Publications by authors named "Hans-Juergen Wester"

30 Publications

  • Page 1 of 1

CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line H. pylori eradication.

Blood 2021 Sep 15. Epub 2021 Sep 15.

Medical University of Vienna, Vienna, Austria.

Post-treatment evaluation of gastric mucosa-associated lymphoid tissue (MALT) lymphoma currently relies on esophagogastroduodenoscopy with histological assessment of biopsies. Overexpression of the G-protein-coupled C-X-C chemokine receptor type 4 (CXCR4) has been previously observed in MALT lymphoma. The aim of this prospective study was to evaluate PET with the novel CXCR4 tracer [68Ga]Pentixafor as a potential alternative to follow-up biopsies for assessment of residual disease (non-complete remission (CR)) after first-line H. pylori (HP) eradication. Forty-six post-HP eradication [68Ga]Pentixafor-PET/MRI examinations of 26 gastric MALT lymphoma patients, and 20 [68Ga]Pentixafor-PET/MRI examinations of 20 control group patients without lymphoma, were analyzed. In the MALT lymphoma group, time-matched gastric biopsies were used as reference standard, and showed CR in six cases. Pooled examination-based accuracy, sensitivity, specificity, and positive and negative predictive value of [68Ga]Pentixafor-PET for detection of residual gastric MALT lymphoma at follow-up, were 97.0%, 95.0%, 100.0%, 100.0%, and 92.9%, respectively. Maximum and mean PET standardized uptake values showed moderate correlation with immunohistochemistry-based CXCR4+ cell counts, with correlation coefficients of r=0.51 and r=0.52 (P=0.008 and P=0.006). In conclusion, CXCR4 imaging with [68Ga]Pentixafor-PET may represent a promising test for assessment of residual gastric MALT lymphomas after HP eradication.
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http://dx.doi.org/10.1182/blood.2021013239DOI Listing
September 2021

PSMA-ligand uptake can serve as a novel biomarker in primary prostate cancer to predict outcome after radical prostatectomy.

EJNMMI Res 2021 Aug 21;11(1):76. Epub 2021 Aug 21.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Background: The prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP).

Methods: In this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUV), SUV, tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed.

Results: At a median follow-up after RP of 38 months (interquartile range (IQR) 22-53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUV (IA vs. IB stage, log-rank, p = 0.022).

Conclusion: Preoperative miTNM classification from Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification.
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http://dx.doi.org/10.1186/s13550-021-00818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380207PMC
August 2021

The Influence of Specific Activity on the Biodistribution of F-rhPSMA-7.3: A Retrospective Analysis of Clinical Positron Emission Tomography Data.

J Nucl Med 2021 Aug 12. Epub 2021 Aug 12.

Nuclear Medicine, TU Munich.

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal organ and tumor uptake of the PSMA ligand, F-rhPSMA-7.3, in patients with prostate cancer. The biodistribution of F-rhPSMA-7.3 on PET/CT scans performed with a high specific activity (media = 178.9MBq/µg, = 42) and a low specific activity (media = 19.3MBq/µg, = 42) were compared. Tracer uptake by the parotid gland, submandibular gland and spleen was moderately, but significantly lower in the "low specific activity" group than in the "high specific activity" group (median SUVmean 16.7 vs. 19.2; 18.1 vs. 22.3, and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. A 10-fold decrease in specific activity has only minor effects on the biodistribution of F-rhPSMA-7.3. These findings suggest that F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to F-fluorodeoxyglucose.
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http://dx.doi.org/10.2967/jnumed.121.262471DOI Listing
August 2021

Pentixafor PET/CT for imaging of chemokine receptor 4 expression in esophageal cancer - a first clinical approach.

Cancer Imaging 2021 Feb 12;21(1):22. Epub 2021 Feb 12.

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

Background: Expression of CXCR4, a chemokine (C-X-C motif) receptor that plays a central role in tumor growth and metastasis of circulating tumor cells, has been described in a variety of solid tumors. A high expression of CXCR4 has a prognostic significance with regard to overall and progression-free survival and offers a starting point for targeted therapies. In this context, [68]Ga-Pentixafor-Positron Emission Tomography/Computer Tomography (PET/CT) offers promising possibility of imaging the CXCR4 expression profile. We set out to compare a [18F] fluorodeoxyglucose (FDG)-PET/CT and a [68Ga]Pentixafor-PET/CT in (re-)staging and radiation planning of patients with localized esophageal cancer.

Materials And Methods: In this retrospective analysis, ten patients, with adeno- or squamous cell carcinoma of the esophagus (n = 3 and n = 7, respectively), which were scheduled for radio (chemo) therapy, were imaged using both Pentixafor and FDG PET/CT examinations. All lesions were visually rated as Pentixafor and FDG positive or negative. For both tracers, SUVmax was measured all lesions and compared to background. Additionally, immunohistochemistry of CXCR4 was obtained in patients undergoing surgery.

Results: FDG-positive tumor-suspicious lesions were detected in all patients and a total of 26 lesions were counted. The lesion-based analysis brought equal status in 14 lesions which were positive for both tracers while five lesions were FDG positive and Pentixafor negative and seven lesions were FDG negative, but Pentixafor positive. Histopathologic correlation was available in seven patients. The CXCR4 expression of four non-pretreated tumour lesion samples was confirmed immunohistochemically.

Conclusion: Our data shows that additional PET/CT imaging with Pentixafor for imaging the CXCR4 chemokine receptor is feasible but heterogeneous in both newly diagnosed and pretreated recurrent esophageal cancer. In addition, the Pentixafor PET/CT may serve as complementary tool for radiation field expansion in radiooncology.
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http://dx.doi.org/10.1186/s40644-021-00391-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881561PMC
February 2021

Automated synthesis of [F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions.

EJNMMI Radiopharm Chem 2021 Jan 23;6(1). Epub 2021 Jan 23.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([F]Ga-rhPSMA-7.1, - 7.2, - 7.3 and - 7.4) and after a preclinical isomer selection process, [F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex).

Methods: [F]Fluoride in highly enriched [O]HO was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K ⊂ 2.2.2]OH in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. F-for-F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [F]Ga-rhPSMA-7; 83 for [F]Ga-rhPSMA-7.3).

Results: The automated production of [F]Ga-rhPSMA-7 and the single isomer [F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31-130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50-450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively.

Conclusion: This investigation demonstrates that F-for-F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.
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http://dx.doi.org/10.1186/s41181-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826325PMC
January 2021

CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET.

Theranostics 2021 1;11(2):567-578. Epub 2021 Jan 1.

Dept. of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.

For PET imaging of mantle cell lymphoma (MCL), [F]FDG (2-deoxy-2-[F]fluoro-D-glucose) is the currently recommended radiotracer, although uptake is variable and bone marrow evaluation is limited. In this prospective study, we evaluated the novel CXCR4 (G-protein-coupled C-X-C chemokine receptor type 4) tracer [Ga]Pentixafor in MCL patients, and compared it to [F]FDG. MCL patients underwent [Ga]Pentixafor-PET/MRI, and, if required for routine purposes, also [F]FDG-PET/MRI, before treatment. PET was evaluated separately for 23 anatomic regions (12 lymph node stations and 11 organs/tissues), using MRI as the main reference standard. Standardized uptake values (SUV and SUV) and tumor-to-background ratios (TBR and TBR) were calculated. General Estimation Equations (GEE) were used to compare [Ga]Pentixafor-PET and [F]FDG-PET sensitivities and positive predictive values (PPV). For bone marrow involvement, where biopsy served as the main reference standard, and splenic involvement, receiver operating characteristic curves were used to determine the optimal SUV and TBR cut-off values, and areas under the curve (AUC) were calculated. Twenty-two MCL patients were included. [Ga]Pentixafor-PET sensitivity (100%) was significantly higher than for [F]FDG-PET (75.2%) (<0.001), and PPV was slightly, but not significantly lower (94.0%.vs. 96.5%; =0.21). SUVs and TBRs were significantly higher for [Ga]Pentixafor-PET than for [F]FDG-PET (<0.001 in all cases); the greatest difference was observed for mean TBR, with 4.9 for [Ga]Pentixafor-PET and 2.0 for [F]FDG-PET. For bone marrow involvement, [Ga]Pentixafor-PET SUV showed an AUC of 0.92; and for splenic involvement, TBR showed an AUC of 0.81. [Ga]Pentixafor-PET may become an alternative to [F]FDG-PET in MCL patients, showing clearly higher detection rates and better tumor-to-background contrast.
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http://dx.doi.org/10.7150/thno.48620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738870PMC
August 2021

Positive Predictive Value and Correct Detection Rate of F-rhPSMA-7 PET in Biochemically Recurrent Prostate Cancer Validated by Composite Reference Standard.

J Nucl Med 2021 Jul 13;62(7):968-974. Epub 2020 Nov 13.

School of Medicine, Department of Nuclear Medicine, Technical University Munich, Munich, Germany.

The objective of this retrospective study was to assess the detection rate (DR), positive predictive value (PPV), and correct detection rate (CDR) of F-rhPSMA-7 PET/CT in biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) using composite validation. F-rhPSMA-7 PET/CT scans of patients with BCR between July 2017 and June 2018 were retrospectively reviewed. All suspicious lesions were recorded. The reference standard was histopathology or combinations of histopathology, imaging, or prostate-specific antigen (PSA) follow up, defined as composite reference standard. DR was calculated as the proportion of PSMA PET-positive patients to all patients independent of the reference standard, whereas the CDR was the percentage of patients who had at least 1 true-positive PSMA PET lesion localized that corresponded with the reference standard. The PPV was defined as the proportion of patients who had true-positive to all positive findings. The correlation between DR and patient characteristics was evaluated. A total of 532 patients with a median PSA level of 0.97 ng/mL (interquartile range: 0.41-2.46 ng/mL) were included. Of these, 162 patients had composite follow-up at a median duration of 5.6 mo (range: 1.1-14.2 mo). The proportion of patients who had no lesion visualized on PET/CT, localized disease, and any distant metastases (M1) were 20%, 43%, and 37%, respectively. PET DR among all patients was 80%. On a per-patient basis, the PPV of F-rhPSMA-7 PET/CT in the composite cohort was 88%, and the CDR was 70%. The PPV in the histopathology-proven cohort was 91%, and the CDR in this subgroup was 73%. In patients with PSA levels ≥ 1 ng/mL the DR and PPV were 90% and 91%, respectively, resulting in a CDR of 82%. In patients with PSA levels < 1 ng/mL, the DR and PPV were 69% and 85%, respectively, resulting in a CDR of 59%. There was a significant positive correlation between F-rhPSMA-7 PET/CT detection efficacy and stratified PSA levels ( = 0.005), as well as PSA nadir after prostatectomy ( < 0.001). F-rhPSMA-7 PET/CT offers high PPV in BCR after RP. Its CDR is dependent on the prescan PSA value with excellent CDR in patients with PSA ≥ 1 ng/mL.
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http://dx.doi.org/10.2967/jnumed.120.255661DOI Listing
July 2021

Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4.

Eur Heart J 2020 10;41(37):3564-3575

Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Aims: Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction.

Methods And Results: Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = -0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up.

Conclusion: Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.
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http://dx.doi.org/10.1093/eurheartj/ehaa598DOI Listing
October 2020

Prospective non-invasive evaluation of CXCR4 expression for the diagnosis of MALT lymphoma using [Ga]Ga-Pentixafor-PET/MRI.

Theranostics 2019 27;9(12):3653-3658. Epub 2019 May 27.

Department of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Austria.

MALT lymphomas express the chemokine receptor CXCR4 on a regular basis, and [68Ga]Ga-Pentixafor-PET has been shown to quantify CXCR4 expression non-invasively. We, therefore, aimed to evaluate [68Ga]Ga-Pentixafor-PET/MRI for the non-invasive assessment of MALT lymphomas.

Methods: We included 36 MALT lymphoma patients, who had not undergone previous systemic or radiation therapy, in our prospective, IRB-approved, proof-of-concept study. Involved anatomic regions were the orbit (n=14), stomach (n=10), lungs (n=5), and other sites (soft-tissues n=3; adrenal gland, tonsils, parotid gland, and urinary bladder n=1, respectively). MRI sequences included an axial 2-point Dixon T1 VIBE SPAIR 3D sequence for PET attenuation correction; a coronal T2 HASTE sequence; and an axial echo-planar imaging SPAIR-based diffusion-weighted sequence (DWI) obtained during free-breathing (b-values, 50 and 800), with corresponding ADC (apparent diffusion coefficient) maps.

Results: In 33/36 patients, there were MALT lymphomas with an increased uptake of [68Ga]Ga-Pentixafor; all current lymphoma manifestations showed an increased uptake and, accordingly, were positive on the PET/MRI. The remaining three patients had undergone surgery for their orbital MALT lymphomas prior to PET/MRI. Mean SUVmax was 8.6 ± 4.7, mean SUVmean was 4.7 ± 1.8, and mean SUVpeak was 8.0 ± 4.2. The mean SUVmax of the liver was 1.8, and the mean tumor-to-liver ratio was 2.9 ± 2.0. There were no significant differences in SUVmax (P=0.22), SUVmean (P=0.53), SUVpeak (P=0.29), or SUVt/l (P=0.92) between the four anatomic regions (orbit, stomach, lungs, other). The mean tumor volume was 146 ± 499.

Conclusions: Our results thus indicate that [68Ga]Ga-Pentixafor-PET is feasible for the assessment of MALT lymphomas, with a good tumor-to-background ratio in terms of radiotracer uptake.
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http://dx.doi.org/10.7150/thno.31032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587159PMC
July 2020

[68Ga]Ga-Pentixafor PET/MRI for CXCR4 Imaging of Chronic Lymphocytic Leukemia: Preliminary Results.

Invest Radiol 2018 07;53(7):403-408

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna.

Objectives: This prospective proof-of-principle study aimed to determine whether [Ga]Ga-Pentixafor uptake, which reflects CXCR4 expression, is higher in the bone marrow of chronic lymphocytic leukemia (CLL) than in other oncological diseases without bone marrow infiltration and can therefore be used for CLL imaging.

Materials And Methods: Thirteen CLL patients and 20 controls (10 with pancreatic adenocarcinoma and 10 with mucosa-associated lymphoid tissue lymphoma) with histologically proven cancer underwent [Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging. Standardized [Ga]Ga-Pentixafor uptake values (SUVmax, SUVmean) were measured in the bone marrow of the pelvis, the lumbar vertebra L4, and the bony structure with the visually highest tracer uptake ("hottest lesion"). Mean apparent diffusion coefficient values were also measured in the pelvis. Serum leukocyte count (gram per liter), lymphocyte percentage (percent), lactate dehydrogenase (unit per liter), β2-microglobulin (milligram per deciliter), and C-reactive protein (milligram per deciliter) were measured. Statistical analyses comprised analysis of variance with Games-Howell post hoc tests and Spearman correlation coefficients.

Results: SUVmax and SUVmean differed significantly between CLL and pancreatic adenocarcinoma in the pelvis (P = 0.032 and P = 0.008) and lumbar vertebra L4 (both P < 0.001). SUVmean also differed in the pelvis (P = 0.020) and L4 (P = 0.041), and SUVmax in L4 (P = 0.019), between CLL and mucosa-associated lymphoid tissue lymphoma. Receiver operating characteristic-based areas under the curve for separation of CLL from the control groups were greatest for the SUVmax of the bony structure with the strongest [Ga]Ga-Pentixafor uptake (0.94) and the SUVmax of L4 (0.92). There was no significant correlation between [Ga]Ga-Pentixafor uptake and pelvic apparent diffusion coefficients or serum parameters.

Conclusions: [Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging may possibly be useful for CXCR4-based CLL imaging.
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http://dx.doi.org/10.1097/RLI.0000000000000469DOI Listing
July 2018

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Hypertension 2018 02 26;71(2):317-325. Epub 2017 Dec 26.

From the Department of Internal Medicine I, Endocrinology and Diabetes Unit (B.H., C.T.F., M.F., K.L., S.H.), Department of Nuclear Medicine (A.S., K.H., A.K.B., C.B.), and Comprehensive Cancer Center Wuerzburg (T.D., M.F.), University Hospital of Wuerzburg, University of Wuerzburg, Germany; Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Italy (P.M., T.A.W., S.M.); Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Germany (F.B., M.R., T.A.W., Y.R.); Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Germany (M.M.); Endocrinology in Charlottenburg, Berlin, Germany (M.Q.); Department of General, Visceral, and Transplant Surgery, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Germany (N.R.); Department of Pathology, University of Würzburg, Germany (V.W.); Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, MS (C.E.G.-S.); Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Germany (A.-C.R.); ENDOC, Center for Endocrine Tumors, Hamburg, Germany (S.P.); Pharmaceutical Radiochemistry, Technische Universität München, Garching bei München, Germany (H.-J.W.); and Scintomics GmbH, Fürstenfeldbruck, Germany (S.K.).

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09975DOI Listing
February 2018

Targeting CXCR4 with [Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?

Oncotarget 2017 Nov 27;8(57):96732-96737. Epub 2017 May 27.

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

C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [Ga]Pentixafor-PET/CT. 2'-[F]fluoro-2'-deoxy-D-glucose ([F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [F]FDG-PET depicted active lesions in all patients, [Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.
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http://dx.doi.org/10.18632/oncotarget.18235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722518PMC
November 2017

Clinical Molecular Imaging of Chemokine Receptor CXCR4 Expression in Atherosclerotic Plaque Using Ga-Pentixafor PET: Correlation with Cardiovascular Risk Factors and Calcified Plaque Burden.

J Nucl Med 2018 02 3;59(2):266-272. Epub 2017 Aug 3.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany

The CXC-motif chemokine receptor 4 (CXCR4) represents a promising target for molecular imaging of different CXCR4-positive cell types in cardiovascular diseases such as atherosclerosis and arterial wall injury. The aim of this study was to assess the prevalence, pattern, and clinical correlates of arterial wall accumulation of Ga-pentixafor, a specific CXCR4 ligand for PET. The data for 51 patients who underwent Ga-pentixafor PET/CT for noncardiovascular indications were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed qualitatively and semiquantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with calcified plaque burden and cardiovascular risk factors. Focal arterial uptake of Ga-pentixafor was seen at 1,411 sites in 51 (100%) of patients. Ga-pentixafor uptake was significantly associated with calcified plaque burden ( < 0.0001) and cardiovascular risk factors including age ( < 0.0001), arterial hypertension ( < 0.0001), hypercholesterolemia ( = 0.0005), history of smoking ( = 0.01), and prior cardiovascular events ( = 0.0004). Both the prevalence ( < 0.0001) and the signal intensity ( = 0.009) of Ga-pentixafor uptake increased as the number of risk factors increased. Ga-pentixafor PET/CT is suitable for noninvasive, highly specific PET imaging of CXCR4 expression in the atherosclerotic arterial wall. Arterial wall Ga-pentixafor uptake is significantly associated with surrogate markers of atherosclerosis and is linked to the presence of cardiovascular risk factors. Ga-pentixafor signal is higher in patients with a high-risk profile and may hold promise for identification of vulnerable plaque.
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http://dx.doi.org/10.2967/jnumed.117.196485DOI Listing
February 2018

CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma.

Theranostics 2017 8;7(6):1589-1597. Epub 2017 Apr 8.

Department of Internal Medicine II, Division of Hematology and Medical Oncology, University Hospital Würzburg, Würzburg, Germany.

C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.
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http://dx.doi.org/10.7150/thno.19050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436514PMC
February 2018

Multiple Time-Point 68Ga-PSMA I&T PET/CT for Characterization of Primary Prostate Cancer: Value of Early Dynamic and Delayed Imaging.

Clin Nucl Med 2017 Jun;42(6):e286-e293

From the Departments of *Nuclear Medicine, †Medical Physics and Radiation Protection, ‡Urology and Urological Oncology, and §Radiation and Special Oncology, Hannover Medical School, Hannover; and ∥Department of Pharmaceutical Radiochemistry, Technical University Munich, Munich, Germany.

Purpose: The aims of this study were to gain mechanistic insights into prostate cancer biology using dynamic imaging and to evaluate the usefulness of multiple time-point Ga-prostate-specific membrane antigen (PSMA) I&T PET/CT for the assessment of primary prostate cancer before prostatectomy.

Methods: Twenty patients with prostate cancer underwent Ga-PSMA I&T PET/CT before prostatectomy. The PET protocol consisted of early dynamic pelvic imaging, followed by static scans at 60 and 180 minutes postinjection (p.i.). SUVs, time-activity curves, quantitative analysis based on a 2-tissue compartment model, Patlak analysis, histopathology, and Gleason grading were compared between prostate cancer and benign prostate gland.

Results: Primary tumors were identified on both early dynamic and delayed imaging in 95% of patients. Tracer uptake was significantly higher in prostate cancer compared with benign prostate tissue at any time point (P ≤ 0.0003) and increased over time. Consequently, the tumor-to-nontumor ratio within the prostate gland improved over time (2.8 at 10 minutes vs 17.1 at 180 minutes p.i.). Tracer uptake at both 60 and 180 minutes p.i. was significantly higher in patients with higher Gleason scores (P < 0.01). The influx rate (Ki) was higher in prostate cancer than in reference prostate gland (0.055 [r = 0.998] vs 0.017 [r = 0.996]).

Conclusions: Primary prostate cancer is readily identified on early dynamic and static delayed Ga-PSMA ligand PET images. The tumor-to-nontumor ratio in the prostate gland improves over time, supporting a role of delayed imaging for optimal visualization of prostate cancer.
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http://dx.doi.org/10.1097/RLU.0000000000001589DOI Listing
June 2017

Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients.

Clin Nucl Med 2017 Jan;42(1):e29-e34

From the *Department of Nuclear Medicine, †Division of Endocrinology, Department of Internal Medicine I, ‡Comprehensive Cancer Center, and §Department of Radiology, University Hospital of Würzburg, Würzburg; ∥Pharmaceutical Radiochemistry, Technische Universität München, Munich; ¶Scintomics GmbH, Fürstenfeldbruck, Germany; and **Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Purpose: Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor with limited treatment options. Preclinical studies confirmed overexpression of the chemokine receptor 4 (CXCR4) in this cancer type. This study aimed to analyze the role of CXCR4 imaging using Ga-pentixafor for ACC staging and selection of patients for CXCR4-directed endoradiotherapy.

Methods: Thirty patients with histologically proven advanced, metastasized ACC underwent F-FDG PET/CT and Ga-pentixafor PET/CT within a time interval of 3 ± 4 days to evaluate suitability for CXCR4-directed endoradiotherapy. Scans were analyzed retrospectively for visual extent of ACC and SUVmax/mean of the tumor lesions. Ga-pentixafor PET was compared with F-FDG PET, the reference imaging standard. All patients were rated for suitability of CXCR4-directed endoradiotherapy considering patient's history, previous treatment, and CXCR4 expression of FDG-positive lesions compared with background activity within the same organ.

Results: All patients had lesions that were positive for both F-FDG and Ga-pentixafor PET and were rated as positive for disease. In 2 patients (7%), Ga-pentixafor PET identified more lesions compared with F-FDG PET. In 5 patients (17%) and 10 patients (33%), complementary and comparable information, respectively, was provided by dual-tracer imaging. In 13 patients (43%), more tumor lesions were identified by F-FDG PET compared with Ga-pentixafor PET. The F-FDG uptake of the malignant lesions was significantly higher (P < 0.01) than the SUVmax/mean for Ga-pentixafor. Overall, 70% of the patients were rated as suitable or potentially suitable for CXCR4-directed treatment.

Conclusions: Ga-pentixafor allows in vivo imaging of CXCR4 expression in patients with advanced ACC and may serve as companion diagnostic tool in selecting patients for potential CXCR4-directed endoradiotherapy. Seventy percent of the patients with advanced, metastasized ACC may be suitable for a CXCR4-directed treatment after failure of standard treatment options.
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http://dx.doi.org/10.1097/RLU.0000000000001435DOI Listing
January 2017

Impact of Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy.

EJNMMI Res 2016 Dec 26;6(1):78. Epub 2016 Oct 26.

Department of Radiation Oncology, Klinikum Ansbach, Ansbach, Germany.

Background: Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity.

Results: Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months.

Conclusions: Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.
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http://dx.doi.org/10.1186/s13550-016-0233-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081978PMC
December 2016

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013.

J Nucl Med 2016 Oct;57(Suppl 3):97S-104S

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Bad Berka, Germany

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with Lu-PSMA ligands. Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.
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http://dx.doi.org/10.2967/jnumed.115.170167DOI Listing
October 2016

Radiation Dosimetry for Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: Absorbed Dose in Normal Organs and Tumor Lesions.

J Nucl Med 2017 03 22;58(3):445-450. Epub 2016 Sep 22.

Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is increasingly used in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed doses for normal organs and tumor lesions using Lu-PSMA I&T (I&T is imaging and therapy) in patients undergoing up to 4 cycles of radioligand therapy. Results were compared with pretherapeutic Glu-NH-CO-NH-Lys-(Ahx)-[Ga(HBEDCC)] (Ga-PSMA-HBED-CC) PET. A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third, and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30-120 min, 24 h, and 6-8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pretherapeutic Ga-PSMA-HBED-CC PET/CT. Absorbed doses for individual cycles were calculated using OLINDA/EXM. SUVs from pretherapeutic PET were compared with absorbed doses and with change of SUV. The mean whole-body effective dose for all cycles was 0.06 ± 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 ± 0.21 Gy/GBq for the kidneys; 0.12 ± 0.06 Gy/GBq for the liver; and 0.55 ± 0.14 Gy/GBq for the parotid, 0.64 ± 0.40 Gy/GBq for the submandibular, and 3.8 ± 1.4 Gy/GBq for the lacrimal glands. Absorbed organ doses were relatively constant among the 4 different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2 ± 2.6 Gy/GBq (range, 0.22-12 Gy/GBq). Doses to tumor lesions gradually decreased, with 3.5 ± 2.9 Gy/GBq for the first, 3.3 ± 2.5 Gy/GBq for the second, 2.7 ± 2.3 Gy/GBq for the third, and 2.4 ± 2.2 Gy/GBq for the fourth cycle. SUVs of pretherapeutic PET moderately correlated with absorbed dose ( = 0.44, < 0.001 for SUV; = 0.43, < 0.001 for SUV) and moderately correlated with the change of SUV ( = 0.478, < 0.001 for SUV, and = 0.50, < 0.001 for SUV). Organ- and tumor-absorbed doses for Lu-PSMA I&T are comparable to recent reports and complement these with information on an excellent correlation between the 4 therapy cycles. With the kidneys representing the critical organ, a cumulative activity of 40 GBq of Lu-PSMA I&T appears to be safe and justifiable. The correlation between pretherapeutic SUV and absorbed tumor dose emphasizes the need for PSMA-ligand PET imaging for patient selection.
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http://dx.doi.org/10.2967/jnumed.116.178483DOI Listing
March 2017

68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT.

Clin Nucl Med 2016 Jul;41(7):515-21

From the Departments of *Nuclear Medicine, †Urology, and ‡Radiation Oncology, University Hospital of Würzburg, Würzburg; §Department of Radiation Oncology, Klinikum Ansbach, Ansbach; ∥Department of Nuclear Medicine, Technische Universität München, Munich, Germany; ¶Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA; #Department of Nuclear Medicine-PET/CT Oncologic & Endocrine Sections, Rovigo Hospital, Rovigo, Italy; **Department of Radiology, University Hospital of Würzburg, Würzburg, Germany; ††Scintomics GmbH, Fürstenfeldbruck; and ‡‡Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany.

Purpose: Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT.

Patients And Methods: One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel).

Results: The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively.

Conclusions: The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.
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http://dx.doi.org/10.1097/RLU.0000000000001197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006491PMC
July 2016

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.

J Nucl Med 2016 Feb 12;57(2):248-51. Epub 2015 Nov 12.

Department of Internal Medicine II, Division of Hematology and Medical Oncology, Universitätsklinikum Würzburg, Würzburg, Germany.

Unlabelled: Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand ((68)Ga-pentixafor) for diagnostic receptor targeting, (177)Lu- and (90)Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy.

Methods: CXCR4 target expression was demonstrated by baseline (68)Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic (177)Lu-pentixather dosimetry was performed before (177)Lu-pentixather or (90)Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue.

Results: A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in (18)F-FDG uptake.

Conclusion: CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma.
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http://dx.doi.org/10.2967/jnumed.115.167361DOI Listing
February 2016

Biodistribution and radiation dosimetry for the chemokine receptor CXCR4-targeting probe 68Ga-pentixafor.

J Nucl Med 2015 Mar 19;56(3):410-6. Epub 2015 Feb 19.

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

Unlabelled: (68)Ga-pentixafor is a promising PET tracer for imaging the expression of the human chemokine receptor 4 (CXCR4) in vivo. The whole-body distribution and radiation dosimetry of (68)Ga-pentixafor were evaluated.

Methods: Five multiple-myeloma patients were injected intravenously with 90-158 MBq of (68)Ga-pentixafor (mean ± SD, 134 ± 25 MBq), and a series of 3 rapid multiple-bed-position whole-body scans were acquired immediately afterward. Subsequently, 4 static whole-body scans followed at 30 min, 1 h, 2 h, and 4 h after administration of the radiopharmaceutical. Venous blood samples were obtained. Time-integrated activity coefficients were determined from multiexponential regression of organ region-of-interest data normalized to the administered activity, for example, the time-dependent percentages of the injected activity per organ. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM.

Results: The effective dose based on 150 MBq of (68)Ga-pentixafor was 2.3 mSv. The highest organ-absorbed doses (for 150 MBq injected) were found in the urinary bladder wall (12.2 mGy), spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Other organ mean absorbed doses were as follows: 2.7 mGy, liver; 2.1 mGy, red marrow; 1.7 mGy, testes; and 1.9 mGy, ovaries.

Conclusion: (68)Ga-pentixafor exhibits a favorable dosimetry, delivering absorbed doses to organs that are lower than those delivered by (18)F-FDG- or (68)Ga-labeled somatostatin receptor ligands.
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http://dx.doi.org/10.2967/jnumed.114.151647DOI Listing
March 2015

High interstitial fluid pressure is associated with low tumour penetration of diagnostic monoclonal antibodies applied for molecular imaging purposes.

PLoS One 2012 8;7(5):e36258. Epub 2012 May 8.

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The human epithelial cell adhesion molecule (EpCAM) is highly expressed in a variety of clinical tumour entities. Although an antibody against EpCAM has successfully been used as an adjuvant therapy in colon cancer, this therapy has never gained wide-spread use. We have therefore investigated the possibilities and limitations for EpCAM as possible molecular imaging target using a panel of preclinical cancer models. Twelve human cancer cell lines representing six tumour entities were tested for their EpCAM expression by qPCR, flow cytometry analysis and immunocytochemistry. In addition, EpCAM expression was analyzed in vivo in xenograft models for tumours derived from these cells. Except for melanoma, all cell lines expressed EpCAM mRNA and protein when grown in vitro. Although they exhibited different mRNA levels, all cell lines showed similar EpCAM protein levels upon detection with monoclonal antibodies. When grown in vivo, the EpCAM expression was unaffected compared to in vitro except for the pancreatic carcinoma cell line 5072 which lost its EpCAM expression in vivo. Intravenously applied radio-labelled anti EpCAM MOC31 antibody was enriched in HT29 primary tumour xenografts indicating that EpCAM binding sites are accessible in vivo. However, bound antibody could only be immunohistochemically detected in the vicinity of perfused blood vessels. Investigation of the fine structure of the HT29 tumour blood vessels showed that they were immature and prone for higher fluid flux into the interstitial space. Consistent with this hypothesis, a higher interstitial fluid pressure of about 12 mbar was measured in the HT29 primary tumour via "wick-in-needle" technique which could explain the limited diffusion of the antibody into the tumour observed by immunohistochemistry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036258PLOS
September 2012

The sensitivity of [11C]choline PET/CT to localize prostate cancer depends on the tumor configuration.

Clin Cancer Res 2011 Jun 14;17(11):3751-9. Epub 2011 Apr 14.

Department of Nuclear Medicine,Technische Universität München, München, Germany.

Purpose: To evaluate the dependency of the sensitivity of [(11)C]choline positron emission tomography/computed tomography (PET/CT) for detecting and localizing primary prostate cancer (PCa) on tumor configuration in the histologic specimen.

Experimental Design: Forty-three patients with biopsy-proven PCa were included. They underwent radical prostatectomy within 31 days after [(11)C]choline PET/CT. The transaxial image slices and the histologic specimens were analyzed by comparing the respective slices. Maximum standardized uptake values (SUV(max)) were calculated in each segment and correlated with histopathology. The tumor configuration in the histologic specimen was grouped as: I, unifocal; II, multifocal; III, rind-like shaped; IV, size <5 mm. Data analysis included the investigation of detection of PCa by SUV(max), the assessment of the influence of potential contributing factors on tumor prediction, and the evaluation of whether SUV could discriminate cancer tissue from benign prostate hyperplasia (BPH), prostatitis, HGPIN (high-grade prostate intraepithelial neoplasm), or normal prostate tissue. General estimation equation models were used for statistical analysis.

Results: Tumor configuration in histology was classified as I in 21 patients, as II in 9, as III in 5, and as IV in 8. The prostate segment involved by cancer is identified in 79% of the patients. SUV(max) was located in the same side of the prostate in 95% of patients. Tumor configuration was the only factor significantly negatively influencing tumor prediction (P < 0.001). PCa-SUV(max) (median SUV(max) = 4.9) was not significantly different from BPH-SUV (median SUV(max) = 4.5) and prostatitis-SUV (median SUV(max) = 3.9), P = 0.102 and P = 0.054, respectively.

Conclusions: The detection and localization of PCa in the prostate with [(11)C]choline PET/CT is impaired by tumor configuration. Additionally, in our patient population, PCa tissue could not be distinguished from benign pathologies in the prostate.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2093DOI Listing
June 2011

Restricted water diffusibility as measured by diffusion-weighted MR imaging and choline uptake in (11)C-choline PET/CT are correlated in pelvic lymph nodes in patients with prostate cancer.

Mol Imaging Biol 2011 Apr;13(2):352-61

Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.

Purpose: (11)C-Choline-positron emission tomography (PET)/computed tomography (CT) is increasingly used in patients with prostate cancer. Another promising technique for assessment of tumor biology is diffusion-weighted MR imaging (DWI). The aim of the study was to compare the functional parameters standardized uptake value (SUV) in PET and apparent diffusion coefficient (ADC) value in DWI of lymph nodes in prostate cancer patients.

Procedures: Fourteen patients with prostate cancer underwent DWI at 1.5T and (11)C-Choline-PET/CT. ADC values and SUVs of all lymph nodes larger than 5 mm (n = 55) were compared by using linear regression analysis. Performance of DWI and (11)C-Choline PET was assessed by receiver operator characteristic curve analysis using histopathology or clinical follow-up as standard of reference.

Results: ADC values and SUV showed a moderate but highly significant inverse correlation (r = -0.5144, p < 0.0001). In lymph nodes with low ADC values, the dispersion of SUV was more pronounced. Moreover, a highly significant difference was observed for mean ADC values and SUV in lymph nodes considered as benign or malignant by follow-up/histopathology (ADC 1.60 ± 0.24 vs. 1.09 ± 0.23 × 10(-3) mm(2)/s; SUV 1.82 ± 0.57 vs. 4.68 ± 03.12; p < 0.0001, respectively).

Conclusion: These pilot data propose the ADC value in DWI as a new potential imaging biomarker which might provide additional information on tumor pathophysiology compared to the SUV in (11)C-Choline PET/CT.
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http://dx.doi.org/10.1007/s11307-010-0337-6DOI Listing
April 2011

In vivo characterization of proliferation for discriminating cancer from pancreatic pseudotumors.

J Nucl Med 2008 Sep 14;49(9):1437-44. Epub 2008 Aug 14.

Department of Nuclear Medicine, Technische Universität München, Munich, Germany.

Unlabelled: We have determined the ability of PET with the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to detect pancreatic cancer and to differentiate malignant from benign pancreatic lesions.

Methods: In this prospective study, (18)F-FLT PET was performed on 31 patients with undefined pancreatic lesions. Routine diagnostic procedures included endoscopic ultrasound, MRI, or multislice helical CT of the upper gastrointestinal tract in all patients. Uptake of (18)F-FLT was evaluated semiquantitatively by calculation of mean and maximal standardized uptake values (SUVs). Results were correlated to the reference methods, which were histopathology (23/31) or cytology/clinical follow-up (8/31).

Results: All 10 benign pancreatic lesions were negative on (18)F-FLT PET and showed only background activity (specificity, 100%; 90% confidence interval, 74%-100%). On visual interpretation, 15 of 21 malignant tumors presented as focal (18)F-FLT uptake higher than the surrounding background (sensitivity, 71.4%; 90% confidence interval, 52%-89%). (18)F-FLT PET missed 4 well-differentiated and 2 T1 cancers. Mean (18)F-FLT uptake was 3.1 in all malignant tumors (median, 2.8; range, 1.3-8.5), 3.7 in tumors with visual tracer uptake (median, 3.2; range, 2.1-8.5), and significantly higher in malignant than in benign tumors (mean/median, 1.4; range, 1.2-1.7; P<0.001). For discriminating cancer from benign pancreatic lesions, receiver-operating-characteristic analysis indicated a sensitivity of 81% and specificity of 100% (area under the curve, 0.93) using a mean (18)F-FLT SUV cutoff of 1.8 (maximal (18)F-FLT SUV: area under the curve, 0.92; SUV cutoff, 2.1).

Conclusion: In this pilot study, focal uptake of the in vivo proliferation marker (18)F-FLT was detected exclusively in malignant tumors. (18)F-FLT PET may therefore be useful as a diagnostic adjunct for differentiating cancer from benign pancreatic lesions.
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http://dx.doi.org/10.2967/jnumed.108.052027DOI Listing
September 2008

SPECT/CT.

J Nucl Med 2008 Aug 16;49(8):1305-19. Epub 2008 Jul 16.

Department of Nuclear Medicine, Technische Universität München, München, Germany.

In view of the commercial success of integrated PET/CT scanners, there is an increasing interest in comparable SPECT/CT systems. SPECT in combination with CT enables a direct correlation of anatomic information and functional information, resulting in better localization and definition of scintigraphic findings. Besides anatomic referencing, the added value of CT coregistration is based on the attenuation correction capabilities of CT. The number of clinical studies is limited, but pilot studies have indicated a higher specificity and a significant reduction in indeterminate findings. The superiority of SPECT/CT over planar imaging or SPECT has been demonstrated in bone scintigraphy, somatostatin receptor scintigraphy, parathyroid scintigraphy, and adrenal gland scintigraphy. Also, rates of detection of sentinel nodes by biopsy can be increased with SPECT/CT. This review highlights recent technical developments in integrated SPECT/CT systems and summarizes the current literature on potential clinical uses and future directions for SPECT/CT in cardiac, neurologic, and oncologic applications.
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http://dx.doi.org/10.2967/jnumed.107.050195DOI Listing
August 2008

Expression and clinical significance of glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus.

BMC Cancer 2008 Mar 10;8:70. Epub 2008 Mar 10.

Institute of Pathology, TU München, München, Germany.

Background: Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis.

Methods: Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival.

Results: GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031).

Conclusion: We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.
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http://dx.doi.org/10.1186/1471-2407-8-70DOI Listing
March 2008

PET/CT with Gluc-Lys-([(18)F]FP)-TOCA: correlation between uptake, size and arterial perfusion in somatostatin receptor positive lesions.

Eur J Nucl Med Mol Imaging 2008 Feb 3;35(2):264-71. Epub 2007 Oct 3.

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

Purpose: Somatostatin receptor (sstr) positive tumours vary widely in uptake of radiolabelled somatostatin (sst) analogues. This study determinates variability in lesion uptake of the glycosylated sst analogon N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(2-[(18)F]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate (Gluc-Lys([(18)F]FP)-TOCA) and correlates it with lesion size and arterial perfusion as measured on computed tomography (CT).

Methods: Ten patients with metastasized neuroendocrine carcinomas were investigated with positron emission tomography PET/CT (Biograph 16, Siemens, Germany). Lesion standardized uptake values (SUVs) were determined at approximately 50 min post tracer injection according to a 60% isocontour volume of interest around each lesion. Lesion size and enhancement in the arterial phase (hounsfield units, HUs) were derived from CT.

Results: 114 lesions in the upper abdomen had a correlate on both, PET and CT. Variability in lesion SUVs was high (SUV(mean) 22 +/- 13). Intraindividually, there was a sigmoid positive correlation between lesion SUV and lesion diameter indicating partial volume effects. Residual variability in lesions > or =3 cm (> or =2.5 cm) ranged down to about half (third) of the maximum lesion uptake and remained unexplained by partial volume effects. No correlation with measured HU in the arterial phase was found, neither intraindividually nor interindividually.

Conclusion: Partial volume effects were a major source of intraindividual variability in tumour tracer uptake. Lesions below 2.5 to 3 cm should thus be used with caution when performing dose calculations. In larger lesions residual variability in uptake must be considered; it may be due to variable sstr2 expression on the tumours' cell surfaces.
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http://dx.doi.org/10.1007/s00259-007-0576-1DOI Listing
February 2008

Imaging of angiogenesis in cardiology.

Eur J Nucl Med Mol Imaging 2007 Jun;34 Suppl 1:S9-19

Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany.

In the past decade, there have been major improvements in our understanding of angiogenesis at the genetic, molecular and cellular levels. Concentrated efforts in this area have led to new therapeutic approaches to ischaemic heart disease using angiogenic factors, gene therapy and progenitor cells. Despite very promising experimental results in animal studies, large clinical trials have failed to confirm the results in patients with coronary artery disease. Important questions such as selection of growth factors and donor cells, as well as the timing, dose and route of administration, have been raised and need to be answered. Molecular imaging approaches which may provide specific markers of the angiogenic process (e.g. integrin expression in endothelial cells) have been introduced and are expected to address some of these questions. Although few clinical imaging results are currently available, animal studies suggest the potential role of molecular imaging for characterisation of the angiogenetic process in vivo and for the monitoring of therapeutic effects.
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http://dx.doi.org/10.1007/s00259-007-0436-zDOI Listing
June 2007
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