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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

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

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

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.

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.

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. 194 patients with DTC treated at our center from 1996 to 2014 following thyroidectomy and routine 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. 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.ZIEL: Ziel dieser Studie war, die Auswirkung der FDG-PET(/CT)-Bildgebung bei der Behandlung des differenzierten Schilddrüsenkarzinoms bei Rezidivverdacht zu analysieren. Primäre Endpunkte waren Gesamt-, ereignisfreies und krankheitsspezifisches Überleben. Sekundäre Endpunkte waren biochemisches Therapieansprechen, Therapien und Sensitivität sowie Spezifität des PET(/CT). In die Studie wurden 194 Patienten eingeschlossen, die in unserer Klinik von 1996 bis 2014 im Anschluss an die Thyreoidektomie und ablative Patienten der PET-Gruppe wiesen generell ab Inklusion mehr Merkmale auf, die mit einer höheren Krankheitslast einhergehen. Dies resultierte nicht in statistisch signifikanten Unterschieden der Überlebenszeiten. Wurde eine PET(/CT)-Bildgebung durchgeführt, erhielten die Patienten signifikant weniger Radioiodtherapien in den ersten 9 Monaten nach Inklusion (63,1 % PET; 82,2 % non-PET). Gleichzeitig wurden tendenziell mehr Patienten operative Therapien zugeführt (27,5 % PET; 13,3 % non-PET). Das biochemische Therapieansprechen unterschied sich nicht signifikant. Der frühe Einsatz der PET(/CT)-Bildgebung bei Rezidivverdacht des differenzierten Schilddrüsenkarzinoms kann den Behandlungspfad verändern, indem diejenigen Patienten identifiziert werden, die von weiteren RIT wahrscheinlich nicht profitieren und stattdessen operativen Therapien zugeführt werden können.

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.

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

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

Zusammenfassung Einleitung Der postoperative Hypoparathyreoidismus kann erhebliche akute Symptome, relevante Folgeerkrankungen und weitreichende Auswirkungen auf die Lebensqualität verursachen. Die sozioökonomische Bedeutung ist hoch. Eine individualisierte Nachsorge mit besonderer Berücksichtigung gefährdeter Patienten könnte die Versorgungsqualität verbessern. Am eigenen Patientengut unseres Schilddrüsenzentrums (Kompetenzzentrum DGAV) analysierten wir Versorgungsstrukturen und -qualität und zeigen Verbesserungspotenziale auf. Material und Methoden Konsekutive Serie von 420 Patienten mit totaler Thyreoidektomie im Zeitraum 08/2012 bis 08/2014, Follow-Up 8–32 Monate. Gruppe I (Untersuchungskollektiv): 197 Patienten mit Calcium (Ca) im Serum (i. S.) am 1. postop. Tag Ergebnisse Teilnahmequote bei der Follow-Up-Untersuchung 30,6 % (117/382). Häufigkeiten für Hypoparathyreoidismus: 47 % passager, 6 % permanent. Symptomzahl und empfundene Belastung bei Patienten mit Hypoparathyreoidismus nahezu identisch zum Vergleichskollektiv. Nachsorge erfolgte bei 96 % durch den Hausarzt. Kein Patient mit einem Serumcalcium ≤ 2,1 mmol/l in der Follow-Up-Untersuchung wurde nicht substituiert. Bei 33 % der substituierten Pat. mit permanentem Hypoparathyreoidismus war die Substitutionstherapie nicht ausreichend. 24 % aller 110 Patienten mit normwertigem PTH in der Follow-Up-Untersuchung erhielten eine Substitutionsmedikation trotz überwiegend (76 %) regelmäßiger Ca-Kontrollen beim Hausarzt. Schlussfolgerung In der ambulanten hausärztlichen Versorgung von Patienten mit Hypoparathyreoidismus stellten wir sowohl Merkmale einer Über- als auch einer Unterversorgung fest. Hieraus lassen sich zur Verbesserung Zielparameter ableiten: 1. Engmaschige Nachsorge, 2. Ausreichende Substitutionstherapie für alle Patienten mit einem permanenten Hypoparathyreoidismus, 3. Zeitgerechte Beendigung der Substitutionstherapie für alle Patienten mit normwertigem Parathormon.

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.

Zusammenfassung Hintergrund Der permanente postoperative Hypoparathyreoidismus ist die häufigste Komplikation nach einer totalen Thyreoidektomie mit erheblichen möglichen Folgeerkrankungen, Beeinträchtigung der Lebensqualität und hoher sozioökonomischer Bedeutung. Zielsetzung Identifikation von Risikofaktoren für den permanenten postoperativen Hypoparathyreoidismus. Material und Methoden 420 Patienten unseres Schilddrüsenzentrums erhielten zwischen 08/2012 und 08/2014 eine totale Thyreoidektomie. 382 gingen in die Studie ein. An einer Follow-up-Untersuchung zwischen 8 und 32 Monaten nach der Operation nahmen 117 teil. Ergebnisse Mit einem permanenten postoperativen Hypoparathyreoidismus waren assoziiert: erniedrigter PTH-Wert am 1. postoperativen Tag, Verzicht bzw. Nichterfordernis einer Redon-Drainage und eine lange Krankenhausverweildauer. Die Assoziationen waren ausgeprägt, jedoch nicht signifikant. Diskussion Wir ermittelten Hinweise auf Prädiktoren für den permanenten postoperativen Hypoparathyreoidismus. Eine Validierung als relevante Risikofaktoren sollte in größeren Multicenterstudien erfolgen. Die Kenntnis von Risikofaktoren könnte zur Vermeidung dieser Komplikation und zur gezielten Nachsorgebetreuung gefährdeter Patienten dienen.

Minimal extrathyroidal extension (mETE) of papillary thyroid microcarcinoma (PTMC) is no longer considered in the new eighth edition of the staging manual of the American Joint Committee on Cancer and the International Union Against Cancer. Therefore, PTMC with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear whether mETE is associated with higher aggressiveness in PTMC. Therefore, the aim of this study was to investigate whether mETE is associated with a higher risk of lymph node metastases (LNMs) or distant metastases. Methods: In total, 721 patients with PTMC presenting at our department for postoperative counseling from May 1983 to August 2012 were included in this retrospective analysis (median follow-up time, 9.30 y). The impact of mETE on the presence of LNMs at thyroidectomy and relapse through LNMs and distant metastases was assessed by logistic regression and Fine–Gray model analyses. Results: mETE was present in 10.7% (n = 77) of patients and was an independent risk factor for LNMs 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 LNMs (over 5 y: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 y: 7.8% vs. 1.1%; P < 0.001) than did patients without mETE. mETE was an independent risk factor for relapse through LNMs and distant metastases in multivariable analysis (hazard ratio of 7.78 and 95% CI of 2.87–21.16 for LNMs [P < 0.001]; hazard ratio of 4.09 and 95% CI of 1.25–13.36 for distant metastases [P = 0.020]). Conclusion: mETE is a statistically significant and independent risk factor for relapse through LNMs and distant metastases in PTMC. Therefore, future studies should evaluate whether patients with mETE and PTMC might benefit from intensified surveillance and therapy.

Minimal extrathyroidal extension (mETE) of papillary thyroid microcarcinoma (PTMC) is no longer considered in the new eighth edition of the staging manual of the American Joint Committee on Cancer and the International Union Against Cancer. Therefore, PTMC with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear whether mETE is associated with higher aggressiveness in PTMC. Therefore, the aim of this study was to investigate whether mETE is associated with a higher risk of lymph node metastases (LNMs) or distant metastases. Methods: In total, 721 patients with PTMC presenting at our department for postoperative counseling from May 1983 to August 2012 were included in this retrospective analysis (median follow-up time, 9.30 y). The impact of mETE on the presence of LNMs at thyroidectomy and relapse through LNMs and distant metastases was assessed by logistic regression and Fine-Gray model analyses. Results: mETE was present in 10.7% (n = 77) of patients and was an independent risk factor for LNMs 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 LNMs (over 5 y: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 y: 7.8% vs. 1.1%; P < 0.001) than did patients without mETE. mETE was an independent risk factor for relapse through LNMs and distant metastases in multivariable analysis (hazard ratio of 7.78 and 95% CI of 2.87-21.16 for LNMs [P < 0.001]; hazard ratio of 4.09 and 95% CI of 1.25-13.36 for distant metastases [P = 0.020]). Conclusion: mETE is a statistically significant and independent risk factor for relapse through LNMs and distant metastases in PTMC. Therefore, future studies should evaluate whether patients with mETE and PTMC might benefit from intensified surveillance and therapy.

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.

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

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.

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 synth...

Aim To study the clinical yield of diagnostic whole body 131I scintigraphy (DxWBS) in the follow-up of differentiated thyroid carcinoma (DTC) patients in relation to stimulated thyroglobulin (sTg) in the initial post-ablation setting, as well as in the setting of repeated monitoring in course of further DTC follow-up.

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.

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.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).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.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.Der postoperative Hypoparathyreoidismus kann erhebliche akute Symptome, relevante Folgeerkrankungen und weitreichende Auswirkungen auf die Lebensqualität verursachen. Die sozioökonomische Bedeutung ist hoch. Eine individualisierte Nachsorge mit besonderer Berücksichtigung gefährdeter Patienten könnte die Versorgungsqualität verbessern. Am eigenen Patientengut unseres Schilddrüsenzentrums (Kompetenzzentrum DGAV) analysierten wir Versorgungsstrukturen und -qualität und zeigen Verbesserungspotenziale auf.Konsekutive Serie von 420 Patienten mit totaler Thyreoidektomie im Zeitraum 08/2012 bis 08/2014, Follow-Up 8–32 Monate. Gruppe I (Untersuchungskollektiv): 197 Patienten mit Calcium (Ca) im Serum (i. S.) am 1. postop. Tag 2,1 mmol/l und/oder Parathormon (PTH) 15 pg/ml. Gruppe II (Kontrollkollektiv): 223 Patienten mit Ca i. S. am 1. postop. Tag ≥ 2,1 mmol/l und PTH ≥ 15 pg/ml. Zielparameter bei Follow-Up: Ca- und PTH-Wert, Symptome, Lebensqualität und ambulante Versorgungsqualität durch Hausarzt (Fragebogen).Teilnahmequote bei der Follow-Up-Untersuchung 30,6 % (117/382). Häufigkeiten für Hypoparathyreoidismus: 47 % passager, 6 % permanent. Symptomzahl und empfundene Belastung bei Patienten mit Hypoparathyreoidismus nahezu identisch zum Vergleichskollektiv. Nachsorge erfolgte bei 96 % durch den Hausarzt. Kein Patient mit einem Serumcalcium ≤ 2,1 mmol/l in der Follow-Up-Untersuchung wurde nicht substituiert. Bei 33 % der substituierten Pat. mit permanentem Hypoparathyreoidismus war die Substitutionstherapie nicht ausreichend. 24 % aller 110 Patienten mit normwertigem PTH in der Follow-Up-Untersuchung erhielten eine Substitutionsmedikation trotz überwiegend (76 %) regelmäßiger Ca-Kontrollen beim Hausarzt.In der ambulanten hausärztlichen Versorgung von Patienten mit Hypoparathyreoidismus stellten wir sowohl Merkmale einer Über- als auch einer Unterversorgung fest. Hieraus lassen sich zur Verbesserung Zielparameter ableiten: 1. Engmaschige Nachsorge, 2. Ausreichende Substitutionstherapie für alle Patienten mit einem permanenten Hypoparathyreoidismus, 3. Zeitgerechte Beendigung der Substitutionstherapie für alle Patienten mit normwertigem Parathormon.

Permanent postoperative hypoparathyreoidism remains the most frequent complication after total thyreoidectomy with severe long-term morbidity, impairment of quality of life and economic implications.Identification of risk factors for permanent postoperative hypoparathyreoidism.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.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.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.Der permanente postoperative Hypoparathyreoidismus ist die häufigste Komplikation nach einer totalen Thyreoidektomie mit erheblichen möglichen Folgeerkrankungen, Beeinträchtigung der Lebensqualität und hoher sozioökonomischer Bedeutung.Identifikation von Risikofaktoren für den permanenten postoperativen Hypoparathyreoidismus.420 Patienten unseres Schilddrüsenzentrums erhielten zwischen 08/2012 und 08/2014 eine totale Thyreoidektomie. 382 gingen in die Studie ein. An einer Follow-up-Untersuchung zwischen 8 und 32 Monaten nach der Operation nahmen 117 teil.Mit einem permanenten postoperativen Hypoparathyreoidismus waren assoziiert: erniedrigter PTH-Wert am 1. postoperativen Tag, Verzicht bzw. Nichterfordernis einer Redon-Drainage und eine lange Krankenhausverweildauer. Die Assoziationen waren ausgeprägt, jedoch nicht signifikant.Wir ermittelten Hinweise auf Prädiktoren für den permanenten postoperativen Hypoparathyreoidismus. Eine Validierung als relevante Risikofaktoren sollte in größeren Multicenterstudien erfolgen. Die Kenntnis von Risikofaktoren könnte zur Vermeidung dieser Komplikation und zur gezielten Nachsorgebetreuung gefährdeter Patienten dienen.

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.

Purpose Based on a single older study it is established dogma that TSH levels should be ≥30 mU/l at the time of postoperative 131I ablation in differentiated thyroid cancer (DTC) patients. We sought to determine whether endogenous TSH levels, i.e. after levothyroxine withdrawal, at the time of ablation influence ablation success rates, recurrence-free survival and DTC-related mortality.

Background and Objectives To investigate if patients with thyroid carcinoma having N1a disease are at the same risk with N1b using the collective of the well-defined European prospective Multicentre Study Differentiated Thyroid Cancer (MSDS). Methods Overall (OS) and event free survival (EFS) were calculated. Cox multivariable regression analysis was performed in order to calculate Hazard ratios (HR). Results EFS was significantly decreased only in patients with N1b metastasis as compared to N0 patients and became worse when N1a was concomitantly affected. A superior survival in favor of N1a patients as compared to N1b patients with regard to EFS was also observed. The patients having N1a disease showed no differences in the EFS as compared to N0. OS did not differ significantly in any of the groups. There was an increased HR for events with regards to histology, T-stage, tumor size, UICC stage and cervical lymph node metastasis. Tumor size showed a significantly increased risk for OS. Conclusions Patients with pT3b and pT4a tumors with N1b are of higher risk for relapse, albeit not affecting overall survival. Patients with N1a are of no higher risk. The risk stratification of these patients may be adapted accordingly. J. Surg. Oncol. 2015 111:9–14. © 2015 Wiley Periodicals, Inc.

The aim of this study was to compare the overall survival of a large, single-center cohort of patients who had differentiated thyroid cancer (DTC) with that of a matched general population.We analyzed 2,428 consecutive patients who had DTC and underwent treatment from 1965 to 2013 at the Department of Nuclear Medicine, University Hospital of Münster, Münster, Germany, according to international standards. Patients were classified on the basis of the current, seventh edition of the American Joint Committee on Cancer/Union for International Cancer Control classification system. Additionally, a subgroup analysis with regard to age at diagnosis was performed. The overall survival of the patients was compared with the expected survival of the general population on the basis of age and sex, as provided by the Federal Statistical Office of Germany.Compared with the expected survival, the overall survival of patients with stage I disease paradoxically was significantly better (P0.001). In the subgroup analysis, a significantly lower mortality rate was observed in elderly patients (≥60 y old) with stage I disease. On the other hand, patients between 20 and 45 y of age and with distant metastases at diagnosis had a significantly increased standardized mortality rate. In contrast, other patients with stage II disease and more than 45 y old had a normal mortality rate. The mortality rate was significantly increased in all patients with stage IVC disease.Older patients with more limited disease paradoxically had better survival than would be expected on the basis of age and sex, whereas young adults as well as patients more than 45 y old and with distant metastases had increased mortality rates. For all other DTC patients, regardless of age or TNM stage, no significant survival difference was seen.

Integrins are heterodimeric transmembrane protein receptors consisting of different α and β subunits. α(v)β(3) integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, whereas α(IIb)β(3) is a receptor for, e.g., fibrinogen and mediates platelet aggregation. In this study, a near-infrared fluorescent imaging probe has been designed and synthesized by conjugating fluorescent dyes to a non-peptidic, pharmacophore-based ligand, based on a molecular modeling design approach. Affinity values were determined, and in vitro cell binding assays and preliminary in vivo xenograft studies in nude mice were performed to evaluate target binding. Competition assays revealed excellent binding and selectivity to α(v)β(3) compared to that for α(IIb)β(3). In vitro, the probe showed high target binding on α(v)β(3)-positive M-21 cells and negligible binding to α(v)β(3)-negative MCF-7 cells. In vivo, the tracer is able to image target expression in U-87 xenografts with a maximum signal-to-noise ratio (SNR) of 2.5:1 at 24 h after injection.

SummaryObjective The seventh edition of the American Joint Committee on Cancer (AJCC) has more detailed staging categories for differentiated thyroid cancer (DTC) than the fifth edition. The aim was to compare potential alterations in the disease-specific (DSS), event-free (EFS) and overall survival (OS), after reclassification from the fifth to the seventh edition. Methods Data of 2460 patients with DTC referred to our centre were reclassified from the fifth to the seventh edition of AJCC. DSS, EFS and OS were calculated using the Kaplan-Meier method and compared by the log-rank test. The relative abilities of each edition to predict survival were calculated by the proportion of variance explained (PVE). Results After reclassification to the seventh edition, there was an increase in stage I and IV patients from 58·1% to 65·0% and from 6·2% to 10·1%, respectively, and a corresponding decrease in stage II and III patients from 22·4% to 12·5% and 13·3% to 12·4%, respectively. As to DSS, the seventh edition had only a marginally higher PVE value than the fifth edition. With respect to EFS, the predictability of the seventh edition was even inferior to that of the fifth edition. Similarly, with regard to OS, the PVE value was slightly better for the older edition. Furthermore, a comparison only for those patients affected by the reclassification revealed no differences for DSS, EFS or OS between classifications. Conclusion When comparing the stages of the seventh with the fifth edition of the AJCC for DTC, there was no significant difference in predicting DSS, EFS and OS.

Konventionelle Ansatze in der onkologischen Therapie wie Operation, Chemotherapie und/oder Strahlenbehandlung fuhren bei vielen Patienten nicht zu einer Verbesserung des Uberlebens, sind aber oft mit erheblichen Nebenwirkungen verbunden. Durch die aktuelle Forschung auf dem Gebiet der molekularen Medizin ist ein Therapieansatz hinzugekommen, den man als „zielgerichtete Therapie“ („targeted therapy“) bezeichnet. Recherche und Auswertung von Literatur. Auf der Grundlage des Verstandnisses der Pathogenese von Erkrankungen werden auf molekularer Ebene Medikamente entwickelt, die spezifisch auf die entscheidenden Zielmolekule der jeweiligen Erkrankung wirken. Im Rahmen der Indikationsstellung und Verlaufskontrolle unter zielgerichteten Therapien haben sowohl die mikroskopische (optische) Bildgebung operativer Praparate – eingeschlossen molekularpathologische Untersuchungsmethoden – als auch die makroskopische (molekulare) Bildgebung einen besonderen Stellenwert. Der kombinierte Einsatz dieser komplementaren Verfahren wird als „multiscale imaging“ bezeichnet. Es besteht die Aussicht auf individualisierte und nebenwirkungsarmere Therapien fur Patienten mit onkologischen Erkrankungen. Eine wichtige Rolle spielen dabei PET/CT-Gerate der neuen Generation, die Verfugbarkeit „neuer“ Radionuklide und die Anwendung von Proteomik und Genomik auf der Basis der Entschlusselung des humanen Genoms.

A series of new 4- or 5-substituted pyrrolidine derivatives of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin bearing additional n-butyl or 4-fluorobutyl groups at the isatin nitrogen were prepared and their inhibitory activities have been tested against caspases-3 and -7, which are known to participate in the execution of the programmed cell death, called apoptosis. Several analogues fluorinated at the 4-position of the pyrrolidine ring were also synthesized since such inhibitors might be developed as 18F-radiotracers for molecular imaging of activated caspases in vivo by PET. Enantiomerically pure diastereomeric 4-fluoropyrrolidinyl derivatives inhibited the enzymes in the nanomolar scale, i.e.100–1000 times more efficient than the corresponding 4-methoxy analogues. The 4,4-difluorinated compound showed the best result with IC50 = 362 nM and 178 nM for the aforementioned caspases. In contrast, the 4-methoxy and 4-trifluoromethyl analogues exhibited less inhibition potencies for the enzymes in the μM scale, whereas all 4-OPEG4 (PEG4 = tetraethyleneglycol) and 5-methoxymethyl derivatives were inactive.

SummaryThe clinical significance of 18F-FDG-PET/CT in the follow-up of patients with differentiated thyroid carcinoma was evaluated and the results were compared with those of 18F-FDGPET, 131I-whole-body scintigraphy including SPECT/CT (WBS) and ultrasound. In addition, it was the aim to investigate the impact of 18F-FDG-PET/CT on the therapeutic management. Patients, methods: 327 patients (209 women, 118 men; mean age 53 ± 18 years) with differentiated thyroid cancer (242 papillary, 75 follicular, 6 mixed, 1 Hürthle cell and 3 poorly differentiated tumours) were analyzed retrospectively at four tertiary referral centres. 289 18F-FDG-PET/CT and 118 18F-FDG-PET studies were performed in these patients between 2007 and 2010. In addition, an overall clinical evaluation was performed, including cytology, histology, thyroglobulin level, ultrasound, WBS, and subsequent clinical course in order to compare the molecular imaging results. Finally, the change in therapeutic management due to findings of 18F-FDG-PET/CT was investigated. Results: The sensitivity of 18F-FDG-PET/CT was 92%, the specificity was 95%. Sensitivity and specificity of 18F-FDG-PET alone were 67% and 93%, respectively. WBS showed a sensitivity of 65% and a specificity of 94%. The corresponding values of ultrasound were 37% and 94%, respectively. The sensitivity of 18F-FDG-PET/CT in the group of patients with a negative WBS (n=194) amounted to 96%. When 18F-FDG-PET/CT and WBS were considered in combination, tumour tissue was missed in only 2 out of 133 patients; when 18F-FDG-PET and WBS were combined, tumour tissue was missed in 1 out of 24 patients. 18F-FDG-PET/CT resulted in management change in 43% (n=57/133) with a decision on surgical approach in 20% (n=27/133). Conclusions: 18F-FDG-PET/CT is superior to 18F-FDG-PET alone in patients with differentiated thyroid cancer and has a direct impact on the therapeutic management of patients with suspected local recurrence or metastases, particularly in those with negative WBS.

SummaryDifferentiated thyroid carcinomas (DTC) have an excellent prognosis, with 10-year overall survival rates over 90%. In addition, DTC patients benefit from their lifelong medical surveillance. The aim of the study was to compare the patients’ overall survival with that of a matched general population. Patients and methods: We have analyzed 1497 consecutive patients with DTC, who underwent radioiodine therapy in Münster, Germany, according to international standards. We classified our patients according to the current 7th edition of the UICC (Union Internationale Contre le Cancer) classification and we compared the overall survival of the patients with the expected survival based on age and sex of the general population as provided by the Federal Statistical Office, Germany. Results: There were no significant differences in overall survival rates between DTC patients of the cohort in stages I to IVa compared to the expected survival based on age and sex of the general population. However, patients in stage IVc showed a significantly worse overall survival rate using the log-rank test (p < 0.0001). Conclusion: Patients with DTC showed excellent overall survival rates in stages I, II, III and IVa. All patients, except for those in stage IVc (M1 ≥ 45 years), had overall survival rates similar to the general population.

As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4R)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula 1. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC50 values in the nanomolar range, also demonstrating no off-target effects toward the other tested Zn2+-dependent metalloproteases (ADAMs and meprins). Utilizing the structure of the (2S,4S)-configured 4-hydroxyproline derivative 4, a selective picomolar inhibitor of MMP-13, the radiolabeled counterpart [18F]4 was successfully synthesized. The radiotracer’s biodistribution in mice as well as its serum stability were evaluated for assessing its potential use ...

To study the clinical yield of diagnostic whole bodyData of 1420 thyroidectomized and radioiodine remnant-ablated DTC patients following a well-defined therapy and standardized follow-up protocol were evaluated. DxWBS and sTg were evaluated separately and in combination for various follow-up time points. The factual administration of the recorded indication for further oncologic therapy (excluding radioiodine therapies given for minimal normal remnants) within the following 4 months after follow-up served as the standard of reference. Furthermore, DxWBS was compared to post therapy WBS and SPECT(/CT) if available. Subgroup analysis was carried out for DTC patients45 years old at diagnosis without distant metastasis. The diagnostic impact of cervical ultrasound was not assessed.sTg can identify the patients at risk better than DxWBS. Furthermore, the most sensitive time point to assess response appears to be a time point beyond 3 months after RRA. When information received from both imaging and laboratory measurements are concordant, i.e. both construe absence of remaining disease, only a small fraction of patients (2%) required treatment in the future. The strongest effect was observed 12 months after RRA. Only 0.9% of the negative DxWBS patients with concordant sTg below the functional sensitivity at this time point required treatment thereafter.A complete omission of DxWBS in the post-RRA surveillance of DTC is justified once DxWBS is negative and sTg is below the functional sensitivity (with no evidence of thyroglobulin antibodies), as patients showing this combination of test results (especially 12 months after RRA) show an at worst marginal risk of recurrence. In all other cases DxWBS may still be justified.

The purpose of this study was to determine whether [(68)Ga]DOTATATE PET/MRI with diffusion-weighted imaging (DWI) can replace or complement [(18)F]FDG PET/CT in patients with radioactive-iodine (RAI)-refractory differentiated thyroid cancer (DTC).The study population comprised 12 patients with elevated thyroglobulin and a negative RAI scan after thyroidectomy and RAI remnant ablation who underwent both [(18)F]FDG PET/CT and [(68)Ga]DOTATATE PET/MRI within 8 weeks of each other. The presence of recurrent cancer was evaluated on a per-patient, per-organ and per-lesion basis. Histology, and prior and follow-up examinations served as the standard of reference.Recurrent or metastatic tumour was confirmed in 11 of the 12 patients. [(68)Ga]DOTATATE PET(/MRI) correctly identified the tumour burden in all 11 patients, whereas in one patient local relapse was missed by [(18)F]FDG PET/CT. In the lesion-based analysis, overall lesion detection rates were 79/85 (93 %), 69/85 (81 %) and 27/82 (33 %) for [(18)F]FDG PET/CT, [(68)Ga]DOTATATE PET/MRI and DWI, respectively. [(18)F]FDG PET(/CT) was superior to [(68)Ga]DOTATATE PET(/MRI) in the overall evaluation and in the detection of pulmonary metastases. In the detection of extrapulmonary metastases, [(68)Ga]DOTATATE PET(/MRI) showed a higher sensitivity than [(18)F]FDG PET(/CT), at the cost of lower specificity. DWI achieved only poor sensitivity and was significantly inferior to [(18)F]FDG PET in the lesion-based evaluation in the detection of both extrapulmonary and pulmonary metastases.[(18)F]FDG PET/CT was more sensitive than [(68)Ga]DOTATATE PET/MRI in the evaluation of RAI-refractory DTC, mostly because of its excellent ability to detect lung metastases. In the evaluation of extrapulmonary lesions, [(68)Ga]DOTATATE PET(/MRI) was more sensitive and [(18)F]FDG PET(/CT) more specific. Furthermore, DWI did not provide additional information and cannot replace [(18)F]FDG PET for postoperative monitoring of patients with suspected RAI-refractory DTC.

Endothelin (ET) receptor dysregulation has been described in a number of pathophysiological processes, including cardiovascular disorders, renal failure, and cancer. The aim of this study was to evaluate the expression of the ET-A receptor (ETAR) in murine models of thyroid carcinoma using optical imaging methods. A recently developed near-infrared fluorescent tracer was first assessed in isolated artery preparations for its functional performance in comparison with known ETAR antagonists BQ123 and PD156707. Before evaluation of the tracer in vivo, different thyroid carcinoma cell lines were characterized with respect to their ET receptor expression by RT-PCR and autoradiography. In vivo, sc and orthotopic papillary thyroid tumor xenografts were clearly visualized by fluorescence reflectance imaging and fluorescence-mediated tomography up to 48 h after injection of the tracer. Binding specificity of the probe was demonstrated by predosing with PD156707 as a competing inhibitor. In conclusion, optical imaging with a fluorescent ETAR tracer allows the noninvasive imaging of tumor-associated ETAR expression in vivo. In the future, this technique may help surgeons to evaluate lesion dimensions in intraoperative settings (e.g. thyroidectomy). (Endocrinology 153: 2907-2918, 2012)

SummaryAim: Radioiodine remnant ablation (RRA) after (near-)total thyroidectomy (TE) is a key element in patients with differentiated thyroid cancer (DTC). The use of exogenous TSH stimulation (rhTSH) prior to RRA has shown promising results as compared to conventional thyroid hormone withdrawal (THW). As yet, the efficacy of RRA after brief THW and single rhTSH administration has not been assessed. Patients, methods: The study sample comprised 147 patients with DTC referred to our center between May 2008 and September 2010. All patients received TE with subsequent RRA. None of these 147 patients had evidence of distant metastasis. 93 patients had endogenous TSH stimulation 4–5 weeks after surgery (group I) and twenty-six received two rhTSH injections (group II). 28 patients were treated with a single rhTSH injection after a brief THW (group III). RRA-Efficacy was assessed three months after therapy by diagnostic whole-body scan and measurement of the tumour marker thyroglobulin (Tg) under TSH stimulation. Results: Three categories of success were defined for remnant ablation. Based on the definition of successful remnant ablation no visible uptake and a Tg ≤ 2.0 ng/ ml (category 1) was seen in 62/93 patients in group I, in 17/26 patients in group II (p = n.s.) and in 12/28 patients in group III (p < 0.05). Visible radioiodine uptake and a Tg ≤ 2.0 ng/ml (category 2) was seen in 16/28 patients of group III and thus significantly more frequent than in group I (28/93 patients) (p < 0.01). However, patients in group III (16/28 patients) and group II (8/26 patients) showed no significant difference in this category (p = n.s.). Visible radioiodine uptake and a Tg > 2.0 ng/ml (category 3) was found in 3/93 patients in group I and 1/26 patients in group II but in no patient in group III. Conclusion: The third strategy of remnant ablation using a single injection of rhTSH after a brief THW period resulted in a significant higher rate of patients with residual uptake in the thyroid bed and a Tg level below 2 ng/ml three months after remnant ablation in comparison to THW. However, the overall efficacy of the third protocol was not significantly different as compared to two rhTSH injections. Under the aspect of the supply shortage of rhTSH the combined endogenous and exogenous TSH stimulation may be an attractive alternative for remnant ablation in differentiated thyroid cancer.

Systemic cancer is the second most common cause of death in developed countries and metastatic brain tumour the most common tumour of the central nervous system (CNS). As the incidence of brain metastases appears to be rising, more accurate non-invasive imaging modalities for diagnosis, prognosis, prediction and follow-up of treatment are requisites for efficient patient management. Positron emission tomography (PET) imaging has the ability to evaluate different aspects of tumour microenvironment on the molecular and cellular level and impact the workup of patients with brain metastasis. This article reviews the current application of PET imaging in patients with metastatic brain disease.

In general, differentiated thyroid carcinomas have an excellent prognosis. In addition to the biological behavior of this tumor entity this is based on optimized diagnostic procedures as well as a standardized therapeutic management and after-care. The combination of surgery, radioiodine ablation and levothyroxine medication is an effective therapeutic algorithm recommended by national and international guidelines. Thereby, survival rates of 80-100% can be achieved. In this respect, a correct risk-stratification is of particular importance which relies primarily on the UICC/AJCC TNM-classification to determine the local tumor extent and lymph node or distant metastasis. In the literature, several distinct prognostic scores have been defined accounting for different risk factors. Patient age at diagnosis, tumor size, extrathyroidal growth, lymph node and distant metastases are the most commonly used parameters integrated into these scores. Prospective studies on the long-term prognosis of patients with differentiated thyroid carcinomas are rare because of the favourable prognosis requiring long-term follow-up times and large patients cohorts. In general, this can only be achieved by multicentre studies. Retrospective analyses of large patient populations, however, can help to identify reliable risk factors of patients with differentiated thyroid carcinomas.

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). β-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 (ΔKPQ) 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. β-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. β-Adrenoceptor density was reduced in LQT3 hearts. Acute β-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. β-Adrenoceptor density is reduced, and β-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and β-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.

The endothelin (ET) axis plays a major role in cardiovascular diseases and a number of human cancers. This review summarizes the work that has been published in the past ten years using labeled endothelin receptor ligands for the visualization of endothelin receptor expression in vivo.

The expression and function of endothelin (ET) receptors is abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. In this study, we prepared two [(18)F]-fluorinated derivatives of the non-peptide ET(A) receptor antagonist PD 156707 and evaluated their ET receptor binding potencies. Ex vivo as well as in vivo biodistribution studies in mice were performed, as well as the metabolism of the radiotracer, which was examined by metabolite analysis in mice and rats. All tested derivatives of PD 156707 exhibited potent in vitro pharmacological characteristics with K(i) values comparable to that of the lead compound. The biodistribution studies showed a high accumulation of the tracer in bile and intestine. In vivo we were able to show that the visualization of the heart as a major target organ with high ET(A)R expression is possible.