Publications by authors named "Hubertus Hautzel"

59 Publications

N-staging in large cell neuroendocrine carcinoma of the lung: diagnostic value of [F]FDG PET/CT compared to the histopathology reference standard.

EJNMMI Res 2021 Jul 22;11(1):68. Epub 2021 Jul 22.

Department of Thoracic Surgery and Endoscopy, West German Lung Center, Ruhrlandklinik - University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression, LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[F]-fluoro-deoxyglucose ([F]FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of [F]FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the [F]FDG PET/CT findings.

Methods: Between 03/2014 and 12/2020, 46 patients with LCNEC were included in this single center retrospective analysis. All underwent [F]FDG PET/CT for pre-operative staging and subsequently either surgery (n = 38) or mediastinoscopy (n = 8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for [F]FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference.

Results: Per patient 14 ± 7 (range 4-32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients, the final stage was pN1, in 5/46 pN2 and in 2/46 pN3. [F]FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. In the four false positive cases, the [F]FDG uptake of the lymph nodes was 33 to 67% less in comparison with that of the respective LCNEC primary. Interrater-reliability was high with a strong level of agreement (κ = 0.82).

Conclusions: In LCNEC N-staging with [F]FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by [F]FDG PET/CT. In [F]FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate [F]FDG uptake as compared to the LCNEC primary.
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http://dx.doi.org/10.1186/s13550-021-00811-9DOI Listing
July 2021

PROGNOSTIC VALUE OF POST-INDUCTION CHEMOTHERAPY VOLUMETRIC PET/CT PARAMETERS FOR STAGE IIIA/B NON-SMALL CELL LUNG CANCER PATIENTS RECEIVING DEFINITIVE CHEMORADIOTHERAPY.

J Nucl Med 2021 May 20. Epub 2021 May 20.

1. Department for Radiotherapy, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany 2. German Cancer Consortium, Partner Site University Hospital Essen, Essen, Germany.

The aim of this follow-up analysis of the ESPATUE phase-3 trial was to explore the prognostic value of post-induction chemotherapy PET metrics in patients with stage III non-small cell lung cancer (NSCLC) who were assigned to receive definitive chemoradiotherapy. All eligible patients stage IIIA (cN2) and stage IIIB of the trial received induction chemotherapy consisting of 3 cycles of cisplatin/paclitaxel and chemoradiotherapy up to 45 Gy/1.5 Gy per fraction twice-a-day, followed by a radiation-boost with 2 Gy once per day with concurrent cisplatin/vinorelbine. The protocol definition prescribed a total dose of 65-71 Gy. F-FDG-PET/CT (PETpre) was performed at study entry and before concurrent chemoradiotherapy (interim-PET; PETpost). Interim PETpost metrics and known prognostic clinical parameters were correlated in uni- and multivariable survival analyses. Leave-one-out cross-validation was used to show internal validity. Ninety-two patients who underwent F-FDG-PET/CT after induction chemotherapy were enrolled. Median MTVpost value was 5.9 ml. Altogether 85 patients completed the whole chemoradiation with the planned total dose of 60-71 Gy. In univariable proportional hazard analysis, each of the parameters MTVpost, SUV(post) and TLGmax(post) was associated with overall survival ( < 0.05). Multivariable survival analysis, including clinical and post-induction PET parameters, found TLGmax(post) (hazard ratio: 1.032 (95%-CI: 1.013-1.052) per 100 ml increase) and total radiation dose (hazard ratio: 0.930 (0.902-0.959) per Gray increase) significantly related with overall survival in the whole group of patients, and also in patients receiving a total dose ≥ 60 Gy. The best leave-one-out cross-validated 2 parameter classifier contained TLGmax(post) and total radiation dose. TLGmax(post) was associated with time to distant metastases ( = 0.0018), and SUV(post) with time to loco-regional relapse ( = 0.039) in multivariable analysis of patients receiving a total dose ≥ 60 Gy. Post-induction chemotherapy PET parameters demonstrated prognostic significance. Therefore, an interim F-FDG-PET/CT is a promising diagnostic modality for guiding individualized treatment intensification.
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http://dx.doi.org/10.2967/jnumed.120.260646DOI Listing
May 2021

Insights into immunometabolism: A dataset correlating the FDG PET/CT maximum standard uptake value of the primary tumor with the CCL18 serum level in non-small cell lung cancer.

Data Brief 2021 Apr 18;35:106859. Epub 2021 Feb 18.

Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, West German Cancer Center, University Hospital, University of Duisburg-Essen, Essen, Germany.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the western world [1]. Despite multiple therapeutic and diagnostic advances, the overall survival is low and recurrence of NSCLC is a common problem with different treatment regimens. The inclusion of fluorine fluorodeoxyglucose (FDG) positron emission tomography (PET) in combination with computed tomography (CT) in clinical practice was revolutionary for the staging of NSCLC [2]. FDG-PET/CT provides morphological, functional, and metabolic information about the tumor, which is usually highly, metabolically active. Due to the increased glucose uptake, FDG is actively accumulatedin the tumor tissues, resulting in an increased standardized uptake value (SUV). The tumor tissue itself consists of neoplastic cells, extracellular matrix, fibroblasts, and various immune cells. These immune cells include tumor-infiltrating lymphocytes, regulatory T cells, and macrophages. Macrophages have different activation patterns and play an essential role in inflammation and cancer. In particular, tumor-associated macrophages (TAMs) are a specialized group of alternatively activated or M2 macrophages. TAMs release several chemokines that are different from those released by classically activated macrophages found in an inflammatory environment. One of the most important chemokines released by TAMs is CC-chemokine ligand 18 (CCL18). Although CCL18 is present in healthy subjects, its levels are significantly elevated in the serum of patients with NSCLC. It correlates with overall survival and tumor stage in several malignant diseases [3,4]. A recurring problem is that increased glucose metabolism can be found in the inflammatory tissue, which can also lead to an increased SUV in FDG PET/CT, lowering its oncological specificity [5]. In a previous study, we demonstrated that serum CCL18 levels can be used to differentiate between patients with NSCLC and healthy subjects [3]. Hence, we investigated the correlation between serum CCL18 levels and the maximum standardized uptake value (SUV) of the primary tumor using FDG-PET/CT. We found a significant correlation between the SUV of the primary tumor and the serum CCL18 level. The data are important because they can be used to draw conclusions about immunometabolism. Furthermore, they can serve as basis for future prospective clinical studies.
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http://dx.doi.org/10.1016/j.dib.2021.106859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905341PMC
April 2021

Preoperative chest computed tomography evaluation for predicting intraoperative lung resection strongly depends on interpreters experience.

Lung Cancer 2021 04 18;154:23-28. Epub 2021 Feb 18.

Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany. Electronic address:

Objectives: Preoperative planning of lung resection extent is decisive for preoperative functional work-up and selection for multimodal treatment. It is mainly based on preoperative chest CT. We aimed at evaluating chest CT adequacy to predict the extent of lung resection and hypothesized a relation with CT interpreters' level of experience.

Materials And Methods: A pseudonymized CT library was built from patients who had curative intent lung resection for centrally located NSCLC. CT library was interpreted by 20 thoracic surgery residents or attendings. Interpreters were blinded to intraoperative findings and scored one point when lung resection was adequately planned. Points were summed up in a score from 0 to 20. Interpreters' experience was evaluated through nine variables: age, position (resident vs. attending), years of experience in evaluating chest CTs, number of anatomic resections and sleeve resections attended as first assistant or performed as surgeon in presence of a teaching assistant or as main surgeon/teaching assistant. Variables characterizing interpreters' experience were divided into equal sized groups. Independent sample T-test and one-way ANOVA/Tukey post hoc tests were used to compare scores between groups.

Results: CT library included 20 patients. Lung resections were lobectomy (n = 7, 35 %), sleeve lobectomy (n = 10, 50 %), sleeve bilobectomy (n = 2, 10 %), pneumonectomy (n = 1, 5%). Twenty interpreters scored a median of 10 (4-14). Attending surgeons had significantly higher mean scores (11.2 ± 1.3) compared to residents (7.7 ± 2.3, p = 0.001). All scores were significantly different between groups related to interpreters' levels of experience, except for interpreters'age.

Conclusion: Preoperative CT evaluation for predicting intraoperative lung resection for centrally located NSCLC strongly depends on interpreters' experience.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.004DOI Listing
April 2021

Impact of EBUS-TBNA in addition to [F]FDG-PET/CT imaging on target volume definition for radiochemotherapy in stage III NSCLC.

Eur J Nucl Med Mol Imaging 2021 08 5;48(9):2894-2903. Epub 2021 Feb 5.

Department of Radiotherapy, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany.

PURPOSE/INTRODUCTION: [F]FDG-PET/CT is the standard imaging-technique for radiation treatment (RT) planning in locally advanced non-small cell lung cancer (NSCLC). The purpose of this study was to examine the additional value of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) to standard PET/CT for mediastinal lymph-node (LN) staging and its impact on clinical target volume (CTV).

Materials And Methods: All consecutive patients with primary stage III NSCLC who underwent [F]FDG-PET/CT and EBUS-TBNA prior to RT were analyzed from 12/2011 to 06/2018. LN-stations were assessed by an expert-radiologist and a nuclear medicine-physician. CTV was evaluated by two independent radiation oncologists. LNs were grouped with increasing distance along the lymphatic chains from primary tumor into echelon-1 (ipsilateral hilum), echelon-2 (LN-station 7 and ipsilateral 4), and echelon-3 (remaining mediastinum and contralateral hilum).

Results: A total of 675 LN-stations of which 291 were positive for tumor-cells, were sampled by EBUS-TBNA in 180 patients. The rate of EBUS-positive LNs was 43% among all sampled LNs. EBUS-positivity in EBUS-probed LNs decreased from 85.8% in echelon-1 LNs to 42.4%/ 9.6% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). The false discovery rate of PET in comparison with EBUS results rose from 5.3% in echelon-1 to 32.9%/ 69.1% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). Sensitivity and specificity of FDG-PET/CT ranged from 85 to 99% and 67 to 80% for the different echelons. In 22.2% patients, EBUS-TBNA finding triggered changes of the treated CTV, compared with contouring algorithms based on FDG-avidity as the sole criterion for inclusion. CTV was enlarged in 6.7% patients due to EBUS-positivity in PET-negative LN-station and reduced in 15.5% by exclusion of an EBUS-negative but PET-positive LN-station.

Conclusion: The false discovery rate of [F]FDG-PET/CT increased markedly with distance from the primary tumor. Inclusion of systematic mediastinal LN mapping by EBUS-TBNA in addition to PET/CT has the potential to increase accuracy of target volume definition, particularly in echelon-3 LNs. EBUS-TBNA is recommended as integral part of staging for radiochemotherapy in stage III NSCLC.
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http://dx.doi.org/10.1007/s00259-021-05204-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263445PMC
August 2021

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

Clin Endocrinol (Oxf) 2021 Jun 4;94(6):1004-1011. Epub 2021 Feb 4.

Division for Specific Endocrinology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany.

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.
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http://dx.doi.org/10.1111/cen.14419DOI Listing
June 2021

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

Rev Neurosci 2020 Aug;31(6):569-588

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.
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http://dx.doi.org/10.1515/revneuro-2019-0112DOI Listing
August 2020

Superior Vena Cava Syndrome Induced Collateral Circulation on 99mTc-Macroaggregated Albumin Lung Perfusion Scintigraphy.

Clin Nucl Med 2020 Oct;45(10):e435-e438

From the Departments of Nuclear Medicine.

Perfusion lung scintigraphy using SPECT/CT is one mainstay in diagnosing pulmonary embolism. Although typically almost all tracer will be accumulated in the lung capillaries, occasionally abnormal uptake can be detected. As superior vena cava syndrome leads to aberrant blood flow, tracer injected to an arm vein might partly circumvent the pulmonary capillary bed and accumulate in well-perfused anatomical structures. In this case, next to the commonly described liver enhancement, more prominent pseudo-uptake of various thoracic vertebrae was observable. However, a time-related FDG PET/CT demonstrated only the hepatic pseudo-uptake. Taken together, careful assessment of superior vena cava syndrome patient studies is highly recommended.
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http://dx.doi.org/10.1097/RLU.0000000000003127DOI Listing
October 2020

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

Hematol Oncol 2020 Aug 18;38(3):244-256. Epub 2020 Feb 18.

Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund, Germany.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV ) and SUV thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUV approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm using SUV and 460 cm using SUV . For iPET response, the respective thresholds were 46.9% SUV reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV and SUV , and 29% and 25% for iPET response by ΔSUV and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV and 3.206 (1.524-6.743) for SUV . At iPET, it was 3.910 (1.891-8.087) for ΔSUV and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
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http://dx.doi.org/10.1002/hon.2697DOI Listing
August 2020

Differential effects of D-cycloserine and amantadine on motor behavior and D receptor binding in the nigrostriatal and mesolimbic system of the adult rat.

Sci Rep 2019 11 6;9(1):16128. Epub 2019 Nov 6.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, D-40225, Düsseldorf, Germany.

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine DR binding in the brain of adult rats in relation to motor behavior. DR binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased DR binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased DR binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of DR binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of DR binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.
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http://dx.doi.org/10.1038/s41598-019-52185-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834679PMC
November 2019

Integration of Bronchoscopic Transesophageal Ultrasound Examination of the Left Adrenal Gland into Routine Lung Cancer Staging Workup: A Prospective Trial.

Respiration 2020;99(1):43-49. Epub 2019 Oct 16.

Division of Interventional Pneumology, Department of Pulmonary Medicine, Ruhrlandklinik, University Medicine Essen, Essen, Germany.

Background: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed.

Objective: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure.

Methods: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA.

Results: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications.

Conclusions: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup.
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http://dx.doi.org/10.1159/000503396DOI Listing
April 2021

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

Eur J Nucl Med Mol Imaging 2019 Jul 16;46(7):1542-1550. Epub 2019 Mar 16.

Department of Nuclear Medicine, University Dusseldorf, Medical Faculty, 40225, Dusseldorf, Germany.

Purpose: To assess whole-body magnetic resonance imaging (wb-MRI) for detection of biochemical recurrence in comparison to Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (Ga-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 Ga-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. Ga-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 Ga-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 Ga-PSMA PET/CT. Additionally, Ga-PSMA PET/CT provided superior diagnostic confidence in identifying Pca lesions (2.7 ± 0.7 vs. 2.3 ± 0.6, p = 0.044).

Conclusion: Ga-PSMA PET/CT significantly out-performed wb-MRI in the detection of biochemical recurrence in Pca patients after radical prostatectomy.
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http://dx.doi.org/10.1007/s00259-019-04308-5DOI Listing
July 2019

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

World J Urol 2019 Oct 14;37(10):2081-2090. Epub 2019 Jan 14.

Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.

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.
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http://dx.doi.org/10.1007/s00345-019-02633-wDOI Listing
October 2019

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity.

Pharmacol Biochem Behav 2019 04 11;179:156-170. Epub 2019 Jan 11.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Purpose: The present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine DR binding in relation to motor and exploratory activity in the rat.

Methods: DR binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region.

Results: 40 mg/kg AMA reduced DR binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased DR binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge.

Conclusions: Results showed reductions of DR binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.
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http://dx.doi.org/10.1016/j.pbb.2018.12.010DOI Listing
April 2019

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Ann Hematol 2019 Apr 4;98(4):897-907. Epub 2019 Jan 4.

Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
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http://dx.doi.org/10.1007/s00277-018-3578-0DOI Listing
April 2019

Acute anxiety disorder, major depressive disorder, bipolar disorder and schizophrenia are related to different patterns of nigrostriatal and mesolimbic dopamine dysfunction.

Rev Neurosci 2019 05;30(4):381-426

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Dopamine (DA) receptor and transporter dysfunctions play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) in the manic (BDman) or depressive (BDdep) state and schizophrenia (SZ). We performed a PUBMED search, which provided a total of 239 in vivo imaging studies with either positron emission tomography (PET) or single-proton emission computed tomography (SPECT). In these studies, DA transporter binding, D1 receptor (R) binding, D2R binding, DA synthesis and/or DA release in patients with the primary diagnosis of acute AD (n=310), MDD (n=754), BDman (n=15), BDdep (n=49) or SZ (n=1532) were compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BDman, BDdep and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and/or receptor binding sites. In contrast to AD and SZ, in MDD, BDman and BDdep, neostriatal DA function was normal, whereas MDD, BDman, and BDdep were characterized by the increased availability of prefrontal and frontal DA. In contrast to AD, MDD, BDman and BDdep, DA function in SZ was impaired throughout the nigrostriatal and mesolimbocortical system with an increased availability of DA in the striatothalamocortical and a decreased availability in the mesolimbocortical pathway.
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http://dx.doi.org/10.1515/revneuro-2018-0037DOI Listing
May 2019

Increased Numbers of Circulating Tumor Cells in Thyroid Cancer Patients.

Horm Metab Res 2018 Aug 6;50(8):602-608. Epub 2018 Aug 6.

Division for Specific Endocrinology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany.

Circulating tumor cells (CTCs) have been shown to be a valuable prognostic marker for different solid cancers. Within the present study we quantified CTCs in thyroid cancer (TC) patients. Special focus was given to disease-free PTC patients with undetectable serum thyroglobulin (Tg) levels. Altogether, 67 TC patients (33 papillary, 20 follicular, 14 medullary) were included in the study. CTC numbers, which were normalized to 3.3×10 peripheral blood mononuclear cells, were correlated with clinical outcome. TC patients had significantly higher CTC numbers compared to controls. The number of CTCs correlated to the initial tumor stage. Importantly, in comparison to controls, differentiated TC patients with serum Tg levels<0.3 ng/ml (no evidence of tumor recurrence) revealed a significantly higher amount of CTCs, also associated to their former tumor stage. Regarding the tumor-free papillary TC (PTC) patients the number of CTCs additionally correlated to the time point of radioiodine (RI) therapy: PTC patients with RI therapies>8 years before CTC measurement had significantly higher CTC numbers compared to those with RI therapy<8 years ago. We found a clear correlation between the number of CTCs and the tumor stage. Importantly, PTC patients who are in remission may still have increased numbers of CTCs. Follow-up analyses in these patients will reveal whether these data will have a clinical impact.
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http://dx.doi.org/10.1055/a-0651-4913DOI Listing
August 2018

GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain.

Front Behav Neurosci 2018 14;12:38. Epub 2018 Mar 14.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

The present study assessed the effects of the GABA receptor (R) agonist muscimol (MUS), and the GABAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine DRs in relation to motor and exploratory behaviors in the rat. DR binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region. After MUS, DR binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ ≤ 0.012). In all these areas, except for the thalamus, DR binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, DR binding was significantly elevated in caudateputamen ( = 0.022) and thalamus ( = 0.047) relative to baseline. DR binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time. Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.
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http://dx.doi.org/10.3389/fnbeh.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862131PMC
March 2018

Evaluation of Practical Interpretation Hurdles in 68Ga-PSMA PET/CT in 55 Patients: Physiological Tracer Distribution and Incidental Tracer Uptake.

Clin Nucl Med 2017 Jul;42(7):e322-e327

From the Departments of *Diagnostic and Interventional Radiology, and †Nuclear Medicine, University Dusseldorf, Medical Faculty, Dusseldorf; ‡Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Juelich Research Center, Juelich; and §Department of Urology, University Dusseldorf, Medical Faculty, Dusseldorf, Germany.

Purpose: To investigate the physiologic Ga-PSMA distribution and evaluate focal or diffuse radiotracer uptake in nonprostate cancer malignancies and in incidental findings.

Methods: Ga-PSMA PET/CT scans in 55 men performed for prostate cancer (49) or renal cell carcinoma (6) staging were analyzed retrospectively. Two radiologists evaluated the datasets in 2 reading sessions. First, physiological Ga-PSMA uptake was evaluated. Second, scans were analyzed for incidental uptake. SUVmax and SUVmean were recorded. Other imaging modalities, histopathology, or clinical follow-up served as standard of reference.

Results: Homogenous Ga-PSMA uptake of the lacrimal glands (SUVmax, 15.7 ± 7.2), parotid glands (SUVmax, 24.4 ± 8.1), submandibular glands (SUVmax, 26.7 ± 7.1), vocal cords (SUVmax, 8.4 ± 3), Waldeyer ring (SUVmax, 10.4 ± 4.3), liver (SUVmax, 8.2 ± 2.5), spleen (SUVmax, 10.9 ± 3.9), kidneys (SUVmax, 66.4 ± 25.4), and pars descendens duodeni (SUVmax, 17.6 ± 8.9) was observed in all patients. In 65% and 36%, respectively, homogenous Ga-PSMA uptake of the colon descendens (SUVmax, 10.6 ± 9.2) and the rectum (SUVmax, 3.7 ± 1.1) was found. Approximately 22% exhibited a Ga-PSMA uptake of the thyroid (SUVmax, 4.5 ± 1.2), and 21% exhibited a Ga-PSMA uptake of the knee's synovia (SUVmax, 2.9 ± 0.2). Furthermore, Ga-PSMA uptake was found in 1 patient because of fibrous dysplasia of the right os ilium (SUVmax, 7.7).

Conclusions: Physiologic distribution of Ga-PSMA comprises uptake in lacrimal and salivary glands, vocal cords, Waldeyer ring, liver, spleen, and kidneys as well as various parts of the intestine. Moreover, nonspecific tracer uptake is regularly found in the thyroid and the synovia of the knee. Incidental Ga-PSMA uptake can occasionally reveal nonprostate cancer-associated remodeling processes, such as fibrous dysplasia.
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http://dx.doi.org/10.1097/RLU.0000000000001672DOI Listing
July 2017

Different patterns of dopaminergic and serotonergic dysfunction in manic, depressive and euthymic phases of bipolar disorder.

Nuklearmedizin 2017 4;56(5):191-200. Epub 2018 Jan 4.

A variety of alterations in brain neurotransmitter systems has been proposed as the cause of bipolar disorder (BD). We conducted a PUBMED search, which provided a total of 45 in vivo investigations with PET and SPECT, in which binding to serotonin transporter (SERT), 5-HT receptor (R), 5-HTR, dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), DR, DR, muscarinic M2R and nicotinic ß2-nAChR as well as dopamine synthesis and/or dopamine release were assessed in BD patients in the manic (6 studies, 39 patients, 77 controls), depressive (15 studies, 248 patients, 488 controls) or eu- thymic condition (18 studies, 265 patients, 293 controls) and in mixed collectives of BD patients (6 studies, 55 patients, 80 controls). The retrospective analysis revealed a complex pattern of dysregulations within and between neurotransmitter systems, which is causally linked to the acute and euthymic states of BD. While increased mesencephalic, limbic and parietotemporoccipital serotonin and increased frontal dopamine underlie mania, the depressive state is characterized by decreased frontal and limbic serotonin, increased frontal and limbic acetylcholine and increased frontal dopamine. Also in euthymia, no normalization of receptor and transporter densities was observed. Alterations of regulation states of bindings sites, however, act together to achieve a normalization of mesencephalic, limbic and cortical serotonin.
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http://dx.doi.org/10.3413/Nukmed-0893-17-04DOI Listing
November 2018

GABAergic control of neostriatal dopamine D receptor binding and behaviors in the rat.

Pharmacol Biochem Behav 2017 02 21;153:76-87. Epub 2016 Dec 21.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Purpose: The present study assessed the influence of the GABA receptor agonist muscimol and the GABA receptor antagonist bicuculline on neostriatal dopamine D receptor binding in relation to motor and exploratory behaviors in the rat.

Methods: D receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30min in an open field prior to administration of [I]S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([I]IBZM). For baseline and challenges, striatal equilibrium ratios (V″) were computed as estimation of the binding potential.

Results: Muscimol but not bicuculline reduced D receptor binding relative to baseline and to saline. Travelled distance, duration of rearing and frequency of rearing and of head-shoulder motility were lower after muscimol compared to saline. In contrast, duration of rearing and grooming and frequency of rearing, head-shoulder motility and grooming were elevated after bicuculline relative to saline. Moreover, bicuculline decreased duration of sitting and head-shoulder motility.

Conclusions: The muscimol-induced decrease of motor/exploratory behaviors can be related to an elevation of striatal dopamine levels. In contrast, bicuculline is likely to elicit a decline of synaptic dopamine, which, however, is compensated by the time of D receptor imaging studies. The results indicate direct GABAergic control over D receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.
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http://dx.doi.org/10.1016/j.pbb.2016.12.012DOI Listing
February 2017

Epitope-Specific Antitumor Immunity Suppresses Tumor Spread in Papillary Thyroid Cancer.

J Clin Endocrinol Metab 2017 07;102(7):2154-2161

Division for Specific Endocrinology, Medical Faculty, University of Duesseldorf, 40225 Duesseldorf, Germany.

Context: Papillary thyroid cancer (PTC) is characterized by a lymphocytic infiltration. PTC patients with lymphocytic infiltration may have a better clinical outcome.

Objective: Characterization of tumor epitope-specific immunity and correlation analyses with the clinical outcome.

Patients: 150 PTC patients; 40 Hashimoto thyroiditis (HT) patients; 21 healthy controls; 27,239 healthy whites (for HLA typing).

Main Outcome Measures: HLA class I restricted thyroperoxidase (TPO) and thyroglobulin (Tg) epitope-specific T cells (tetramer analyses), correlation analyses between HLA class II phenotypes, T cell immunity, and the clinical course.

Results: The frequency of TPO- and Tg-specific CD8+ T cells in PTC patients was largely increased compared with healthy controls (TPO and Tg, P < 0.005 and P < 0.005) and was similar to those in HT patients. HLA-DQB1*03-positive PTC patients had a significantly lower risk [risk ratio (RR), 0.170; 95% confidence interval (CI), 0.037 to 0.755; P < 0.05] and HLA-DRB1*03-positive and HLA-DQB1*02-positive PTC patients a significantly higher risk (HLA-DRB1*03: RR, 4.400; 95% CI, 1.378 to 14.05; P < 0.05; HLA-DQB1*02: RR, 3.692; 95% CI, 1.102 to 12.38; P < 0.05) for distant metastases, compared with patients with other haplotypes. HLA-DQB1*03-positive PTC patients revealed an increased responsiveness of tumor epitopes in vitro. These tumor epitope-specific CD8+ T cells were also found in lymph node metastases of HLA-DQB1*03-positive PTC patients.

Conclusion: We demonstrate a tumor epitope-specific immunity in PTC patients and the protective role of HLA-DQB1*03 against metastatic spread. These results have direct implications for new treatment options with immune checkpoint inhibitors.
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http://dx.doi.org/10.1210/jc.2016-2469DOI Listing
July 2017

11C-acetate positron-emission tomography/computed tomography imaging for detection of recurrent disease after radical prostatectomy or radiotherapy in patients with prostate cancer.

BJU Int 2017 09 5;120(3):337-342. Epub 2016 Dec 5.

Department of Urology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Objectives: To evaluate, in a prospective study, the effectiveness of computed tomography (CT)-matched 11C-acetate (AC) positron-emission tomography (PET) in patients with prostate cancer (PCa) who had prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or radiotherapy (RT).

Patients And Methods: In 103 relapsing patients after RP (n = 97) or RT (n = 6) AC-PET images and CT scans were obtained. In patients with AC-PET-positive results with localized PCa recurrence, detected lesions were resected and histologically verified or, after local RT, followed-up by PSA testing. Patients with distant disease on AC-PET were treated with androgen deprivation/chemotherapy.

Results: Of 103 patients, 42 were AC-PET-positive. PSA levels were <1.0, <2.0 and <4.0 ng/mL in six, 16 and 20 patients, respectively. In 25/42 patients AC-PET suggested lymph node metastases: 16/25 patients underwent surgery (10/16 metastasis, 6/16 inflammation); 9/25 patients underwent RT of lymph node metastases, which was followed by decreasing PSA level. In 17/42 patients who had distant disease, systemic treatment was commenced. Combining patients who underwent surgery and those who underwent RT, 19/25 patients were true-positive in terms of AC-PET (positive predictive value 76%). In 5/19 patients, PSA level was <2.0 ng/mL, in 2/19 patients it was <1.0 ng/mL and in 14/19 patients it was 5.4-23.1 ng/mL. In AC-PET-positive patients after surgery or RT (without androgen deprivation), median (range) time to renewed PSA increase was 6 (5-9) months.

Conclusions: Only a minority of patients with relapsing PCa appear to benefit from AC-PET for guiding potential local treatment. False-positive results show that factors other than tumour metabolism induce increased AC uptake. The time free of recurrence after local treatment was shorter than expected.
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http://dx.doi.org/10.1111/bju.13706DOI Listing
September 2017

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

Synapse 2016 09 30;70(9):369-77. Epub 2016 May 30.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, D-40225, Germany.

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.
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http://dx.doi.org/10.1002/syn.21911DOI Listing
September 2016

Corrigendum: Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2016 15;10:36. Epub 2016 Mar 15.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

[This corrects the article on p. 352 in vol. 9, PMID: 26778989.].
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http://dx.doi.org/10.3389/fnbeh.2016.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791392PMC
March 2016

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

Eur J Nucl Med Mol Imaging 2017 Jan 21;44(1):102-107. Epub 2016 Mar 21.

Medical Faculty, Department of Nuclear Medicine, University Dusseldorf, 40225, Dusseldorf, Germany.

Purpose: To evaluate the diagnostic potential of whole-body PET/CT using a Ga-labelled PSMA ligand in renal cell carcinoma (RCC).

Methods: Six patients with histopathologically proven RCC underwent Ga-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 (TBR) were calculated for primary RCCs in relation to the surrounding normal renal parenchyma. Metastasis-to-background SUVmax ratios (MBR) 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 TBR of the primary RCCs was only 0.2 ± 0.3 (range 0.02 - 0.7). Eight metastases showed focal Ga-PSMA uptake (SUVmax 9.9 ± 8.3, range 3.4 - 25.6). The mean MBR of these PET-positive metastases was 11.7 ± 0.2 (range 4.4 - 28.1). All PET-negative metastases were subcentimetre lung metastases.

Conclusion: Ga-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.
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http://dx.doi.org/10.1007/s00259-016-3360-2DOI Listing
January 2017

Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2015 6;9:352. Epub 2016 Jan 6.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) D2 receptor binding in relation to motor and exploratory behaviors in the rat.

Methods: D2 receptor binding was measured in baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. Additional rats received injections of saline. For baseline and challenges, striatal equilibrium ratios (V[Formula: see text]) were computed as estimation of the binding potential. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [(123)I]IBZM. D2 receptor binding was measured with small animal SPECT 2 h after radioligand administration for 60 min.

Results: Both L-DOPA doses significantly reduced D2 receptor binding relative to baseline and led to significantly less ambulation, less head-shoulder motility, and more sitting relative to saline. Moreover, 10 mg/kg L-DOPA induced less head-shoulder motility, more sitting, and more grooming than 5 mg/kg L-DOPA. Analysis of time-behavior curves showed that L-DOPA-treated animals relative to saline exhibited a faster rate of decrease of ambulation frequency and a slower rate of decrease of both duration and frequency of head-shoulder motility from a lower maximum level.

Conclusions: The reductions of striatal D2 receptor binding after L-DOPA may be conceived to reflect elevated concentrations of synaptic DA. L-DOPA-treated animals showed less ambulation and less head-shoulder motility than saline-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster rate of decrease of ambulation frequency and the lower maximum levels of both head-shoulder motility duration and frequency may be interpreted in terms of influence of increased DA availability on behavioral habituation to a novel environment.
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http://dx.doi.org/10.3389/fnbeh.2015.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701934PMC
January 2016

Different patterns of 5-HT receptor and transporter dysfunction in neuropsychiatric disorders--a comparative analysis of in vivo imaging findings.

Rev Neurosci 2016 Jan;27(1):27-59

Impairment of serotonin receptor and transporter function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ). We conducted a PubMed search, which provided a total of 136 in vivo studies with PET and SPECT, in which 5-HT synthesis, 5-HT transporter binding, 5-HT1 receptor binding or 5-HT2 receptor binding in patients with the primary diagnosis of acute AD, MDD, BD or SZ was compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BD and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and receptor binding sites.
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http://dx.doi.org/10.1515/revneuro-2015-0014DOI Listing
January 2016

Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study.

Front Neurol 2015 3;6:167. Epub 2015 Aug 3.

Department of Epileptology, University of Bonn , Bonn , Germany.

Background: Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab.

Case Presentation: We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR(+) CD8(+) T-lymphocytes (fCD8(+)TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8(+)TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8(+)TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described.

Conclusion: The correlation of the fCD8(+)TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8(+)TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.
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http://dx.doi.org/10.3389/fneur.2015.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522569PMC
August 2015