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Item does not contain fulltext, Treatment with tyrosine kinase inhibitors (TKIs), especially nilotinib, often results in hyperglycemia, which may further increase cardiovascular disease risk in patients with chronic myeloid leukemia (CML). The mechanism underlying the TKI-induced glucose dysregulation is not clear. TKIs are suggested to affect insulin secretion but also insulin sensitivity of peripheral tissue has been proposed to play a role in the pathogenesis of TKI-induced hyperglycemia. Here, we aimed to assess whether skeletal muscle glucose uptake and insulin responses are altered in nondiabetic patients with CML receiving TKI treatment. After a glycogen-depleted exercise bout, an intravenous glucose bolus (0.3 g/kg body weight) was administered to monitor 2-h glucose tolerance and insulin response in 14 patients with CML receiving nilotinib, 14 patients with CML receiving imatinib, and 14 non-CML age- and gender-matched controls. A dynamic [(18)F]-FDG PET scan during a hyperinsulinemic-euglycemic clamp was performed in a subgroup of 12 male patients with CML to assess m. quadriceps glucose uptake. We showed that patients with CML treated with nilotinib have an increased insulin response to intravenous glucose administration after muscle glycogen-depleted exercise. Despite the increased insulin response to glucose administration in patients with CML receiving nilotinib, glucose disappearance rates were significantly slower in nilotinib-treated patients when compared with controls in the first 15 min after glucose administration. Although [(18)F]-FDG uptake in m. quadriceps was not different, patients receiving nilotinib showed a trend toward decreased glucose infusion rates during euglycemic clamping when compared with patients receiving imatinib. Together, these findings indicate disturbed skeletal muscle glucose handling in patients with CML receiving nilotinib therapy.NEW & NOTEWORTHY In this study, we have shown that non-diabetic patients with CML receiving nilotinib therapy show early

01 februari 2023, Item does not contain fulltext, AIMS/HYPOTHESIS: The role of beta cell mass in the balance of glucose control and hypoglycaemic burden in people with type 1 diabetes is unclear. We applied positron emission tomography (PET) imaging with radiolabelled exendin to compare beta cell mass among people with type 1 diabetes and either low glucose variability (LGV) or high glucose variability (HGV). METHODS: All participants with either LGV (n=9) or HGV (n=7) underwent a mixed-meal tolerance test to determine beta cell function and wore a blinded continuous glucose monitor for a week. After an i.v. injection with [(68)Ga]Ga-NODAGA-exendin-4, PET images were acquired for the quantification of pancreatic uptake of radiolabelled exendin. The mean standardised uptake value (SUVmean) of the pancreas was used to determine the amount of beta cell mass. RESULTS: Participants with LGV had lower HbA(1c) (46.0 mmol/mol [44.5-52.5] [6.4% (6.3-7)] vs 80 mmol/mol [69.0-110] [9.5% (8.5-12.2)], p=0.001) and higher time in range (TIR) (75.6% [73.5-90.3] vs 38.7% [25.1-48.5], p=0.002) than those with HGV. The SUVmean of the pancreas was higher for the LGV than for the HGV group (5.1 [3.6-5.6] vs 2.9 [2.1-3.4], p=0.008). The AUC(C-peptide):AUC(glucose) ratio was numerically, but not statistically, higher in the LGV compared with the HGV group (2.7×10(-2) [6.2×10(-4)-5.3×10(-2)] vs 9.3×10(-4) [4.7×10(-4)-5.2×10(-3)], p=0.21). SUVmean correlated with the AUC(C-peptide):AUC(glucose) ratio (Pearson r=0.64, p=0.01), as well as with the TIR (r=0.64, p=0.01) and the SD of interstitial glucose levels (r=-0.66, p=0.007). CONCLUSION/INTERPRETATION: Our data show higher beta cell mass in people with type 1 diabetes and LGV than in those with HGV, independent of beta cell function.

Item does not contain fulltext, Imaging with radiolabeled exendin enables detection and characterization of glucagon-like peptide 1 receptors (GLP-1Rs) in vivo with high specificity. The novel radiotracer [(68)Ga]Ga-NODAGA-exendin-4 forms a stable complex after a simple and fast labeling procedure. Beta-cell mass in the islets of Langerhans can be visualized using [(68)Ga]Ga-NODAGA-exendin-4, which is promising for research into diabetes mellitus (DM) pathophysiology. Furthermore, this radiotracer enables very sensitive detection of insulinomas, resulting from vast overexpression of GLP-1Rs, and seems promising for the detection of focal lesions in congenital hyperinsulinism (CHI). Here, we describe the procedures involved in [(68)Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) imaging including the radiolabeling of the NODAGA-exendin conjugate with (68)Ga, quality controls, and PET/CT.

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Contains fulltext : 249486.pdf (Publisher’s version ) (Open Access), Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in pancreatic islets, especially in beta-cells, and highly expressed in human insulinomas and gastrinomas. In recent years several GLP-1R-avid radioligands have been developed to image insulin-secreting tumors or to provide a tentative quantitative in vivo biomarker of pancreatic beta-cell mass. Exendin-4, a 39-amino acid peptide with high binding affinity to GLP-1R, has been labeled with Ga-68 for imaging with positron emission tomography (PET). Preparation conditions may influence the quality and in vivo behavior of tracers. Starting from a published synthesis and quality controls (QCs) procedure, we have developed and validated a new rapid and simple UV-Radio-HPLC method to test the chemical and radiochemical purity of [(68)Ga]Ga-NODAGA-exendin-4, to be used in the clinical routine. Methods: Ga-68 was obtained from a (68)Ge/(68)Ga Generator (GalliaPharma((R))) and purified using a cationic-exchange cartridge on an automated synthesis module (Scintomics GRP((R))). NODAGA-exendin-4 contained in the reactor (10 microg) was reconstituted with HEPES and ascorbic acid. The reaction mixture was incubated at 100 degrees C. The product was purified through HLB cartridge, diluted, and sterilized. To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document released by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH), adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. Therefore, a range of concentrations of Ga-NODAGA-exendin-4, NODAGA-exendin-4 (5, 4, 3.125, 1.25, 1, and 0.75 mug/mL) and [(68)Ga]Ga-NODAGA-exendin-4 were analyzed. To validate the entire production process, three consecutive batches of [(68)Ga]Ga-NODAGA-exendin-4 were tested. Results: Exc

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Contains fulltext : 244205.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 245157.pdf (Publisher’s version ) (Open Access), Stimulation of glucagon-like peptide-1 (GLP-1) receptors increases the insulin release in the pancreas during high glucose levels, and also stimulates a feeling of satiety. Likewise, synthetic GLP-1 receptor agonists derived from exendin are used successfully in the treatment of type-2 diabetes mellitus and obesity. Interestingly, preclinical and clinical studies further suggest that GLP-1 receptor agonists may decrease motor, behavioral, and cognitive symptoms in (animal models) Parkinson's disease and Alzheimer's disease and may slow down neurodegeneration. These observations suggest stimulation of GLP-1 receptors in the brain. The GLP-1 positron emission tomography (PET) tracer (68)Ga-NODAGA-exendin-4 has been developed and successfully used for imaging in humans. In an ongoing study on the effects of bariatric surgery on GLP-1 receptor expression, we performed (68)Ga-NODAGA-exendin-4 PET in obese subjects. Here we evaluated whether GLP-1 receptor binding could be visualized in the central nervous system in 10 obese subjects (seven woman; body mass index: mean +/- SD: 39 +/- 4.4 kg/m(2)) before bariatric surgery. Although we observed clear uptake in the pituitary area (mean SUVmax 4.3 +/- 2.3), we found no significant uptake in other parts of the brain. We conclude that (68)Ga-NODAGA-exendin-4 PET cannot be used to analyze GLP-1 receptors in the brain of obese subjects.

Radboud University, 09 juni 2021, Promotor : Gotthardt, M. Co-promotores : Lith, S.A. van, Brom, M., Contains fulltext : 233606.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 241457.pdf (Publisher’s version ) (Open Access)

Canine appendicular osteosarcoma is commonly treated with limb amputation; however, limb-sparing options are frequently desired or necessary for a subset of patients. We evaluated 123 patients and 130 sites treated with stereotactic body radiation therapy (SBRT). Eighty-two out of 98 dogs (84%) had maximum lameness improvement at a median of 3 weeks for a median of 6 months duration. Histopathologic evaluation of available samples from amputation or necropsy revealed >80% tumor necrosis in 50% of limbs consistent with local disease control. Of evaluable patients, 41% fractured and 21% pursued an amputation after treatment. Fine needle aspirate (n = 52) and needle core biopsy (n = 28) did not result in increased fracture risk compared to those without tumor sampling (n = 50). Median survival time (MST) was 233 days and time to first event was 143 days. Gross tumor volume and planned target volume were significantly inversely associated with survival and tumor location was significantly associated with survival. Dogs with salvage amputation had a significantly longer MST compared to those without (346 vs 202 days; P = .04). The presence of metastatic disease at the time of treatment in 15 dogs did not significantly impact survival time (200 vs 237 days without metastasis; P = .58). Skin side effects correlated significantly with dose with 33% of patients with acute grade 3 effects developing consequential late grade 3 effects. While SBRT improves lameness in most patients, further investigation is needed to identify candidates with minimal early fracture risk prior to initiating therapy.

Contains fulltext : 226801.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 216680.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 221584.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 229511.pdf (Publisher’s version ) (Open Access), OBJECTIVE: In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX. METHODS: After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis. RESULTS: 28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT. CONCLUSION: Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.

Contains fulltext : 204628.pdf (publisher's version ) (Closed access)

Contains fulltext : 205513.pdf (publisher's version ) (Open Access), BACKGROUND: Disturbances in adipose tissue glucose uptake may play a role in the pathogenesis of type 2 diabetes, yet its examination by 2-deoxy-2-[(18) F]fluorodeoxyglucose ([(18) F]FDG) PET/CT is challenged by relatively low uptake kinetics. We tested the hypothesis that performing [(18) F]FDG PET/CT during a hypoglycaemic clamp would improve adipose tissue tracer uptake to allow specific comparison of adipose tissue glucose handling between people with or without type 2 diabetes. DESIGN: We enrolled participants with or without diabetes who were at least overweight, to undergo a hyperinsulinaemic hypoglycaemic clamp or a hyperinsulinaemic euglycaemic clamp (n = 5 per group). Tracer uptake was quantified using [(18) F]FDG PET/CT. RESULTS: Hypoglycaemic clamping increased [(18) F]FDG uptake in visceral adipose tissue of healthy participants (P = 0.002). During hypoglycaemia, glucose uptake in visceral adipose tissue of type 2 diabetic participants was lower as compared to healthy participants (P < 0.0005). No significant differences were observed in skeletal muscle, liver or pancreas. CONCLUSIONS: The present findings indicate that [(18) F]FDG PET/CT during a hypoglycaemic clamp provides a promising new research tool to evaluate adipose tissue glucose metabolism. Using this method, we observed a specific impairment in visceral adipose tissue [(18) F]FDG uptake in type 2 diabetes, suggesting a previously underestimated role for adipose tissue glucose handling in type 2 diabetes.

Contains fulltext : 209104.pdf (publisher's version ) (Open Access), Insulinomas, neuroendocrine tumors arising from pancreatic beta cells, often show overexpression of the glucagon-like peptide-1 receptor. Therefore, imaging with glucagon-like peptide analog exendin-4 can be used for diagnosis and preoperative localization. This review presents an overview of the development and clinical implementation of exendin-based tracers for nuclear imaging, and the potential use of exendin-4 based tracers for optical imaging and therapeutic applications such as peptide receptor radionuclide therapy or targeted photodynamic therapy.