Diagnostics

2021

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13 pages, 1237 KiB

Open AccessArticle

Incidence, Clinical Presentation and Trends in Indication for Diagnostic Work-Up of Small Intestinal and Pancreatic Neuroendocrine Tumors

by Anna Bryan Stensbøl, Jesper Krogh, Pernille Holmager, Marianne Klose, Peter Oturai, Andreas Kjaer, Carsten Palnæs Hansen, Birgitte Federspiel, Seppo W. Langer, Ulrich Knigge and Mikkel Andreassen

Diagnostics 2021, 11(11), 2030; https://doi.org/10.3390/diagnostics11112030 - 3 Nov 2021

Cited by 16 | Viewed by 2201

Abstract

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis [...] Read more.

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010–2011 vs. 2019–2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. Methods: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010–2011 and 2019–2020. Results: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p < 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). Conclusion: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized. Full article

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11 pages, 1194 KiB

Open AccessArticle

Effect of Liraglutide on Vascular Inflammation Evaluated by [⁶⁴Cu]DOTATATE

by Emilie H. Zobel, Rasmus S. Ripa, Bernt J. von Scholten, Viktor Rotbain Curovic, Lars Jorge Diaz, Tine W. Hansen, Peter Rossing and Andreas Kjaer

Diagnostics 2021, 11(8), 1431; https://doi.org/10.3390/diagnostics11081431 - 8 Aug 2021

Cited by 7 | Viewed by 2891

Abstract

Quantification of vascular inflammation before and after treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may help reveal mechanistic pathways underlying the cardiovascular benefits of these drugs. We assessed change in vascular inflammation in the carotid arteries over 26 weeks by copper-64-labeled [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic [...] Read more.

Quantification of vascular inflammation before and after treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may help reveal mechanistic pathways underlying the cardiovascular benefits of these drugs. We assessed change in vascular inflammation in the carotid arteries over 26 weeks by copper-64-labeled [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid]-D-Phe1, Tyr3-octreotate ([⁶⁴Cu]DOTATATE) PET in 30 participants included in a substudy of a double-blind trial where persons with type 2 diabetes (T2D) were randomized to liraglutide (n = 15) or placebo (n = 15) for 26 weeks. Mean age (SD) was 66.4 (7.2) years, HbA_1c 56.4 (9.2) mmol/mol and BMI 28.9 (4.6) kg/m². Weight and HbA_1c were significantly reduced by liraglutide vs. placebo (p ≤ 0.01). The [⁶⁴Cu]DOTATATE uptake (mean standardized uptake values) was significantly reduced in the liraglutide-treated group (−0.11 [95% confidence interval −0.19 to −0.03], p = 0.01) and not changed significantly in the placebo group (−0.07 [−0.14 to 0.01], p = 0.08). The mean difference between groups did not reach significance (−0.04 [−0.15 to 0.07], p = 0.44). In conclusion, [⁶⁴Cu]DOTATATE uptake was reduced in persons with T2D treated with liraglutide. However, the reduction compared to placebo did not reach statistical significance, perhaps due to limited power. A reduction in vascular inflammation with liraglutide could help explain the cardiovascular protection observed with GLP-1 RAs in outcome studies but warrants further and larger studies. Full article

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12 pages, 3305 KiB

Open AccessArticle

Long-Term Follow-Up of Thyroid Incidentalomas Visualized with 18F-Fluorodeoxyglucose Positron Emission Tomography—Impact of Thyroid Scintigraphy in the Diagnostic Work-Up

by Kirsten Korsholm, Michala Reichkendler, Louise Alslev, Åse Krogh Rasmussen and Peter Oturai

Diagnostics 2021, 11(3), 557; https://doi.org/10.3390/diagnostics11030557 - 19 Mar 2021

Cited by 1 | Viewed by 2078

Abstract

Our objective was to evaluate the frequency of malignancy in incidental thyroidal uptake on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a cohort of Danish patients, and furthermore to evaluate the impact of thyroid scinti-graphy in the diagnostic work-up. All whole-body PET/CT [...] Read more.

Our objective was to evaluate the frequency of malignancy in incidental thyroidal uptake on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a cohort of Danish patients, and furthermore to evaluate the impact of thyroid scinti-graphy in the diagnostic work-up. All whole-body PET/CT reports from 1 January 2010 to 31 December 2013 were retrospectively reviewed and further analyzed if visually increased thyroidal FDG uptake was reported. Patient electronic files were searched for further thyroid evaluation. Of 13,195 18F-FDG-PET/CT scans in 9114 patients, 312 PET/CT reports mentioned incidental thyroid FDG-uptake, and 279 patients were included in the study (3.1%). The thyroid was further investigated in 137 patients (49%), and 75 patients underwent thyroid scintigraphy. A total of 57 patients had a thyroid biopsy and 21 proceeded to surgery. Surgical specimens displayed malignancy in 10 cases, and one thyroid malignancy was found by autopsy. Hence, 11 patients were diagnosed with thyroid malignancies among 279 patients with incidental thyroid 18F-FDG uptake (3.9%). In 34 patients, a biopsy was avoided due to the results of the thyroid scintigraphy. We conclude that patients with thyroid incidentalomas can benefit from further diagnostic work-up including a thyroid scintigraphy. Full article

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10 pages, 7784 KiB

Open AccessArticle

Initial Experience with ⁶⁴Cu-DOTATATE Digital PET of Patients with Neuroendocrine Neoplasms: Comparison with Analog PET

by Mathias Loft, Camilla B. Johnbeck, Esben A. Carlsen, Helle H. Johannesen, Peter Oturai, Seppo W. Langer, Ulrich Knigge and Andreas Kjaer

Diagnostics 2021, 11(2), 350; https://doi.org/10.3390/diagnostics11020350 - 19 Feb 2021

Cited by 5 | Viewed by 3317

Abstract

The recent introduction of solid-state detectors in clinical positron emission tomography (PET) scanners has significantly improved image quality and spatial resolution and shortened acquisition time compared to conventional analog PET scanners. In an initial evaluation of the performance of our newly acquired Siemens [...] Read more.

The recent introduction of solid-state detectors in clinical positron emission tomography (PET) scanners has significantly improved image quality and spatial resolution and shortened acquisition time compared to conventional analog PET scanners. In an initial evaluation of the performance of our newly acquired Siemens Biograph Vision 600 PET/CT (digital PET/CT) scanner for ⁶⁴Cu-DOTATATE imaging, we compared PET/CT acquisitions from patients with neuroendocrine neoplasms (NENs) grades 1 and 2 and stable disease on CT who were scanned on both our Siemens Biograph 128 mCT PET/CT (analog PET/CT) and digital PET/CT within 6 months as part of their routine clinical management. Five patients fulfilled the criteria and were included in the analysis. The digital PET acquisition time was less than 1/3 of the analog PET acquisition time (digital PET, mean (min:s): 08:20 (range, 07:59–09:45); analog PET, 25:28 (24:39–28:44), p < 0.001). All 44 lesions detected on the analog PET with corresponding structural correlates on the CT were also found on the digital PET performed 137 (107–176) days later. Our initial findings suggest that digital ⁶⁴Cu-DOTATATE PET can successfully be performed in patients with NENs using an image acquisition time of only 1/3 of what is used for an analog ⁶⁴Cu-DOTATATE PET. Full article

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2020

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13 pages, 819 KiB

Open AccessArticle

Limited Diagnostic Utility of Chromogranin A Measurements in Workup of Neuroendocrine Tumors

by Jonas Baekdal, Jesper Krogh, Marianne Klose, Pernille Holmager, Seppo W. Langer, Peter Oturai, Andreas Kjaer, Birgitte Federspiel, Linda Hilsted, Jens F. Rehfeld, Ulrich Knigge and Mikkel Andreassen

Diagnostics 2020, 10(11), 881; https://doi.org/10.3390/diagnostics10110881 - 29 Oct 2020

Cited by 7 | Viewed by 3391

Abstract

Background: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. Objective: To assess the positive predictive value [...] Read more.

Background: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. Objective: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. Method: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. Results: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. Conclusion: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA. Full article

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11 pages, 2214 KiB

Open AccessArticle

⁶⁴Cu-DOTATATE Positron Emission Tomography (PET) of Borrelia Burgdorferi Infection: In Vivo Imaging of Macrophages in Experimental Model of Lyme Arthritis

by Anne Skovsbo Clausen, Mathilde Ørbæk, Regitze Renee Pedersen, Peter Oestrup Jensen, Anne-Mette Lebech and Andreas Kjaer

Diagnostics 2020, 10(10), 790; https://doi.org/10.3390/diagnostics10100790 - 6 Oct 2020

Cited by 7 | Viewed by 3325

Abstract

Macrophages play a key role in the inflammatory response in Lyme arthritis (LA) and could be a target for diagnosing and monitoring active Borrelia burgdorferi sensu lato (Bb) infection. Therefore, we evaluated the potential of macrophage imaging using ⁶⁴Cu-DOTATATE PET/CT [...] Read more.

Macrophages play a key role in the inflammatory response in Lyme arthritis (LA) and could be a target for diagnosing and monitoring active Borrelia burgdorferi sensu lato (Bb) infection. Therefore, we evaluated the potential of macrophage imaging using ⁶⁴Cu-DOTATATE PET/CT for detection of Bb activity in a murine model of LA. LA was established in C3H/HeNRj mice infected with Bb B31 strain ML23 pBBE22luc. Bioluminescence imaging was performed to detect migration of spirochetes and inflammatory phagocytes to the joints. Three weeks post-infection ⁶⁴Cu-DOTATATE PET/CT imaging was performed at an early (3 h) and late (48 h) time point. Plasma levels of a systemic macrophage marker in plasma CD163 were measured. ⁶⁴Cu-DOTATATE uptake in infected joints was increased at the early (p < 0.0001) and late time points (p = 0.0005) compared with uptake in non-infected controls. No significant difference in plasma levels of CD163 was measured. ⁶⁴Cu-DOTATATE PET allows for in vivo detection and quantification of LA locally in the joints through non-invasive visualization of macrophages. In contrast, measurement of a systemic macrophage marker in plasma, CD163, did not allow to detect disease. We suggest that ⁶⁴Cu-DOTATATE PET could become a valuable diagnostic tool for in situ detection of Bb infection-related inflammation. Full article

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14 pages, 976 KiB

Open AccessReview

Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications

by David Kalfert, Marie Ludvikova, Martin Pesta, Jaroslav Ludvik, Lucie Dostalova and Ivana Kholová

Diagnostics 2020, 10(8), 563; https://doi.org/10.3390/diagnostics10080563 - 5 Aug 2020

Cited by 47 | Viewed by 3650

Abstract

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, [...] Read more.

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology. Full article

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23 pages, 1211 KiB

Open AccessReview

Imaging-Based Prediction of Molecular Therapy Targets in NSCLC by Radiogenomics and AI Approaches: A Systematic Review

by Gaia Ninatti, Margarita Kirienko, Emanuele Neri, Martina Sollini and Arturo Chiti

Diagnostics 2020, 10(6), 359; https://doi.org/10.3390/diagnostics10060359 - 30 May 2020

Cited by 51 | Viewed by 6882

Abstract

The objective of this systematic review was to analyze the current state of the art of imaging-derived biomarkers predictive of genetic alterations and immunotherapy targets in lung cancer. We included original research studies reporting the development and validation of imaging feature-based models. The [...] Read more.

The objective of this systematic review was to analyze the current state of the art of imaging-derived biomarkers predictive of genetic alterations and immunotherapy targets in lung cancer. We included original research studies reporting the development and validation of imaging feature-based models. The overall quality, the standard of reporting and the advancements towards clinical practice were assessed. Eighteen out of the 24 selected articles were classified as “high-quality” studies according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The 18 “high-quality papers” adhered to Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) with a mean of 62.9%. The majority of “high-quality” studies (16/18) were classified as phase II. The most commonly used imaging predictors were radiomic features, followed by visual qualitative computed tomography (CT) features, convolutional neural network-based approaches and positron emission tomography (PET) parameters, all used alone or combined with clinicopathologic features. The majority (14/18) were focused on the prediction of epidermal growth factor receptor (EGFR) mutation. Thirty-five imaging-based models were built to predict the EGFR status. The model’s performances ranged from weak (n = 5) to acceptable (n = 11), to excellent (n = 18) and outstanding (n = 1) in the validation set. Positive outcomes were also reported for the prediction of ALK rearrangement, ALK/ROS1/RET fusions and programmed cell death ligand 1 (PD-L1) expression. Despite the promising results in terms of predictive performance, image-based models, suffering from methodological bias, require further validation before replacing traditional molecular pathology testing. Full article

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2016

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206 KiB

Open AccessReview

First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

by Johann Von Felden, Kornelius Schulze, Ines Gil-Ibanez, Tobias Werner and Henning Wege

Diagnostics 2016, 6(4), 44; https://doi.org/10.3390/diagnostics6040044 - 28 Nov 2016

Cited by 12 | Viewed by 7044

Abstract

Advanced hepatocellular carcinoma (HCC) with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC) classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI) sorafenib is the only proven active substance [...] Read more.

Advanced hepatocellular carcinoma (HCC) with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC) classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI) sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) is helpful to identify patients who do not benefit from sorafenib treatment. Full article

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Open AccessArticle

Interobserver and Intraobserver Reproducibility with Volume Dynamic Contrast Enhanced Computed Tomography (DCE-CT) in Gastroesophageal Junction Cancer

by Martin Lundsgaard Hansen, Eva Fallentin, Thomas Axelsen, Carsten Lauridsen, Rikke Norling, Lars Bo Svendsen and Michael Bachmann Nielsen

Diagnostics 2016, 6(1), 8; https://doi.org/10.3390/diagnostics6010008 - 1 Feb 2016

Cited by 4 | Viewed by 6133

Abstract

The purpose of this study was to assess inter- and intra-observer reproducibility of three different analytic methods to evaluate quantitative dynamic contrast-enhanced computed tomography (DCE-CT) measures from gastroesophageal junctional cancer. Twenty-five DCE-CT studies with gastroesophageal junction cancer were selected from a previous longitudinal [...] Read more.

The purpose of this study was to assess inter- and intra-observer reproducibility of three different analytic methods to evaluate quantitative dynamic contrast-enhanced computed tomography (DCE-CT) measures from gastroesophageal junctional cancer. Twenty-five DCE-CT studies with gastroesophageal junction cancer were selected from a previous longitudinal study. Three radiologists independently reviewed all scans, and one repeated the analysis eight months later for intraobserver analysis. Review of the scans consisted of three analysis methods: (I) Four, fixed small sized regions of interest (2-dimensional (2D) fixed ROIs) placed in the tumor periphery, (II) 2-dimensional regions of interest (2D-ROI) along the tumor border in the tumor center, and (III) 3-dimensional volumes of interest (3D-VOI) containing the entire tumor volume. Arterial flow, blood volume and permeability (k^trans) were recorded for each observation. Inter- and intra-observer variability were assessed by Intraclass Correlation Coefficient (ICC) and Bland-Altman statistics. Interobserver ICC was excellent for arterial flow (0.88), for blood volume (0.89) and for permeability (0.91) with 3D-VOI analysis. The 95% limits of agreement were narrower for 3D analysis compared to 2D analysis. Three-dimensional volume DCE-CT analysis of gastroesophageal junction cancer provides higher inter- and intra-observer reproducibility with narrower limits of agreement between readers compared to 2D analysis. Full article

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2015

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22792 KiB

Open AccessReview

Ultrasonography of the Kidney: A Pictorial Review

by Kristoffer Lindskov Hansen, Michael Bachmann Nielsen and Caroline Ewertsen

Diagnostics 2016, 6(1), 2; https://doi.org/10.3390/diagnostics6010002 - 23 Dec 2015

Cited by 50 | Viewed by 74860

Abstract

Ultrasonography of the kidneys is essential in the diagnosis and management of kidney-related diseases. The kidneys are easily examined, and most pathological changes in the kidneys are distinguishable with ultrasound. In this pictorial review, the most common findings in renal ultrasound are highlighted. [...] Read more.

Ultrasonography of the kidneys is essential in the diagnosis and management of kidney-related diseases. The kidneys are easily examined, and most pathological changes in the kidneys are distinguishable with ultrasound. In this pictorial review, the most common findings in renal ultrasound are highlighted. Full article

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1297 KiB

Open AccessCase Report

Use of Molecular Imaging Markers of Glycolysis, Hypoxia and Proliferation (¹⁸F-FDG, ⁶⁴Cu-ATSM and ¹⁸F-FLT) in a Dog with Fibrosarcoma: The Importance of Individualized Treatment Planning and Monitoring

by Kamilla Westarp Zornhagen, Malene M. Clausen, Anders E. Hansen, Ian Law, Fintan J. McEvoy, Svend A. Engelholm, Andreas Kjær and Annemarie T. Kristensen

Diagnostics 2015, 5(3), 372-382; https://doi.org/10.3390/diagnostics5030372 - 11 Sep 2015

Cited by 3 | Viewed by 7597

Abstract

Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management of cancer patients. A dog with fibrosarcoma was imaged using [...] Read more.

Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management of cancer patients. A dog with fibrosarcoma was imaged using ¹⁸F-FDG, ⁶⁴Cu-ATSM, and ¹⁸F-FLT before, during, and after 10 fractions of 4.5 Gy radiotherapy. Uptake of all tracers decreased during treatment. Fluctuations in ¹⁸F-FDG and ¹⁸F-FLT PET uptakes and a heterogeneous spatial distribution of the three tracers were seen. Tracer distributions partially overlapped. It appears that each tracer provides distinct information about tumor heterogeneity and treatment response. Full article

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Open AccessReview

Neuroendocrine Carcinomas of the Gastroenteropancreatic System: A Comprehensive Review

by Emma Elizabeth Ilett, Seppo W. Langer, Ingrid Holst Olsen, Birgitte Federspiel, Andreas Kjær and Ulrich Knigge

Diagnostics 2015, 5(2), 119-176; https://doi.org/10.3390/diagnostics5020119 - 8 Apr 2015

Cited by 84 | Viewed by 11665

Abstract

To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. [...] Read more.

To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. Concentrating on GEP-NECs, we can conclude that survival times are poor, with a median of only 4–16 months depending on disease stage and primary site. Further, this aggressive disease appears to be on the rise, with incidence numbers increasing while survival times are stagnant. Treatment strategies concerning surgery are often undecided and second-line chemotherapy is not yet established. After an analysis of over 2600 articles, we can conclude that there is indeed more empirical literature concerning GEP-NECs available than previously assumed. This unique review is based on 333 selected articles and contains detailed information concerning all aspects of GEP-NECs. Namely, the classification, histology, genetic abnormalities, epidemiology, origin, biochemistry, imaging, treatment and survival of GEP-NECs are described. Also, organ-specific summaries with more detail in relation to disease presentation, diagnosis, treatment and survival are presented. Finally, key points are discussed with directions for future research priorities. Full article

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Open AccessArticle

Pharmacokinetic Analysis of ⁶⁴Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice

by Fan Li, Jesper Tranekjær Jørgensen, Jacob Madsen and Andreas Kjaer

Diagnostics 2015, 5(2), 96-112; https://doi.org/10.3390/diagnostics5020096 - 27 Mar 2015

Cited by 1 | Viewed by 6641

Abstract

The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with ⁶⁴Cu-ATSM and extract useful physiological parameters. Methods: Tumor-bearing mice underwent 90-min dynamic PET scans with [...] Read more.

The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with ⁶⁴Cu-ATSM and extract useful physiological parameters. Methods: Tumor-bearing mice underwent 90-min dynamic PET scans with ⁶⁴Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis, parametric maps of model rate constants k₁, k₃ and K_i were generated and compared to ⁶⁴Cu-ATSM uptake. Results: Based on the AIC, an irreversible two-tissue compartment model was selected for voxel-wise pharmacokinetic analysis. Of the extracted parameters, k₁ (~perfusion) showed a strong correlation with early tracer uptake (mean spearman R = 0.88) 5 min post injection (pi). Moreover, positive relationships were found between late tracer uptake (90 min pi) and both k₃ and the net influx rate constant, K_i (mean spearman R = 0.56 and R = 0.86; respectively). Conclusion: This study shows the feasibility to extract relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of ⁶⁴Cu-ATSM as a hypoxia-specific PET tracer. Full article

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2014

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Open AccessArticle

An Improved Neutral a-Glucosidase Assay for Assessment of Epididymal Function—Validation and Comparison to the WHO Method

by Frank Eertmans, Veerle Bogaert, Tanita Van Poecke and Barbara Puype

Diagnostics 2014, 4(1), 1-11; https://doi.org/10.3390/diagnostics4010001 - 9 Jan 2014

Cited by 7 | Viewed by 9362

Abstract

Neutral a-glucosidase (NAG) activity in human seminal plasma is an important indicator for epididymis functionality. In the present study, the classic World Health Organization (WHO) method has been adapted to enhance assay robustness. Changes include modified enzyme reaction buffer composition and usage of [...] Read more.

Neutral a-glucosidase (NAG) activity in human seminal plasma is an important indicator for epididymis functionality. In the present study, the classic World Health Organization (WHO) method has been adapted to enhance assay robustness. Changes include modified enzyme reaction buffer composition and usage of an alternative enzyme inhibitor for background correction (glucose instead of castanospermine). Both methods have been tested in parallel on 144 semen samples, obtained from 94 patients/donors and 50 vasectomized men (negative control), respectively. Passing-Bablok regression analysis demonstrated equal assay performance. In terms of assay validation, analytical specificity, detection limit, measuring range, precision, and cut-off values have been calculated. These data confirm that the adapted method is a reliable, improved tool for NAG analysis in human semen. Full article

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2013

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162 KiB

Open AccessFeature PaperArticle

Gene Expression of Glucose Transporter 1 (GLUT1), Hexokinase 1 and Hexokinase 2 in Gastroenteropancreatic Neuroendocrine Tumors: Correlation with F-18-fluorodeoxyglucose Positron Emission Tomography and Cellular Proliferation

by Tina Binderup, Ulrich Peter Knigge, Birgitte Federspiel, Peter Sommer, Jane Preuss Hasselby, Annika Loft and Andreas Kjaer

Diagnostics 2013, 3(4), 372-384; https://doi.org/10.3390/diagnostics3040372 - 29 Oct 2013

Cited by 16 | Viewed by 9198

Abstract

Neoplastic tissue exhibits high glucose utilization and over-expression of glucose transporters (GLUTs) and hexokinases (HKs), which can be imaged by ¹⁸F-Fluorodeoxyglucose-positron emission tomography (FDG-PET). The aim of the present study was to investigate the expression of glycolysis-associated genes and to compare this [...] Read more.

Neoplastic tissue exhibits high glucose utilization and over-expression of glucose transporters (GLUTs) and hexokinases (HKs), which can be imaged by ¹⁸F-Fluorodeoxyglucose-positron emission tomography (FDG-PET). The aim of the present study was to investigate the expression of glycolysis-associated genes and to compare this with FDG-PET imaging as well as with the cellular proliferation index in two cancer entities with different malignant potential. Using real-time PCR, gene expression of GLUT1, HK1 and HK2 were studied in 34 neuroendocrine tumors (NETs) in comparison with 14 colorectal adenocarcinomas (CRAs). The Ki67 proliferation index and, when available, FDG-PET imaging was compared with gene expression. Overexpression of GLUT1 gene expression was less frequent in NETs (38%) compared to CRAs (86%), P = 0.004. HK1 was overexpressed in 41% and 71% of NETs and CRAs, respectively (P = 0.111) and HK2 was overexpressed in 50% and 64% of NETs and CRAs, respectively (P = 0.53). There was a significant correlation between the Ki67 proliferation index and GLUT1 gene expression for the NETs (R = 0.34, P = 0.047), but no correlation with the hexokinases. FDG-PET identified foci in significantly fewer NETs (36%) than CRAs (86%), (P = 0.04). The gene expression results, with less frequent GLUT1 and HK1 upregulation in NETs, confirmed the lower metabolic activity of NETs compared to the more aggressive CRAs. In accordance with this, fewer NETs were FDG-PET positive compared to CRA tumors and FDG uptake correlated with GLUT1 gene expression. Full article

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Open AccessArticle

Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

by Yin Wu, Andreas Klaus Pfeifer, Rebecca Myschetzky, Rajendra Singh Garbyal, Palle Rasmussen, Ulrich Knigge, Michael Bzorek, Michael Holmsgaard Kristensen and Andreas Kjaer

Diagnostics 2013, 3(4), 344-355; https://doi.org/10.3390/diagnostics3040344 - 2 Oct 2013

Cited by 26 | Viewed by 8604

Abstract

Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known [...] Read more.

Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that ¹⁷⁷Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy. Full article

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Open AccessArticle

Computed Tomography (CT) Perfusion in Abdominal Cancer: Technical Aspects

by Martin Lundsgaard Hansen, Rikke Norling, Carsten Lauridsen, Eva Fallentin, Lene Bæksgaard, Klaus Fuglsang Kofoed, Lars Bo Svendsen and Michael Bachmann Nielsen

Diagnostics 2013, 3(2), 261-270; https://doi.org/10.3390/diagnostics3020261 - 3 Apr 2013

Cited by 11 | Viewed by 9557

Abstract

Computed Tomography (CT) Perfusion is an evolving method to visualize perfusion in organs and tissue. With the introduction of multidetector CT scanners, it is now possible to cover up to 16 cm in one rotation, and thereby making it possible to scan entire [...] Read more.

Computed Tomography (CT) Perfusion is an evolving method to visualize perfusion in organs and tissue. With the introduction of multidetector CT scanners, it is now possible to cover up to 16 cm in one rotation, and thereby making it possible to scan entire organs such as the liver with a fixed table position. Advances in reconstruction algorithms make it possible to reduce the radiation dose for each examination to acceptable levels. Regarding abdominal imaging, CT perfusion is still considered a research tool, but several studies have proven it as a reliable non-invasive technique for assessment of vascularity. CT perfusion has also been used for tumor characterization, staging of disease, response evaluation of newer drugs targeted towards angiogenesis and as a method for early detection of recurrence after radiation and embolization. There are several software solutions available on the market today based on different perfusion algorithms. However, there is no consensus on which protocol and algorithm to use for specific organs. In this article, the authors give an introduction to CT perfusion in abdominal imaging introducing technical aspects for calculation of perfusion parameters, and considerations on patient preparation. This article also contains clinical cases to illustrate the use of CT perfusion in abdominal imaging. Full article

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Open AccessArticle

A Rapid, Multiplexed, High-Throughput Flow-Through Membrane Immunoassay: A Convenient Alternative to ELISA

by Sujatha Ramachandran, Mitra Singhal, Katherine G. McKenzie, Jennifer L. Osborn, Amit Arjyal, Sabina Dongol, Stephen G. Baker, Buddha Basnyat, Jeremy Farrar, Christiane Dolecek, Gonzalo J. Domingo, Paul Yager and Barry Lutz

Diagnostics 2013, 3(2), 244-260; https://doi.org/10.3390/diagnostics3020244 - 2 Apr 2013

Cited by 29 | Viewed by 14040

Abstract

This paper describes a rapid, high-throughput flow-through membrane immunoassay (FMIA) platform. A nitrocellulose membrane was spotted in an array format with multiple capture and control reagents for each sample detection area, and assay steps were carried out by sequential aspiration of sample and [...] Read more.

This paper describes a rapid, high-throughput flow-through membrane immunoassay (FMIA) platform. A nitrocellulose membrane was spotted in an array format with multiple capture and control reagents for each sample detection area, and assay steps were carried out by sequential aspiration of sample and reagents through each detection area using a 96-well vacuum manifold. The FMIA provides an alternate assay format with several advantages over ELISA. The high surface area of the membrane permits high label concentration using gold labels, and the small pores and vacuum control provide rapid diffusion to reduce total assay time to ~30 min. All reagents used in the FMIA are compatible with dry storage without refrigeration. The results appear as colored spots on the membrane that can be quantified using a flatbed scanner. We demonstrate the platform for detection of IgM specific to lipopolysaccharides (LPS) derived from Salmonella Typhi. The FMIA format provides analytical results comparable to ELISA in less time, provides integrated assay controls, and allows compensation for specimen-to-specimen variability in background, which is a particular challenge for IgM assays. Full article

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Open AccessReview

Catecholamines and Neurodegeneration in Parkinson’s Disease—From Diagnostic Marker to Aggregations of α-Synuclein

by Hideyuki Sawada, Tomoko Oeda and Kenji Yamamoto

Diagnostics 2013, 3(2), 210-221; https://doi.org/10.3390/diagnostics3020210 - 25 Mar 2013

Cited by 8 | Viewed by 8540

Abstract

Parkinson’s disease is the second most prevalent disease of the brain. It is characterized by midbrain dopaminergic neuronal degeneration accompanied by Lewy bodies, intra-cytoplasmic neuronal inclusions that consist mainly of alpha-synuclein. The cardinal motor features are muscular rigidity, bradykinesia, and resting tremor and, [...] Read more.

Parkinson’s disease is the second most prevalent disease of the brain. It is characterized by midbrain dopaminergic neuronal degeneration accompanied by Lewy bodies, intra-cytoplasmic neuronal inclusions that consist mainly of alpha-synuclein. The cardinal motor features are muscular rigidity, bradykinesia, and resting tremor and, in advanced cases, postural instability. Symptoms are relieved by dopamine replacement therapy, but progress slowly. Clinical diagnosis is made according to medical history, neurological examinations and the response to anti-Parkinsonian drugs. There are no laboratory tests for diagnosis of the disease; however, for development of disease-modifying treatment, early diagnosis by objective laboratory test is required. Recently, postsynaptic sympathetic norepinephrine nerve terminals were found to be degenerated as well as mesencephalic dopaminergic neurons. Cardiac norepinephrine denervation can be seen by meta-iodine-benzyl guanidine scintigraphy, and may be a reliable diagnostic marker. Degeneration of norepinephrinergic and dopaminergic neurons suggests that catecholamines may play a central role in the neurodegeneration in Parkinson’s disease. Recently several studies showed that alpha-synuclein aggregates in cells exposed to dopamine. Here, we review findings relating to an early diagnostic marker for detecting degeneration of the peripheral sympathetic nerves, and propose the hypothesis that catecholamines cause alpha-synuclein to aggregate and play an important role in disease pathogenesis. Full article

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Open AccessArticle

Analysis of Predictive Values Based on Individual Risk Factors in Multi-Modality Trials

by Katharina Lange and Edgar Brunner

Diagnostics 2013, 3(1), 192-209; https://doi.org/10.3390/diagnostics3010192 - 15 Mar 2013

Cited by 8 | Viewed by 6062

Abstract

The accuracy of diagnostic tests with binary end-points is most frequently measured by sensitivity and specificity. However, from the clinical perspective, the main purpose of a diagnostic agent is to assess the probability of a patient actually being diseased and hence predictive values [...] Read more.

The accuracy of diagnostic tests with binary end-points is most frequently measured by sensitivity and specificity. However, from the clinical perspective, the main purpose of a diagnostic agent is to assess the probability of a patient actually being diseased and hence predictive values are more suitable here. As predictive values depend on the pre-test probability of disease, we provide a method to take risk factors influencing the patient’s prior probability of disease into account, when calculating predictive values. Furthermore, approaches to assess confidence intervals and a methodology to compare predictive values by statistical tests are presented. Hereby the methods can be used to analyze predictive values of factorial diagnostic trials, such as multi-modality, multi-reader-trials. We further performed a simulation study assessing length and coverage probability for different types of confidence intervals, and we present the R-Package facROC that can be used to analyze predictive values in factorial diagnostic trials in particular. The methods are applied to a study evaluating CT-angiography as a noninvasive alternative to coronary angiography for diagnosing coronary artery disease. Hereby the patients’ symptoms are considered as risk factors influencing the respective predictive values. Full article

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Open AccessReview

Strain Elastography Ultrasound: An Overview with Emphasis on Breast Cancer Diagnosis

by Jonathan F. Carlsen, Caroline Ewertsen, Lars Lönn and Michael B. Nielsen

Diagnostics 2013, 3(1), 117-125; https://doi.org/10.3390/diagnostics3010117 - 25 Feb 2013

Cited by 53 | Viewed by 12730

Abstract

Strain elastography (SE), which estimates tissue strain, is an adjunct to the conventional ultrasound B-mode examination. We present a short introduction to SE and its clinical use. Furthermore, we present an overview of the 10 largest studies performed on the diagnostic accuracy of [...] Read more.

Strain elastography (SE), which estimates tissue strain, is an adjunct to the conventional ultrasound B-mode examination. We present a short introduction to SE and its clinical use. Furthermore, we present an overview of the 10 largest studies performed on the diagnostic accuracy of SE in breast cancer diagnostics. Eight of 10 studies presented data for both SE and B-mode imaging. Seven studies showed better specificity and accuracy for SE than for B-mode imaging in breast cancer diagnosis. Four studies showed an increase in specificity and accuracy when combining B-mode imaging with SE. The ways of combining B-mode imaging with SE in the diagnosis of breast cancer differed between the five studies. We believe that further studies are needed to establish an optimal algorithm for the combination of B-mode ultrasound and SE in breast cancer. Full article

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Open AccessReview

Natriuretic Peptides in Kawasaki Disease: the Myocardial Perspective

by Nagib Dahdah and Anne Fournier

Diagnostics 2013, 3(1), 1-12; https://doi.org/10.3390/diagnostics3010001 - 10 Jan 2013

Cited by 13 | Viewed by 7768

Abstract

Making a diagnosis of Kawasaki disease with certainty may be challenging, especially since the recognition of cases with incomplete diagnostic criteria and its consequences. In order to build the diagnostic case in daily practice, clinicians rely on clinical criteria established over four decades [...] Read more.

Making a diagnosis of Kawasaki disease with certainty may be challenging, especially since the recognition of cases with incomplete diagnostic criteria and its consequences. In order to build the diagnostic case in daily practice, clinicians rely on clinical criteria established over four decades ago, aided by non specific laboratory tests, and above all inspired by experience. We have recently studied the diagnostic value of N-terminal pro B-type natriuretic peptide to improve the diagnostic certainty of cases with complete or incomplete clinical criteria. Our working hypothesis was based on the fact that myocarditis is present in nearly all Kawasaki disease patients supported by histology data. In this paper, we review these facts and the myocardial perspective from the diagnostic and the mechanistic standpoints. Full article

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2012

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Open AccessArticle

Importance of Attenuation Correction (AC) for Small Animal PET Imaging

by Henrik H. El Ali, Rasmus Poul Bodholdt, Jesper Tranekjær Jørgensen, Rebecca Myschetzky and Andreas Kjaer

Diagnostics 2012, 2(4), 42-51; https://doi.org/10.3390/diagnostics2040042 - 9 Oct 2012

Cited by 22 | Viewed by 10478

Abstract

The purpose of this study was to investigate whether a correction for annihilation photon attenuation in small objects such as mice is necessary. The attenuation recovery for specific organs and subcutaneous tumors was investigated. A comparison between different attenuation correction methods was performed. [...] Read more.

The purpose of this study was to investigate whether a correction for annihilation photon attenuation in small objects such as mice is necessary. The attenuation recovery for specific organs and subcutaneous tumors was investigated. A comparison between different attenuation correction methods was performed. Methods: Ten NMRI nude mice with subcutaneous implantation of human breast cancer cells (MCF-7) were scanned consecutively in small animal PET and CT scanners (MicroPET^TM Focus 120 and ImTek’s MicroCAT^TM II). CT-based AC, PET-based AC and uniform AC methods were compared. Results: The activity concentration in the same organ with and without AC revealed an overall attenuation recovery of 9–21% for MAP reconstructed images, i.e., SUV without AC could underestimate the true activity at this level. For subcutaneous tumors, the attenuation was 13 ± 4% (9–17%), for kidneys 20 ± 1% (19–21%), and for bladder 18 ± 3% (15–21%). The FBP reconstructed images showed almost the same attenuation levels as the MAP reconstructed images for all organs. Conclusions: The annihilation photons are suffering attenuation even in small subjects. Both PET-based and CT-based are adequate as AC methods. The amplitude of the AC recovery could be overestimated using the uniform map. Therefore, application of a global attenuation factor on PET data might not be accurate for attenuation correction. Full article

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