[¹⁸F]FDG Uptake and Expression of Immunohistochemical Markers Related to Glycolysis, Hypoxia, and Proliferation in Indeterminate Thyroid Nodules

Purpose: The current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation in benign and malignant thyroid nodules of indeterminate cytology. Procedures: Using a case–control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [18F]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [18F]FDG-positive malignant, [18F]FDG-positive benign, and [18F]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxia-inducible factor-1 alpha (HIF1α; monocarboxylate transporter 4 (MCT4); carbonic anhydrase IX (CA-IX); vascular endothelial growth factor (VEGF); sodium-iodide symporter (NIS); and Ki-67. Marker expression was scored using an immunoreactive score. Unsupervised cluster analysis was performed. The immunoreactive score was correlated to the maximum and peak standardized uptake values (SUVmax, SUVpeak) and SUVmax ratio (SUVmax of nodule/background SUVmax of contralateral, normal thyroid) of the [18F]FDG-PET/CT using the Spearman’s rank correlation coefficient and compared between the three groups using Kruskal–Wallis tests. Results: The expression of GLUT1, GLUT3, HK2, and MCT4 was strongly positively correlated with the SUVmax, SUVpeak, and SUVmax ratio. The expression of GLUT1 (p = 0.009), HK2 (p = 0.02), MCT4 (p = 0.01), and VEGF (p = 0.007) was statistically significantly different between [18F]FDG-positive benign nodules, [18F]FDG-positive thyroid carcinomas, and [18F]FDG-negative benign nodules. In both [18F]FDG-positive benign nodules and [18F]FDG-positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [18F]FDG-negative benign nodules. VEGF expression was higher in [18F]FDG-positive thyroid carcinomas as compared to [18F]FDG-negative and [18F]FDG-positive benign nodules. Conclusions: Our results suggest that [18F]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations.</p

[¹⁸F]FDG Uptake and Expression of Immunohistochemical Markers Related to Glycolysis, Hypoxia, and Proliferation in Indeterminate Thyroid Nodules

Purpose: The current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation in benign and malignant thyroid nodules of indeterminate cytology. Procedures: Using a case–control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [18F]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [18F]FDG-positive malignant, [18F]FDG-positive benign, and [18F]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxia-inducible factor-1 alpha (HIF1α; monocarboxylate transporter 4 (MCT4); carbonic anhydrase IX (CA-IX); vascular endothelial growth factor (VEGF); sodium-iodide symporter (NIS); and Ki-67. Marker expression was scored using an immunoreactive score. Unsupervised cluster analysis was performed. The immunoreactive score was correlated to the maximum and peak standardized uptake values (SUVmax, SUVpeak) and SUVmax ratio (SUVmax of nodule/background SUVmax of contralateral, normal thyroid) of the [18F]FDG-PET/CT using the Spearman’s rank correlation coefficient and compared between the three groups using Kruskal–Wallis tests. Results: The expression of GLUT1, GLUT3, HK2, and MCT4 was strongly positively correlated with the SUVmax, SUVpeak, and SUVmax ratio. The expression of GLUT1 (p = 0.009), HK2 (p = 0.02), MCT4 (p = 0.01), and VEGF (p = 0.007) was statistically significantly different between [18F]FDG-positive benign nodules, [18F]FDG-positive thyroid carcinomas, and [18F]FDG-negative benign nodules. In both [18F]FDG-positive benign nodules and [18F]FDG-positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [18F]FDG-negative benign nodules. VEGF expression was higher in [18F]FDG-positive thyroid carcinomas as compared to [18F]FDG-negative and [18F]FDG-positive benign nodules. Conclusions: Our results suggest that [18F]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations.</p

DiapixUK: task materials for the elicitation of multiple spontaneous speech dialogs

The renewed focus of attention on investigating spontaneous speech samples in speech and language research has increased the need for recordings of speech in interactive settings. The DiapixUK task is a new and extended set of picture materials based on the Diapix task by Van Engen et al. (2010) where two people are recorded while conversing to solve a ‘spot the difference’ task. The new task materials allow for multiple recordings of the same speaker pairs due to a larger set of picture pairs which have a number of tested features: equal difficulty across all twelve picture pairs, no learning effect of completing more than one picture task and balanced contributions from both speakers. The new materials also provide extra flexibility making them useful in a wide range of research projects; they are multi-layered electronic images that can be adapted to suit different research needs. This paper presents details of the development of the DiapixUK materials along with data taken from a large corpus of spontaneous speech which demonstrate its new features. Current and potential applications of the task are also discussed

Validation of In Vivo Nodal Assessment of Solid Malignancies with USPIO-Enhanced MRI: A Workflow Protocol

Background: In various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superpara-magnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented, which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology. Methods: In patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious of harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens. Results: Matching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology, which allowed for analyses on a nodal, or at least on a nodal station, basis. Conclusions: A workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed for the analysis at a nodal basis, or at least nodal station basis, of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced, MRI-detected lymph nodes

Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments.

Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful biophysical technique being increasingly applied to a wide variety of problems. As the HDX-MS community continues to grow, adoption of best practices in data collection, analysis, presentation and interpretation will greatly enhance the accessibility of this technique to nonspecialists. Here we provide recommendations arising from community discussions emerging out of the first International Conference on Hydrogen-Exchange Mass Spectrometry (IC-HDX; 2017). It is meant to represent both a consensus viewpoint and an opportunity to stimulate further additions and refinements as the field advances

Donor Specific Antibody Surveillance and Graft Outcomes in Pediatric Kidney Transplant Recipients

Thesis (Master's)--University of Washington, 2017-06Introduction: The development of de novo donor-specific antibodies (dnDSA) has been associated with rejection and graft loss in kidney transplantation, and DSA screening is now recommended in all kidney transplant recipients. However, the clinical significance of dnDSA in patients with a stable creatinine remains unclear. Methods: We performed a retrospective cohort study of 103 patients receiving a first, kidney alone transplant between 12/1/2007 and 12/31/2013. Inclusion criteria were age <18 years old at the time of transplant and at least two years of DSA monitoring. All patients underwent DSA screening every 3 months post-transplant with additional testing as clinically indicated. No treatment was given for DSAs in the absence of biopsy-proven rejection. Results: 20 patients (19%) developed dnDSA in the setting of a stable creatinine and 13 patients (13%) developed dnDSA in the setting of an elevated creatinine. Median follow-up time post-transplant was 4.1 (IQR 2.9-5.7) years. In a Cox proportional hazards regression controlling for age, type of transplant, delayed graft function, cold ischemia time, and baseline eGFR post-transplant, developing dnDSA with a stable creatinine was not associated with time to 30% decline in eGFR (HR 0.88, 95%CI 0.30-2.00 p=0.598) or graft loss. dnDSA with an elevated creatinine was associated with a 2.8 times increased risk of decline in graft function (95% CI 1.08-7.27 p=0.034) and a 7.34 times increased risk of graft loss (95%CI 1.37-39.23 p=0.020) compared to transplant recipients who did not develop dnDSA. The presence of dnDSA with a stable creatinine was associated with an increased risk of rejection within 3 years (RR 2.53 95%CI 1.49-4.3 p=0.0002) and moderate interstitial fibrosis and tubular atrophy at 2 years post-transplant (aOR 26.8 95%cI 1.91-138 p=0.015). Conclusion: The clinical setting in which dnDSA is first detected impacts the association between dnDSA and graft function. dnDSA with a stable creatinine is associated with future rejection episodes and IFTA, but does not correlate with time to 30% decline in eGFR. dnDSA with an elevated creatinine is associated with a 30% decline in graft function, graft loss, and rejection. Further research is needed to clarify the role of dnDSA screening in pediatric kidney transplantation

Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: A Pediatric Nephrology Research Consortium study

BackgroundNeutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed.MethodsWe performed a multicenter retrospective cohort study of children with neutropenia within the first 180 days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection.ResultsOf 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5 mcg/kg for 3 (IQR 2–7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim–sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p = .313) and was associated with a higher rate of neutropenia relapse (p = .002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12–0.53) p < .001) but there was no association with incidence of bacterial infection or rejection within 90 days of neutropenic episode.ConclusionG-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172325/1/petr14202_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172325/2/petr14202.pd