Diagnostic Performance of [18F]TFB PET/CT Compared with Therapeutic Activity [131I]Iodine SPECT/CT and [18F]FDG PET/CT in Recurrent Differentiated Thyroid Carcinoma.

[18F]tetrafluoroborate ([18F]TFB) is an emerging PET tracer with excellent properties for human sodium iodide symporter (NIS)-based imaging in patients with differentiated thyroid cancer (DTC). The aim of this study was to compare [18F]TFB PET with high-activity posttherapeutic [131I]iodine whole-body scintigraphy and SPECT/CT in recurrent DTC and with [18F]FDG PET/CT in suspected dedifferentiation. Methods: Twenty-six patients treated with high-activity radioactive [131I]iodine therapy (range, 5.00-10.23 GBq) between May 2020 and November 2022 were retrospectively included. Thyroid-stimulating hormone was stimulated by 2 injections of recombinant thyroid-stimulating hormone (0.9 mg) 48 and 24 h before therapy. Before treatment, all patients underwent [18F]TFB PET/CT 40 min after injection of a median of 321 MBq of [18F]TFB. To study tracer kinetics in DTC lesions, 23 patients received an additional scan at 90 min. [131I]iodine therapeutic whole-body scintigraphy and SPECT/CT were performed at a median of 3.8 d after treatment. Twenty-five patients underwent additional [18F]FDG PET. Two experienced nuclear medicine physicians evaluated all imaging modalities in consensus. Results: A total of 62 suspected lesions were identified; of these, 30 lesions were [131I]iodine positive, 32 lesions were [18F]TFB positive, and 52 were [18F]FDG positive. Three of the 30 [131I]iodine-positive lesions were retrospectively rated as false-positive iodide uptake. Tumor-to-background ratio measurements at the 40- and 90-min time points were closely correlated (e.g., for the tumor-to-background ratio for muscle, the Pearson correlation coefficient was 0.91; P < 0.001; n = 49). We found a significant negative correlation between [18F]TFB uptake and [18F]FDG uptake as a potential marker for dedifferentiation (Pearson correlation coefficient, -0.26; P = 0.041; n = 62). Conclusion: Pretherapeutic [18F]TFB PET/CT may help to predict the positivity of recurrent DTC lesions on [131I]iodine scans. Therefore, it may help in the selection of patients for [131I]iodine therapy. Future prospective trials for iodine therapy guidance are warranted. Lesion [18F]TFB uptake seems to be inversely correlated with [18F]FDG uptake and therefore might serve as a dedifferentiation marker in DTC.

Influence of N-arylsulfonamido d-valine N-substituents on the selectivity and potency of matrix metalloproteinase inhibitors.

To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N-substituted N-arylsulfonamido d-valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)-d-valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1' substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2' substituent) were almost as active as the lead structure 1, making the latter derivative a suitable fluorescence imaging tool.

Postoperative thyroglobulin as a yard-stick for radioiodine therapy: decision tree analysis in a European multicenter series of 1317 patients with differentiated thyroid cancer.

PURPOSE: An accurate postoperative assessment is pivotal to inform postoperative 131I treatment in patients with differentiated thyroid cancer (DTC). We developed a predictive model for post-treatment whole-body scintigraphy (PT-WBS) results (as a proxy for persistent disease) by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, TSH, and Tg were identified as potential predictors and were put into regression algorithm (conditional inference tree, ctree) to develop a risk stratification model for predicting the presence of metastases in PT-WBS. RESULTS: The lymph node (N) stage identified a partition of the population into two subgroups (N-positive vs N-negative). Among N-positive patients, a Tg value > 23.3 ng/mL conferred a 83% probability to have metastatic disease compared to those with lower Tg values. Additionally, N-negative patients were further substratified in three subgroups with different risk rates according to their Tg values. The model remained stable and reproducible in the iterative process of cross validation. CONCLUSIONS: We developed a simple and robust decision tree model able to provide reliable informations on the probability of persistent/metastatic DTC after surgery. These information may guide post-surgery 131I administration and select patients requiring curative rather than adjuvant 131I therapy schedules.

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

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.

Predictors of Anxiety and Depression in Differentiated Thyroid Cancer Survivors: Results of a Cross-Sectional Study.

Background: Despite an excellent survival rate, impairments are recognized in the quality of life and emotional well-being of differentiated thyroid cancer (DTC) survivors. Predictors for anxiety and depression in DTC patients are not well characterized. Objective: To identify predictors for anxiety and depression in DTC survivors. Methods: In this cross-sectional study, all DTC survivors presenting for follow-up between 2014 and 2019 in a tertiary referral hospital were asked to complete the "Hospital Anxiety and Depression Scale" (HADS). Depression (HADS-D) and anxiety (HADS-A) subscores were dichotomized for analysis. Univariate and multivariable logistic regression analyses were performed to identify predictors of anxiety and depression. Inverse probability weighting was applied to correct for bias due to nonresponse. Results: Six hundred forty patients meeting study inclusion criteria completed the HADS questionnaire (73% female, mean age 50 years). Of these, 37.6% and 15.7% of patients demonstrated HADS-A and HADS-D scores ≥8. Female sex, elevated body mass index (BMI), permanent recurrent laryngeal nerve damage (RLND), permanent hypoparathyroidism (PH), comorbidities classified in chapter XIX of the International Classification of Diseases, 10th Revision (ICD-10; external causes of morbidity and mortality), and comorbidities in chapter XXI of ICD-10 (factors influencing health status and contact with health services) were independent predictors for elevated anxiety scores with adjusted odds ratios of 1.9 ([CI 1.2-3.2], p < 0.01), 1.0 ([CI 1.0-1.1], p = 0.02), 2.6 ([CI 1.0-6.3], p = 0.04), 2.0 ([CI 1.1-3.5], p = 0.02), 5.5 ([CI 1.0-29.6], p < 0.05), and 1.7 ([CI 1.1-2.6], p = 0.03). PH, elevated anti-Tg titer, comorbidities of the digestive system (chapter XI of ICD-10), and comorbidities of the genitourinary system (chapter XIV of ICD-10) were independent predictors for depression with adjusted odds ratios of 2.2 ([CI 1.2-4.2], p = 0.01), 1.0 ([CI 1.0-1.0], p = 0.04), 3.0 ([CI 1.5-6.1], p < 0.01), and 2.4 ([CI 1.0-5.7], p = 0.04). Conclusions: Female sex, elevated BMI, RLND, PH, and comorbidities classified in chapter XIX and chapter XXI of ICD-10 are predictors for anxiety in DTC patients. PH, elevated anti-Tg titer, comorbidities of the digestive system, and comorbidities of the genitourinary system are predictors for depression in DTC patients. Physicians involved in the follow-up of DTC patients should devote particular attention to the emotional well-being in DTC patients with PH or permanent RLND.

Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study.

PURPOSE: Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC. PATIENTS AND METHODS: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic. RESULTS: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0-421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each. CONCLUSIONS: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164.

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

Objective: Anaplastic 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. Design: Database mining. Methods: FDA-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. Conclusions: While 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.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis.

Background: A limited number of targeted therapy options exist for papillary thyroid cancer (PTC) to date. Based on genetic alterations reported by the "The Cancer Genome Atlas (TCGA)", we explored whether PTC shows alterations that may be targetable by drugs approved by the FDA for other solid cancers. Methods: Databases of the National Cancer Institute and MyCancerGenome were screened to identify FDA-approved drugs for targeted therapy. Target genes were identified using Drugbank. Genetic alterations were classified into conferring drug sensitivity or resistance using MyCancerGenome, CiViC, TARGET, and OncoKB. Genomic data for PTC were extracted from TCGA and mined for alterations predicting drug response. Results: A total of 129 FDA-approved drugs with 128 targetable genes were identified. One hundred ninety-six (70%) of 282 classic, 21 (25%) of 84 follicular, and all 30 tall-cell variant PTCs harbored druggable alterations: 259 occurred in 29, 39 in 19, and 31 in 2 targetable genes, respectively. The BRAF V600 mutation was seen in 68% of classic, 16% of follicular variant, and 93% of tall-cell variant PTCs. The RET gene fusion was seen in 8% of classic PTCs, NTRK1 and 3 gene fusions in 3%, and other alterations in <2% of classic variant PTCs. Ninety-nine of 128 (77%) FDA-approved targetable genes did not show any genetic alteration in PTC. Beside selective and non-selective BRAF-inhibitors, no other FDA-approved drug showed any frequent predicted drug sensitivity (<10%). Conclusion: Treatment strategies need to focus on resistance mechanisms to BRAF inhibition and on genetic alteration-independent alternatives rather than on current targeted drugs.

Minimal extrathyroid extension in papillary micro carcinoma of the thyroid is an independent risk factor for relapse through lymph node and distant metastases.

Aims: Minimal extrathyroid extension (mETE) is no longer considered in the new 8th edition of the AJCC/UICC staging system. Therefore, papillary thyroid microcarcinoma with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear if mETE is associated with higher aggressiveness in papillary thyroid microcarcinoma. Therefore, the aim of this study was to investigate if mETE is associated with higher risk of lymph node or distant metastases. Methods: 721 patients with thyroid papillary microcarcinoma presenting at our department for postoperative counseling from 05/1983 to 8/2012 were included in this retrospective analysis (median follow-up time 9.30 years). The impact of mETE on the presence of lymph node metastases at thyroidectomy and relapse through lymph node and distant metastases was assessed by logistic regression and Fine-Gray model analyses. Results: 10.7% (n = 77) of patients had mETE. mETE was an independent risk factor for lymph node metastases at thyroidectomy with an adjusted odds ratio of 4.33 (95%CI: 2.02-9.60, p<0.001) in multivariable analysis. Patients with mETE had significantly more relapses through lymph node (over 5 years: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 years: 7.8% vs. 1.1%; P < 0.001) compared to patients without mETE. mETE was an independent risk factor for relapse through lymph node and distant metastases in multivariable analysis (hazard ratio: 7.78, 95%CI: 2.87-21.16, p< 0.001 and 4.09, 95%CI: 1.25-13.36, P = 0.020). Conclusion: mETE is a statistically significant and independent risk factor for relapse through lymph node and distant metastases in papillary microcarcinoma. Therefore, future studies should evaluate, if patients with mETE and microcarcinoma might benefit from intensified surveillance and therapy.

The Role of Radiotherapy for Patients With Thyroid Cancer in the Modern Era.

BACKGROUND/AIM: Thyroid cancer (TC) is a relatively rare malignancy. The mainstay treatment is surgery followed by radioactive iodine (RAI) and medical systemic treatments. The role of external beam radiotherapy (EBRT) in TC is controversial regarding the survival benefits. The aim of this study was to analyse the effectiveness of EBRT for different forms of TC in different stages. PATIENTS AND METHODS: Between January 1990 and 2016, 75 patients underwent 255 radiotherapy (RT) courses at our Institution. Local control (LC) and progression-free survival (PFS) were analyzed. RESULTS: The cohort consisted of 22 patients who received curative RT and 53 patients who received RT in a palliative setting. The estimated 5-year LC for the curative group was 92±8% and the palliative group 78±7%. The estimated 5-year PFS for the curative group was 27±9% and for palliative group 31±6%. CONCLUSION: The addition of RT in TC seems to be safe and effective. Our analysis showed an excellent local control (median >15 years) regardless of the treatment setting.

Impact of FDG-PET on therapy management and outcome of differentiated thyroid carcinoma patients with elevated thyroglobulin despite negative iodine scintigraphy.

AIM: The objective of this study was to assess the impact of implementing FDG-PET imaging in treatment algorithms for differentiated thyroid cancer with suspected recurrence. Primary end points were overall, event-free and disease-specific survival. Secondary end points were therapies, disease control and the sensitivity and specificity of PET imaging. METHODS: 194 patients with DTC treated at our center from 1996 to 2014 following thyroidectomy and routine 131I ablation with no remaining 131I uptake in whole-body scans but persisting or rising thyroglobulin values were enrolled in this retrospective analysis. Of these, 149 (76.8 %) received an 18F-FDG scan (PET group) whereas the remaining 45 patients (23.2 %) did not (non-PET group). Survival, disease-specific characteristics at inclusion, disease control and therapies were compared. RESULTS: Patients of the PET group generally showed characteristics associated with higher disease activity from inclusion onwards. This did not translate to statistically significant differences in survival. If PET imaging was performed following inclusion, patients received significantly less radioiodine treatments during the first nine months after inclusion (63.1 % of the PET-group vs 82.2 % of the non-PET group). Simultaneously, patients tended to receive more surgeries following PET imaging (27.5 % PET-group vs 13.3 % non-PET group). No significant differences regarding disease control were observed. CONCLUSION: The early use of FDG-PET imaging in cases of suspected recurrence or existence of dedifferentiated DTC can lead to changes in therapy management, specifically identifying patients unlikely to benefit from additional radioiodine therapy who would instead qualify for surgical therapy methods.

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 ([131I]iodine) or limited availability ([124I]iodine). In contrast, [18F]tetrafluoroborate (TFB) is a novel radiolabeled PET substrate of hNIS, results in PET images with high-quality and low radiation doses, and should therefore be suited for imaging of DTC. The aim of the present study was to compare the diagnostic performance of [18F]TFB-PET to the clinical reference standard [131I]iodine scintigraphy in patients with recurrent DTC. METHODS: Twenty-five patients with recurrent DTC were included in this retrospective analysis. All patients underwent [18F]TFB-PET combined with either CT or MRI due to newly discovered elevated TG levels, antiTG levels, sonographically suspicious cervical lymph nodes, or combinations of these findings. Correlative [131I]iodine whole-body scintigraphy (dxWBS) including SPECT-CT was present for all patients; correlative [18F]FDG-PET-CT was present for 21 patients. Histological verification of [18F]TFB positive findings was available in 4 patients. RESULTS: [18F]TFB-PET detected local recurrence or metastases of DTC in significantly more patients than conventional [131I]iodine dxWBS and SPECT-CT (13/25 = 52% vs. 3/25 = 12%, p = 0.002). The diagnosis of 6 patients with cervical lymph node metastases that showed mildly increased FDG metabolism but negative [131I]iodine scintigraphy was changed: [18F]TFB-PET revealed hNIS expression in the metastases, which were therefore reclassified as only partly de-differentiated (histological confirmation present in two patients). Highest sensitivity for detecting recurrent DTC had the combination of [18F]TFB-PET-CT/MRI with [18F]FDG-PET-CT (64%). CONCLUSION: In the present cohort, [18F]TFB-PET shows higher sensitivity and accuracy than [131I]iodine WBS and SPECT-CT in detecting recurrent DTC. The combination of [18F]TFB-PET with [18F]FDG-PET-CT seems a reasonable strategy to characterize DTC tumor manifestations with respect to their differentiation and thereby also individually plan and monitor treatment. Future prospective studies evaluating the potential of [18F]TFB-PET in recurrent DTC are warranted.

Optimizing the Biodistribution of Radiofluorinated Barbiturate Tracers for Matrix Metalloproteinase Imaging by Introduction of Fluorescent Dyes as Pharmacokinetic Modulators.

Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of life-threatening diseases. Therefore, MMP imaging-for example, with radiolabeled MMP inhibitors (MMPIs)-potentially represents a valuable tool for clinical diagnostics using noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Despite numerous preclinical imaging approaches, translation to a clinical setting has not yet been successful. We introduce and oppose three potential radiofluorinated MMP-targeted imaging probes, modified by the introduction of pentamethine cyanine (Cy5) dyes and therefore containing both radio- as well as fluorescent label with respect to their capability to assess MMP activity in vivo by means of scintigraphic (PET) and/or fluorescent (NIRF) imaging. New hybrid MMPI tracer candidates, structurally based on radiofluorinated pyrimidine-2,4,6-triones (barbiturates) from previous approaches, were synthesized by convenient two-step syntheses. In the first step, Cy5 dyes, varying in the number of sulfonate groups (nSO3- = 1, 2, or 4) and bearing an additional "clickable" alkyne moiety, were coupled to the barbiturate MMPI by amide formation. In the second step, the [18F]fluoride radiolabel was introduced into the resulting Cy5 dye conjugates by "radio-click" chemistry. Biodistribution studies of these hybrid tracer candidates were assessed and compared in C57BL/6 mice by PET as well as fluorescence imaging. MMP activity was imaged in a MMP-positive mouse model of irritant contact dermatitis (ICD) by PET and sequential fluorescence reflectance imaging (FRI), respectively. In vivo data were validated by scintillation counting, gelatin zymography, and MMP-histology. Three new potential hybrid MMP imaging probes were prepared, differing essentially in the number of sulfonate groups, introduced by Cy5 dye components. Although the hydrophilicity of these compounds was substantially increased, 10a (nSO3- = 1) and 10b (nSO3- = 2) were still rapidly eliminated via unfavorable hepatobiliary pathways, as observed in earlier approaches. Only 11 (nSO3- = 4) showed delayed in vivo clearance and a shift towards higher renal elimination. In the chosen mouse model of ICD, only 11 (nSO3- = 4) significantly accumulated in the inflamed mouse ear, which could be precisely visualized by means of PET and FRI.

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 > 10 mm were classified according to ATA, EU-TIRADS, and ACR-TIRADS and correlated to their functional status as assessed by 99mTc-pertechnetate scintigraphy. 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.

[Risk Factors for Permanent Postoperative Hypoparathyreoidism]. / Risikofaktoren für den permanenten postoperativen Hypoparathyreoidismus.

BACKGROUND: Permanent postoperative hypoparathyreoidism remains the most frequent complication after total thyreoidectomy with severe long-term morbidity, impairment of quality of life and economic implications. OBJECTIVE: Identification of risk factors for permanent postoperative hypoparathyreoidism. MATERIAL AND METHODS: 420 patients received total thyreoidectomy in our endocrine centre between 08/2012 und 08/2014, of whom 382 were included in the study. 117 patients underwent a follow-up investigation between 8 and 32 months postoperatively. RESULTS: We determined a low parathyroid hormone level on postoperative day 1, non-application of a drain and a prolonged postoperative hospital stay as being associated with permanent postoperative hypoparathyreoidism. No association was found between postoperative hypoparathyroidism and autotransplantation of a parathyroid gland. Associations were strong but not significant. DISCUSSION: We identified associated factors for permanent postoperative hypoparathyreoidism. Larger multicentre studies should be performed for validation as possible relevant risk factors. Knowledge of risk factors might help to avoid this complication and to manage close follow-up and therapy in patients affected.

[Outpatient quality of care for permanent postoperative hypoparathyroidism]. / Ambulante Versorgungsqualität für den permanenten postoperativen Hypoparathyreoidismus.

BACKGROUND: Postoperative hypoparathyreoidism can cause severe symptoms, relevant sequelae and far reaching impairments of quality of life. Socio-economic effects are considerable. Individual follow-up of patients at risk could improve quality of care. We analysed quality of care for patients with hypoparathyreoidism after thyreoidectomy at our centre of endocrine surgery (Kompetenzzentrum DGAV) and tried to identify potentials for improvement. METHODS: 420 consecutive patients underwent thyreoidectomy (patients with hyperparathyreoidism excluded) between 08/2012 and 08/2014, follow-up 8-32 months. Group I (study group): 197 patients with calcium (Ca) in blood serum on postoperative day 1 < 2,1 mmol/l and/or parathyroide hormone (PTH) < 15 pg/ml. Group II (control group): 223 patients with Ca ≥ 2 mmol/l and PTH ≥ 15 pg/ml on postoperative day 1. Outcome parameters at follow-up: Ca-, PTH-level, symptoms, quality of life and quality of care by general practitionor in long-term outpatient care (questionnaire). RESULTS: Participation rate at follow-up was 30,6 % (117/382). Rate of postopertive hypoparathyreoidism: 47 % temporary, 6 % permanent. Number of symptoms and perceived burden was identical in patients with hypoparathyreoidism compared to patients in the control group. Long-term outpatient postoperative care was performed in 96 % by general practitionors. No patient with a calcium level in blood serum ≤ 2,1 mmol/l was not on calcium and/or vitamin D medication at the time of follow-up. 33 % of patients with hypoparathyreoidism received insufficient calcium and/or vitamin D medication. 24 % of all 117 patients screened received calcium/or vitamin D medication despite normal blood levels and regular blood tests by general practitionors (rate 76 %) at the time of follow-up. CONCLUSIONS: We found features of under-, as well as of over-treatment by general practitionors in patients with postoperative hypoparathyreoidism. From this we deduct target parameters for improvement of outpatient long-term care after thyreoidectomy: 1. Close follow-up, 2. Sufficient calcium and/or vitamin D medication in all patients with postoperative hypoparathyreoidism, 3. On-time termination of medication in patients with normal postoperative parathyroid hormone levels.

Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies.

The Zn2+-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d- and l-proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l-proline-based tertiary amine 41g ((S)-N-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (Ki = 1.4 µM) over several human MMPs.

177Lu-DOTATATE Therapy in Radioiodine-refractory Differentiated Thyroid Cancer: A Single Center Experience.

INTRODUCTION: Patients with radioiodine-refractory differentiated thyroid cancer (RrDTC) have a rather poor prognosis and are in need of novel treatments. As RrDTCs can in some cases express somatostatin receptors (SSRT), targeting of these receptors by Ga/Lu-DOTATATE could evolve as a novel theranostic option. METHODS: Five RrDTC patients with limited further therapeutic options and documented expression of SSRT using Ga-DOTATATE-PET/CT received 2 to 4 cycles of PRRT with Lu-DOTATATE. Response to therapy was assessed by thyroglobulin (Tg) and morphological and metabolic criteria based on interim and follow-up Ga-DOTATATE-PET/CTs. Analysis was performed on a per-patient basis. RESULTS: In the post-therapy evaluation, only one out of five patients showed a partial response, whereas three patients had a progressive disease. One patient had discordant findings between stable imaging results albeit rising Tg levels. CONCLUSION: In this case study of five patients, Lu-DOTATATE therapy showed only heterogeneous response and efficacy in RrDTC patients despite good lesional uptake in pre-therapeutic PET.

Design, (Radio)Synthesis, and in Vitro and in Vivo Evaluation of Highly Selective and Potent Matrix Metalloproteinase 12 (MMP-12) Inhibitors as Radiotracers for Positron Emission Tomography.

Dysregulated levels of activated matrix metalloproteinases (MMPs) are linked to different pathologies, such as cancer, atherosclerosis, neuroinflammation, and arthritis. Therefore, imaging of MMPs with positron-emission tomography (PET) represents a powerful tool for the diagnosis of MMP-associated diseases. Moreover, to distinguish between the distinct functions and roles of individual MMPs in particular pathophysiological processes, their specific imaging must be realized with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors (MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs showing excellent inhibition of MMP-12 and selectivity for MMP-12 over other MMPs were prepared. MMP-12 is a key enzyme in diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Because of their promising in vitro properties, three candidates (4, 9, and 19) were selected from this library, and radiofluorinated analogues ([18F]4, [18F]9, and [18F]19) were successfully synthesized. Initial in vitro serum stability and in vivo biodistribution studies of the radiolabeled MMPIs with PET demonstrated their potential benefit for preferable MMP-12 imaging.