Publications by authors named "Markus Essler"

152 Publications

Evaluating a Machine Learning Tool for the Classification of Pathological Uptake in Whole-Body PSMA-PET-CT Scans.

Tomography 2021 07 29;7(3):301-312. Epub 2021 Jul 29.

Department of Nuclear Medicine, University Hospital Bonn, 53127 Bonn, Germany.

The importance of machine learning (ML) in the clinical environment increases constantly. Differentiation of pathological from physiological tracer-uptake in positron emission tomography/computed tomography (PET/CT) images is considered time-consuming and attention intensive, hence crucial for diagnosis and treatment planning. This study aimed at comparing and validating supervised ML algorithms to classify pathological uptake in prostate cancer (PC) patients based on prostate-specific membrane antigen (PSMA)-PET/CT. Retrospective analysis of Ga-PSMA-PET/CTs of 72 PC patients resulted in a total of 77 radiomics features from 2452 manually delineated hotspots for training and labeled pathological (1629) or physiological (823) as ground truth (GT). As the held-out test dataset, 331 hotspots (path.:128, phys.: 203) were delineated in 15 other patients. Three ML classifiers were trained and ranked to assess classification performance. As a result, a high overall average performance (area under the curve (AUC) of 0.98) was achieved, especially to detect pathological uptake (0.97 mean sensitivity). However, there is still room for improvement to detect physiological uptake (0.82 mean specificity), especially for glands. The ML algorithm applied to manually delineated lesions predicts hotspot labels with high accuracy on unseen data and may be an important tool to assist in clinical diagnosis.
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http://dx.doi.org/10.3390/tomography7030027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396250PMC
July 2021

[Interdisciplinary expert consensus on innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer].

Urologe A 2021 Aug 18. Epub 2021 Aug 18.

Klinik und Poliklinik für Nuklearmedizin, Universitätsmedizin Rostock, Schillingallee 35, 18057, Rostock, Deutschland.

Background: Numerous diagnostic and therapeutic innovations in the treatment of advanced prostate cancer, both in the hormone-sensitive and in the castration-resistant situation, recently led to a new orientation in the management of this tumor. However, there are potential indications beyond the ones covered by the S3 guideline on early detection, diagnosis and therapy of prostate cancer in clinical care that might be helpful for patients.

Objectives: Since July 2018, an interdisciplinary group of experts from nuclear medicine, radiologists, radio-oncologists and urologists developed a consensus paper on state-of-the-art innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer.

Conclusions: Provided by the working group are suggestions and strategies to improve the implementation of new imaging techniques such as multiparametric magnetic resonance imaging (mpMRI), PSMA-PET/CT (prostate-specific membrane antigen-positron emission tomography/computed tomography) and innovative therapeutic options (radium-223 dichloride, lutetium-177-PSMA) in the complex treatment of metastatic castration-resistant prostate cancer (mCRPC).
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http://dx.doi.org/10.1007/s00120-021-01598-2DOI Listing
August 2021

Decision-support for treatment with Lu-PSMA: machine learning predicts response with high accuracy based on PSMA-PET/CT and clinical parameters.

Ann Transl Med 2021 May;9(9):818

Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.

Background: Treatment with radiolabeled ligands to prostate-specific membrane antigen (PSMA) is gaining importance in the treatment of patients with advanced prostate carcinoma. Previous imaging with positron emission tomography/computed tomography (PET/CT) is mandatory. The aim of this study was to investigate the role of radiomics features in PSMA-PET/CT scans and clinical parameters to predict response to Lu-PSMA treatment given just baseline PSMA scans using state-of-the-art machine learning (ML) methods.

Methods: A total of 2,070 pathological hotspots annotated in 83 prostate cancer patients undergoing PSMA therapy were analyzed. Two main tasks are performed: (I) analyzing correlation of averaged (per patient) values of radiomics features of individual hotspots and clinical parameters with difference in prostate specific antigen levels (ΔPSA) in pre- and post-therapy as a therapy response indicator. (II) ML-based classification of patients into responders and non-responders based on averaged features values and clinical parameters. To achieve this, machine learning (ML) algorithms and linear regression tests are applied. Grid search, cross validation (CV) and permutation test were performed to assure that the results were significant.

Results: Radiomics features (PET_Min, PET_Correlation, CT_Min, CT_Busyness and CT_Coarseness) and clinical parameters such as Alp1 and Gleason score showed best correlations with ΔPSA. For the treatment response prediction task, 80% area under the curve (AUC), 75% sensitivity (SE), and 75% specificity (SP) were obtained, applying ML support vector machine (SVM) classifier with radial basis function (RBF) kernel on a selection of radiomics features and clinical parameters with strong correlations with ΔPSA.

Conclusions: Machine learning based on Ga-PSMA PET/CT radiomics features holds promise for the prediction of response to Lu-PSMA treatment, given only base-line Ga-PSMA scan. In addition, it was shown that, the best correlating set of radiomics features with ΔPSA are superior to clinical parameters for this therapy response prediction task using ML classifiers.
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http://dx.doi.org/10.21037/atm-20-6446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246232PMC
May 2021

Fibroblast activation protein inhibitor (FAPi) positive tumour fraction on PET/CT correlates with Ki-67 in liver metastases of neuroendocrine tumours.

Nuklearmedizin 2021 Jul 13. Epub 2021 Jul 13.

Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.

Aim: Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [Ga]Ga-DATA5 m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET.

Methods: Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [Ga]Ga-DATA5 m.SA.FAPi, [18F]FDG and [Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67.

Results: FDG correlated positively (rho = 0.543, p < 0.05) and DOTATOC correlated negatively (rho = -0.618, p < 0.05) with Ki-67, the correlation coefficients were in the moderate range. There was no significant correlation between FAPi and Ki-67 (rho = 0.382, p > 0.05). FAPi correlated positively (rho = 0.770, p < 0.01) and DOTATOC correlated negatively (rho = -0.828, p < 0.01) with Ki-67, both significantly with high correlation coefficients. FDG also correlated significantly with Ki-67, with a moderate correlation coefficient (rho = 0.524, p < 0.05). The ratio FAPi:DOTATOC showed a significant and strong correlation with Ki-67 (rho = 0.808, p < 0.01).

Conclusion: The ratio FAPi:DOTATOC might serve as a clinical parameter for the assessment of dedifferentiation and aggressiveness of liver metastases in patients with NET. [Ga]Ga-DATA5 m.SA.FAPi might hold potential for identification of high-risk patients. Further studies are warranted to evaluate its prognostic significance in comparison to [F]FDG in patients with NET.
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http://dx.doi.org/10.1055/a-1521-8604DOI Listing
July 2021

Lutetium-177-prostate-specific membrane antigen ligand following radium-223 treatment in men with bone-metastatic castration-resistant prostate cancer: real-world clinical experience.

J Nucl Med 2021 Jun 24. Epub 2021 Jun 24.

Johns Hopkins University, United States.

We analyzed real-world clinical outcomes of sequential alpha-/beta-emitter therapy for metastatic castration-resistant prostate cancer (mCRPC). We assessed safety and overall survival in 26 patients who received lutetium-177-prostate-specific membrane antigen ligand (Lu-PSMA) following radium-223 in the ongoing non-interventional Radium-223 alpha Emitter Agent Safety Study in mCRPC popUlation for long-teRm Evaluation (REASSURE; NCT02141438). Patients received radium-223 for a median 6 injections and subsequent Lu-PSMA for a median 3.5 months (≥4th therapy in 69%). The median time between radium-223 and Lu-PSMA treatment was 8 months (range 1-31). Grade 3 hematologic events occurred in 9/26 patients (during or after Lu-PSMA treatment in 5/9 patients; 8/9 patients had also received docetaxel). Median overall survival was 28.0 months from radium-223 start and 13.2 months from Lu-PSMA start. Although the small sample size precludes definitive conclusions, these preliminary data, especially Lu-PSMA treatment duration, suggest feasibility of Lu-PSMA use after radium-223 in this real-world setting.
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http://dx.doi.org/10.2967/jnumed.121.262240DOI Listing
June 2021

No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.

BMC Cancer 2021 May 10;21(1):526. Epub 2021 May 10.

Department of Integrated Oncology, CIO Bonn, Center for Integrated Oncology ABCD, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany.

Methods: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression).

Results: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives.

Conclusion: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.
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http://dx.doi.org/10.1186/s12885-021-08141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108356PMC
May 2021

[Impact of COVID-19 on Nuclear Medicine Procedures in Germany 2020 - Results of a National Survey].

Nuklearmedizin 2021 Jun 1;60(3):210-215. Epub 2021 Apr 1.

Klinik für Nuklearmedizin, Universitätsklinikum Essen, Essen, Germany.

Introduction:  The COVID-19 pandemic imposed an unimaginable challenge to the healthcare systems worldwide. This online survey captured the impact of the COVID-19 pandemic on nuclear medicine services in Germany comparing 2020 to 2019.

Materials And Methods:  A web-based questionnaire was developed to record the 2020 numbers of nuclear medicine procedures and, in particular, the change compared with 2019. The changes in nuclear medicine diagnostics and therapy were queried, as well as the extent to which "Coronavirus SARS-CoV-2" recommendations provided by the DGN were implemented.

Results:  91 complete responses were recorded and evaluated. This corresponds to about 20 % of all German nuclear medicine facilities. Nuclear medicine diagnostic tests showed a decrease in scintigraphies for thyroid (15.9 %), bone (8.8 %), lung (7.6 %), sentinel lymph nodes (5.5 %), and myocardium (1.4 %) with small increases in PET/CT examinations (1.2 %) compared with 2019. Among nuclear medicine therapies, reductions were highest for benign indications (benign thyroid 13.3 %, RSO 7.7 %), while changes from 2019 were less pronounced for malignant indications (PRRT: + 2.2 %, PSMA: + 7.4 %, SIRT: -5.9 %, and RJT for thyroid carcinoma -2.4 %). The DGN recommendations for action were fully or partially applied in 90 %.

Conclusions:  The initial significant reduction in nuclear medicine procedures in the first three weeks of the COVID-19 pandemic did not continue, but there was no compensation of the previously not performed services. The decrease in diagnostics and therapy procedures of benign diseases was particularly severe.
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http://dx.doi.org/10.1055/a-1446-7641DOI Listing
June 2021

Case report: Breast metastasis in a prostate cancer patient.

Nuklearmedizin 2021 Aug 18;60(4):302-303. Epub 2021 Mar 18.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Bonn, Bonn, Germany.

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http://dx.doi.org/10.1055/a-1310-3633DOI Listing
August 2021

Longterm Survial after Re-challenge with Radiumdichlorid - a Case Report.

Nuklearmedizin 2021 Aug 18;60(4):299-301. Epub 2021 Feb 18.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Bonn, Bonn, Germany.

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http://dx.doi.org/10.1055/a-1345-3150DOI Listing
August 2021

[Nursing in Nuclear medicine - decisive factor for future Theranostics].

Nuklearmedizin 2021 02 3;60(1):5-6. Epub 2021 Feb 3.

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http://dx.doi.org/10.1055/a-1255-5280DOI Listing
February 2021

Estimating the Potential of Radiomics Features and Radiomics Signature from Pretherapeutic PSMA-PET-CT Scans and Clinical Data for Prediction of Overall Survival When Treated with Lu-PSMA.

Diagnostics (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Department of Nuclear Medicine, University Hospital Bonn, 53127 Bonn, Germany.

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PSMA-PET/CT) scans can facilitate diagnosis and treatment of prostate disease. Radiomics signature (RS) is widely used for the analysis of overall survival (OS) in cancer diseases. This study aims at investigating the role of radiomics features (RFs) and RS from pretherapeutic gallium-68 (Ga)-PSMA-PET/CT findings and patient-specific clinical parameters to analyze overall survival of prostate cancer (PC) patients when treated with lutethium-177 (Lu)-PSMA. A cohort of 83 patients with advanced PC was retrospectively analyzed. Average values of 73 RFs of 2070 malignant hotspots as well as 22 clinical parameters were analyzed for each patient. From the Cox proportional hazard model, the least absolute shrinkage and selection operator (LASSO) regularization method is used to select most relevant features (standardized uptake value (SUV) and kurtosis with the coefficients of 0.984 and -0.118, respectively) and to calculate the RS from the RFs. Kaplan-Meier (KM) estimator was used to analyze the potential of RFs and conventional clinical parameters, such as metabolic tumor volume (MTV) and standardized uptake value (SUV) for the prediction of survival. As a result, SUV, kurtosis, the calculated RS, SUV, as well as Hemoglobin (Hb)1, C-reactive protein (CRP)1, and ECOG1 (clinical parameters) achieved -values less than 0.05, which suggest the potential of findings from Ga-PSMA-PET/CT scans as well as patient-specific clinical parameters for the prediction of OS for patients with advanced PC treated with Lu-PSMA therapy.
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http://dx.doi.org/10.3390/diagnostics11020186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912143PMC
January 2021

Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status.

J Alzheimers Dis 2021 ;79(2):493-509

German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald.

Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer's continuum in the 2018 NIA-AA research framework.

Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus.

Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB).

Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups).

Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum.
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http://dx.doi.org/10.3233/JAD-200472DOI Listing
September 2021

[In Reply: Invisible Hand - Re: [68Ga]Ga-DATA5m.SA.FAPi PET/CT: Specific Tracer-uptake in Focal Nodular Hyperplasia and potential Role in Liver Tumor Imaging].

Nuklearmedizin 2020 12 17;59(6):456. Epub 2020 Dec 17.

Nuklearmedizinische Klinik und Poliklinik, Universitätsklinikum Bonn, Deutschland.

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http://dx.doi.org/10.1055/a-1288-7582DOI Listing
December 2020

Tumor heterogeneity for differentiation between liver tumors and normal liver tissue in 18F-FDG PET/CT.

Nuklearmedizin 2021 Feb 3;60(1):25-32. Epub 2020 Nov 3.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Bonn, Germany.

Aim:  Malignancies show higher spatial heterogeneity than normal tissue. We investigated, if textural parameters from FDG PET describing the heterogeneity function as tool to differentiate between tumor and normal liver tissue.

Methods:  FDG PET/CT scans of 80 patients with liver metastases and 80 patients with results negative upper abdominal organs were analyzed. Metastases and normal liver tissue were analyzed drawing up to three VOIs with a diameter of 25 mm in healthy liver tissue of the tumoral affected and results negative liver, whilst up to 3 metastases per patient were delineated. Within these VOIs 30 different textural parameters were calculated as well as SUV. The parameters were compared in terms of intra-patient and inter-patient variability (2-sided t test). ROC analysis was performed to analyze predictive power and cut-off values.

Results:  28 textural parameters differentiated healthy and pathological tissue (p < 0.05) with high sensitivity and specificity. SUV showed ability to differentiate but with a lower significance. 15 textural parameters as well as SUV showed a significant variation between healthy tissues out of tumour infested and negative livers. Mean intra- and inter-patient variability of metastases were found comparable or lower for 6 of the textural features than the ones of SUV. They also showed good values of mean intra- and inter-patient variability of VOIs drawn in liver tissue of patients with metastases and of results negative ones.

Conclusion:  Heterogeneity parameters assessed in FDG PET are promising to classify tissue and differentiate malignant lesions usable for more personalized treatment planning, therapy response evaluation and precise delineation of tumors for target volume determination as part of radiation therapy planning.
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http://dx.doi.org/10.1055/a-1270-5568DOI Listing
February 2021

Differentiation of acute myeloid leukemia (AML) cells with ATRA reduces F-FDG uptake and increases sensitivity towards ABT-737-induced apoptosis.

Leuk Lymphoma 2021 03 3;62(3):630-639. Epub 2020 Nov 3.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Acute myeloid leukemia (AML) is a malignant disease of the bone marrow, comprising various subtypes. We have investigated seven different AML cell lines that showed different sensitivities toward the inducer of apoptosis ABT-737, with IC concentrations ranging from 9.9 nM to 1.8 µM. Besides, the AML cell lines revealed distinct differences in F-FDG uptake ranging from 4.1 to 11.0%. Moreover, the Pearson coefficient (0.363) suggests a moderate correlation between F-FDG uptake and the IC values of ABT-737. Differentiation of the AML cell lines NB-4 and AML-193 with all-trans-retinoic-acid (ATRA) induced a significant increase in sensitivity towards ABT-737 along with a reduced uptake of F-FDG. Therefore, F-FDG uptake could be predictive on sensitivity to treatment with ABT-737. Furthermore, because differentiation treatment of AML cells using ATRA reduced F-FDG uptake and increased sensitivity towards ABT-737, a combined treatment regimen with ATRA and ABT-737 might be a promising therapeutic option in the future.
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http://dx.doi.org/10.1080/10428194.2020.1839648DOI Listing
March 2021

Editorial: Artikelserie „Rechtliche Grundlagen der Radiochemie“.

Nuklearmedizin 2020 09 28;59(5):346-347. Epub 2020 Sep 28.

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http://dx.doi.org/10.1055/a-1223-7093DOI Listing
September 2020

Assessing the quality of life of patients with metastatic castration-resistant prostate cancer with bone metastases receiving [223Ra]RaCl2 therapy.

Medicine (Baltimore) 2020 Sep;99(38):e22287

Department of Nuclear Medicine, University Hospital Bonn, Bonn.

[Ra]RaCl2 dichloride treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with improved overall survival (OS) and a delay in the time to the first symptomatic skeletal-related event. The aim of this study was to evaluate the quality of life (QoL) of patients with mCRPC receiving [Ra]RaCl2 treatment using the European Organization for Research and Treatment of Cancer (EORTC) validated questionnaire form.Thirty patients with mCRPC were included in this study. The patients were administered the EORTC QLQ-C30 (version 3.0) questionnaire at 5 time points: before [Ra]RaCl2 treatment, after the first cycle, after the third cycle, after the fifth cycle, and at the end of the treatment.Median age at diagnosis was 65.2 years (range, 49.1-75.5). There was a significant 25% drop in the median alkaline phosphatase levels: 101 U/L (range, 58-594) vs. 75 U/L (39-649) before and during treatment, respectively (P = .003). The median dose of [Ra]RaCl2 for all patients was 4.1 MBq (range, 3.35-6.55), and the majority of patients received 5 treatment cycles (range 3-6). Seventeen patients were alive at the end of treatment (56.7%). The median OS was 26 months (range, 19.8-32.2). All of the patients filled out the questionnaires at the first 3 time points; the fourth survey included 28 patients, and only 23 patients completed the fifth questionnaire. Compared to the baseline, only the scale "role functioning" showed a temporary worsening after the first therapy cycle (P = .03). In subsequent cycles, its mean value rose to initial levels. All other functional and symptom scales, as well as global health status, remained constant over all 5 time points and showed no significant changes (P > .05).[Ra]RaCl2 therapy does not adversely impair the health-related QoL of patients with mCRPC and bone metastasis. Only patients' role functioning worsened temporarily after the first therapy cycle but stabilized in subsequent treatment cycles.
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http://dx.doi.org/10.1097/MD.0000000000022287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505355PMC
September 2020

Machine Learning Facilitates Hotspot Classification in PSMA-PET/CT with Nuclear Medicine Specialist Accuracy.

Diagnostics (Basel) 2020 Aug 22;10(9). Epub 2020 Aug 22.

Department of Nuclear Medicine, University Hospital Bonn, 53127 Bonn, Germany.

Gallium-68 prostate-specific membrane antigen positron emission tomography Ga-PSMA-PET) is a highly sensitive method to detect prostate cancer (PC) metastases. Visual discrimination between malignant and physiologic/unspecific tracer accumulation by a nuclear medicine (NM) specialist is essential for image interpretation. In the future, automated machine learning (ML)-based tools will assist physicians in image analysis. The aim of this work was to develop a tool for analysis of Ga-PSMA-PET images and to compare its efficacy to that of human readers. Five different ML methods were compared and tested on multiple positron emission tomography/computed tomography (PET/CT) data-sets. Forty textural features extracted from both PET- and low-dose CT data were analyzed. In total, 2419 hotspots from 72 patients were included. Comparing results from human readers to those of ML-based analyses, up to 98% area under the curve (AUC), 94% sensitivity (SE), and 89% specificity (SP) were achieved. Interestingly, textural features assessed in native low-dose CT increased the accuracy significantly. Thus, ML based on Ga-PSMA-PET/CT radiomics features can classify hotspots with high precision, comparable to that of experienced NM physicians. Additionally, the superiority of multimodal ML-based analysis considering all PET and low-dose CT features was shown. Morphological features seemed to be of special additional importance even though they were extracted from native low-dose CTs.
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http://dx.doi.org/10.3390/diagnostics10090622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555620PMC
August 2020

Improving quality of life in patients with metastatic prostate cancer following one cycle of 177Lu-PSMA-617 radioligand therapy: a pilot study.

Nuklearmedizin 2020 Dec 21;59(6):409-414. Epub 2020 Aug 21.

Department of Psychosomatic Medicine and Psychotherapy, University Hospital of Bonn, Germany.

Introduction:  To evaluate the clinical therapeutic response of PSMA targeted radioligand therapy with Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer. The current study analyzed disease-related quality of life (QoL) in patients undergoing PSMA therapy with a special focus on the association with simultaneous PSA response.

Methods:  Thirty patients (age range 50-87 years, median 73.5 years) undergoing Lu-PSMA-617 therapy from 2014 to 2016 at our institution were included in this pilot study. Health-related QoL was assessed by EORTC QLQ-C30 questionnaire filled in at baseline and two months after initializing the PSMA-therapy. The treatment response was evaluated under three categories with regard to changes in (a) global health status and other functional scales, (b) disease-related symptoms, and (c) effects of PSA values.

Results:  Most patients underwent three treatment cycles (n = 12); at least 2 cycles (n = 6) or at most 8 cycles (n = 1) were performed. Out of 30 cases, PSA response after the first cycle was observed in 73 % (n = 22). Compared to baseline, QoL was significantly improved at 2-month follow-up revealing increase in global health status (p = 0.025), role functioning (p = 0.017) and emotional functioning (0.010), and decrease in pain (p = 0.033). Global health status variation can be explained up to 20.5 % by response in PSA (p = 0.012), this improved with PSA reduction.

Conclusion:  PSMA radioligand therapy seems to be an effective treatment option of metastatic castration-resistant prostate cancer patients as it improves their QoL in terms of increasing global health and mitigation of disease-related pain.
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http://dx.doi.org/10.1055/a-1234-5891DOI Listing
December 2020

Programmed cell death protein 1 (PD-1)-inhibition in hepatocellular carcinoma (HCC): a single center experience.

Scand J Gastroenterol 2020 Sep 21;55(9):1057-1062. Epub 2020 Jul 21.

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

Background: The prognosis for advanced Hepatocellular carcinoma (HCC)is still very poor. Despite initial usefulness of immune checkpoint inhibitor (PD-1), phase 3 trials failed to show significant benefit of PD-1 inhibition with nivolumab or pembrolizumab in the first and second line therapy of HCC. Clinical evidence of PD-1 inhibition in patients with advanced and heavily pretreated HCC outside clinical trials is extremely limited. In this study, we analyzed the clinical experience with PD-1 inhibition in patients with heavily pretreated HCC.

Methods: Between May 2016 and January 2019 14 patients with advanced and heavily pretreated HCC were treated with nivolumab or pembrolizumab at the University Hospital Bonn, Germany. Base line characteristics prior to immunotherapy, immunohistochemistry of different immunological markers, beneficial outcome and safety were recorded and retrospectively analyzed.

Results: Immunotherapy with PD-1 inhibition was well tolerated and resulted in significant clinical benefit as last line therapy. Median overall survival (OS) was 6.6 months (95%CI:3.9-11.8), progression-free survival (PFS) was 5.3 months (95%CI:2.4-11.7) and overall response rate (ORR) was 30.8%. One patient reached a complete remission.

Conclusions: Despite numerous pretreatments, PD-1 inhibition was well tolerated and showed clinical benefit in patients with heavily pretreated HCC.
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http://dx.doi.org/10.1080/00365521.2020.1794539DOI Listing
September 2020

DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis-Challenges and Critical Points in Implementation into Clinical Routine.

Molecules 2020 Jun 30;25(13). Epub 2020 Jun 30.

Positronpharma SA, Rancagua 878, Providencia 7500921, Chile.

The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope of this work is the presentation and discussion of problems encountered during this process. Briefly, the radiolabelling process and purification, as well as the quality control published, did not meet the expectations. The constant effort setting up an automated radiolabelling procedure resulted in (a) an enhanced manual method using coated glass reactors, (b) a combination of three different reliable radio thin-layer chromatography (TLC) methods instead of the published and (c) a preliminary radio high-pressure liquid chromatography (HPLC) method for identification of the compound. Additionally, an automated radiolabelling process was developed, but it requires further improvement, e.g., in terms of a reactor vessel or purification of the crude product. The published purification method was found to be unsuitable for clinical routine, and an intense screening did not lead to a satisfactory result; here, more research is necessary. To sum up, implementation of DOTA-ZOL was possible but revealed a lot of critical points, of which not all could be resolved completely yet.
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http://dx.doi.org/10.3390/molecules25132988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412164PMC
June 2020

Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics.

Invest New Drugs 2020 12 4;38(6):1717-1729. Epub 2020 Jun 4.

Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Venusberg-Campus 1, D-53127, Bonn, Germany.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was performed by gene ontology (GO) annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Protein-protein interaction (PPI) network, module enrichment, and hub gene identification were constructed and visualized by the online Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. A total of 22 and 17 integrated human DEGs in hypothyroidism and hyperthyroidism group related to anti-CTLA-4 therapy were identified, respectively. Functional enrichment analysis revealed 24 GO terms and 1 KEGG pathways in the hypothyroid group and 21 GO terms and 2 KEGG pathways in the hyperthyroid group. After PPI network construction, the top five hub genes associated with hypothyroidism were extracted, including ALB, MAPK1, SPP1, PPARG, and MIF, whereas those associated with hyperthyroidism were ALB, FCGR2B, CD44, LCN2, and CD74. The identification of the candidate key genes and enriched signaling pathways provides potential biomarkers for autoimmune thyroid dysfunction related to anti-CTLA-4 therapy and might contribute to the future diagnosis and management of IRAEs for cancer patients.
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http://dx.doi.org/10.1007/s10637-020-00952-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575511PMC
December 2020

Sialoscintigraphy - Shopworn or Bestselling? A Traditional Procedure with New Prominent Role in Theranostics and Immuno-Oncology.

Nuklearmedizin 2020 Sep 18;59(5):375-380. Epub 2020 May 18.

Department of Nuclear Medicine, University Medical Center Bonn, Bonn, Germany.

Sialoscintigraphy has been used in nuclear imaging for almost sixty years. It allows functional assessment and quantification of all large salivary glands. Physiological function of the salivary glands is essential for the preservation of the oral mucosa, the sense of taste and dental health. Impaired salivary gland function may lead to reduced or even absent salivation resulting in various complaints such as loss of taste reducing quality of life. During the recent years clinical relevance of assessment of salivary gland function has been rising. As novel radiopharmaceuticals such as 225Ac-PSMA or 177Lu-PSMA may cause damage to the salivary glands in a subset of patients, reliable methods for quantification of salivary gland function are vital for therapy planning and follow-up. Standardized protocols for the implementation and interpretation of this procedure are necessary to achieve comparable results from individual theranostic centers and to facilitate multicenter trials. Sialocintigraphy is also of clinical relevance for immunooncology. Treatments with checkpoint inhibitors such as Ipilimumab or Nivulomab frequently cause autoimmune disorders affecting the salivary glands that may lead to reduced production of saliva and finally loss of taste. Therefore, standardized procedure protocols for sialoscintigraphy are also important for general oncology.Here we suggest a protocol for sialoscintigraphy that may be used as standard in centers for theranostics or immunooncology and discuss the potential future role of this traditional procedure.
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http://dx.doi.org/10.1055/a-1152-2279DOI Listing
September 2020

[NuklearMedizin 2020: Welcome to Leipzig].

Authors:
Markus Essler

Nuklearmedizin 2020 04 8;59(2):56-58. Epub 2020 Apr 8.

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http://dx.doi.org/10.1055/a-1121-9367DOI Listing
April 2020

Nuclear medicine in SARS-CoV-2 pandemia: 18F-FDG-PET/CT to visualize COVID-19.

Nuklearmedizin 2020 Jun 7;59(3):276-280. Epub 2020 Apr 7.

Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.

The current outbreak of coronavirus SARS-CoV-2 has reached multiple countries worldwide. While the number of newly diagnosed cases and fatalities is rising quickly, far-reaching measures were enacted to prevent further spread. Diagnosis relies on clinical presentation, exposure history, PCR using specimens from the respiratory tract together with computed tomography (CT) imaging. One of the hallmarks of a critical course of COVID-19 is the development of severe acute respiratory distress syndrome (ARDS). As management of COVID-19 can be considered a multi-disciplinary approach involving various medical specialties, we here review the first F-FDG-PET/CT scans of COVID-19 to discuss how Nuclear Medicine could contribute to management of this disease.
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http://dx.doi.org/10.1055/a-1152-2341DOI Listing
June 2020

Textural features in FDG-PET/CT can predict outcome in melanoma patients to treatment with Vemurafenib and Ipililumab.

Nuklearmedizin 2020 Jun 7;59(3):228-234. Epub 2020 Apr 7.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Bonn, Bonn, Germany.

Aim:  Recently, textural parameters assessed in FDG-PET/CT as surrogate marker for tumor heterogeneity have been shown to provide prognostic power. Therefore, we investigated the use of such parameters in FDG-PET/CT examinations before the start of immunotherapy with vemurafenib or ipilimumab in patients with malignant melanoma.

Methods:  In this retrospective analysis 26 patients with histologically proven advanced melanoma were included. FGD-PET/CT was performed before the start of treatment either with vemurafenib (n = 9) or ipilimumab (n = 17) and tumors were analyzed for textural parameters as well as conventional PET features. Lesions were classified as responding or not responding following PERCIST criteria. ROC analysis was performed to analyze the predictive power and cut-off values. In addition, the change of maximum SUV of the lesions between pretherapeutic PET/CT and another PET/CT performed about 12 weeks after start of treatment was evaluated and correlated with the pretreatment parameters.

Results:  In both groups, six textural parameters showed statistically significant predictive power as well as the metabolic tumor volume. In the group treated with vemurafenib eight additional textural parameters as well as the maximum and mean SUV and the TLG showed significance. A statistically significant correlation between the change of maximum SUV in the course of treatment and the pretherapeutic parameters was found in both treatment groups for three textural features.

Conclusion:  In patients with malignant melanoma textural parameters in pretherapeutic FDG-PET/CT examinations seem to have prognostic power for treatment response of immunotherapy with vemurafenib and ipilimumab. This can be an important step towards personalized tumor therapy.
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http://dx.doi.org/10.1055/a-1140-5458DOI Listing
June 2020
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