F-labeled glycoconjugate of PD156707 for imaging ET A receptor expression in thyroid carcinoma by positron emission tomography

Abstract: Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ET A receptor (ET A R) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ET A R (4.5 nM) over ET B R (1.2 µM)

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.status: publishe

Molecular Imaging in Oncology

XVI, 416 p.online resource

Prevalence of hyperfunctioning thyroid nodules among those in need of fine needle aspiration cytology according to ATA 2015, EU-TIRADS, and ACR-TIRADS

Purpose!#!Given the large number of patients with thyroid nodules, improvement of the specificity of current ultrasound-based thyroid nodule classification systems (ATA, EU-TIRADS, and ACR-TIRADS) is warranted to reduce the number of diagnostic thyroidectomies. Thyroid scintigraphy has been shown to demonstrate hyperfunctional nodules, associated with a low malignancy risk, in euthyroid patients. However, it is not known if thyroid scintigraphy could improve specificity of current classification systems. The aim of this study, therefore, was to determine the frequency of hyperfunctional nodules among those nodules in need of fine needle aspiration cytology (FNA) according to current classification systems and to test if nodule functional status is associated with sonographic features.!##!Methods!#!Five hundred sixty-six euthyroid patients (TSH 0.55-4.20 μU/ml) presenting for thyroid nodule workup including thyroid sonography and scintigraphy at our department between 09/2013 and 02/2018 were included in this retrospective study. All nodules &amp;gt; 10 mm were classified according to ATA, EU-TIRADS, and ACR-TIRADS and correlated to their functional status as assessed by !##!Results!#!Ultrasound detected 1029 thyroid nodules ≥ 10 mm, including 545 nodules ≥ 15 mm. Prevalence of hyperfunctional nodules among those with recommendation for FNA according to ATA 2015, EU-TIRADS, and ACR-TIRADS was 6.4%, 6.9%, and 6.5% for nodules ≥ 10 mm and 7.2%, 7.6%, and 7.5% only considering nodules ≥ 15 mm. No sonographic feature was correlated to hyperfunctionality of nodules.!##!Conclusion!#!In euthyroid patients, thyroid scintigraphy demonstrates hyperfunctionality, which cannot be predicted by ultrasound, in up to 6.9% of nodules in need of FNA according to ultrasound-based classifications. Given the known low risk of malignancy in hyperfunctional nodules, thyroid scintigraphy can lower the frequency of fine needle aspirations and-potentially-the frequency of diagnostic hemithyroidectomies in euthyroid patients

Incremental diagnostic value of [18F]tetrafluoroborate PET-CT compared to [131I]iodine scintigraphy in recurrent differentiated thyroid cancer

Introduction!#!Efficient therapy of recurrent differentiated thyroid cancer (DTC) is dependent on precise molecular imaging techniques targeting the human sodium iodide symporter (hNIS), which is a marker both of thyroid and DTC cells. Various iodine isotopes have been utilized for detecting DTC; however, these come with unfavorable radiation exposure and image quality ([!##!Methods!#!Twenty-five patients with recurrent DTC were included in this retrospective analysis. All patients underwent [!##!Results!#![!##!Conclusion!#!In the present cohort,

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

Simple Summary Adrenocortical carcinoma is a rare disease for which in silico analysis may help to identify therapy options. Here, we look at the potential of already FDA-approved drugs and therapies in clinical trials based on genes mutated in ACC and genomic alterations known to be targeted by these drugs. Overall, 67% of the ACCs presented in silico drugability, especially for new emerging options such as TP53-modulating drugs or Wnt signaling pathway inhibitors. These results might help plan future clinical trials. In rare diseases such as adrenocortical carcinoma (ACC), in silico analysis can help select promising therapy options. We screened all drugs approved by the FDA and those in current clinical studies to identify drugs that target genomic alterations, also known to be present in patients with ACC. We identified FDA-approved drugs in the My Cancer Genome and National Cancer Institute databases and identified genetic alterations that could predict drug response. In total, 155 FDA-approved drugs and 905 drugs in clinical trials were identified and linked to 375 genes of 89 TCGA patients. The most frequent potentially targetable genetic alterations included TP53 (20%), BRD9 (13%), TERT (13%), CTNNB1 (13%), CDK4 (7%), FLT4 (7%), and MDM2 (7%). We identified TP53-modulating drugs to be possibly effective in 20-26% of patients, followed by the Wnt signaling pathway inhibitors (15%), Telomelysin and INO5401 (13%), FHD-609 (13%), etc. According to our data, 67% of ACC patients exhibited genomic alterations that might be targeted by FDA-approved drugs or drugs being tested in current clinical trials. Although there are not many current therapy options directly targeting reported ACC alterations, this study identifies emerging options that could be tested in clinical trials

Anaplastic thyroid cancer: genome-based search for new targeted therapy options

ObjectiveAnaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC. DesignDatabase mining. MethodsFDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response. Results In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response. ConclusionsWhile ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options