Thyroglobulin Antibodies and Tumor Epitope-Specific Cellular Immunity in Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients.

The 5-HT1A receptor agonist 8-OH-DPAT modulates motor/exploratory activity, recognition memory and dopamine transporter binding in the dorsal and ventral striatum.

In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.

BRAFV600E and BRAF-WT Specific Antitumor Immunity in Papillary Thyroid Cancer.

One feature of papillary thyroid cancer (PTC) is the frequently present somatic BRAFV600E mutation. PTCs are also characterized by a lymphocytic infiltration, which may correlate with an improved clinical outcome. The objective of the study was the characterization of BRAFV600E specific anti-immunity in PTC patients and correlation analyses with the clinical outcome. Fourteen HLA A2 positive PTC patients were included into the study of whom tumor tissue samples were also available. Of those, 8 PTC patients revealed a somatic BRAFV600E mutation. All PTC patients were also MHC class II typed. Tetramer analyses for detection of MHC class I and MHC class II-restricted, BRAFV600E epitope-specific T cells using unstimulated and peptide-stimulated T cells were performed; correlation analyses between MHC phenotypes, T cell immunity, and the clinical course were performed. In regard to unstimulated T cells, a significantly higher amount of BRAFV600E epitope specific T cells was detected compared to a control tetramer. Importantly, after overnight peptide stimulation a significantly higher number of BRAFV600E positive and BRAF WT epitope-specific T cells could be seen. In regard to the clinical course, however, no significant differences were seen, neither in the context of the initial tumor size, nor in the context of lymph node metastases or peripheral metastastic spread. In conclusion, we clearly demonstrated a BRAF-specific tumor immunity in PTC-patients which is, however, independent of a BRAFV600E status of the PTC patients.

18F-FDG-PET/CT in relapsed multiple myeloma: Are prognostic thresholds different from first-line therapy?

PURPOSE: While 18F-FDG PET/CT yields valuable prognostic information for patients in first-line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first-line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first-line setting. METHODS: Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG-PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET-positive extramedullary lesions (EMD) were analysed. RESULTS: For the number of FLs, the prognostic value was demonstrated with a cut-off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above-mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001). CONCLUSION: The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first-line setting but also in relapsed MM.

Radioiodine therapy reduces the frequency of circulating tumour cells in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of the study was the quantification of circulating tumour cells (CTCs) in differentiated thyroid cancer (DTC) patients before and 6 weeks after radioiodine therapy (RIT). CONTEXT: Circulating tumour cells (CTCs) were described more recently in cancer patients, mostly correlating with poor outcome and advanced metastases. DESIGN: Peripheral blood for identification and quantification of CTC before RIT or/and 6 weeks after RIT was provided by 55 DTC patients that received RIT for remnant tissue ablation. PATIENTS: 13 follicular thyroid cancer (FTC) patients, 31 papillary thyroid cancer (PTC) patients and 11 patients having the follicular variant PTC (FV-PTC) were included. MEASUREMENTS: Peripheral blood mononuclear cells (PBMCs) were isolated and EpCAM-positive CTCs were counted by immune fluorescent staining. RESULTS: A CTC positivity of 31.8% before RIT could be observed. Six weeks after RIT, the CTC positivity was reduced to 13.6%. Paired data at both time points of blood sampling could be gathered for n = 33 DTC patients. These patients had significantly higher CTC numbers before RIT than 6 weeks afterwards (0.27 ± 0.47 vs 0.05 ± 0.15, P = .0215). Additionally, significantly reduced CTC numbers were also demonstrated in pre-RIT CTC-positive patients (0.88 ± 0.43 vs 0.05 ± 0.16, P = .0039). CONCLUSION: Our results indicate a reducing effect on the number of CTCs by RIT. Therefore, CTC enumeration should be considered as efficient tool for treatment monitoring during RIT.

Prospective comparison of the diagnostic accuracy of 18F-FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients.

OBJECTIVES: To compare the diagnostic performance of [18F]FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients. MATERIAL AND METHODS: A cohort of 154 therapy-naive patients with newly diagnosed, histopathologically proven breast cancer was enrolled in this study prospectively. All patients underwent a whole-body [18F]FDG PET/MRI, computed tomography (CT) scan, and a bone scintigraphy prior to therapy. All datasets were evaluated regarding the presence of bone metastases. McNemar χ2 test was performed to compare sensitivity and specificity between the modalities. RESULTS: Forty-one bone metastases were present in 7/154 patients (4.5%). Both [18F]FDG PET/MRI and MRI alone were able to detect all of the patients with histopathologically proven bone metastases (sensitivity 100%; specificity 100%) and did not miss any of the 41 malignant lesions (sensitivity 100%). CT detected 5/7 patients (sensitivity 71.4%; specificity 98.6%) and 23/41 lesions (sensitivity 56.1%). Bone scintigraphy detected only 2/7 patients (sensitivity 28.6%) and 15/41 lesions (sensitivity 36.6%). Furthermore, CT and scintigraphy led to false-positive findings of bone metastases in 2 patients and in 1 patient, respectively. The sensitivity of PET/MRI and MRI alone was significantly better compared with CT (p < 0.01, difference 43.9%) and bone scintigraphy (p < 0.01, difference 63.4%). CONCLUSION: [18F]FDG PET/MRI and MRI are significantly better than CT or bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. Both CT and bone scintigraphy show a substantially limited sensitivity in detection of bone metastases. KEY POINTS: • [18F]FDG PET/MRI and MRI alone are significantly superior to CT and bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. • Radiation-free whole-body MRI might serve as modality of choice in detection of bone metastases in breast cancer patients.

Incidental 18F-FDG uptake in the colon: value of contrast-enhanced CT correlation with colonoscopic findings.

OBJECTIVES: To evaluate the impact of morphological information derived from contrast-enhanced CT in the characterization of incidental focal colonic uptake in 18F-FDG PET/CT examinations. METHODS: A total of 125 patients (female: n = 53, male: n = 72) that underwent colonoscopy secondary to contrast-enhanced, full-dose PET/CT without special bowel preparation were included in this retrospective study. PET/CT examinations were assessed for focal colonic tracer uptake in comparison with the background. Focal tracer uptake was correlated with morphological changes of the colonic wall in the contrast-enhanced CT images. Colonoscopy reports were evaluated for benign, inflammatory, polypoid, precancerous, and cancerous lesions verified by histopathology, serving as a reference standard. Sensitivity, specificity, PPV, NPV, and accuracy for detection of therapeutic relevant findings were calculated for (a) sole focal tracer uptake and (b) focal tracer uptake with correlating CT findings in contrast-enhanced CT. RESULTS: In 38.4% (48/125) of the patients, a focal 18F-FDG uptake was observed within 67 lesions. Malignant lesions were endoscopically and histopathologically diagnosed in eleven patients, and nine of these were detected by focal 18F-FDG uptake. A total of 34 lesions with impact on short- or long-term patient management (either being pre- or malignant) were detected. Sensitivity, Specificity, PPV, NPV, and accuracy for sole 18F-FDG uptake for this combined group were 54%, 69%, 29%, 85%, and 65%. Corresponding results for focal 18F-FDG uptake with correlating CT findings were 38%, 90%, 50%, 86%, and 80%. This resulted in a statistically significant difference for diagnostic accuracy (p = 0.0001) CONCLUSION: By analyzing additional morphological changes in contrast-enhanced CT imaging, the specificity of focal colonic 18F-FDG uptake for precancerous and cancerous lesions can be increased but leads to a considerate loss of sensitivity. Therefore, every focal colonic uptake should be followed up by colonoscopy.

Prospective comparison of whole-body MRI and 68Ga-PSMA PET/CT for the detection of biochemical recurrence of prostate cancer after radical prostatectomy.

PURPOSE: To assess whole-body magnetic resonance imaging (wb-MRI) for detection of biochemical recurrence in comparison to 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) in prostate cancer (Pca) patients after radical prostatectomy. METHODS: This was a prospective trial including 28 consecutive patients (mean age 65.3 ± 9.0 years) with newly documented biochemical recurrence of Pca (mean prostate-specific antigen, PSA, 2.09 ± 1.95 ng/ml) following radical prostatectomy. All patients underwent both wb-MRI including a dedicated pelvic imaging protocol and PET/CT with 166 ± 35 MBq 68Ga-PSMA within a time window of 11 ± 10 days. PET/CT and MRI datasets were separately evaluated regarding Pca lesion count, type, localization and diagnostic confidence (three-point Likert scale, 1-3) by two nuclear medicine specialists and two radiologists, respectively. The reference standard was based on histopathological results, PSA levels following targeted salvage irradiation and follow-up imaging. Lesion-based and patient-based detection rates were compared using the chi-squared test. Differences in diagnostic confidence were assessed using the Welch test. RESULTS: A total of 56 Pca lesions were detected in 20 of the 28 patients. 68Ga-PSMA PET/CT detected 56 of 56 lesions (100%) in 20 patients (71.4%), while wb-MRI detected 13 lesions (23.2%) in 11 patients (39.3%). The higher detection rate with 68Ga-PSMA PET/CT was statistically significant on both a per-lesion basis (p < 0.001) and a per-patient basis (p = 0.0167). In 8 patients (28.6%) no relapse was detectable by either modality. All lesions detected by wb-MRI were also detected by 68Ga-PSMA PET/CT. Additionally, 68Ga-PSMA PET/CT provided superior diagnostic confidence in identifying Pca lesions (2.7 ± 0.7 vs. 2.3 ± 0.6, p = 0.044). CONCLUSION: 68Ga-PSMA PET/CT significantly out-performed wb-MRI in the detection of biochemical recurrence in Pca patients after radical prostatectomy.

Oncological outcome of patients treated with spot-specific salvage lymphnode dissection (sLND) for positron-emission tomography (PET)-positive prostate cancer (PCa) relapse.

OBJECTIVES: To report pre-, postoperative and oncological outcomes in patients treated with spot-specific sLND for patients with exclusive nodal recurrence after PCa primary treatment. MATERIALS AND METHODS: With regard to salvage treatment failure (sTF), 46 consecutive patients, undergoing 52 sLND for nodal recurrence detected by PET/CT scan were stratified in 3 groups (group A: post-sLND PSA nadir < 0.01 ng/ml and in follow-up reaching a value > 0.2 ng/ml, group B: post-sLND PSA nadir > 0.01 ng/ml and in follow-up reaching a value equal to pre-sLND PSA; group C: additional salvage treatment administration). Surgical outcome of patients was analyzed by descriptive statistics (Student's t test for continuous variables, Chi-square and Fisher's test for categorial ones). Time to sTF of each group was analyzed and compared by Kaplan-Meier method and correlations regarding sTF and pre-sLND PSA, time from PCa primary treatment to PET/CT scan, time from PCa primary treatment to sLND and number of positive PET/CT scan spots were assessed. RESULTS: Median PSA at PET/CT scan was 2.9 ng/ml (IQR 1.2-6.1). Open and laparoscopic sLND were performed in 40/52 (77%) and 12/52 (23%), respectively. Median number of removed lymph nodes was 6 (IQR 4-13). Histological report was positive for PCa in 39/52 sLND (75%). Median blood loss was 50 ml (IQR 0-50, range 0-600). Median length of hospital stay was 5 days (IQR 4-6). 4 and 7 patients had low-grade (I/II) and high-grade (≥ III) Clavien-Dindo complications, respectively. Readmission rates at 30 and 90 days were 5/52 (9.6%) and 1/52 (2%), respectively. sTF was observed in 2/7 (group A), 12/12 (group B) and 22/22 patients (group C). Median time to sTF in group B and C was 3.5 (IQR 1.7-13.2) and 4 months (IQR 2.0-10), respectively. CONCLUSION: Even spot-specific PET/CT sLND harbors a measurable (CD > III) morbidity in 1 out of 7 patients. Only patients with positive histological report and a PSA nadir < 0.01 ng/ml after sLND seem to experience a long-term benefit. Patients with a PSA nadir > 0.01 ng/ml have a delay of systemic treatment of up to 4 months. sLND remains an experimental approach and long-term oncological benefit needs an improved selection of patients.

Diagnostic potential of PET/CT using a 68Ga-labelled prostate-specific membrane antigen ligand in whole-body staging of renal cell carcinoma: initial experience.

PURPOSE: To evaluate the diagnostic potential of whole-body PET/CT using a 68Ga-labelled PSMA ligand in renal cell carcinoma (RCC). METHODS: Six patients with histopathologically proven RCC underwent 68Ga-PSMA PET/CT. Each PET/CT scan was evaluated in relation to lesion count, location and dignity. SUVmax was measured in primary tumours and PET-positive metastases. Tumour-to-background SUVmax ratios (TBRSUVmax) were calculated for primary RCCs in relation to the surrounding normal renal parenchyma. Metastasis-to-background SUVmax ratios (MBRSUVmax) were calculated for PET-positive metastases in relation to gluteal muscle. RESULTS: Five primary RCCs and 16 metastases were evaluated. The mean SUVmax of the primary RCCs was 9.9 ± 9.2 (range 1.7 - 27.2). Due to high uptake in the surrounding renal parenchyma, the mean TBRSUVmax of the primary RCCs was only 0.2 ± 0.3 (range 0.02 - 0.7). Eight metastases showed focal 68Ga-PSMA uptake (SUVmax 9.9 ± 8.3, range 3.4 - 25.6). The mean MBRSUVmax of these PET-positive metastases was 11.7 ± 0.2 (range 4.4 - 28.1). All PET-negative metastases were subcentimetre lung metastases. CONCLUSION: 68Ga-PSMA PET/CT appears to be a promising method for detecting RCC metastases. However, no additional diagnostic value in assessing the primary tumour was found.

DAT versus D2 receptor binding in the rat striatum: l-DOPA-induced motor activity is better predicted by reuptake than release of dopamine.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.

FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow-Up Study.

OBJECTIVE: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS). BACKGROUND: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available. METHODS: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19). RESULTS: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences. CONCLUSION: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding.

Diagnostic accuracy of ultrasound, ¹8F-FDG-PET/CT, and fused ¹8F-FDG-PET-MR images with DWI for the detection of cervical lymph node metastases of HNSCC.

OBJECTIVE: This study aimed to compare (18)F-fluorodesoxyglucose positron emission tomography/MRI ((18)F-FDG-PET-MRI) fusion images, including diffusion-weighted imaging (DWI), (18)F-FDG-PET/CT, and ultrasound (US) regarding their performance in nodal staging of patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Eighteen patients prospectively underwent ultrasound examination, (18)F-FDG- PET/CT, and MRI before oral tumor resection and bilateral neck dissection. PET data sets were fused with contrast-enhanced T1-weighted MR images. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for nodal detection were calculated for all the imaging modalities. Furthermore, the accuracy of the correct N-staging was calculated for all methods. Detailed histopathology served as the standard of reference. RESULTS: The sensitivity, specificity, PPV, NPV, and accuracy for detection of lymph node metastases were 63, 99, 86, 96, and 95 % for ultrasound; 30, 97, 56, 92, and 90 % for (18)F-FDG-PET/CT; 52, 96, 59, 94, and 91 % for (18)F-FDG-PET-MRI; and 53, 97, 67, 95, and 92 % for (18)F-FDG-PET-MRI plus DWI, respectively. There was no significant difference in the diagnostic accuracy for lymph node metastasis detection between (18)F-FDG-PET-MRI and (18)F-FDG-PET/CT (p = 0.839) and between (18)F-FDG-PET-MRI plus DWI and (18)F-FDG-PET/CT (p = 0.286), respectively. US was significantly more accurate than (18)F-FDG-PET/CT (p = 0.009), whereas no significant difference was seen between (18)F-FDG-PET-MRI and US (p = 0.223) or (18)F-FDG-PET-MRI plus DWI and US (p = 0.115). The nodal stage was correctly rated by (18)F-FDG-PET-MRI in eight patients, (18)F-FDG-PET-MRI plus DWI in nine patients, US in 12 patients, and (18)F-FDG-PET/CT in five out of 18 patients. CONCLUSION: Software-based fusion of (18)F-FDG-PET-MRI and (18)F-FDG-PET-MRI plus DWI may not increase nodal detection and N-staging performance in patients with oral malignancies compared to US and (18)F-FDG-PET/CT. CLINICAL RELEVANCE: Surgical staging of cervical lymph nodes will not be replaced even by advanced imaging modalities in the near future.

5-HT1A and 5-HT2A receptor effects on recognition memory, motor/exploratory behaviors, emotionality and regional dopamine transporter binding in the rat.

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.

2,5-Dimethoxy-4-iodoamphetamine and altanserin induce region-specific shifts in dopamine and serotonin metabolization pathways in the rat brain.

PURPOSE: For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat. METHODS: Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography. RESULTS: DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP. CONCLUSIONS: DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.

[Breakeven Analysis for Imaging Devices: Basic Introduction with Presentation of a User-Friendly Tool for in-clinic Calculation Using PET/CT as an Example]. / Gewinnschwellenanalyse bei Bildgebungsgeräten: Grundlegende Einführung mit Vorstellung eines nutzungsfreundlichen Tools zur klinikinternen Kalkulation am Beispiel PET/CT.

BACKGROUND: Imaging devices such as PET/CT are becoming increasingly important in view of the growing range of innovative nuclear medicine diagnostic procedures. Since the procurement and commissioning as well as the ongoing operation of imaging devices leads to comparatively high costs, it is of great interest for clinics and practices to know the number of scans from which the (planned) device operation leads to a profit. In the following, we will introduce the breakeven point analysis and present a calculation tool that users in nuclear medicine clinics and practices can use in everyday operations using PET/CT as an example. METHODS: In the breakeven point analysis, the intersection point is determined from which the organisation- or device-specific revenues exceed the total costs incurred for personnel, material resources, etc. For this purpose, the fixed and variable (planned) cost components for the procurement and operation of the device must be prepared on the cost side and the respective device-related (planned) revenue structure on the revenue side. RESULTS: The authors present the break-even analysis method with the data processing required for this using the example of the planned procurement or ongoing operation of a PET/CT. In addition, a calculation tool was developed, that interested users can use to prepare a device-specific break-even analysis. For this purpose, various cost and revenue data are discussed, which have to be compiled and processed within the clinic and entered into prepared spreadsheets. CONCLUSION: The breakeven point analysis can be used to determine the profit/loss (point) for the (planned) operation of imaging devices such as PET/CT. Users from imaging clinics/practices and administration can adapt the calculation tool presented to their specific facility and thus use it as a basic document for both the planned procurement and the ongoing operational control of imaging devices in everyday clinical practice.

Intra-Individual Comparison of Physiologic [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 Uptake in Ganglia in Patients with Prostate Cancer: A Retrospective, Monocentric Analysis.

BACKGROUND: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. METHODS: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56-85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. RESULTS: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. CONCLUSION: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.

Head-to-Head Intra-Individual Comparison of Biodistribution and Tumor Uptake of [18F]FAPI-74 with [18F]FDG in Patients with PDAC: A Prospective Exploratory Study.

BACKGROUND: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called "desmoplastic reaction", leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with 68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with 18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. METHODS: This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1-15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61-91 min) and 66.4 ± 6.3 min (range 60-76 min), respectively, after administration of 200 ± 94 MBq (range 79-318 MBq) and 235 ± 88 MBq (range 90-321 MBq), respectively. Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. RESULTS: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. CONCLUSION: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.