clinical implications for personalizing therapy decisions, including nutritional support.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-169844 (URN)10.1080/0284186X.2020.1744716 (DOI)000523671400001 ()32228271 (PubMedID)
Available from: 2020-05-26 Created: 2020-05-26 Last updated: 2020-05-26
Kuttner, S., Wickstrøm, K. K., Kalda, G., Dorraji, S. E., Martin-Armas, M., Oteiza, A., . . . Axelsson, J. (2020). Machine learning derived input-function in a dynamic 18F-FDG PET study of mice. Biomedical Physics & Engineering Express, 6(1), Article ID 015020.
Open this publication in new window or tab >>Machine learning derived input-function in a dynamic 18F-FDG PET study of mice
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2020 (English)In: Biomedical Physics & Engineering Express, ISSN 2057-1976, Vol. 6, no 1, article id 015020Article in journal (Refereed) Published
Abstract [en]

Tracer kinetic modelling, based on dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used to quantify glucose metabolism in humans and animals. Knowledge of the arterial input-function (AIF) is required for such measurements. Our aim was to explore two non-invasive machine learning-based models, for AIF prediction in a small-animal dynamic FDG PET study. 7 tissue regions were delineated in images from 68 FDG PET/computed tomography mouse scans. Two machine learning-based models were trained for AIF prediction, based on Gaussian processes (GP) and a long short-term memory (LSTM) recurrent neural network, respectively. Because blood data were unavailable, a reference AIF was formed by fitting an established AIF model to vena cava and left ventricle image data. The predicted and reference AIFs were compared by the area under curve (AUC) and root mean square error (RMSE). Net-influx rate constants, Ki , were calculated with a two-tissue compartment model, using both predicted and reference AIFs for three tissue regions in each mouse scan, and compared by means of error, ratio, correlation coefficient, P value and Bland-Altman analysis. The impact of different tissue regions on AIF prediction was evaluated by training a GP and an LSTM model on subsets of tissue regions, and calculating the RMSE between the reference and the predicted AIF curve. Both models generated AIFs with AUCs similar to reference. The LSTM models resulted in lower AIF RMSE, compared to GP. Ki from both models agreed well with reference values, with no significant differences. Myocardium was highlighted as important for AIF prediction, but AIFs with similar RMSE were obtained also without myocardium in the input data. Machine learning can be used for accurate and non-invasive prediction of an image-derived reference AIF in FDG studies of mice. We recommend the LSTM approach, as this model predicts AIFs with lower errors, compared to GP.

Place, publisher, year, edition, pages
Institute of Physics Publishing (IOPP), 2020
Keywords
PET, input-function, machine learning, compartment modelling
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-169439 (URN)10.1088/2057-1976/ab6496 (DOI)000520403000001 ()
Available from: 2020-04-03 Created: 2020-04-03 Last updated: 2020-04-03Bibliographically approved
Papenberg, G., Karalija, N., Salami, A., Rieckmann, A., Andersson, M., Axelsson, J., . . . Bäckman, L. (2019). Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning. Cerebral Cortex, Article ID bhz142.
Open this publication in new window or tab >>Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning
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2019 (English)In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, article id bhz142Article in journal (Refereed) Epub ahead of print
Abstract [en]

Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.

Keywords
catechol-O-methyltransferase, [11C] raclopride, dopamine D2 receptors, episodic memory, working memory
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-169317 (URN)10.1093/cercor/bhz142 (DOI)31504282 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County CouncilMax Planck Society
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2020-03-31
Karalija, N., Papenberg, G., Wåhlin, A., Johansson, J., Andersson, M., Axelsson, J., . . . Nyberg, L. (2019). C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition. Journal of cognitive neuroscience, 31(2), 314-325
Open this publication in new window or tab >>C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition
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2019 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 31, no 2, p. 314-325Article in journal (Refereed) Published
Abstract [en]

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-11-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-11-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-11-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-11-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-11-raclopride BP was increased in T-homozygotes. Importantly, C-11-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-11-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-11-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

Place, publisher, year, edition, pages
MIT Press, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155630 (URN)10.1162/jocn_a_01354 (DOI)000454429400011 ()30407135 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2020-05-04Bibliographically approved
Karalija, N., Wåhlin, A., Ek, J., Rieckmann, A., Papenberg, G., Salami, A., . . . Nyberg, L. (2019). Cardiovascular factors are related to dopamine integrity and cognition in aging. Annals of Clinical and Translational Neurology, 6(11), 2291-2303
Open this publication in new window or tab >>Cardiovascular factors are related to dopamine integrity and cognition in aging
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2019 (English)In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 6, no 11, p. 2291-2303Article in journal (Refereed) Published
Abstract [en]

Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

Methods: The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study.

Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance.

Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-165743 (URN)10.1002/acn3.50927 (DOI)000496520700016 ()31663685 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County CouncilMax Planck SocietySwedish Research Council
Available from: 2019-12-10 Created: 2019-12-10 Last updated: 2020-03-05Bibliographically approved
Salami, A., Garrett, D. D., Wåhlin, A., Rieckmann, A., Papenberg, G., Karalija, N., . . . Nyberg, L. (2019). Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.. Journal of Neuroscience, 39(3), 537-547
Open this publication in new window or tab >>Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.
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2019 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 3, p. 537-547Article in journal (Refereed) Published
Abstract [en]

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

Keywords
PET, aging, dopamine, fMRI, working memory
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-155492 (URN)10.1523/JNEUROSCI.1493-18.2018 (DOI)000455849400013 ()30478031 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-02-08Bibliographically approved
de Boer, L., Axelsson, J., Chowdhury, R., Riklund, K., Dolan, R. J., Nyberg, L., . . . Guitart-Masip, M. (2019). Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning. Proceedings of the National Academy of Sciences of the United States of America, 116(1), 261-270
Open this publication in new window or tab >>Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 1, p. 261-270Article in journal (Refereed) Published
Abstract [en]

Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.

Place, publisher, year, edition, pages
National Academy of Sciences, 2019
Keywords
decision making, dopamine, Pavlovian bias, instrumental learning, positron emission tomography
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155637 (URN)10.1073/pnas.1816704116 (DOI)000454707700042 ()30563856 (PubMedID)
Funder
Swedish Research Council, VR521-2013-2589
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Jonasson, L. S., Nyberg, L., Axelsson, J., Kramer, A. F., Riklund, K. & Boraxbekk, C.-J. (2019). Higher striatal D2-receptor availability in aerobically fit older adults but non-selective intervention effects after aerobic versus resistance training. NeuroImage, 202, Article ID 116044.
Open this publication in new window or tab >>Higher striatal D2-receptor availability in aerobically fit older adults but non-selective intervention effects after aerobic versus resistance training
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2019 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 202, article id 116044Article in journal (Refereed) Published
Abstract [en]

There is much evidence that dopamine is vital for cognitive functioning in aging. Here we tested the hypothesis that aerobic exercise and fitness influence dopaminergic neurotransmission in the striatum, and in turn performance on offline working-memory updating tasks. Dopaminergic neurotransmission was measured by positron emission tomography (PET) and the non-displacable binding potential (BPND) of [11C]raclopride, i.e. dopamine (DA) D2-receptor (D2R) availability. Fifty-four sedentary older adults underwent a six-months exercise intervention, performing either aerobic exercise or stretching, toning, and resistance active control training. At baseline, higher aerobic fitness levels (VO2peak) were associated with higher BPND in the striatum, providing evidence of a link between an objective measure of aerobic fitness and D2R in older adults. BPND decreased substantially over the intervention in both groups but the intervention effects were non-selective with respect to exercise group. The decrease was several times larger than any previously estimated annual decline in D2R, potentially due to increased endogenous DA. Working-memory was unrelated to D2R both at baseline and following the intervention. To conclude, we provide partial evidence for a link between physical exercise and DA. Utilizing a PET protocol able to disentangle both D2R and DA levels could shed further light on whether, and how, aerobic exercise impacts the dopaminergic system in older adults.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Aerobic exercise, Fitness, Dopamine, D2, Working memory, Raclopride
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162742 (URN)10.1016/j.neuroimage.2019.116044 (DOI)000491861000044 ()31352122 (PubMedID)2-s2.0-85069908673 (Scopus ID)
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-11-20Bibliographically approved
Papenberg, G., Jonasson, L. S., Karalija, N., Johansson, J., Koehncke, Y., Salami, A., . . . Backman, L. (2019). Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride. Brain Structure and Function, 224(8), 2871-2882
Open this publication in new window or tab >>Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride
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2019 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 224, no 8, p. 2871-2882Article in journal (Refereed) Published
Abstract [en]

The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [C-11]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C-11]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C-11]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.

Keywords
[C-11]raclopride, Dopamine D2, 3 receptors, Inter-individual differences, Structural-equation deling, COBRA study
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-165669 (URN)10.1007/s00429-019-01938-1 (DOI)000489147300018 ()31444615 (PubMedID)
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Rutegård, M., Båtsman, M., Axelsson, J., Brynolfsson, P., Brännström, F., Rutegård, J., . . . Riklund, K. (2019). PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study. Cancer Imaging, 19, Article ID 52.
Open this publication in new window or tab >>PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study
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2019 (English)In: Cancer Imaging, ISSN 1740-5025, E-ISSN 1470-7330, Vol. 19, article id 52Article in journal (Refereed) Published
Abstract [en]

PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Rectal neoplasm, Rectal tumour, Staging, Lymph nodes, Tumour deposits, PET, CT, FDG-PET, CT, PET
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-161991 (URN)10.1186/s40644-019-0237-1 (DOI)000477054900002 ()31337428 (PubMedID)
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3731-3612

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