| 1. |
- Björk, Jonas, et al.
(författare)
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Prospects for improved glomerular filtration rate estimation based on creatinine—results from a transnational multicentre study
- 2020
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Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 13:4, s. 674-683
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Tidskriftsartikel (refereegranskat)abstract
- Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved.MethodsIn a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation.Results7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%.ConclusionsNone of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.
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| 2. |
- Dam, Gitte, et al.
(författare)
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Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:3/4, s. 217-224
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. Methods: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. Results: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. Conclusions: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.
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| 3. |
- Ilan, Ezgi, et al.
(författare)
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Tumor-to-blood ratio for assessment of somatostatin receptor density in neuroendocrine tumors using 68Ga-DOTATOC and 68Ga-DOTATATE.
- 2020
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 61:2, s. 217-221
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Tidskriftsartikel (refereegranskat)abstract
- PET/CT with 68Ga-DOTA-somatostatin analogs has been tested for therapy monitoring in patients with neuroendocrine tumors (NETs). However, standardized uptake values (SUV) in tumors do not correlate with the net influx rate (Ki), as a representation of the somatostatin receptor (SSTR) expression. In this study, tumor-to-blood-ratio (TBR) was evaluated as an alternative tool for semi-quantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake and as a therapy monitoring tool for patients with NETs. Methods: Twenty-two NET patients underwent a 45-min dynamic PET/CT scan after injection of 68Ga-DOTATOC and/or 68Ga-DOTATATE. Ki was determined using the Patlak method and TBR was calculated for the 40-45 min time interval. Results: A linear relation was found between Ki and TBR, with a square of Pearson correlation (R2) of 0.98 and 0.93 for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. Conclusion: High correlation was found between Ki and TBR. Hence, TBR reflects SSTR density more accurately than SUV and is suggested as the preferred metrics for semi-quantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake.
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| 4. |
- Jahn, Ulrika, et al.
(författare)
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177Lu-DOTATATE peptide receptor radionuclide therapy : dose response in small intestinal neuroendocrine tumors
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:7-8, s. 662-670
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Peptide receptor radionuclide therapy (PRRT) has during the last few years been frequently used in patients with progressive, disseminating, well-differentiated neuroendocrine tumors (NETs).Objective: To study whether the absorbed dose in small intestinal NET (SI-NET) metastases from PRRT with 177Lu-DOTATATE is related to tumor shrinkage.Materials and Methods: Dosimetry for 1 tumor was performed in each of 25 SI-NET patients based on sequential SPECT/CT 1, 4, and 7 days after 177Lu-DOTATATE infusion. The SPECT data were corrected for the partial volume effect based on previous phantom measurements, and the unit density sphere model from OLINDA was used for absorbed dose calculations. Morphological therapy response was assessed by CT/MRI regarding tumor diameter, tumor volume, total liver tumor volume, liver volume, and overall tumor response according to RECIST 1.1. Plasma chromogranin A and urinary 5-hydroxy-indole-acetic-acid were measured during PRRT and follow-up to assess biochemical response.Results: At the time of best response with respect to tumor diameter and volume shrinkage, the median absorbed dose was 128.6 Gy (range 28.4–326.9) and 140 Gy (range 50.9–487.4), respectively. All metrics regarding tumor shrinkage and biochemical response were unrelated to the absorbed dose. A correlation was, however, found between the administered radioactivity and the tumor volume shrinkage (p = 0.01) and between the administered radioactivity and RECIST 1.1 response (p = 0.01).Conclusions: It was not possible to demonstrate a tumor dose-response relationship in SI-NET metastases with the applied dosimetry method, contrary to what was previously shown for pancreatic NETs.
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| 5. |
- Lindström, Elin, et al.
(författare)
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Evaluation of block-sequential regularized expectation maximization reconstruction of 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate whole-body examinations acquired on a digital time-of-flight PET/CT scanner
- 2020
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Ingår i: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Block-sequential regularized expectation maximization (BSREM) is a fully convergent iterative image reconstruction algorithm. We hypothesize that tracers with different distribution patterns will result in different optimal settings for the BSREM algorithm. The aim of this study was to evaluate the image quality with variations in the applied β-value and acquisition time for three positron emission tomography (PET) tracers. NEMA image quality phantom measurements and clinical whole-body digital time-of-flight (TOF) PET/computed tomography (CT) examinations with 68Ga-DOTATOC (n = 13), 18F-fluoride (n = 10), and 11C-acetate (n = 13) were included. Each scan was reconstructed using BSREM with β-values of 133, 267, 400, and 533, and ordered subsets expectation maximization (OSEM; 3 iterations, 16 subsets, and 5-mm Gaussian post-processing filter). Both reconstruction methods included TOF and point spread function (PSF) recovery. Quantitative measures of noise, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) were analysed for various acquisition times per bed position (bp).RESULTS: The highest β-value resulted in the lowest level of noise, which in turn resulted in the highest SNR and lowest SBR. Noise levels equal to or lower than those of OSEM were found with β-values equal to or higher than 400, 533, and 267 for 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate, respectively. The specified β-ranges resulted in increased SNR at a minimum of 25% (P < 0.0001) and SBR at a maximum of 23% (P < 0.0001) as compared to OSEM. At a reduced acquisition time by 25% for 68Ga-DOTATOC and 18F-fluoride, and 67% for 11C-acetate, BSREM with β-values equal to or higher than 533 resulted in noise equal to or lower than that of OSEM at full acquisition duration (2 min/bp for 68Ga-DOTATOC and 18F-fluoride, 3 min/bp for 11C-acetate). The reduced acquisition time with β 533 resulted in increased SNR (16-26%, P < 0.003) and SBR (6-18%, P < 0.0001 (P = 0.07 for 11C-acetate)) compared to the full acquisition OSEM.CONCLUSIONS: Within tracer-specific ranges of β-values, BSREM reconstruction resulted in increased SNR and SBR with respect to conventional OSEM reconstruction. Similar SNR, SBR, and noise levels could be attained with BSREM at relatively shorter acquisition times or, alternatively, lower administered dosages, compared to those attained with OSEM.
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| 6. |
- Lubberink, Mark, et al.
(författare)
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In vivo instability of 177Lu-DOTATATE during peptide receptor radionuclide therapy
- 2020
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 61:9, s. 1337-1340
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Tidskriftsartikel (refereegranskat)abstract
- Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors.Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography.Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection.Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.
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| 7. |
- Madar Johansson, Miralda, et al.
(författare)
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The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease
- 2020
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:42, s. 14305-14324
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus suis is part of the pig commensal microbiome but strains can also be pathogenic, causing pneumonia and meningitis in pigs as well as zoonotic meningitis. According to genomic analysis, S. suis is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Because the strategies to target pathogenic S. suis are limited, new therapeutic approaches are needed. The virulence factor S. suis adhesin P (SadP) recognizes the galabiose Gal alpha 1-4Gal-oligosaccharide. Based on its oligosaccharide fine specificity, SadP can be divided into subtypes P-N and P-O. We show here that subtype P-N is distributed in the systemic strains causing meningitis, whereas type P-O is found in asymptomatic carriage and respiratory strains. Both types of SadP are shown to predominantly bind to pig lung globotriaosylceramide (Gb3). However, SadP adhesin from systemic subtype P-N strains also binds to globotetraosylceramide (Gb4). Mutagenesis studies of the galabiose-binding domain of type P-N SadP adhesin showed that the amino acid asparagine 285, which is replaced by an aspartate residue in type P-O SadP, was required for binding to Gb4 and, strikingly, was also required for interaction with the glycomimetic inhibitor phenylurea-galabiose. Molecular dynamics simulations provided insight into the role of Asn-285 for Gb4 and phenylurea-galabiose binding, suggesting additional hydrogen bonding to terminal GalNAc of Gb4 and the urea group. Thus, the Asn-285-mediated molecular mechanism of type P-N SadP binding to Gb4 could be used to selectively target S. suis in systemic disease without interfering with commensal strains, opening up new avenues for interventional strategies against this pathogen.
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| 8. |
- Mahanti, Mukul, et al.
(författare)
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Epimers Switch Galectin-9 Domain Selectivity : 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal
- 2020
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 11:1, s. 34-39
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Tidskriftsartikel (refereegranskat)abstract
- A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.
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| 9. |
- Naeser, Ylva, et al.
(författare)
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TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3years by clinical examinations only.MethodsThe TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is >1300. Patients are randomized to clinical examinations for 3years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.DiscussionThis is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.ResultsThe first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.Trial registrationClinicalTrials.gov, NCT 03116412. Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412
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| 10. |
- Pavel, M., et al.
(författare)
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Gastroenteropancreatic neuroendocrine neoplasms : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
- 2020
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 31:7, s. 844-860
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine neoplasms (NENs) arise from the diffuse neuroendocrine cell system and may occur at many different disease sites. Most frequently, these neoplasms occur in the digestive system, followed by the lung. The term NEN encompasses well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NECs represent only 10%–20% of all NENs. The main focus of these guidelines is on sporadic small intestinal (SI)-NENs and pancreatic NENs (Pan-NENs) since these are the most prevalent NENs at advanced disease stages. In general, the management of other gastrointestinal NENs follows the same principles as in SI- or Pan-NENs taking into consideration key features of NENs such as proliferative activity, somatostatin receptor (SSTR) expression, tumour growth rate and extent of the disease.
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