Individualized treatment of differentiated thyroid cancer: The value of surgery in combination with radioiodine imaging and therapy - A German position paper from Surgery and Nuclear Medicine. / Individualisierte Behandlung von differenziertem Schilddrüsenkrebs: Der Wert der Operation in Kombination mit Radiojodbildgebung und -therapie ­ Ein deutsches Positionspapier aus der Chirurgie und Nuklearmedizin.

A consensus statement about indications for post-surgical radioiodine therapy (RIT) in differentiated thyroid cancer patients (DTC) was recently published by the European Thyroid Association (ETA) 1. This publication discusses indications for RIT on the basis of an individual risk assessment. Many of the conclusions of this consensus statement are well founded and accepted across the disciplines involved. However, especially from the perspective of nuclear medicine, as the discipline responsible for indicating and executing RIT, some of the recommendations may require further clarification with regard to their compatibility with established best practice and national standards of care. Assessment of the indications for RIT is strongly dependent on the weighing up of benefits and risks. On the basis of longstanding clinical experience in nuclear medicine, RIT represents a highly specific precision medicine procedure of proven efficacy with a favorable side-effect profile. This distinguishes RIT significantly from other adjuvant oncological therapies and has resulted in the establishment of this procedure as a usually well-tolerated, standard safety measure. With regard to its favorable risk/benefit ratio, this procedure should not be unnecessarily restricted, in the interest of offering reassurance to the patients. Both patients' interests and regional/national differences need to be taken into account. We would therefore like to comment on the recent consensus from the perspective of authors and to provide recommendations based on the respective published data.

The diagnostic challenge of coexistent sarcoidosis and thyroid cancer - a retrospective study.

BACKGROUND: Sarcoid lesions may mimic metastatic disease or recurrence in thyroid cancer (TC) patients as both diseases may affect the lungs and lymph nodes. We present the first study to systematically evaluate the clinical course of patients with (TC) after adjuvant radioactive iodine therapy (RIT) and concomitant sarcoidosis of the lung or the lymph nodes. METHODS: We screened 3285 patients and retrospectively identified 16 patients with TC (11 papillary thyroid cancer (PTC), 3 follicular thyroid cancer (FTC), 1 oncocytic PTC, 1 oncocytic FTC) and coexisting sarcoidosis of the lung and/or the lymph nodes treated at our institute. All patients had undergone thyroidectomy and initial adjuvant RIT. Challenges in diagnosing and the management of these patients were evaluated during long term follow-up (median 4.9 years (0.8-15.0 years)). RESULTS: Median age at first diagnosis of TC was 50.1 years (33.0-71.5 years) and of sarcoidosis 39.4 years (18.0-63.9 years). During follow-up, physicians were able to differentiate between SA and persistent or recurrent TC in 10 of 16 patients (63%). Diagnosis was complicated by initial negative thyroglobulin (Tg), positive Tg antibodies and non-specific imaging findings. Histopathology can reliably distinguish between SA and TC in patients with one suspicious lesion. CONCLUSION: Physicians should be aware of the rare coexistence of sarcoidosis and TC. Lymphadenopathy and pulmonary lesions could be metastases, sarcoidosis or even a mix of both. Therefore, this rare patient group should receive a thorough work up including histopathological clarification and, if necessary, separately for each lesion.

Clinical impact of follicular oncocytic (Hürthle cell) carcinoma in comparison with corresponding classical follicular thyroid carcinoma.

PURPOSE: There are controversial debates if patients with Hürthle cell carcinoma, also known as oxyphilic or oncocytic cell follicular thyroid carcinoma, have a poorer outcome. In this study, we systematically evaluated the clinical outcome in a large patient cohort following thyroidectomy and initial I-131 radioactive iodine therapy (RIT). METHODS: We retrospectively evaluated a total of 378 patients with diagnosed oncocytic follicular Hürthle cell carcinoma (OFTC) (N = 126) or with classical follicular thyroid carcinoma (FTC) (N = 252). Patients received thyroidectomy and complementary I-131 RIT. Clinical data regarding basic demographic characteristics, tumor grade, persistent disease and recurrence during follow-up, and disease-free, disease-specific, and overall survival were collected during follow-up of 6.9 years (interquartile range 3.7; 11.7 years). Univariate and multivariate analyses were used to identify factors associated with disease-related and overall survival. RESULTS: Before and after matching for risk factors, recurrence was significantly more frequently diagnosed in OFTC patients during follow-up (17% vs. 8%; p value 0.037). Likewise, OFTC patients presented with a reduced mean disease-free survival of 17.9 years (95% CI 16.0-19.8) vs. 20.1 years (95% CI 19.0-21.1) in FTC patients (p value 0.027). Multivariate analysis revealed OFTC (HR 0.502; 95% CI 0.309-0.816) as the only independent prognostic factor for disease-free survival. Distant metastases of OFTC patients were significantly less iodine-avid (p value 0.014). Mean disease-specific and overall survival did not differ significantly (p value 0.671 and 0.687) during follow-up of median 6.9 years (3.7; 11.7 years). CONCLUSIONS: Our study suggests that recurrence is more often seen in OFTC patients. OFTC patients have a poorer prognosis for disease-free survival. Thus, OFTC and FTC behave differently and should be categorized separately. However, patients suffering from OFTC present with the same overall and disease-specific survival at the end of follow-up indifferent to FTC patients after initial RIT.

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy.

The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

Effects of the Minimal Extrathyroidal Extension on Early Response Rates after (Adjuvant) Initial Radioactive Iodine Therapy in PTC Patients.

BACKGROUND: Extrathyroidal extension of differentiated thyroid cancer is a poor outcome factor but seems to be less significant in minimal extrathyroidal extension (mETE). However, the impact of mETE on response rate after (adjuvant) initial radioactive iodine (RAI) therapy remains unclear. We therefore compared response rates of patients with classical and follicular variants of papillary thyroid cancer (PTC) according to the updated eighth tumor-node-metastasis (TNM) classification to a control group. METHODS: 455 patients with T3 (primary tumor > 4 cm) PTC according to the seventh classification who underwent total thyroidectomy followed by RAI therapy were screened. Patients formerly classified as T3 PTC solely due to mETE were reclassified into patients with T1 (primary tumor ≤ 2 cm) or T2 (primary tumor > 2 cm but ≤ 4 cm) +mETE and compared to a control group of T1/T2 -mETE PTC patients. RESULTS: 138/455 patients were reclassified as T1/2 +mETE and compared to 317/455 T1/T2 -mETE control patients. At initial presentation, +mETE patients showed significantly higher rates of cervical lymph node metastases (p-value 0.001). Response rates were comparable in both groups (p-value n.s.). N1a/N1b-stage (Hazard ratio, HR 0.716; 95% CI 0.536-0.956, p-value 0.024) was identified as an independent prognostic factor for lower response rates. CONCLUSION: Response rates after RAI therapy were comparable in PTC patients irrespective of mETE but with higher rates of lymph node metastases.

Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter (NIS) gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells.

Purpose: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the NIS gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs). Experimental Design: NIS induction in heat-treated HSP70B-NIS-MSCs was verified by 125I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by 123I-scintigraphy. The most effective uptake regime was then selected for 131I therapy. Results: The HSP70B promoter showed low basal activity in vitro and was significantly induced in response to heat. In vivo, the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated 131I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups. Conclusions: The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic NIS gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.

Long-term outcome of rare oncocytic papillary (Hürthle cell) thyroid carcinoma following (adjuvant) initial radioiodine therapy.

PURPOSE: Oncocytic (Hürthle cell) papillary thyroid carcinoma (OPTC) is a rare variant of the papillary thyroid carcinoma (PTC) which comprises approximately 1 to 11 % of PTC cases. Its clinical course and prognosis have not been comprehensively documented and the clinical outcome remains a controversial issue. Therefore, we investigated the long-term prognosis after thyroidectomy and (adjuvant) initial radioactive iodine therapy (RIT) of OPTC compared to PTC. METHODS: A total of 563 patients (47 with OPTC and 516 with PTC) with a median follow-up of 9.9 (0.3; 23.5) years were studied. All patients underwent thyroidectomy followed by (adjuvant) initial RIT. Data on the patients' demographics, pathology, laboratory findings, imaging studies, treatment, and follow-up including recurrence, and disease-specific survival were collected. Cox's multivariate regression model was used to identify independent prognostic factors for survival. RESULTS: OPTC patients were significantly older (55.2 ± 12.3 years) than PTC patients (50.3 ± 13.5) at the time of initial diagnosis (p value 0.016). Initial tumor size was larger in the OPTC group (2.8 ± 1.8 cm for OPTC patients, 1.5 ± 1.2 cm for PTC patients, p value < 0.001). Before matching, OPTC patients presented more often with evidence of disease at the last visit of follow-up (p value 0.046). However, this difference was not observed anymore after matching for risk factors (p value 0.637). Disease-specific survival did not differ significantly. Age (HR, 1.183; 95% CI, 1.097-1.276) was identified as an independent prognostic factor for disease-specific survival. OPTC patients predominantly showed a recurrence of distant metastasis within a shorter time despite being not statistically significant. CONCLUSION: At initial diagnosis, OPTC shows significant differences in terms of age and initial tumor size compared to PTC. Patients suffering from OPTC present with the same clinical long-term outcome indifferent to PTC after (adjuvant) initial RIT after matching.

Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION: EudraCT 2009-012576-27, NCT0112 6645.

Identification and characterization of myocardial metastases in neuroendocrine tumor patients using 68Ga-DOTATATE PET-CT.

BACKGROUND: Focal 68Ga-DOTATATE PET lesions within the myocardium of neuroendocrine tumor (NET) patients are observed in clinical practice. We determined the frequency and characteristics of lesions that are consistent with cardiac metastasis and assessed the lesion detection rate of conventional imaging. METHODS: 629 patients who underwent 68Ga-DOTATATE PET-CT at a supraregional comprehensive cancer center on NET were included from a consecutive registry. Inclusion criteria were: (1) focal 68Ga-DOTATATE tracer uptake within the myocardium in more than two sequential PET exams, and (2) contrast-enhanced CT. To determine the diagnostic accuracy of conventional CT imaging, a case-control cohort with a ratio of 1:3 was used. PET and CT were independently analyzed by two blinded readers. Cohen's κ was assessed for interreader agreement. Descriptive statistics were applied for frequencies and characteristics and group comparisons were analyzed using the Fisher's exact test. RESULTS: The prevalence of myocardial metastases related to the registry was 2.4% (15 of 629 NET patients fulfilling the inclusion criteria), for a total of 21 myocardial 68Ga-DOTATATE foci detected. Myocardial lesions were most frequently located in the left ventricle (43%) and the septum (43%). No patient demonstrated a pericardial effusion. Patients with myocardial metastases did not differ in demographics, tumor grading, disease stage or circulating tumor markers compared to the overall registry (all p > 0.05). Higher Ki67-Indices were observed (p = 0.049) for patients with myocardial metastases. Interreader agreement for PET assessment was excellent (Cohen's κ = 1.0). CT reading showed a sensitivity of 19% (95% confidence interval: 6-43%) at a specificity of 100% (95% confidence interval: 90-100%). CONCLUSIONS: 68Ga-DOTATATE PET enables detection of myocardial metastatic lesions in NET patients. In contrast, standard morphologic CT imaging provides very limited sensitivity.

Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties?

BACKGROUND: After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine positron emission tomography (18F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases. METHODS: Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBRmax and TBRmean) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to-peak (TTPmin). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation. RESULTS: Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow-up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2-99.1 months). 18F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBRmax 2.9 vs. 2.0, p < 0.001; TBRmean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBRmax and 1.95 for TBRmean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTPmin were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %. CONCLUSIONS: In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions.

Rate of elimination of radioiodine-avid lymph node metastases of differentiated thyroid carcinoma by postsurgical radioiodine ablation. A bicentric study.

SPECT/CT detects radioiodine-positive cervical lymph node metastases (LNMs) of differentiated thyroid carcinoma (DTC) at the time of postsurgical radioablation (RA). Preliminary evidence indicates that the majority of LNMs are successfully treated by RA. The aim of this study was to confirm this evidence in a bicentric setting and to evaluate whether size is a predictor for successful elimination. PATIENTS AND METHODS: Since 01/2007 and 05/2008, respectively, SPECT/spiral-CT is performed routinely in all patients with DTC at RA in two University Clinics. The outcome of iodine-positive LNMs identified by SPECT/CT until 12/2012 was analyzed by follow-up diagnostic 131I scans and serum thyreoglobulin (Tg) values. LNM volume and short-axis diameter were evaluated as prognostic factors by a receiver-operating characteristic (ROC) analysis. RESULTS: 79 patients with 97 iodine-positive LNMs were included. Surgery was carried out in 8 patients with 13 LNMs due to the presence of additional iodine-negative lesions. Of the remaining 84 LNMs, 74 (88%) were successfully treated as demonstrated by radioiodine scans at follow-up. 10 LNMs persisted. 67/70 LNMs smaller than 0.9 ml were treated successfully, whereas this was the case of only 6/14 exceeding this threshold. Using this cut-off level to predict treatment success, sensitivity, specificity, positive and negative predictive value were 92%, 73%, 96%, and 57%. Results for short-axis diameter (cut-off level < 1cm) were 90%, 69%, 94% and 56%. CONCLUSION: RA is effective in the treatment of the majority of 131I-positive LNMs identified in SPECT/CT images. In this study, 88% of iodine-positive LNM in DTC were successfully treated by radioiodine given at RA. Both LNM volume and diameter are reliable predictors of treatment success.

N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus.

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-µPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-µPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of µPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus.

PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.

UNLABELLED: We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). METHODS: Seventy-three patients underwent (18)F-FDG PET/CT before and after 2-4 cycles of neoadjuvant chemotherapy with RHT for STS. Progression-free survival (PFS) and time to local and distant progression were among other factors correlated with response according to PET Response Criteria in Solid Tumors (PERCIST 1.0) and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). RESULTS: Metabolic response by PERCIST (n = 44/73) was an independent predictor for PFS (P = 0.002; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.68) and time to local or distant progression. Other independent predictors for PFS by multivariate analysis were adjuvant radiotherapy (P = 0.010; HR, 0.39; 95% CI, 0.20-0.80) and a baseline tumor size less than 5.7 cm (P = 0.012; HR, 0.43; 95% CI, 0.22-0.83). Response by RECIST 1.1 was seen in a small group of patients (n = 22/73) and allowed prediction of PFS for patients with sarcoma outside the abdomen (P = 0.048; HR, 0.13; 95% CI, 0.02-0.98). CONCLUSION: Metabolic response by (18)F-FDG PET predicts PFS and time to local and distant progression after 2-4 cycles of neoadjuvant chemotherapy plus RHT for STS.

Extrastriatal binding of [¹²³I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls.

PURPOSE: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls. METHODS: SPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding. RESULTS: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2 ± 1.3 % for the thalamus and 6.8 ± 2.9 % for the pons was shown. CONCLUSION: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

Effects of acute detoxification of the herbal blend 'Spice Gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study.

We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.

FET-PET assessed recurrence pattern after radio-chemotherapy in newly diagnosed patients with glioblastoma is influenced by MGMT methylation status.

BACKGROUND AND PURPOSE: The aim of the present study was to evaluate factors predicting the recurrence pattern determined by [(18)F]FET-PET imaging in patients with newly diagnosed glioblastoma after combined radio-chemotherapy treated according to the EORTC/NCIC trial. MATERIAL AND METHODS: Seventy-nine patients with newly diagnosed GBM treated with radiotherapy plus temozolomide (75 mg/m(2)/d) followed by adjuvant cyclic (5/28 days) temozolomide (150-200 mg/m(2)) were retrospectively analysed. Recurrence patterns were assessed by means of positron-emission-tomography with [(18)F]FET and additional MRI; in 54 patients MGMT methylation status was evaluated. RESULTS: Whilst 49.4% of the patients had an in-field recurrence, 12.6% an ex-field recurrence and 3.8% a recurrence at the field margin, 34.2% of the patients did not relapse during follow-up (median 595 days). Considering all patients included in this study, 41.5% (12/29) of the MGMT methylated population had no relapse, 37.9% (11/29) had an in-field-recurrence and 20.7% (6/29) an ex-field/marginal recurrence, whilst 28.0% (7/25) of the MGMT unmethylated population had no relapse, 64.0% (16/25) had an in-field-recurrence and 8.0% (2/25) an ex-field/marginal recurrence (p=0.15). CONCLUSIONS: After the administration of temozolomide concomitant with and adjuvant to radiotherapy in patients with glioblastoma, the pattern determined by [(18)F]FET-PET seems to be associated with MGMT methylation status.

Validation of the octamouse for simultaneous 18F-fallypride small-animal PET recordings from 8 mice.

UNLABELLED: Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D(2/3) ligand (18)F-fallypride serving as a test substance for brain receptor imaging. METHODS: The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the (18)F-fallypride binding potential (BP(ND)) in the striatum were tested in groups of mice receiving (18)F-fallypride at 2 different specific activities (140 and 50 GBq/µmol), with and without scatter correction. Finally, the relationship between BP(ND) and injected dose of (18)F-fallypride (3.5-17 MBq/mouse) was tested. RESULTS: Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of (18)F-fallypride BP(ND) in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BP(ND) by a mean of 6%; covariances of the inter- and intraoperator variability of BP(ND) were 10%. There was a positive correlation between radiochemical dose and BP(ND) with (R(2) = 0.53) and without (R(2) = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum. CONCLUSION: The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of (18)F-fallypride BP(ND) was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BP(ND) on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify (18)F-fallypride BP(ND) in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of diverse radioligands.

Real versus imagined locomotion: a [18F]-FDG PET-fMRI comparison.

The cortical, cerebellar and brainstem BOLD-signal changes have been identified with fMRI in humans during mental imagery of walking. In this study the whole brain activation and deactivation pattern during real locomotion was investigated by [(18)F]-FDG-PET and compared to BOLD-signal changes during imagined locomotion in the same subjects using fMRI. Sixteen healthy subjects were scanned at locomotion and rest with [(18)F]-FDG-PET. In the locomotion paradigm subjects walked at constant velocity for 10 min. Then [(18)F]-FDG was injected intravenously while subjects continued walking for another 10 min. For comparison fMRI was performed in the same subjects during imagined walking. During real and imagined locomotion a basic locomotion network including activations in the frontal cortex, cerebellum, pontomesencephalic tegmentum, parahippocampal, fusiform and occipital gyri, and deactivations in the multisensory vestibular cortices (esp. superior temporal gyrus, inferior parietal lobule) was shown. As a difference, the primary motor and somatosensory cortices were activated during real locomotion as distinct to the supplementary motor cortex and basal ganglia during imagined locomotion. Activations of the brainstem locomotor centers were more prominent in imagined locomotion. In conclusion, basic activation and deactivation patterns of real locomotion correspond to that of imagined locomotion. The differences may be due to distinct patterns of locomotion tested. Contrary to constant velocity real locomotion (10 min) in [(18)F]-FDG-PET, mental imagery of locomotion over repeated 20-s periods includes gait initiation and velocity changes. Real steady-state locomotion seems to use a direct pathway via the primary motor cortex, whereas imagined modulatory locomotion an indirect pathway via a supplementary motor cortex and basal ganglia loop.

FDG-PET mapping the brain substrates of visuo-constructive processing in Alzheimer's disease.

The anatomical basis of visuo-constructive impairment in AD is widely unexplored. FDG-PET can be used to determine functional neuronal networks underlying specific cognitive performance in the human brain. In the present study, we determined the pattern of cortical metabolism that was associated with visuo-constructive performance in AD. We employed two widely used visuo-constructive tests that differ in their demand on visual perception and processing capacity. Resting state FDG-PET scans were obtained in 29 probable AD patients, and cognitive tests were administered. We made a voxel-based regression analysis of FDG uptake to scores in visual test performance, using the SPM5 software. Performance in the CERAD Drawing test correlated with FDG uptake in the bilateral inferior temporal gyri, bilateral precuneus, right cuneus, right supramarginal gyrus and right middle temporal gyrus covering areas of dorsal and ventral visual streams. In contrast, performance in the more complex RBANS Figure Copy test correlated with FDG uptake in the bilateral fusiform gyri, right inferior temporal gyrus, left anterior cingulate gyrus, left parahippocampal gyrus, right middle temporal gyrus and right insula, encompassing the ventral visual stream and areas of higher-level visual processing. The study revealed neuronal networks underlying impaired visual test performance in AD. The extent of involvement of visual and higher order association cortex increased with greater test complexity. From a clinical point of view, both of these widely used visual tests evaluate the integrity of complementary cortical networks and may contribute complementary information on the integrity of visual processing in AD.

A fronto-parietal network is mediating improvement of motor function related to repetitive peripheral magnetic stimulation: A PET-H2O15 study.

Repetitive peripheral magnetic stimulation (RPMS) is a focused and painless stimulation method, in which muscle contractions are elicited by depolarization of the terminal motor branches. Clinical-experimental investigations on different disorders of sensorimotor integration in the last decade have shown that RPMS can be used for the rehabilitation of motor functions after stroke. It is supposed that this therapeutic effect is based on the RPMS-induced proprioceptive inflow to the CNS. To analyze the conditioning effects of RPMS on reorganization of the motor system on cortical level positron emission tomography (PET) is used. Regional cerebral blood flow (rCBF) has been measured using H(2)O(15)-PET in eight patients with arm paresis following focal cerebral ischemic infarction before and after treatment using RPMS on upper arm flexor muscles. Behavioral measures showed a significant improvement of kinematics of finger movements and a reduction of spasticity in the affected arm following RPMS treatment. The recovery was associated with significant increase of neural activation within the superior posterior parietal lobe and the premotor cortex (PM) areas. The increase of activation of the parieto-premotor network following RPMS treatment indicates a significant conditioning effect of RPMS on the cortical level. These results emphasize the positive therapeutic effect of RPMS and describe the physiological bases of its function on the central level.