Publications by authors named "Matthias Eiber"

217 Publications

Detection efficacy of F-rhPSMA-7.3 PET/CT and impact on patient management in patients with biochemical recurrence of prostate cancer after radical prostatectomy and prior to potential salvage treatment.

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

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

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of F-labeled PSMA-targeting agents. F-rhPSMA-7.3 is a lead compound which is currently under investigation in two multicenter phase III trials for PET-imaging. Here, we report the first retrospective data on its detection efficacy and potential impact on clinical management in a homogeneous cohort of patients with biochemical recurrence after radical prostatectomy, and prior to any salvage therapy. 242 patients (median [range] PSA, 0.60 [0.2-60.8] ng/mL) who underwent F-rhPSMA-7.3 PET/CT were retrospectively selected from the institutions' database. Images were re-read by an experienced nuclear medicine physician. Lesion detection rates were stratified by PSA. Further, potential management before and after PET was assessed by an interdisciplinary simulated tumor board and categorized (major vs. minor vs. no therapeutic change). The distribution of management change identified in each PSA subgroup was determined. In total, 176/242 (72.7%) patients showed PSMA-ligand positive findings. F-rhPSMA-7.3 detection rates were 61.8% (63/102), 67.9% (38/56), 81.1% (30/37) and 95.7% (45/47) for PSA-levels of 0.2-<0.5 ng/mL, 0.5-<1 ng/mL, 1-<2 ng/mL and ≥2 ng/mL, respectively. F-rhPSMA-7.3 PET/CT revealed local recurrence, pelvic lymph node metastases, retroperitoneal lymph nodes metastases, supradiaphragmatic lymph nodes, bone metastases, and visceral metastases in 48.8% ( = 118), 28.9% ( = 70), 6.6% ( = 16), 1.2% ( = 3), 13.2% ( = 32) and 1.2% ( = 3) of patients, respectively. Notably, bone lesions were identified in 8.8% of patients (9/102) with PSA <0.5 ng/mL. Results from the interdisciplinary simulated tumor board indicated change of therapeutic management in 153/242 patients (63.2%) with 54/242 (22.3%) considered major and 99/242 (40.9%) minor, respectively. F-rhPSMA-7.3 PET/CT did not prompt any therapeutic changes in 64/242 patients (26.4%). F-rhPSMA-7.3 PET offers high detection efficacy in patients with biochemical recurrence after radical prostatectomy, and prior to potential salvage therapy, and results in a potential change in treatment plans in nearly 2/3 of patients. Keywords: Biochemical recurrence; hybrid imaging; positron emission tomography; prostate cancer; prostate-specific membrane antigen.
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http://dx.doi.org/10.2967/jnumed.120.260091DOI Listing
March 2021

E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET.

Eur J Nucl Med Mol Imaging 2021 Feb 19. Epub 2021 Feb 19.

Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.

Rationale: The development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions.

Methods: A panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process.

Results: According to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET.

Conclusions: The E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.
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http://dx.doi.org/10.1007/s00259-021-05245-yDOI Listing
February 2021

Performance of [Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients.

Eur J Nucl Med Mol Imaging 2021 Feb 4. Epub 2021 Feb 4.

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

Purpose: To evaluate the performance of [Ga]Ga-PSMA-11 PET/CT in the diagnosis of recurrent prostate cancer (PC) after prostatectomy in a large multicentre cohort.

Methods: The centres, which contributed to this study, were the departments of nuclear medicine of Heidelberg (Germany), Technical University of Munich (Germany) and Albert Einstein Hospital of São Paulo (Brazil). A total of 2533 patients who were scanned with [Ga]Ga-PSMA-11 PET/CT at 1 h p.i. due to recurrent PC after prostatectomy were included in this retrospective analysis. Exclusion criteria were as follows: patients with untreated primary tumour, previous chemotherapy or Xofigo®; those previously treated with exclusively external beam radiation therapy or HIFU; those referred for PSMA-therapy; and those treated with ADT (including first- and second-generation ADT) within the last 6 months. Potential influences of different factors such as PSA level, PSA doubling-time (PSA), PSA velocity (PSA), Gleason Score (GSC, including the separate analysis of 7a and 7b), age and amount of injected tracer were evaluated in a multivariable analysis.

Results: The rate of pathologic PET/CT-scans was 43% for PSA ≤ 0.2 ng/ml, 58% for PSA > 0.2 to ≤ 0.5, 72% for PSA > 0.5 to ≤ 1.0 and increased to a maximum of 93% for PSA > 10 ng/ml. A pathological PET/CT was significantly (p = 0.001) associated with PSA level and higher GSC. Amount of injected tracer, age, PSA and PSA were not associated with a higher probability of a pathological scan.

Conclusion: [Ga]Ga-PSMA-11 PET/CT at 1 h p.i. confirmed its high performance in the largest patient cohort yet analysed. Tumour detection showed a clear association with higher PSA and higher GSC. No association was found between a pathological [Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSA or PSA.
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http://dx.doi.org/10.1007/s00259-021-05189-3DOI Listing
February 2021

Regional Lymph Node Metastasis on Prostate Specific Membrane Antigen Positron Emission Tomography Correlates with Decreased Biochemical Recurrence-Free and Therapy-Free Survival after Radical Prostatectomy: A Retrospective Single-Center Single-Arm Observational Study.

J Urol 2021 Feb 4:101097JU0000000000001596. Epub 2021 Feb 4.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Purpose: We sought to address the impact of preoperative prostate specific membrane antigen (PSMA) positron emission tomography (PET) findings prior to radical prostatectomy and pelvic lymph node dissection on biochemical recurrence and time to adjuvant or salvage treatment.

Materials And Methods: Between 2013 and 2017, 64 intermediate and 166 high risk (230) prostate cancer patients received Ga-PSMA-11 PET followed by radical prostatectomy and pelvic lymph node dissection. Biochemical recurrence-free and therapy-free survivalwere determined. For all time-to-event analyses, univariable and multivariable Cox proportional hazards models and univariable Kaplan-Meier analyses were applied, with a significance threshold of p <0.05.

Results: The overall sensitivity, specificity, positive predictive value and negative predictive value of PSMA PET for pN1 disease was 48.5%, 95.7%, 82.1% and 82.2%, respectively. Median followup was 30.2 months. Biochemical recurrence occurred in 50.4% (116) of patients and adjuvant or salvage treatment was performed in 46.5% (107). Worst biochemical recurrence-free and therapy-free survival was observed in pN1 patients who also exhibited PSMA PET positive lymph node, followed by pN1 patients without PSMA PET positive lymph node and patients without evidence of lymph node metastasis on histology and PSMA PET (median biochemical recurrence-free survival 1.7 vs. 7.5 vs. >36 months, median therapy-free survival 2.6 vs. 8.9 vs. >36 months).

Conclusions: Patients with positive lymph node on PSMA PET prior to radical prostatectomy have to expect early biochemical recurrence and adjuvant/salvage therapy, despite thorough pelvic lymph node dissection. Therefore, results from PSMA PET can be used for patients' consultation and more stringent followup as well as for planning of neoadjuvant/adjuvant therapy.
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http://dx.doi.org/10.1097/JU.0000000000001596DOI Listing
February 2021

[PSMA radioligand therapy could pose infrastructural challenges for nuclear medicine: results of a basic calculation for the capacity planning of nuclear medicine beds in the German hospital sector].

Nuklearmedizin 2021 Feb 2. Epub 2021 Feb 2.

Lehrstuhl für Management und Innovation im Gesundheitswesen, Universität Witten/Herdecke, Deutschland.

Background:  With the increasing use of the Lu-177-PSMA-RLT for the treatment of advanced castrate resistant prostate cancer (mCRPC), an estimation of the necessary therapy beds in nuclear medicine departments is of great importance in the view of the high number of cases of advanced prostate cancer, and as a basis to avoid a potentially infrastructure-related bottleneck for patient care in this field.

Methods:  The number of therapy beds available in German nuclear medicine departments was included in a basic calculation in view of the overall potential for therapy beds to be expected in the event of a possible approval of a therapeutic agent for the Lu-177-PSMA-RLT for mCRPC patients. A potential expansion of the Lu-PSMA-therapy indications was not taken into account.

Results:  The basic calculation shows for a nationwide nuclear medicine bed capacity of approx. 234 000 treatment days a relatively small bed reserve of approx. 19 000 nuclear medicine bed days, which corresponds to a reserve of 63 beds for the research question. There are regional differences in bed capacity: while for some federal states there is an under-capacity of nuclear medicine therapy beds with an approved Lu-177-PSMA-RLT, this is less the case for other federal states.

Discussion:  This basic calculation shows that the capacity of nuclear medicine therapy beds is likely to be very well utilized with a prospectively approved therapeutic agent for Lu-177-PSMA-RLT, and could even reach its limits in some German federal states. With a prospective expansion of the range of indications or the foreseeable clinical establishment of further therapeutic radiopharmaceuticals, the number of therapy beds could represent a bottleneck factor for the comprehensive patient treatment in the medium term.
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http://dx.doi.org/10.1055/a-1351-0030DOI Listing
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

Comparative preclinical biodistribution, dosimetry and endoradiotherapy in mCRPC using F/Lu-rhPSMA-7.3 and Lu-PSMA I&T.

J Nucl Med 2020 Dec 18. Epub 2020 Dec 18.

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

Radiohybrid prostate-specific membrane antigen (rhPSMA)-ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. Based on preliminary data as diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess biodistribution, dosimetry and therapeutic efficacy of F/Lu-rhPSMA-7.3 in comparison to the established therapeutic agent Lu-PSMA I&T (imaging & therapy). Biodistribution of F/Lu-rhPSMA-7.3 and Lu-PSMA I&T was performed in LNCaP tumor bearing SCID-mice after sacrifice at defined time points up to 7 days ( = 5). Organs and tumors were dissected, injected dose per gram (%ID/g) was determined and dosimetry calculations were performed using OLINDA/EXM1.0. The therapeutic efficacy of a single dose of 30 MBq F/Lu-rhPSMA-7.3 ( = 7) was compared with Lu-PSMA I&T ( = 7) and control groups ( = 6-7) using C4-2 tumor bearing SCID-mice by evaluating tumor growth and survival over 6 weeks post treatment. The biodistribution of F/Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h p.i.) and highest activity uptake in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively at 1 h p.i.) indicating a renal excretion pathway. Compared with Lu-PSMA I&T, F/Lu-rhPSMA-7.3 exhibited an initial (1 h) 2.6-fold higher tumor uptake in LNCaP xenografts and a longer retention (4.5 %ID/g vs. 0.9 %ID/g at 168 h). The tumor dose of F/Lu-rhPSMA-7.3 was substantially higher (e.g. 7.47 µGy/MBq vs. 1.96 µGy/MBq at 200 mm) compared with Lu-PSMA I&T. In most organs absorbed doses were higher for Lu-PSMA I&T. A single dose of F/Lu-rhPSMA-7.3 showed a significantly higher tumor size reduction compared with Lu-PSMA I&T at the end of the experiment ( = 0.0167). At pre-defined termination of the experiment at 6 weeks 7/7 and 3/7 mice were still alive in the F/Lu-rhPSMA-7.3 and Lu-PSMA I&T groups compared to the control groups with 0/7 and 0/6 mice. F/Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation due to similar clearance kinetics and radiation dose to healthy organs, but superior tumor uptake and retention compared with Lu-PSMA I&T. Preliminary treatment experiments showed a favorable anti-tumor response.
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http://dx.doi.org/10.2967/jnumed.120.254516DOI Listing
December 2020

Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy.

Eur Urol 2021 Apr 11;79(4):537-544. Epub 2020 Dec 11.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.

Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.

Design, Setting, And Participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy.

Surgical Procedure: Open salvage surgery with PSMA radioguidance.

Measurements: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated.

Results And Limitations: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group.

Conclusions: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings.

Patient Summary: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival.
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http://dx.doi.org/10.1016/j.eururo.2020.11.012DOI Listing
April 2021

Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA.

Eur Urol 2021 Mar 5;79(3):343-350. Epub 2020 Dec 5.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), partnersite Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time.

Objective: To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA.

Design, Setting, And Participants: Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured.

Results And Limitations: Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8-11.2), 4.1 (95% CI 3-14.8), and 7.7 (95% CI 4.5-12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design.

Conclusions: Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients.

Patient Summary: Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.
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http://dx.doi.org/10.1016/j.eururo.2020.11.013DOI Listing
March 2021

Matched-pair comparison of Ga-PSMA-11 and F-rhPSMA-7 PET/CT in patients with primary and biochemical recurrence of prostate cancer: frequency of non-tumor related uptake and tumor positivity.

J Nucl Med 2020 Dec 4. Epub 2020 Dec 4.

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

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of prostate cancer theranostic agents. F-rhPSMA-7, offers the advantages of F-labelling and low urinary excretion compared with Ga-PSMA-11. Here, we compare frequency of non-tumor related uptake and tumor positivity with Ga-PSMA-11 and F-rhPSMA-7 in patients with primary or recurrent prostate cancer. This retrospective matched-pair comparison matched 160 F-rhPSMA-7 with 160 Ga-PSMA-11 PET/CT studies for primary staging ( = 33) and biochemical recurrence ( = 127) according to clinical characteristics. Two nuclear medicine physicians reviewed all scans, first, identifying all PET-positive lesions, then differentiating lesions suspicious for prostate cancer from those that were benign, based on known pitfalls and ancillary information from CT. For each region, SUV of the lesion with the highest PSMA-ligand uptake was noted. Tumor positivity rates were determined and SUV were compared separately for each tracer. F-rhPSMA-7 and Ga-PSMA-11 PET revealed 566 and 289 PSMA-ligand positive lesions, respectively. Of these, 379 and 100 lesions, equaling 67.0 % and 34.6 % of all PSMA-positive lesions were considered benign, respectively. The distribution of their etiology was similar (42%, 24%, 25% in F-rhPSMA-7 vs. 32%, 24%, 38% in Ga-PSMA-11 for ganglia, bone and unspecific lymph nodes, respectively). All primary tumors were positive with both agents ( = 33 each) while slightly more metastatic lesions were observed with Ga-PSMA-11 in both disease stages (113 for F-rhPSMA-7 and 124 for Ga-PSMA-11). SUV of F-rhPSMA-7 and Ga-PSMA-11 did not differ ( > 0.05) in local recurrence or primary prostate cancer, however, the tumor-to-bladder ratio was significantly higher with F-rhPSMA-7 (4.9±5.3 vs 2.2±3.7, = 0.02 for local recurrence and 9.8±9.7 vs 2.3±2.6, < 0.001 for primary prostate cancer). The tumor positivity rate was consistently high for Ga-PSMA-11 and F-rhPSMA-7. Both tracers revealed a considerable number of areas of uptake that were reliably identified as benign by trained physicians making use of corresponding morphological imaging and known PSMA pitfalls. These were more frequent with F-rhPSMA-7. However, the matched-pair comparison could have introduced a source of bias. Adequate reader training can allow physicians to differentiate benign uptake from disease and be able to benefit from the logistical and clinical advantages of F-rhPSMA-7.
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http://dx.doi.org/10.2967/jnumed.120.251447DOI Listing
December 2020

Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer.

J Nucl Med 2020 Dec 4. Epub 2020 Dec 4.

UCLA.

Prostate-specific membrane antigen targeted radioligand therapy (PSMA-RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA-RLT. Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry. PSMA-RLT significantly improved disease control in a dose-dependent manner. (Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. We identified signaling alterations that may mediate resistance to PSMA-RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.
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http://dx.doi.org/10.2967/jnumed.120.256263DOI Listing
December 2020

First experiences with Lu-177 PSMA therapy in combination with Pembrolizumab or after pretreatment with Olaparib in single patients.

J Nucl Med 2020 Nov 27. Epub 2020 Nov 27.

Department of Nuclear Medicine, University Hospital Ulm, Germany.

Synergistic effects of immunotherapy with pembrolizumab or drugs targeting DNA damage e.g. olaparib could be used to overcome the limitations of radioligand therapy (RLT) with Lu-177 prostate specific membrane antigen (PSMA) in metastasized castrate resistant prostate cancer (mCRPC) patients. Here, we present two patients receiving such combination / sequential therapies. RLT was performed at 6-8 week intervals after they either exhausted or were considered unfit for all approved conventional treatment. Patient 1 was on pembrolizumab for his squamous cell carcinoma of the skin whereas patient 2 received RLT sequentially 4 weeks after a 3 months monotherapy with olaparib. Both patients tolerated RLT without any significant hematotoxicity. Patient 2 showed radiological and biochemical response whereas patient 1 achieved PSA stabilization after 3 therapy cycles. These cases indicate that RLT in combination with pembrolizumab or sequentially after olaparib might be well tolerated in single patients.
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http://dx.doi.org/10.2967/jnumed.120.249029DOI Listing
November 2020

Important pharmacokinetic parameters for individualization of Lu-PSMA therapy: A global sensitivity analysis for a physiologically-based pharmacokinetic model.

Med Phys 2021 Feb 15;48(2):556-568. Epub 2020 Dec 15.

Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, 89081, Germany.

Purpose: The knowledge of the contribution of anatomical and physiological parameters to interindividual pharmacokinetic differences could potentially be used to improve individualized treatment planning for radionuclide therapy. The aim of this study was therefore to identify the physiologically based pharmacokinetic (PBPK) model parameters that determine the interindividual variability of absorbed doses (ADs) to kidneys and tumor lesions in therapy with Lu-labeled PSMA-targeting radioligands.

Methods: A global sensitivity analysis (GSA) with the extended Fourier Amplitude Sensitivity Test (eFAST) algorithm was performed. The whole-body PBPK model for PSMA-targeting radioligand therapy from our previous studies was used in this study. The model parameters of interest (input of the GSA) were the organ receptor densities [R ], the organ blood flows f, and the organ release rates λ. These parameters were systematically sampled NE times according to their distribution in the patient population. The corresponding pharmacokinetics were simulated and the ADs (model output) to kidneys and tumor lesions were collected. The main effect and total effect were calculated using the eFAST algorithm based on the variability of the model output: The main effect of input parameter represents the reduction in variance of the output if the "true" value of parameter would be known. The total effect of an input parameter represents the proportion of variance remaining if the "true" values of all other input parameters except for are known. The numbers of samples NE were increased up to 8193 to check the stability (i.e., convergence) of the calculated main effects and total effects .

Results: From the simulations, the relative interindividual variability of ADs in the kidneys (coefficient of variation CV = 31%) was lower than that of ADs in the tumors (CV up to 59%). Based on the GSA, the most important parameters that determine the ADs to the kidneys were kidneys flow (  = 0.36,  = 0.43) and kidneys receptor density (  = 0.25,  = 0.30). Tumor receptor density was identified as the most important parameter determining the ADs to tumors ( and up to 0.72).

Conclusions: The results suggest that an accurate measurement of receptor density and flow before therapy could be a promising approach for developing an individualized treatment with Lu-labeled PSMA-targeting radioligands.
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http://dx.doi.org/10.1002/mp.14622DOI Listing
February 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 2020 Nov 13. Epub 2020 Nov 13.

School of Medicine, Department of Nuclear Medicine, Technische Universität München, 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. 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, while the CDR was the percentage of patients who had at least one 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 (IQR: 0.41-2.46 ng/mL) were included. Out of these, 162 patients had composite follow-up at a median duration of 5.6 months (range 1.1-14.2 months). 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 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 (P<0.001). F-rhPSMA-7 PET/CT offers high PPV in BCR after RP. Its CDR is dependent on the pre-scan 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
November 2020

Joint Imaging Platform for Federated Clinical Data Analytics.

JCO Clin Cancer Inform 2020 11;4:1027-1038

Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany.

Purpose: Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles.

Methods: The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions.

Results: The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform.

Conclusion: The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.
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http://dx.doi.org/10.1200/CCI.20.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713526PMC
November 2020

An in silico study on the effect of the radionuclide half-life on PET/CT imaging with PSMA-targeting radioligands.

Nuklearmedizin 2021 Feb 16;60(1):33-37. Epub 2020 Oct 16.

Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, Germany.

Aim:  The aim of this work was to systematically investigate the influence of the radionuclide half-life and affinity of prostate-specific membrane antigen (PSMA)-targeting ligands on the activity concentration for PET/CT imaging.

Methods:  A whole-body physiologically-based pharmacokinetic (PBPK) model with individually estimated parameters of 13 patients with metastatic castration-resistant prostate cancer (mCRPC) was used to simulate the pharmacokinetics of PSMA-targeting radioligands. The simulations were performed with Ga (T1/2 = 1.13 h), F (T1/2 = 1.83 h), Cu (T1/2 = 12.7 h) and for different affinities (dissociation constants of 1-0.01 nM) and a commonly used ligand amount of 3 nmol. The activity concentrations were calculated at 1, 2, 3, 4, 8, 12, and 16 h after injection.

Results:  The highest tumor uptake was achieved 1 h p. i. for Ga-PSMA. For F-PSMA, the highest tumor uptake was at 1 h p. i. and 2 h p.i for dissociation constants  = 1 nM and  = 0.1-0.01 nM, respectively. For Cu-PSMA, the highest tumor uptake was at 4 h p. i. for dissociation constant  = 1 nM and at 4 h p. i. (9 patients) and 8 h p. i. (4 patients) for higher affinities. Compared to Ga-PSMA (1 h p. i.), the activity concentrations in the tumor for F-PSMA (2 h p. i.) increased maximum 1.3-fold with minor differences for all affinities. For Cu-PSMA (4 h p. i.), the improvements were in the range of 2.8 to 3.2-fold for all affinities.

Conclusions:  The simulations indicate that the highest tumor-to-background ratio can be achieved after 4 hours in PET/CT using high-affinity Cu-PSMA.
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http://dx.doi.org/10.1055/a-1253-1535DOI Listing
February 2021

Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Compared with Conventional Imaging for Initial Staging of Treatment-naïve Intermediate- and High-risk Prostate Cancer: A Retrospective Single-center Study.

Eur Urol Oncol 2020 Sep 18. Epub 2020 Sep 18.

Institute of Urologic Oncology (IUO), Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; Physics & Biology in Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) imaging in the initial staging of men with prostate cancer (PCa) has yet to be evaluated adequately.

Objective: To investigate the concordance of PSMA PET/CT with conventional imaging (CI) with cross-sectional abdominopelvic and/or radionuclide bone imaging in the initial staging of patients with treatment-naïve PCa.

Design, Setting, And Participants: We performed a post hoc retrospective cohort study of patients enrolled in a prospective single-arm trial (NCT03368547). We included patients with intermediate-risk (IR) and high-risk (HR) PCa who underwent PSMA PET/CT within 6 mo of CI. Patients with any treatment prior to PSMA PET/CT were excluded. Patient- and tumor-specific data, and imaging findings were obtained.

Outcome Measurements And Statistical Analysis: Our primary outcome measurement was the concordance rate of PSMA PET/CT with CI for the identification of N, M1a, M1b, and M1c disease. Descriptive statistics were used.

Results And Limitations: A total of 168 patients with treatment-naïve IR and HR PCa met the inclusion criteria. HR disease accounted for 124/168 (73.8%) patients. The median prostate-specific antigen was 11.4 (6.8-24.6)ng/ml. The rates of nonconcordance between PSMA PET/CT and CI were 34/162 (21.0%), 5/70 (7.1%), 8/92 (8.7%), and 1/71 (1.4%) for N, M1a, M1b, and M1c disease, respectively. PSMA PET/CT assigned a higher stage in 37/168 (22.0%) patients and a lower stage in 12/170 (7.1%) patients. In a subset of 50 patients treated with radical prostatectomy and pelvic lymph node dissection, the prevalence of PSMA PET/CT-positive and that of CI-positive nodal disease were 14% and 4%, and the false negative rates were 30% and 32%, respectively. The principal limitations of this study include the heterogeneity in CI modalities and the 6-mo time frame between CI and PSMA PET.

Conclusions: PSMA PET/CT imaging may serve as a valuable tool in the initial staging of treatment-naïve IR and HR PCa.

Patient Summary: We evaluated how prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) compared with standard imaging (such as computed tomography, bone scan, and prostate magnetic resonance imaging) for initial staging of patients with prostate cancer. Our findings suggest that PSMA PET/CT may detect and rule out more metastatic lesions, which could prove valuable in guiding treatment.
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http://dx.doi.org/10.1016/j.euo.2020.08.012DOI Listing
September 2020

PSMA-PET identifies PCWG3 target populations with superior accuracy and reproducibility when compared to conventional imaging: a multicenter retrospective study.

J Nucl Med 2020 Sep 11. Epub 2020 Sep 11.

Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany.

Prostate-specific membrane antigen (PSMA)-ligand positron-emission-tomography (PSMA-PET) is potentially useful for screening of castration resistant prostate cancer (CRPC) clinical trial target populations. We investigated the impact of PSMA-PET on Prostate Cancer Clinical Trials Working Group 3 (PCWG3) clinical subtype classification when compared to conventional imaging (CI). Multicenter retrospective study enrolling patients with (a) PSMA-PET for CRPC, (b) PSA values ≥1 ng/mL and (c) CI, i.e. CT plus bone scan or whole-body MRI. Clinical PCWG3 subtype was determined for PET vs. CI by three blinded readers. 67 patients were included and PSMA-PET led to up-staging in 15% (10/67) of patients, of these 6/10 (60%) had CI non-metastatic CRPC. PSMA-PET resulted in down-staging in 15% (10/67) of patients. Agreement for PET vs. CI PCWG3 clinical subtype was 0.81 vs. 0.51, 0.74 vs. 0.47, 0.95 vs. 0.72, or 0.59 vs. 0.66 for local, nodal, bone, or visceral disease, respectively. PSMA-PET demonstrated major concordance with CI for per-patient PCWG3 clinical subtype and should be implemented in future CRPC clinical trial screening procedures.
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http://dx.doi.org/10.2967/jnumed.120.246603DOI Listing
September 2020

First Experience Using F-Flubrobenguane PET Imaging in Patients with Suspected Pheochromocytoma or Paraganglioma.

J Nucl Med 2021 Apr 28;62(4):479-485. Epub 2020 Aug 28.

Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Pheochromocytomas and paragangliomas are a rare tumor entity originating from adrenomedullary chromaffin cells in the adrenal medulla or in sympathetic, paravertebral ganglia outside the medulla. Small lesions are especially difficult to detect by conventional CT or MRI and even by SPECT with the currently available radiotracers (e.g., metaiodobenzylguanidine [MIBG]). The novel PET radiotracer F-flubrobenguane could change the diagnostic paradigm in suspected pheochromocytomas and paragangliomas because of its homology with MIBG and the general advantages of PET imaging. The aim of this retrospective analysis was to evaluate F-flubrobenguane in pheochromocytomas and paragangliomas and to investigate the biodistribution in patients. Twenty-three patients with suspected pheochromocytoma or paraganglioma underwent PET/CT or PET/MRI at 63 ± 24 min after injection of 256 ± 33 MBq of F-flubrobenguane. The SUV and SUV of organs were measured with spheric volumes of interest. Threshold-segmented volumes of interest were used to measure the SUV or SUV of the tumor lesions. One reader evaluated all cross-sectional imaging datasets (CT or MRI) separately, as well as the PET hybrid datasets, and reported the lesion number and size. The diagnostic certainty for a positive lesion was scored on a 3-point scale. F-flubrobenguane showed a reproducible, stable biodistribution, with the highest SUV and SUV being in the thyroid gland (30.3 ± 2.2 and 22.5 ± 1.6, respectively), pancreas (12.2 ± 0.8 and 9.5 ± 0.7, respectively), and tumor lesions (16.8 ± 1.7 and 10.1 ± 1.1, respectively) and the lowest SUV and SUV being in muscle (1.1 ± 0.06 and 0.7 ± 0.04, respectively) and the lung (2.5 ± 0.17 and 1.85 ± 0.13, respectively). In a subgroup analysis, a significantly higher average SUV was seen for both pheochromocytoma and paraganglioma than for healthy adrenal glands (11.9 ± 2.0 vs. 9.9 ± 1.5 vs. 3.7 ± 0.2, respectively). In total, 47 lesions were detected. The reader reported more and smaller lesions with higher certainty in PET hybrid imaging than in conventional imaging; however, statistical significance was not reached. Of the 23 (23/47, 49%) lesions smaller than 1 cm, 61% (14/23) were found on hybrid imaging only. Our preliminary data suggest F-flubrobenguane PET to be a new, effective staging tool for patients with suspected pheochromocytoma or paraganglioma. Major advantages are the fast acquisition and high spatial resolution of PET imaging and the intense uptake in tumor lesions, facilitating detection. Further studies are warranted to define the role of F-flubrobenguane PET, particularly in comparison to standard diagnostic procedures such as MRI or I-MIBG SPECT/CT.
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http://dx.doi.org/10.2967/jnumed.120.248021DOI Listing
April 2021

[68Ga-PSMA-11 PET/mpMRI for local detection of primary prostate cancer in men with a negative prior biopsy].

Aktuelle Urol 2021 Apr 27;52(2):143-148. Epub 2020 Aug 27.

Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München.

Introduction And Objective:  Multiparametric MRI (mpMRI) represents the current gold standard for the detection of primary prostate cancer (PC) after a negative biopsy. PSMA PET imaging has been introduced in the diagnostic work-up of PC with high accuracy, but is currently mainly utilised in the setting of biochemical recurrence. This study aimed to determine the efficacy of combined Ga-PSMA-11 PET/mpMRI imaging to detect PC in patients with previously negative prostate biopsies.

Methods:  A total of 57 patients who had undergone at least one prior negative prostate biopsy were included in this retrospective analysis. All patients underwent Ga-PSMA-11 PET/mpMRI imaging of the prostate. mpMRI was evaluated according to the PIRADS classification system and Ga-PSMA-11 PET was rated on a 5-point Likert scale (1: PC highly unlikely; 2: PC unlikely; 3: presence of PC is equivocal; 4: PC likely; 5: PC highly likely). All patients received a systematic random biopsy as well as a targeted transrectal biopsy of lesions suspicious on imaging. Imaging and histological biopsy outcomes were compared on a per-patient basis.

Results:  In the histological analysis, 35/57 (61.4 %) patients harboured PC lesions. In patients with biopsy-proven PC, 21/35 (60.0 %) had a PI-RADS 4 or 5 lesion on mpMRI and 28 /35 (80.0 %) had a PET rating of 4 or 5. Combined Ga-PSMA-11 PET/mpMRI missed only one patient with a Gleason score (GS) 7a tumour (rating of 1 or 2 in both PET and mpMRI). Limitations include the retrospective analysis as well as possible false negative biopsy results even in a fusion biopsy setting.

Conclusion:  In this initial analysis, the combined Ga-PSMA-11 PET/mpMRI proved to be a valuable imaging tool to guide prostate biopsies for the detection of PC in patients with a negative prior biopsy. In this approach, Ga-PSMA-11 PET and mpMRI show partially complementary findings that enhance the detection of PC lesions.
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http://dx.doi.org/10.1055/a-1198-2305DOI Listing
April 2021

False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial.

Eur J Nucl Med Mol Imaging 2021 Feb 17;48(2):501-508. Epub 2020 Aug 17.

Departments of Radiology and Biomedical Imaging and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.

Purpose: Readers need to be informed about potential pitfalls of [Ga]Ga-PSMA-11 PET interpretation.

Methods: Here we report [Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer.

Results: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake.

Conclusion: [Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants.

Trial Registration Number: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.
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http://dx.doi.org/10.1007/s00259-020-04945-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835157PMC
February 2021

Almost 10 years of PET/MR attenuation correction: the effect on lesion quantification with PSMA: clinical evaluation on 200 prostate cancer patients.

Eur J Nucl Med Mol Imaging 2021 Feb 28;48(2):543-553. Epub 2020 Jul 28.

Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich, Germany.

Purpose: After a decade of PET/MR, the case of attenuation correction (AC) remains open. The initial four-compartment (air, water, fat, soft tissue) Dixon-based AC scheme has since been expanded with several features, the latest being MR field-of-view extension and a bone atlas. As this potentially changes quantification, we evaluated the impact of these features in PET AC in prostate cancer patients.

Methods: Two hundred prostate cancer patients were examined with either F- or Ga-prostate-specific membrane antigen (PSMA) PET/MR. Qualitative and quantitative analysis (SUV, SUV, correlation, and statistical significance) was performed on images reconstructed using different AC schemes: Dixon, Dixon+MLAA, Dixon+HUGE, and Dixon+HUGE+bones for F-PSMA data; Dixon and Dixon+bones for Ga-PSMA data. Uptakes were compared using linear regression against standard Dixon.

Results: High correlation and no visually perceivable differences between all evaluated methods (r > 0.996) were found. The mean relative difference in lesion uptake of F-PSMA and Ga-PSMA remained, respectively, within 4% and 3% in soft tissue, and within 10% and 9% in bones for all evaluated methods. Bone registration errors were detected, causing mean uptake change of 5% in affected lesions.

Conclusions: Based on these results and the encountered bone atlas registration inaccuracy, we deduce that including bones and extending the MR field-of-view did not introduce clinically significant differences in PSMA diagnostic accuracy and tracer uptake quantification in prostate cancer pelvic lesions, facilitating the analysis of serial studies respectively. However, in the absence of ground truth data, we advise against atlas-based methods when comparing serial scans for bone lesions.
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http://dx.doi.org/10.1007/s00259-020-04957-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835314PMC
February 2021

Influence of sampling schedules on [Lu]Lu-PSMA dosimetry.

EJNMMI Phys 2020 Jun 17;7(1):41. Epub 2020 Jun 17.

Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Background: Individualized dosimetry is recommended for [Lu]Lu-PSMA radioligand therapy (RLT) which is resource-intensive and protocols are often not optimized. Therefore, a simulation study was performed focusing on the determination of efficient optimal sampling schedules (OSS) for renal and tumour dosimetry by investigating different numbers of time points (TPs).

Methods: Sampling schedules with 1-4 TPs were investigated. Time-activity curves of the kidneys and two tumour lesions were generated based on a physiologically based pharmacokinetic (PBPK) model and biokinetic data of 13 patients who have undergone [Lu]Lu-PSMA I&T therapy. Systematic and stochastic noise of different ratios was considered when modelling time-activity data sets. Time-integrated activity coefficients (TIACs) were estimated by simulating the hybrid planar/SPECT method for schedules comprising at least two TPs. TIACs based on one single SPECT/CT measurement were estimated using an approximation for reducing the number of fitted parameters. For each sampling schedule, the root-mean-squared error (RMSE) of the deviations of the simulated TIACs from the ground truths for 1000 replications was used as a measure for accuracy and precision.

Results: All determined OSS included a late measurement at 192 h p.i., which was necessary for accurate and precise tumour TIACs. OSS with three TPs were identified to be 3-4, 96-100 and 192 h with an additional SPECT/CT measurement at the penultimate TP. Kidney and tumour RMSE of 6.4 to 7.7% and 6.3 to 7.8% were obtained, respectively. Shortening the total time for dosimetry to e.g. 96 h resulted in kidney and tumour RMSE of 6.8 to 8.3% and 9.1 to 11%, respectively. OSS with four TPs showed similar results as with three TPs. Planar images at 4 and 68 h and a SPECT/CT shortly after the 68 h measurement led to kidney and tumour RMSE of 8.4 to 12% and 12 to 16%, respectively. One single SPECT/CT measurement at 52 h yielded good approximations for the kidney TIACs (RMSE of 7.0%), but led to biased tumour TIACs.

Conclusion: OSS allow improvements in accuracy and precision of renal and tumour dosimetry for [Lu]Lu-PSMA therapy with potentially less effort. A late TP is important regarding accurate tumour TIACs.
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http://dx.doi.org/10.1186/s40658-020-00311-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300169PMC
June 2020

[Structured reporting in oncologic hybrid imaging: a consensus recommendation].

Nuklearmedizin 2020 Aug 16;59(4):288-293. Epub 2020 Jun 16.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany.

Since the clinical introduction of PET/CT in the year of 2001 and PET/MRI in the year of 2010, hybrid imaging-guided precision medicine has become an important component of diagnostic algorithms in oncology. The written report represents the primary mode of communication between the referring physician and both the nuclear medicine physician and the radiologist. Reports have considerable impact on patient management and patient outcome, and serve as a legal documentation of the services provided and the expert impression of the interpreting physician. A high-quality hybrid imaging study should result in a likewise high-quality, structured written report which satisfactorily answers the clinical question of the referring physician. In this manuscript, consensus recommendations for structure and content of oncologic hybrid imaging reports and conclusive impressions are provided. Moreover, exemplary structured reports are provided. The recommendations for structured reporting provided in this document should foster further standardization and harmonization of oncologic reports in the context of hybrid imaging. They should also simplify communication with referring physicians and support both acceptance and appreciation of the clinical value of oncologic hybrid imaging. CITATION FORMAT: · Derlin T, Gatidis S, Krause BJ et al. Konsensusempfehlung zur strukturierten Befunderstellung onkologischer PET-Hybridbildgebung. Nuklearmedizin 2020; 59: DOI:10.1055/a-1176-0275.
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http://dx.doi.org/10.1055/a-1176-0275DOI Listing
August 2020

Efficacy and Safety of Lu-labeled Prostate-specific Membrane Antigen Radionuclide Treatment in Patients with Diffuse Bone Marrow Involvement: A Multicenter Retrospective Study.

Eur Urol 2020 08 10;78(2):148-154. Epub 2020 Jun 10.

Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

The Lu-labeled prostate-specific membrane antigen (LuPSMA) radionuclide therapy for metastatic castration-resistant prostate cancer is under investigation in a phase III trial (VISION: NCT03511664). However, patients with diffuse bone involvement, diagnosed with a "superscan" by bone scintigraphy at baseline, were excluded due to a lack of efficacy and safety data. We therefore aimed to investigate the feasibility of LuPSMA in patients with diffuse bone marrow involvement on baseline PSMA-targeted positron emission tomography. The primary end points were prostate-specific antigen (PSA) response (Prostate Cancer Working Group 3 [PCWG3]), hematologic safety profile (Common Terminology Criteria for Common Adverse Events [CTCAE]), and overall survival. Secondary end points of quality of life (assessed with Brief Pain Inventory-Short Form questionnaires) and radiologic response (Response Evaluation Criteria in Solid Tumors [RECIST]) were assessed. Through retrospective screening of databases, we identified 43 eligible patients across four centers worldwide who received 154 cycles of LuPSMA under clinical trials or compassionate access programs. Median baseline PSA was 1000 (interquartile range 431-2151) ng/ml. PSA decline of at least 50% at 12 wk was achieved in 22 (58%) patients, while median time to pain progression was 8.3 (95% confidence interval [CI] 4.1-12.6) mo. Median overall survival was 11.6 (95% CI 8.8-14.3) mo. Objective response in nodal or visceral disease was reported in seven (39%) of 18 patients with RECIST measurable disease. Grade 3 anemia, thrombocytopenia, and neutropenia occurred in nine (22%), seven (17%), and three (8%) patients, respectively. Grade 4 thrombocytopenia was noticed in three (8%) patients. In conclusion, patients with diffuse bone marrow involvement demonstrated similar LuPSMA efficacy and safety to phase II evidence. Acceptable safety outcomes do not support exclusion of patients with a superscan from future LuPSMA treatment protocols. PATIENT SUMMARY: In this report, we investigated the feasibility of prostate-specific membrane antigen (PSMA)-directed radionuclide treatment in patients with metastatic castration-resistant prostate cancer and diffuse bone involvement. We found that, despite a high load of bone metastases, PSMA-targeted therapy remains efficacious and safe when compared with the current phase II trial results.
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http://dx.doi.org/10.1016/j.eururo.2020.05.004DOI Listing
August 2020

A CT-based radiomics model to detect prostate cancer lymph node metastases in PSMA radioguided surgery patients.

Eur J Nucl Med Mol Imaging 2020 12 28;47(13):2968-2977. Epub 2020 May 28.

Department of Radiation Oncology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich (TUM), Ismaninger Straße 22, 81675, Munich, Germany.

Purpose: In recurrent prostate carcinoma, determination of the site of recurrence is crucial to guide personalized therapy. In contrast to prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging, computed tomography (CT) has only limited capacity to detect lymph node metastases (LNM). We sought to develop a CT-based radiomic model to predict LNM status using a PSMA radioguided surgery (RGS) cohort with histological confirmation of all suspected lymph nodes (LNs).

Methods: Eighty patients that received RGS for resection of PSMA PET/CT-positive LNMs were analyzed. Forty-seven patients (87 LNs) that received inhouse imaging were used as training cohort. Thirty-three patients (62 LNs) that received external imaging were used as testing cohort. As gold standard, histological confirmation was available for all LNs. After preprocessing, 156 radiomic features analyzing texture, shape, intensity, and local binary patterns (LBP) were extracted. The least absolute shrinkage and selection operator (radiomic models) and logistic regression (conventional parameters) were used for modeling.

Results: Texture and shape features were largely correlated to LN volume. A combined radiomic model achieved the best predictive performance with a testing-AUC of 0.95. LBP features showed the highest contribution to model performance. This model significantly outperformed all conventional CT parameters including LN short diameter (AUC 0.84), LN volume (AUC 0.80), and an expert rating (AUC 0.67). In lymph node-specific decision curve analysis, there was a clinical net benefit above LN short diameter.

Conclusion: The best radiomic model outperformed conventional measures for detection of LNM demonstrating an incremental value of radiomic features.
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http://dx.doi.org/10.1007/s00259-020-04864-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680305PMC
December 2020

PSMA-PET/CT-based Lymph Node Atlas for Prostate Cancer Patients Recurring After Primary Treatment: Clinical Implications for Salvage Radiation Therapy.

Eur Urol Oncol 2021 Feb 22;4(1):73-83. Epub 2020 May 22.

Department of Radiation Oncology, Technical University Munich (TUM), Munich, Germany; Department of Radiation Sciences (DRS), Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany.

Background: Many patients experience recurrence of prostate cancer after radical prostatectomy.

Objective: The aim of this study was to visually analyze typical patterns of lymph node (LN) involvement for prostate cancer (PC) patients with biochemical recurrence after radical prostatectomy and lymphadenectomy by creating a color-coded heat map using gallium-68 prostate-specific membrane antigen positron emission tomography (Ga-PSMA-PET) imaging. Further, we evaluated which LNs were covered by the Radiation Therapy Oncology Group (RTOG) clinical target volume (CTV) contouring guidelines.

Design, Setting, And Participants: A total of 1653 Ga-PSMA-PET/computed tomography (CT) datasets were screened retrospectively. After meeting the eligibility criteria, 233 patients with 799 LN metastases were included in our study.

Outcome Measurements And Statistical Analysis: We created a comprehensive three-dimensional color-coded LN atlas. Further, the coverage of LN metastases by RTOG CTV was assessed and stratification for risk factors was performed.

Results And Limitations: In the overall, mainly high risk, collective, complete coverage by the standard RTOG CTV was accomplished in 31.0% of all LN metastases. The vast majority of uncovered LNs are situated in the para-aortal, pararectal, paravesical, preacetabular, presacral, and inguinal regions. Concerning examined stratification factors, prostate-specific antigen (PSA) levels at the time of PET/CT imaging had the highest predictive value for extrapelvic metastatic LN spread. Every increase of 1 ng/mL in PSA raises the risk of metastases outside the CTV by a factor of 1.43.

Conclusions: We developed the first LN atlas for patients with recurrent PC using a heat map technique, in order to illustrate hot spots of LN recurrence. The vast majority of detected LNs are not covered by a standard CTV as recommended by the RTOG. Application of the standard RTOG CTV for pelvic irradiation in the salvage setting for high-risk PC patients seems to be inappropriate.

Patient Summary: We visualized typical lymph node recurrence sites for patients after prostate cancer surgery.
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http://dx.doi.org/10.1016/j.euo.2020.04.004DOI Listing
February 2021

PSMA-Ligand PET for Early Castration-Resistant Prostate Cancer: A Retrospective Single-Center Study.

J Nucl Med 2021 01 22;62(1):88-91. Epub 2020 May 22.

Department of Nuclear Medicine, University of Duisburg-Essen, and German Cancer Consortium-University Hospital Essen, Essen, Germany

The low detection rate of conventional imaging and unspecific fluctuations in prostate-specific antigen can hamper early diagnosis of castration-resistant prostate cancer (CRPC). We thus assessed the value of prostate-specific membrane antigen (PSMA) PET/CT in the detection of early CRPC (prostate-specific antigen ≤ 3 ng/mL). We identified 55 patients with early CRPC from our institutional database. PSMA PET/CT and its CT component were interpreted independently by 3 masked readers. The primary endpoint was the per-patient detection rate; secondary endpoints were interobserver agreement and predictors of PET positivity. PSMA PET/CT was positive in 41 of 55 (75%) patients. Sixteen of 55 (29%) patients had local disease only, and 25 of 55 (45%) had M1 disease. Overall, PSMA PET/CT interobserver agreement was substantial by Landis and Koch criteria (Fleiss κ = 0.77). PSMA PET/CT localized prostate cancer lesions in 75% of patients and M1 disease in 45%. Detection of early CRPC facilitates disease-delaying therapies for local or oligometastatic disease. PSMA PET/CT is of value in early CRPC and should be included in the CRPC entry criteria of the European Association of Urology and Prostate Cancer Working Group 3.
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http://dx.doi.org/10.2967/jnumed.120.245456DOI Listing
January 2021

Incidental Finding of Colon Carcinoma Related to High Uptake in 18F-PSMA-1007 PET.

Clin Nucl Med 2020 Jul;45(7):561-562

From the Department of Nuclear Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

We present a 78-year-old man with suspicion of prostate cancer due to a PSA of 200 ng/mL, who underwent F-PSMA-1007 (prostate specific membrane antigen) PET/CT for primary staging. Besides heterogeneous uptake to the prostate, an increased PSMA uptake in the cecum was observed, located in the thickened cecal wall with suspicion of a secondary malignancy. Colonoscopic biopsy followed by hemicolectomy confirmed the diagnosis of colon adenocarcinoma. This case demonstrates the importance of bioptic workup of suspicious findings on PSMA PET/CT, which are unlikely to be related to prostate cancer as PSMA ligand uptake is not exclusively prostate cancer specific.
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http://dx.doi.org/10.1097/RLU.0000000000003081DOI Listing
July 2020

Impact of Ga-PSMA-11 PET on the Management of Recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial.

J Nucl Med 2020 12 1;61(12):1793-1799. Epub 2020 May 1.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California

Prostate-specific membrane antigen (PSMA) ligand PET induces management changes in patients with prostate cancer. We aim to better characterize the impact of Ga-PSMA-11 PET (Ga-PSMA PET) on management of recurrent prostate cancer in a large prospective cohort. We report management changes after Ga-PSMA PET, a secondary endpoint of a prospective multicenter trial in men with biochemical recurrence of prostate cancer. Pre-PET (Q1), post-PET (Q2), and posttreatment (Q3) questionnaires were sent to referring physicians recording site of recurrence and intended (Q1 to Q2 change) and implemented (Q3) therapeutic and diagnostic management. Q1 and Q2 response was collected for 382 of 635 patients (60%, intended cohort), and Q1, Q2, and Q3 response was collected for 206 patients (32%, implemented cohort). An intended management change occurred in 260 of 382 (68%) patients. The intended change was considered major in 176 of 382 (46%) patients. Major changes occurred most often for patients with prostate-specific antigen of 0.5 to less than 2.0 ng/mL (81/147, 55%). By analysis of stage groups, management change was consistent with PET disease location, that is, a majority of major changes toward active surveillance (47%) for unknown disease site (103/382, 27%), toward local or focal therapy (56%) for locoregional disease (126/382, 33%), and toward systemic therapy (69% M1a; 43% M1b/c) for metastatic disease (153/382, 40%). According to Q3 responses, the intended management was implemented in 160 of 206 (78%) patients. In total, 150 intended diagnostic tests, mostly CT ( = 43, 29%) and bone scans or F-NaF PET ( = 52, 35%), were prevented by Ga-PSMA PET; 73 tests, mostly biopsies ( = 44, 60%) as requested by the study protocol, were triggered. According to referring physicians, sites of recurrence were clarified by Ga-PSMA PET, and disease localization translated into management changes in more than half of patients with biochemical recurrence of prostate cancer.
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http://dx.doi.org/10.2967/jnumed.120.242180DOI Listing
December 2020