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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.

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

BackgroundA 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.MethodsDatabases 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.ResultsA 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 BRAF-inhibitors, no other FDA-approved drug showed any frequent predicted drug sensitivity (ConclusionTreatment strategies need to focus on resistance mechanisms to BRAF inhibition and on genetic alteration–independent alternatives rather than on current targeted drugs.

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 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...

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.

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.

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.

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 ...

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.

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.

ContextFor rare and novelRETmutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify theRETmutation into one of the three clinical risk groups.ObjectiveWe analyzed proliferative properties and clinical implications associated with theRETprotooncogene transmembrane domain mutation S649L.DesignThe transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.PatientsFifteen individuals from five kindreds were identified as carriers of aRETprotooncogene mutation in exon 11 codon 649 (TCGSer→TTGLeu). In two out of five index patients, a secondRETmutation (C634W or V804L) was detected.ResultsEight gene carriers were operated on. Histology revealed MTC and C-cell hyperplasia in three index and three screening patients respectively. In all other gene carriers (aged 41–64 years), calcitonin levels were in the normal range, and pentagastrin-stimulated calcitonin levels were RETS649L-expressing NIH3T3 cells exhibited a clear increase of phosphotyrosine and proliferation rate when compared with parental NIH3T3 cells but a significantly lower kinase activity and cell growth rate when compared withRETC634R-expressing cells. When compared withRETC634R, the S649L mutant showed moderate transforming potential with small-sized colonies.ConclusionsOur clinical and in vitro findings indicate that the transmembraneRETS649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.

Summary Aim: According to the procedure guidelines of the German Society of Nuclear Medicine no radioiodine ablation is necessary in patients with papillary microcarcinomas in case of limited surgical resection. Few data are available with respect to the optimal management of patients with small follicular thyroid carcinomas. It was the aim to compare risk-profile and outcome of patients with small papillary (PTC) and follicular thyroid carcinomas (FTC) ≤1 cm. Patients, methods: 1594 patients with thyroid cancer were attended at our department between 1995 and 2006. For the subgroup of 383 patients with small PTC and FTC ≤1 cm a comparative correlation of multifocality, extrathyroidal growth, lymph node spread, distant metastasis, local recurrence and survival was performed. Patients were monitored for a mean follow-up time of six years. Results: A total of 361 patients had PTC and 22 FTC ≤1 cm. At presentation the mean age of the 306 women and 77 men was 49 ± 13 years. An ablative radioiodine therapy was performed in 77% and 100% of patients with small PTC and FTC, respectively. Multifocality (14% vs. 9%), extrathyroidal growth (10% vs. 5%), lymph node spread (14% vs. 5%), local recurrence (0.5% vs. 0%) and progressive disease (1% vs. 0%) were more common in patients with small PTC than FTC, whereas the corresponding values for distant metastasis were 2% vs. 5%, respectively; however, these figures did not reach statistical significance. Eight patients with papillary microcarcinomas died because of nonthyroidal diseases. Conclusion: Our data show no statistically significant differences in the risk-profile and outcome of patients with small PTC and FTC ≤1 cm. Therefore, the decision for or against radioiodine ablation in patients with small differentiated thyroid carcinomas should be discussed individually.

The cellular transport systems and the transport kinetics of [ 123 I]IMT uptake into non-malignant extracranial cells were characterized for the first time. Human fibroblasts were chosen as non-malignant extracranial cells as they are found ubiquitous in the body. [ 123 I]IMT is exclusively transported into fibroblasts via the sodium independent system L. An apparent Michaelis constant K m = 116.2 ± 18.9 μM and a maximum transport velocity V max = 191.6 ± 13.9 pmol ∗ (10 6 cells) −1 ∗ min −1 were calculated for the sodium-independent transport. These results were compared with those determined in two malignantly transformed extracranial cell lines, the human Ewing's sarcoma cell lines VH-64 and CADO-ES-1.

Differentiated thyroid cancer (DTC), comprising follicular and papillary carcinomas, is the most common endocrine tumor. Despite the high percentage of lymphatic and hematogenous metastases, treatment outcomes are very favorable and, with 10-year survival rates of more than 90%, DTC has an excellent prognosis (1–6). Moreover, high quality clinical trials have brought about significant improvements in survival rates among high-risk patients (7). These carcinomas typically remain limited to the thyroid, with distant metastases occurring in only a few patients. Distant metastases with the most favorable prognosis are found in the lungs, followed by bone metastases (8). The survival rate among patients older than 45 years with distant metastases has been shown to be lower than that in the normal population (9). Cerebral metastases remain a very rare complication, occurring in 0.15–1.3% of patients with thyroid carcinoma (10– 12). They are located more frequently in the hemispheres and only very rarely in the cerebellum (13, 14) and pituitary gland (15, 16). These metastases are usually asymptomatic, with only few patients presenting with symptoms such as headache, visual disturbances or ocular muscle weakness. Intracranial metastatic disease is associated with a poor prognosis and less than one year survival after diagnosis (11, 17, 18). The current international guidelines (ATA 2009) recommend complete surgical resection of brain metastases as the first-line treatment (19). If surgical therapy is not feasible, alternative treatments to be discussed include radiotherapy, radioactive iodine (RAI) therapy (provided sufficient concentration of RAI) or a chemotherapy or biological therapy with tyrosin kinase inhibitors within the framework of clinical studies. RAI therapy is not commonly used for the treatment of brain metastases, as there are few data supporting efficacy of this approach. For the purpose of his study, a literature search in PubMed was conducted using the keywords “differentiated thyroid cancer,“ “radioiodine“ and “brain metastases“ or “brain metastasis.“ Only clinical studies and case reports published between 1977 and 2012 which, among other therapies, involved RAI for the treatment of brain metastases were included in the analysis. Furthermore, patients with skull or scalp metastases extending to the brain and patients with non-differentiated thyroid cancer were excluded from the analysis. The Table provides a summary of the literature review. Table Overview of the literature

Both thallium-201 and iodine-123 alpha-methyltyrosine (123I-IMT) have been shown to be useful in the diagnostic evaluation of brain tumours. The aim of this study was to investigate the respective contributions of 201Tl and 123I-IMT single-photon emission tomography (SPET) in the non-invasive evaluation of intracerebral tumours. We analysed 65 patients with the following brain tumours: 8 non-neoplastic lesions, 4 meningiomas, 12 low-grade gliomas, 28 high-grade gliomas, 11 metastases and 2 high-grade lymphomas. 201Tl SPET and 123I-IMT SPET were performed [start of 201Tl SPET: 15 min p.i. (early) and 180 min p.i. (delayed); start of 123I-IMT SPET: 15 min p.i.]. The intensity of uptake was quantified as the ratio between tracer accumulation in the tumour and in the contralateral hemisphere. None of the non-neoplastic lesions or low-grade gliomas expressed marked 201Tl uptake. All malignant tumours except one small metastasis and all meningiomas except one small, cystic and degenerated lesion showed significant 201Tl accumulation [Tl(15')2.0]; 123I-IMT uptake was either absent or intermediate in non-malignant lesions except in two low-grade gliomas; the highest levels were observed in high-grade gliomas followed by metastases and lymphomas (mean IMT: 2.7 vs. 2.1 vs. 1.8), with metastases showing a high variability in 123I-IMT uptake (range: 0.8-3.6). Using 201Tl to distinguish non-neoplastic lesions from malignant tumours and meningiomas, 63 of 65 patients were characterised correctly. In the latter group, high-grade gliomas were correctly identified in 27 of 28 cases by their amino acid uptake. It is concluded that the combination of 201Tl and 123I-IMT surpasses the accuracy of each single test in the differentiation of space-occupying lesions of the brain. Based on these preliminary results, a sequential strategy is proposed involving an initial 201Tl SPET study and an additional 123I-IMT SPET study in the event of positive 201Tl uptake.

Single photon emission computed tomography (SPECT) with 201T1 and 123I-α-methyl tyrosine (123I-IMT) are routine methods for the evaluation of brain tumors. 123-I-IMT transport across the blood brain barrier is mediated by an amino acid carrier, 201T1 accumulation is analogous to cerebral potassium uptake. Patients and Methods: To determine the differences in glioma extension as shown by the 2 methods, 17 patients with malignant gliomas were included in this comparative imaging study: astrocytoma III: n = 6, ependymoma III: n = 1, oligodendroglioma III: n = 1, glioblastoma IV: n = 9. The tomographic image sets were matched anatomically and the slices showing maximal tumor extension were identified in both image sets respectively. Tumor spread was compared visually and the tumor extension was quantified. Results: In gliomas WHO III tumor extension was delineated significantly larger by 123I-IMT-SPECT than by 201T1-SPECT (mean ± SD: 816 ± 281 pixels vs 600 ± 220 pixels, n = 8, p < 0.05). The size of glioblastomas was shown in a comparable manner by the 2 methods (977 ± 571 vs 1,051 ± 588, n = 9, ns, p = 0.57), but there were considerable regional differences between the area of 201T1 uptake and amino acid retention. In the whole group a weak but significant negative correlation between intensity of 201T1 uptake on the one hand and a ratio of the area as depicted by 123I-IMT vs area as depicted by 201T1 on the other hand, was found (n = 17, r = 0.49, p < 0.05). Thus the differences in the delineation of areas became smaller with increasing 201T1 uptake. Conclusions: These preliminary data indicate that the extension of gliomas is depicted differently by the 2 methods. 123I-IMT-SPECT shows a larger tumor extension especially in gliomas WHO III. Since 201T1 uptake has previously been shown to correlate with disruption of the blood brain barrier, 123I-IMT-SPECT may delineate tumor parts without endothelial leakage. This additional information may be helpful in planning surgical or radiation therapy. The advantages of 123I-IMT in this respect decrease with increasing 201T1 uptake and with increasing malignancy.

3-[(123)I]Iodo-l-alpha-methyltyrosine ((123)I-IMT) is used for the diagnosis and monitoring of brain tumours by means of single-photon emission tomography (SPET). To date, little has been known about the system for the transport of (123)I-IMT into brain tumour cells. It is assumed that (123)I-IMT is transported by a specific carrier for large, neutral amino acids (L-system). In this study, rat C6 glioma cells were used to characterize the uptake system of (123)I-IMT and to investigate its precise kinetics. The time course of (123)I-IMT uptake into the cells was examined for a range of 1-60 min. (123)I-IMT uptake rates with varying concentrations of (123)I-IMT (2. 5-50 microM) in the medium were quantified to assess the kinetic parameters of (123)I-IMT transport. Furthermore, competition of (123)I-IMT with other amino acids was investigated to identify the distinct transport systems involved in (123)I-IMT uptake. (123)I-IMT uptake into C6 glioma cells was linear for approximately 10 min and reached a steady-state level within 30 min. The analysis of the rate of uptake of (123)I-IMT at different concentrations was concordant with the predominance of a single uptake system. The apparent Michaelis constant (K(m)) of (123)I-IMT was 26.2+/-1.9 microM, and the maximum transport velocity (V(max)) was 35.4+/-1.7 nmol/mg protein per 10 min. 77%+/-10% of (123)I-IMT transport was sodium independent and 23%+/-3% was sodium dependent. Competitive inhibition of (123)I-IMT uptake by 2-aminobicyclo[2.2. 1]heptane-2-carboxylic acid, alpha-(methylamino)isobutyric acid and naturally occurring amino acids revealed a major (123)I-IMT transport via the sodium-independent system L (72%) and a minor uptake via the sodium-dependent system B(0,+) (17%). Our results show that (123)I-IMT transport into C6 glioma cells is principally mediated by the L-system and to a minor extent by the B(0,+)-system. The kinetic parameters of (123)I-IMT uptake are in the range of those of naturally occurring amino acids.

Technology and probe design.- Computed tomography and magnetic resonance imaging.- Single photon emission computed tomography - tracers.- Non-peptidyl 18F-labelled PET tracers as radioindicators for the noninvasive detection of cancer.- Optical and opto-acoustic imaging.- Multifunctional MRI probes.- Pre-clinical SPECTand SPECT-CT.- Optical imaging.- Applications of small animal PET.- Preclinical molecular imaging using PET and MRI.- Quantitative SPECT/CT.- Optical imaging of breast tumors and of gastrointestinal cancer by laser-induced fluorescence.- FDG PET and PET/CT.- Non-FDG PET/CT.- Future challenges of multimodality imaging.

In respect to the classification of thyroid cancer, there are different scoring systems in use which are based on multivariate analyses. However, traditional TNM classification of the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC) is the most commonly and widely accepted. The AJCC/UICC TNM classification is regularly revised by a panel of thyroid cancer experts. The major alterations of the 5th edition (1997) as compared to the 6th (2002/2003) and the current 7th (2009) edition refer to microcarcinomas, tumours with extrathyroidal extension and lymph node metastases. The rationale and the impact of the changes on scientific research and clinical decision making are presented.

Single-photon emission computed tomography (SPECT) using 3-[(123)I]-iodo-L-alpha-methyltyrosine ([(123)I]-IMT) and positron emission tomography (PET) using 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG) are valuable tools for the distinction between viable tumor and radionecrosis in patients receiving radiotherapy for high-grade gliomas. However, to date, little is known about the early effects of radiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas.To determine the early effects of irradiation on [(123)I]-IMT and [(18)F]-FDG uptake in gliomas, in vitro studies were performed using rat C6 glioma cells. The glioma cells were irradiated with 20 Gy which is a common dose applied to patients receiving intraoperative radiotherapy. Subsequently, the early kinetics of [(123)I]-IMT and [(18)F]-FDG uptake in glioma cells were monitored for 3 days.Micromorphometric examinations of the irradiated glioma cells revealed that about 25% of the viable cells transformed into giant cells. [(123)I]-IMT uptake per 10(5) viable glioma cells was unchanged on the 1st day post irradiation, but showed a significant increase on the 2nd and 3rd day following radiotherapy (p0.01). In addition, there was a moderate increase in [(18)F]- FDG accumulation per 10(5) viable glioma cells during the first 3 days after irradiation (p0.05). The maximum increase in early [(123)I]-IMT uptake 1 h after application surpassed that of [(18)F]-FDG (p0.01).Rat C6 glioma cells show an early increase in [(123)I]-IMT and [(18)F]-FDG uptake following irradiation which may be partly due to giant cell formation. These data suggest that [(123)I]-IMT SPECT and [(18)F]-FDG PET may be promising procedures for the early prediction of the therapeutic response of gliomas to radiotherapy.

Congestive heart failure is the common endpoint of various cardiac diseases representing a leading cause of cardiovascular mortality in Western countries. Characteristic functional alterations of the failing heart are explained by expressional changes of myocardial regulatory proteins; however, little is known about underlying mechanisms regulating cardiac gene expression in the failing heart. Here, we address the specific role of transcription factor CREM for cardiac function in CREM mutant mice with complete inactivation of the CREM gene. We show that CREM mutant mice display distinct alterations of cardiac function resembling characteristic functional defects of the failing heart. Left ventricular hemodynamic assessment of CREM mutant mice revealed impairment of both cardiac contraction and relaxation in basal state, as well as a decreased responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile performance was associated with a selective down-regulation of beta1-adrenergic receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the first evidence that CREM represents an important key regulator of cardiac gene expression, which is essential for normal left ventricular contractile performance and response to beta-adrenoreceptor stimulation.

OBJECTIVE To evaluate the prognostic significance of presence, intensity, and extent of amino acid uptake in patients with suspected primary or recurrent brain tumors. METHODS We retrospectively analyzed 181 consecutive studies of amino acid uptake using single-photon emission computed tomography and the amino acid l-[3-(123)I]iodo-alpha-methyltyrosine (IMT). In a blinded analysis, all studies were evaluated for presence, maximal uptake (IMT(max)), and extent (IMT(ext)) of focal tracer uptake. RESULTS The most frequent tumors were 53 astrocytomas (World Health Organization Grade I-III), 41 glioblastomas, 16 metastases, 13 oligodendrogliomas (Grade II-III), and 10 medulloblastomas. The other patients exhibited various parenchymal tumors or nonneoplastic lesions. IMT uptake was present in 69% of the patients with IMT(max) ranging from 1.4 to 6.2. IMT(max) and IMT(ext) were significant predictors of survival in the whole group. When the group was divided according to primary versus recurrent tumor, only the primary tumors achieved a high level of significance (P < 0.01). When patients without any IMT uptake were excluded from the analysis, statistical significance for both IMT(max) and IMT(ext) was lost. Multiple regression analysis, including IMT(max), IMT(ext), age, and tumor grade, revealed only extent of IMT uptake as an independent predictor of prognosis. CONCLUSION Absence of IMT uptake is a significant predictor of long-term survival in patients with suspected primary or recurrent brain tumors. Only the extent of a given lesion provided minor supplementary prognostic information as compared with histopathology and age. These findings suggest caution in relating high amino acid uptake values to poor prognosis, despite the capability of amino acid imaging to help determine the presence and extent of gliomas.

3-[(123)I]Iodo-L-alpha-methyl tyrosine ([(123)I]IMT) scintigraphy of extracranial malignant tumors has been described, but little is known about the transport systems involved in [(123)I]IMT uptake into extracranial tumor cells. Here, the precise kinetics of [(123)I]IMT transport into human Ewing's sarcoma cells (VH-64) was determined. The apparent Michaelis constant was of high affinity value (K(m)=41.7+/-3.9 microM) and maximum transport velocitiy amounted to V(max)=20.7+/-0.6 nmol x mg protein(-1) x 10 min(-1). Inhibition experiments revealed the predominance of [(123)I]IMT uptake via sodium-independent system L.

Chemotherapeutic or radiotherapeutic regimens are being increasingly used in low grade glioma of childhood. These protocols require methods to monitor tumor activity. We report our experience in eleven patients. The tumors were localized in the optic pathway (3), cerebral cortex (4) and thalamus/hypothalamus (4). Histological diagnoses included low grade astrocytoma (6), gliofibroma (1) and ganglioglioma (2). Two children with neurofibromatosis type 1 (NF-1) and typical optical tumors were not biopsied. 13 episodes of progression were noted including 3 altered diagnoses. This was evident from clinical symptoms in 11/13 episodes, computed tomography (CT) or magnetic resonance imaging (MRI) in 10/13 situations, iodine-123-alpha-methyltyrosine (123I-IMT) single-photon emission computed tomography (SPECT) in 10/10 situations, fluorine-18 fluorodesoxyglucose (18F-FDG) positron emission tomography (PET) in 0/3 and thallium-201 (201Tl) SPECT in 1/1. Seven responses to chemotherapy were recorded. Clinical symptoms indicated this in 7/7 situations, MRI in 5/7, 123I-IMT SPECT in 1/2 and 201Tl SPECT in 1/1. These data suggest that 123I-IMT SPECT is a valuable addition to low grade glioma diagnostic and stress the need for a prospective study.

A 62-year-old woman underwent radical tumour resection and surgical reconstruction of both atria and left ventricle, as well as mitral valve replacement due to initially diagnosed cardiac angiosarcoma in November 2004; surgical intervention was followed by adjuvant chemotherapy. Preoperative tumour staging included whole-body positron emission tomography-CT (PET-CT) with 18-fluorine-2-fluoro-2-desoxy-d …