| 1. |
- Åkerström, Tobias, et al.
(författare)
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Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
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| 2. |
- Andersson, Ellinor, et al.
(författare)
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Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.
- 2016
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 29:6, s. 616-629
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Tidskriftsartikel (refereegranskat)abstract
- We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients.
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| 3. |
- Böörs, Mikael, et al.
(författare)
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Classification by decomposition: a novel approach to classification of symmetric 2 × 2 games
- 2022
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Ingår i: Theory and Decision. - : Springer Science and Business Media LLC. - 0040-5833 .- 1573-7187. ; 93:3, s. 463-508
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we provide a detailed review of previous classifications of 2 × 2 games and suggest a mathematically simple way to classify the symmetric 2 × 2 games based on a decomposition of the payoff matrix into a cooperative and a zero-sum part. We argue that differences in the interaction between the parts is what makes games interesting in different ways. Our claim is supported by evolutionary computer experiments and findings in previous literature. In addition, we provide a method for using a stereographic projection to create a compact 2-d representation of the game space. © 2021, The Author(s).
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| 4. |
- Elf, Anna-Karin, et al.
(författare)
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NAMPT inhibitor GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment of neuroendocrine tumors.
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 288-292
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumors (NETs) can be treated by peptide receptor radionuclide therapy using radiolabeled somatostatin analogs. However, the efficacy of such treatment is low and needs to be optimized.To evaluate the potential radiosensitizing effects of NAMPT inhibition on (177)Lu-DOTATATE treatment in a NET model.Nude mice xenografted with the human NET cell line GOT1 were treated with semi-efficient doses of (177)Lu-DOTATATE (7,5 MBq, i.v.) and/or GMX1778 (100 mg/kg/week, p.o.).Median time to tumor progression (tumor volume larger than at day 0) was 3 days for controls, 7 days for single dose GMX1778, 28 days for single dose (177)Lu-DOTATATE and 35 days for 3 weekly doses of GMX1778. Combined treatment with (177)Lu-DOTATATE and GMX1778 x1 resulted in a median time to progression of 98 days. After (177)Lu-DOTATATE and 3 weekly doses of GMX1778 none of the tumors progressed within 120 days.The NAMPT inhibitor GMX1778 enhances the efficacy of (177)Lu-DOTATATE treatment and induces a prolonged antitumor response. Combinations of radiolabeled somatostatin analogs and radiosensitizing drugs should be further evaluated to optimize the efficacy of peptide receptor radionuclide therapy in NETs.
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| 5. |
- Hagmarker, Linn, et al.
(författare)
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Evaluation of the correlations between the absorbed bone marrow dose and bone marrow response during the first cycle of 177Lu-DOTATATE treatment
- 2017
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Ingår i: European Association of Nuclear Medicine.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The bone marrow is one of the organs at risk during 177Lu-DOTATATE treatments. To monitor the bone marrow function, the levels of hemoglobin, white blood cells and platelet counts serves as a substitute for bone marrow response. The aim of this study is to evaluate different ways to measure hematological reponse and investigate if its possible to acchieve a dose response relationship already after the first treatment cycle, this using an image-based two-compartment method. Significant correlations were found after the first treatment cycle between the absorbed bone marrow dose and the response of platelet counts using nadir, the response rate and a trinomial function.
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| 6. |
- Magnander, Tobias, et al.
(författare)
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A novel statistical analysis method to improve the detection of hepatic foci of (111)In-octreotide in SPECT/CT imaging.
- 2016
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Ingår i: EJNMMI physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Low uptake ratios, high noise, poor resolution, and low contrast all combine to make the detection of neuroendocrine liver tumours by (111)In-octreotide single photon emission tomography (SPECT) imaging a challenge. The aim of this study was to develop a segmentation analysis method that could improve the accuracy of hepatic neuroendocrine tumour detection.
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| 7. |
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| 8. |
- Magnander, Tobias, et al.
(författare)
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Improved detection rate and visualization of liver uptake foci in diagnostic 111In-octreotide SPECT/CT investigations with a novel segmentation analysis
- 2015
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Ingår i: Optimisation in X-ray and Molecular Imaging 2015 - the Fourth Malmö Conference on Medical Imaging, Gothenburg, Sweden, 28-30 May 2015.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Detection of liver tumors will change the course of treatment of neuroendocrine tumours. In nuclear medicine 111In-octreoscan is of high value for detection of neuroendocrine tumours. However, neuroendocrine tumours disseminated to the livers is often challenging to detect from 111In-octreoscan SPECT images due to low uptake, high noise, poor resolution and low contrast. The aim of the present study was to develop a segmentation analysis method for increased diagnostic accuracy of neuroendocrine liver tumours. Methods: For the SPECT reconstruction 120 projections are acquired with 3 degrees spacing around the patient injected with 111In-octreoscan. The projections are reconstructed into a 128x128x128 voxel matrix using OSEM with CT based attenuation correction. The liver is segmented from the SPECT or CT using either an isosurface, region growing or a GPU accelerated level set algorithm. Manual editing finishes the segmentation of the liver. The segmented liver volume of interest, liver VOI, is thresholded at 125 equidistant threshold values between 0 and the maximum voxel value. At each threshold value a connected component labeling algorithm is used to calculate the number of uptake foci (NUF). The normalized NUF (nNUF) is then plotted against the threshold index (ThI), defined as ThI=(cmax-cthr)/cmax, where cmax is the maximal voxel value in the VOI, and cthr is the voxel threshold value. The method is named nNUFTI - normalized Number of Uptake Foci vs ThI. The ThI at 0.25 nNUF was used for analysis of liver tumour involvement. SPECT images from 53 patients without tumour involvement (i.e SPECT negative) in the liver were analysed with nNUFTI. A three year follow up with MRI, SPECT, PET/CT and CT was used to separate the patients into two groups: the healthy group, with still no liver tumours, and the malignant group, shown to have developed tumours in the liver. Results: 40 patients ended up in the healthy group and 13 in the malignant group. The ThI at 0.25 nNUF was significantly different between the groups (p<0.01). A probability function for the ThI values was constructed from the obtained data. This relationship might be a useful guide in the diagnostic decision making. Conclusions: Our new developed method nNUFTI has been shown to perform well. More studies on the nNUFTI method are needed.
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| 9. |
- Svensson, Johanna, et al.
(författare)
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A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.
- 2016
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Ingår i: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- (177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2GBq (3.5-8.3GBq) of (177)Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of (177)Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period.The mean absorbed dose to the bone marrow was estimated to 0.20Gy (0.11-0.37Gy) per 7.4GBq of (177)Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb (p=0.01), WBC (p<0.01) and PLT (p<0.01) counts. The total mean absorbed dose to the bone marrow was 0.64Gy (0.30-1.5Gy) per 24GBq (8.2-37GBq) of (177)Lu-DOTATATE and also correlated with a decrease in Hb (p<0.01), WBC (p=0.01) and PLT (p<0.01) counts.The planar image-based method developed in this study resulted in similar absorbed doses to the bone marrow as reported in earlier studies with blood-based bone marrow dosimetry. The results correlated with haematological toxicity, making it a promising method for estimating bone marrow doses in (177)Lu-DOTATATE treatment without the need for blood and urine sampling.
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| 10. |
- Svensson, Johanna, et al.
(författare)
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Radiation exposure of the spleen during Lu-177-DOTATATE treatment and its correlation with haematological toxicity and spleen volume
- 2016
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Ingår i: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Somatostatin analogue-based radionuclide therapy with Lu-177-DOTATATE is an important treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. In addition to the kidneys, the bone marrow is a major dose-limiting organ. The correlation between developed haematological toxicity and absorbed dose to the bone marrow is poor, which indicates that other factors affect haematological response. The spleen has an important role in the haematopoetic system, including being a reservoir for blood cells. It is also the organ that receives the highest mean absorbed dose during Lu-177-DOTATATE treatment. The aim of this study was to analyse mean absorbed dose to the spleen and its correlation with haematological toxicity, and to explore changes in splenic volume. The study included 41 patients treated with 7.2 GBq (3.5-8.3 GBq) of Lu-177-DOTATATE on two to five occasions. Following each fraction, planar whole-body scans were acquired at 2, 24, 48, and 168 h, and a SPECT/CT at 24 h post-injection. Mean absorbed spleen dose was calculated utilising planar images for time-activity data and SPECT to adjust activity amounts. Splenic volume information was collected from diagnostic CT scans at baseline and follow-up. Results: Median and total absorbed spleen doses were estimated to 4.5 and 15 Gy, respectively. Total absorbed spleen dose correlated with decrease in Hb (p = 0.02), but not WBC (p = 0.31) or PLT (p = 0.65) counts. For patients without bone metastases, mean absorbed spleen dose correlated with decrease in PLT (p = 0.04) but not Hb (p = 0.16) or WBC (p = 0.42) counts. The spleen volume was reduced to 75 % (p < 0.001) of original values (200 vs. 260 ml) at a mean followup of 36 months. Conclusions: Haematological toxicity according to Hb counts was moderately but significantly correlated with total absorbed spleen dose. This supports the possibility that radiation exposure of the spleen affects overall haematological response during Lu-177-DOTATATE treatment.
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