Publications by authors named "Torsten Kuwert"

137 Publications

Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy.

Rheumatology (Oxford) 2021 Aug 27. Epub 2021 Aug 27.

Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands.

Objective: Activated synovial fibroblasts are key effector cells in rheumatoid arthritis (RA). Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using [68Ga]Ga-FAPI-04 in an RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants.

Methods: Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flowcytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received [68Ga]Ga-FAPI-04 and was scanned using PET/CT imaging.

Results: In the RA patient,FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts.

Conclusion: In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
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http://dx.doi.org/10.1093/rheumatology/keab664DOI Listing
August 2021

Quantitative Analysis of Multimodal Skeletal SPECT/CT Reconstructions in Diagnosing Medication-related Osteonecrosis of the Jaw.

Nuklearmedizin 2021 Aug 11. Epub 2021 Aug 11.

Abteilung Mund- Kiefer- und Gesichtschirurgie, Universitätsklinikum Augsburg, Augsburg, Germany.

Aim: Our goal was to assess visual and quantitative aspects of multimodal skeletal SPECT/CT reconstructions (recon) in differentiating necrotic and healthy bone of patients with suspected MRONJ.

Methods: Prior to surgery, 20 patients with suspected MRONJ underwent SPECT/CT of the jaw 3-4 hours after injection of Tc-99m-DPD (622±112.4 MBq). SPECT/CT data were reconstructed using the multimodal xSPECT Bone and xSPECT Quant algorithms as well as the OSEM-algorithm FLASH 3D. For analysis, we divided the jaw into 12 separate regions. Both xSPECT Bone and FLASH 3D datasets were scored on a four-point scale (VIS xSPECT; VIS F3D), based on the intensity of localized tracer uptake. In F3D and xSPECT Quant datasets, local tracer uptake of each region was recorded as semi-quantitative uptake ratio (SQR F3D) or SUVs, respectively. ROC analysis was performed. Postoperative histologic results served as gold standard.

Results: VIS F3D, VIS xSPECT and SQR F3D did not differ significantly in diagnostic accuracy (VIS xSPECT sensitivity=0.64; specificity=0.89). Of the quantitative parameters, SUVpeak yielded the best interobserver reproducibility. SUVpeak was 9.9±7.1 (95%CI: 7.84-11.95) in MRONJ regions, as opposed 3.6±1.8 (95% CI:3.36-3.88) elsewhere, with a cutpoint of 4.5 (sensitivity=0.83; specificity=0.80). Absolute quantitation significantly surpassed VIS and SQR (p<0.05) in accuracy and interobserver agreement (SUVpeak: κ=0.92; VIS xSPECT: κ=0.61; SQR F3D κ=0.66).

Conclusion: Absolute quantitation proved significantly more accurate than visual and semi-quantitative assessment in diagnosing MRONJ, with higher interobserver agreement.
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http://dx.doi.org/10.1055/a-1525-7621DOI Listing
August 2021

Blunt renal trauma-induced hypertension in pediatric patients: a single-center experience.

J Pediatr Urol 2021 Jun 30. Epub 2021 Jun 30.

Clinic of Urology and Pediatric Urology, University Hospital Erlangen, Germany. Electronic address:

Purpose: Children have a greater chance of sustaining a renal injury than adults and higher odds of having a high-grade renal injury. Hypertension is a rare complication of blunt renal trauma, with risk being higher in cases of major renal trauma. We reviewed the cases of pediatric blunt renal trauma-induced hypertension in our tertiary referral center in an attempt to better understand this rare condition.

Study Design: A retrospective evaluation of children under the age of 18 who were admitted to our department during the last 20 years and were diagnosed with blunt renal trauma.

Results: Twenty-three children presented with blunt renal trauma, one of whom was treated with emergency nephrectomy. Four children (18%) developed post-traumatic hypertension. All four cases were associated with a reduction in blood flow to the kidney, either through injury to the renal artery (in three cases) or through extrinsic compression of the kidney by a large perirenal hematoma (Page kidney; in one case). The Page kidney case developed hypertension during the initial hospitalization, and it resolved spontaneously after five months through the gradual resorption of the perirenal hematoma. Among the three cases of renal artery injury, hypertension during the initial hospitalization was only observed in one case, with hypertension in the other two cases manifesting after two months and four years, respectively. All three cases of renal artery injury resulted in a complete loss of function of the injured kidney, and two cases were treated with nephrectomy. Following nephrectomy, the blood pressure level returned to normal within a few days.

Discussion: Development of hypertension following a blunt renal trauma can be heterogenous, with the time of manifestation stretching between days after the accident and years thereafter. Children have a higher risk of renal trauma and, according to published data out of the National Trauma Data Bank, a 20-times higher risk of renal artery injury in comparison to the adult population. Large multicenter studies are required to answer the question of whether children are therefore more prone to blunt renal trauma-induced hypertension than adults.

Conclusions: Our study highlights the importance of blood pressure monitoring in children following blunt renal trauma, as post-traumatic hypertension can develop even years after the accident. In cases of a poorly functioning kidney, nephrectomy may be regarded as a curative therapy.
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http://dx.doi.org/10.1016/j.jpurol.2021.06.026DOI Listing
June 2021

Advanced thyroid carcinomas: neural network analysis of ultrasonographic characteristics.

Thyroid Res 2021 Jun 29;14(1):16. Epub 2021 Jun 29.

Nuklearmedizinische Klinik, Universitätsklinikum Erlangen, Erlangen, Germany.

Background: Ultrasound is the first-line imaging modality for detection and classification of thyroid nodules. Certain characteristics observable by ultrasound have recently been identified that may indicate malignancy. This retrospective cohort study was conducted to test the hypothesis that advanced thyroid carcinomas show distinctive clinical and sonographic characteristics. Using a neural network model as proof of concept, nine clinical/sonographic features served as input.

Methods: All 96 study enrollees had histologically confirmed thyroid carcinomas, categorized (n = 32, each) as follows: group 1, advanced carcinoma (ADV) marked by local invasion or distant metastasis; group 2, non-advanced papillary carcinoma (PTC); or group 3, non-advanced follicular carcinoma (FTC). Preoperative ultrasound profiles were obtained via standardized protocols. The neural network had nine input neurons and one hidden layer.

Results: Mean age and the number of male patients in group 1 were significantly higher compared with groups 2 (p = 0.005) or 3 (p <  0.001). On ultrasound, tumors of larger volume and irregular shape were observed significantly more often in group 1 compared with groups 2 (p <  0.001) or 3 (p ≤ 0.01). Network accuracy in discriminating advanced vs. non-advanced tumors was 84.4% (95% confidence interval [CI]: 75.5-91), with positive and negative predictive values of 87.1% (95% CI: 70.2-96.4) and 92.3% (95% CI: 83.0-97.5), respectively.

Conclusions: Our study has shown some evidence that advanced thyroid tumors demonstrate distinctive clinical and sonographic characteristics. Further prospective investigations with larger numbers of patients and multicenter design should be carried out to show whether a neural network incorporating these features may be an asset, helping to classify malignancies of the thyroid gland.
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http://dx.doi.org/10.1186/s13044-021-00107-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240264PMC
June 2021

Resolution of vascular inflammation in patients with new-onset giant cell arteritis: data from the RIGA study.

Rheumatology (Oxford) 2021 08;60(8):3851-3861

Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Objectives: Efficacy evaluation of GCA treatment is primarily based on non-specific symptoms and laboratory markers. We aimed to assess the change in vascular inflammation in patients with large vessel (LV)-GCA under different treatments using [18F]FDG PET/CT.

Methods: Observational study on patients with new-onset, active LV-GCA starting treatment with either prednisolone monotherapy (PRED) or combination with MTX or tocilizumab (TOC). All patients underwent baseline and follow-up PET/CT. The aorta and its major branches were assessed using PET vascular activity score (PETVAS) by independent readers. Cumulative glucocorticoid doses and cessation of glucocorticoid treatment were documented in all patients.

Results: We included 88 LV-GCA patients, 27 were treated with PRED, 42 with MTX and 19 with TOC. PETVAS decreased from 18.9-8.0 units at follow-up in the overall population (P <0.001). PETVAS changes were numerically higher in patients receiving MTX (-12.3 units) or TOC (-11.7 units) compared with PRED (-8.7). Mean cumulative prednisolone dosages were 5637, 4418 and 2984 mg in patients treated with PRED, MTX and TOC (P =0.002). Risk ratios for glucocorticoid discontinuation at the time of follow-up PET/CT were 6.77 (95% CI: 1.01, 45.29; P =0.049) and 16.25 (95% CI: 2.60, 101.73; P =0.003) for MTX and TOC users compared with PRED users.

Conclusion: Treatment of LV-GCA inhibits vascular inflammation in the aorta and its major branches. While similar control of vascular inflammation was achieved with PRED, MTX and TOC treatments, TOC showed a strong glucocorticoid sparing effect, supporting the concept of initial combination therapy.
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http://dx.doi.org/10.1093/rheumatology/keab332DOI Listing
August 2021

Ultrasound Imaging of Cervical Anatomic Variants.

Curr Med Imaging 2021 ;17(8):966-972

Nuklearmedizinische Klinik, Universitätsklinikum Erlangen, Germany.

Embryologic developmental variants of the thyroid and parathyroid glands may cause cervical anomalies that are detectable in ultrasound examinations of the neck. For some of these developmental variants, molecular genetic factors have been identified. Ultrasound, as the first-line imaging procedure, has proven useful in detecting clinically relevant anatomic variants. The aim of this article was to systematically summarize the ultrasound characteristics of developmental variants of the thyroid and parathyroid glands as well as ectopic thymus and neck cysts. Quantitative measures were developed based on our findings and the respective literature. Developmental anomalies frequently manifest as cysts that can be detected by cervical ultrasound examinations. Median neck cysts are the most common congenital cervical cystic lesions, with a reported prevalence of 7% in the general population. Besides cystic malformations, developmental anomalies may appear as ectopic or dystopic tissue. Ectopic thyroid tissue is observed in the midline of the neck in most patients and has a prevalence of 1/100,000 to 1/300,000. Lingual thyroid accounts for 90% of cases of ectopic thyroid tissue. Zuckerkandl tubercles (ZTs) have been detected in 55% of all thyroid lobes. Prominent ZTs are frequently observed in thyroid lobes affected by autoimmune thyroiditis compared with normal lobes or nodular lobes (P = 0.006). The correct interpretation of the ultrasound characteristics of these variants is essential to establish the clinical diagnosis. In the preoperative assessment, the identification of these cervical anomalies via ultrasound examination is indispensable.
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http://dx.doi.org/10.2174/1573405617666210127162328DOI Listing
January 2021

The Distribution of Pelvic Nodal Metastases in Prostate Cancer Reveals Potential to Advance and Personalize Pelvic Radiotherapy.

Front Oncol 2020 8;10:590722. Epub 2021 Jan 8.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Background: Traditional clinical target volume (CTV) definition for pelvic radiotherapy in prostate cancer consists of large volumes being treated with homogeneous doses without fully utilizing information on the probability of microscopic involvement to guide target volume design and prescription dose distribution.

Methods: We analyzed patterns of nodal involvement in 75 patients that received RT for pelvic and paraaortic lymph node metastases (LNs) from prostate cancer in regard to the new NRG-CTV recommendation. Non-rigid registration-based LN mapping and weighted three-dimensional kernel density estimation were used to visualize the average probability distribution for nodal metastases. As independent approach, the mean relative proportion of LNs observed for each level was determined manually and NRG and non-NRG levels were evaluated for frequency of involvement. Computer-automated distance measurements were used to compare LN distances in individual patients to the spatial proximity of nodal metastases at a cohort level.

Results: 34.7% of patients had pelvic LNs outside NRG-consensus, of which perirectal was most common (25.3% of all patients) followed by left common iliac nodes near the left psoas major (6.7%). A substantial portion of patients (13.3%) had nodes at the posterior edge of the NRG obturator level. Observer-independent mapping consistently visualized high-probability hotspots outside NRG-consensus in the perirectal and left common iliac regions. Affected nodes in individual patients occurred in highly significantly closer proximity than at cohort-level (mean distance, 6.6 cm vs. 8.7 cm, p < 0.001).

Conclusions: Based on this analysis, the common iliac level should extend to the left psoas major and obturator levels should extend posteriorly 5 mm beyond the obturator internus. Incomplete coverage by the NRG-consensus was mostly because of perirectal involvement. We introduce three-dimensional kernel density estimation after non-rigid registration-based mapping for the analysis of recurrence data in radiotherapy. This technique provides an estimate of the underlying probability distribution of nodal involvement and may help in addressing institution- or subgroup-specific differences. Nodal metastases in individual patients occurred in highly significantly closer proximity than at a cohort-level, which supports that personalized target volumes could be reduced in size compared to a "one-size-fits-all" approach and is an important basis for further investigation into individualized field designs.
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http://dx.doi.org/10.3389/fonc.2020.590722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820617PMC
January 2021

Dose voxel kernel prediction with neural networks for radiation dose estimation.

Z Med Phys 2021 Feb 20;31(1):23-36. Epub 2020 Oct 20.

Information Sciences, University of Regensburg, 93053 Regensburg, Germany.

Background: Currently there is an ever increasing interest in Lu-177 targeted radionuclide therapies, which target neuro-endocrine and prostate tumours. For a patient-specific treatment, an individual dosimetry based on SPECT/CT imaging is necessary. The aim of this study is to introduce a dosimetry method, where dose voxel kernels (DVK) are predicted by a neural network.

Methods: Kidneys are considered one of the most critical organs in any radionuclide therapy. Hence we chose kidneys of 26 patients, who underwent Lu-177-DOTATOC or PSMA therapy, as target organs for our dosimetric method. First of all, density kernels with a size of 9×9×9 voxels were considered, and the corresponding DVKs were calculated by Monte Carlo simulations. These kernels were used to train a neural network (NN), which received a density kernel as input and predicted a DVK at the output. To predict the dose distribution of an entire kidney, the organ had to be partitioned into a large number of density kernels. Afterwards the DVKs were predicted by a trained NN, and employed to reconstruct the whole-organ dose distribution by convolution with the activity distribution. This method was compared to the standard method where the activity distribution is convolved with a DVK based on a homogeneous soft tissue kernel.

Results: The number of training kernels amounted to 52,274 density kernels with corresponding MC-derived DVKs. The results serve as proof of principle of the newly proposed method and showed that the NN approach yielded superior results compared to the standard method with no additional computational effort.

Conclusion: The NN approach is an accurate and highly competitive dosimetric method to precisely estimate absorbed radiation dose in critical organs like kidneys in clinical routine. To further improve the results, a larger number of DVKs needs to be computed by Monte Carlo simulations. An extension of the method to other organs is easily conceivable.
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http://dx.doi.org/10.1016/j.zemedi.2020.09.005DOI Listing
February 2021

Dissimilar DNA Damage to Blood Lymphocytes After Lu-Labeled DOTATOC or Prostate-Specific Membrane Antigen Therapy.

J Nucl Med 2021 03 31;62(3):379-385. Epub 2020 Jul 31.

Department of Radiology, University Hospital Erlangen, Erlangen, Germany.

DNA double-strand breaks in cells of radionuclide-treated patients are quantifiable by immunofluorescence microscopy, using phosphorylation of histone-variant H2AX (γ-H2AX) to mark radiation-induced foci (RIFs). Using this method, we compared excess RIFs side by side in recipients of Lu-DOTATOC or Lu-prostate specific membrane antigen-617 (PSMA) radioligands. We also examined relations between blood dose and dose rate, RIFs, and platelet counts. Venous blood samples were obtained from 48 patients subjected to Lu-labeled radioligand therapy (Lu-DOTATOC, 26; Lu-PSMA, 22) to quantify blood lymphocyte RIFs and blood activity concentrations at various time points, including baseline (before injection) and postinjection readings (5 min, 30 min, 4 h, 24 h, 48 h, and 72 h). Absorbed doses and dose rates to blood were derived from sequentially assessed blood activity concentrations and γ-camera imaging. Platelet levels in routine blood tests were monitored for 3 d after injection to assess responses. RIF counts averaged 0.25 ± 0.15 at baseline. Postinjection RIF counts were significantly higher than baseline values, peaking at 5 min (average, 3.93 ± 2.51 min) and declining thereafter. Compared with RIF counts of Lu-DOTATOC, those of Lu-PSMA were significantly higher at 5 min after injection and significantly lower at 72 h after injection. These differences could not be fully explained by blood doses and dose rates, which were significantly higher for Lu-PSMA than for Lu-DOTATOC treatment at every time point. RIF counts overall correlated with dose rates across all time points (Pearson = 0.78; < 0.01) and with absorbed dose until 4 h after injection only (Pearson = 0.42; < 0.01). Declines in platelet concentration correlated significantly with RIFs at 72 h after injection (Pearson = -0.34; < 0.05). Although values generated by the currently used blood dosimetry model correlated with RIF counts, the difference observed in Lu-DOTATOC and Lu-PSMA treatment groups was unexplained. Significantly more RIFs were found in Lu-DOTATOC recipients by comparison, despite lower dose rates and blood doses, exposing a potential limitation.
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http://dx.doi.org/10.2967/jnumed.120.243782DOI Listing
March 2021

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.

Ann Rheum Dis 2020 11 21;79(11):1485-1491. Epub 2020 Jul 21.

Department of Internal Medicine 3, Rheumatology & Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany

Objectives: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG-related disease.

Methods: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; Ga-FAP inhibitor (FAPI)-04), F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, F-FDG and Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data.

Results: Using combination of Ga-FAPI-04 and F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG cells in histology, while Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions.

Conclusion: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
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http://dx.doi.org/10.1136/annrheumdis-2020-217408DOI Listing
November 2020

Estimation of [177Lu]PSMA-617 tumor uptake based on voxel-wise 3D Monte Carlo tumor dosimetry in patients with metastasized castration resistant prostate cancer.

Nuklearmedizin 2020 Sep 14;59(5):365-374. Epub 2020 Jul 14.

Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Objective:  Patients with advanced prostate cancer are suitable candidates for [Lu]PSMA-617 therapy. Integrated SPECT/CT systems have the potential to improve the accuracy of patient-specific tumor dosimetry. We present a novel patient-specific Monte Carlo based voxel-wise dosimetry approach to determine organ and total tumor doses (TTD).

Methods:  13 patients with histologically confirmed metastasized castration-resistant prostate cancer were treated with a total of 18 cycles of [Lu]PSMA-617 therapy. In each patient, dosimetry was performed after the first cycle of [Lu]PSMA-617 therapy. Regions of interest were defined manually on the SPECT/CT images for the kidneys, spleen and all 295 PSMA-positive tumor lesions in the field of view. The absorbed dose to normal organs and to all tumor lesions were calculated by a three dimensional dosimetry method based on Monte Carlo Simulations.

Results:  The average dose values yielded the following results: 2.59 ± 0.63 Gy (1.67-3.92 Gy) for the kidneys, 0.79 ± 0.46 Gy (0.31-1.90 Gy) for the spleen and 11.00 ± 11.97 Gy (1.28-49.10 Gy) for all tracer-positive tumor lesions. A trend towards higher TTD was observed in patients with Gleason Scores > 8 compared to Gleason Scores ≤ 8 and in lymph node metastases compared to bone metastases. A significant correlation was determined between the serum-PSA level before RLT and the TTD (r = -0.57, p < 0.05), as well as between the TTD with the percentage change of serum-PSA levels before and after therapy was observed (r = -0.57, p < 0.05). Patients with higher total tumor volumes of PSMA-positive lesions demonstrated significantly lower kidney average dose values (r = -0.58, p < 0.05).

Conclusion:  The presented novel Monte Carlo based voxel-wise dosimetry calculates a patient specific whole-body dose distribution, thus taking into account individual anatomies and tissue compositions showing promising results for the estimation of radiation doses of normal organs and PSMA-positive tumor lesions.
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http://dx.doi.org/10.1055/a-1204-9932DOI Listing
September 2020

Quantitative SPECT/CT-Technique and Clinical Applications.

Recent Results Cancer Res 2020 ;216:565-590

Clinic of Nuclear Medicine, University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

The continuous development of SPECT over the past 50 years has led to improved image quality and increased diagnostic confidence. The most influential developments include the realization of hybrid SPECT/CT devices, as well as the implementation of attenuation correction and iterative image reconstruction techniques. These developments have led to a preference for SPECT/CT devices over SPECT-only systems and to the widespread adoption of the former, strengthening the role of SPECT/CT as the workhorse of Nuclear Medicine imaging. New trends in the ongoing development of SPECT/CT are diverse. For example, whole-body SPECT/CT images, consisting of acquisitions from multiple consecutive bed positions in the manner of PET/CT, are increasingly performed. Additionally, in recent years, some interesting approaches in detector technology have found their way into commercial products. For example, some SPECT cameras dedicated to specific organs employ semiconductor detectors made of cadmium telluride or cadmium zinc telluride, which have been shown to increase the obtainable image quality by offering a higher sensitivity and energy resolution. However, the advent of quantitative SPECT/CT which, like PET, can quantify the amount of tracer in terms of Bq/mL or as a standardized uptake value could be regarded as most important development. It is a major innovation that will lead to increased diagnostic accuracy and confidence, especially in longitudinal studies and in the monitoring of treatment response. The current work comprises two main aspects. At first, physical and technical fundamentals of SPECT image formation are described and necessary prerequisites of quantitative SPECT/CT are reviewed. Additionally, the typically achievable quantitative accuracy based on reports from the literature is given. Second, an extensive list of studies reporting on clinical applications of quantitative SPECT/CT is provided and reviewed.
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http://dx.doi.org/10.1007/978-3-030-42618-7_17DOI Listing
September 2020

99mTc-MIP-1404 SPECT/CT for Assessment of Whole-Body Tumor Burden and Treatment Response in Patients With Biochemical Recurrence of Prostate Cancer.

Clin Nucl Med 2020 Aug;45(8):e349-e357

From the Department of Nuclear Medicine.

Objective: This study aims to investigate the value of Tc-MIP-1404 SPECT/CT for assessment of whole-body tumor burden and treatment response in patients with biochemical recurrence of prostate cancer who undergo androgen deprivation therapy (ADT) or external beam radiation therapy (EBRT).

Methods: A total of 125 patients with biochemical recurrence of prostate cancer underwent Tc-MIP-1404 SPECT/CT. All 364 prostate-specific membrane antigen (PSMA)-positive lesions in the field of view were assessed quantitatively to calculate PSMA-derived metabolic tumor parameters, including whole-body PSMA tumor volume and whole-body total lesion PSMA. These metrics were correlated with serum prostate-specific antigen (PSA) levels and Gleason scores. In a subset of 50 patients who underwent Tc-MIP-1404 SPECT/CT before the initiation of ADT or EBRT, TL-PSMA and SUVmax were compared with radiographic response assessment by CT based on RECIST 1.1 and to biochemical response (BR) determined by changes in serum PSA levels.

Results: Serum PSA levels correlated with SUVmax, whole-body PSMA tumor volume, and whole-body total lesion PSMA in patients with 1 and in those with more than 1 PSMA-positive lesion (P < 0.05). The correlations were significant for both well-differentiated (Gleason score ≤7) and poorly differentiated tumors (Gleason score ≥8) (P < 0.05). The agreement between TL-PSMA derived from SPECT and BR in patients who underwent Tc-MIP-1404 SPECT/CT before and after initiation of ADT was 80% (95% confidence interval [CI], 0.43-0.91; Cohen κ = 0.68; P < 0.05); in these patients, the agreement between TL-PSMA and CT was 60% (95% CI, 0.20-0.72; Cohen κ = 0.46; P < 0.05) and the agreement between BR and CT was 52% (0.07-0.61; Cohen κ = 0.34; P < 0.05). Comparable results were found for patients who underwent SPECT/CT before and after initiation of EBRT, with the strongest agreement between TL-PSMA and BR (80%; 95% CI, 0.38-0.93; Cohen κ = 0.66; P < 0.05) compared with the agreement between TL-PSMA and CT (60%; 95% CI, 0.13-0.69; Cohen κ = 0.69; P < 0.05) and between BR and CT (48%; 95% CI, 0-0.54; Cohen κ = 0.26; P = 0.11). Discordant findings between SPECT and CT were most likely due to limitations in the assessment of small lymph node metastases and bone involvement, which were detectable on SPECT but not on CT.

Conclusions: The results of our study show that Tc-MIP-1404 SPECT/CT is a promising method for the evaluation of treatment response in patients with biochemical recurrence of prostate cancer who undergo either ADT or EBRT. TL-PSMA for assessment of treatment response has the strongest correlation with serum PSA levels, superior to SUVmax-based evaluation and response assessment based on CT data and RECIST 1.1.
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http://dx.doi.org/10.1097/RLU.0000000000003102DOI Listing
August 2020

DSC Brain Perfusion Using Advanced Deconvolution Models in the Diagnostic Work-up of Dementia and Mild Cognitive Impairment: A Semiquantitative Comparison with HMPAO-SPECT-Brain Perfusion.

J Clin Med 2020 06 9;9(6). Epub 2020 Jun 9.

Departments of Neuroradiology, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Background: SPECT (single-photon emission-computed tomography) is used for the detection of hypoperfusion in cognitive impairment and dementia but is not widely available and related to radiation dose exposure. We compared the performance of DSC (dynamic susceptibility contrast) perfusion using semi- and fully adaptive deconvolution models to HMPAO-SPECT (99mTc-hexamethylpropyleneamine oxime-SPECT).

Material And Methods: Twenty-seven patients with dementia of different subtypes including frontotemporal dementia (FTD) and mild cognitive impairment (MCI) received a multimodal diagnostic work-up including DSC perfusion at a clinical 3T high-field scanner and HMPAO-SPECT. Nineteen healthy control individuals received DSC perfusion. For calculation of the hemodynamic parameter maps, oscillation-index standard truncated singular value decomposition (oSVD, semi-adaptive) as well as Bayesian parameter estimation (BAY, fully adaptive) were performed.

Results: Patients showed decreased cortical perfusion in the left frontal lobe compared to controls (relative cerebral blood volume corrected, rBVc: 0.37 vs 0.27, = 0.048, adjusted for age and sex). Performance of rBVc (corrected for T1 effects) was highest compared to SPECT for detection of frontal hypoperfusion (sensitivity 83%, specificity 80% for oSVD and BAY, area under curve (AUC) = 0.833 respectively, < 0.05) in FTD and MCI. For nonleakage-corrected rBV and for rBF (relative cerebral blood flow), sensitivity of frontal hypoperfusion was above 80% for oSVD and for BAY (rBV: sensitivity 83%, specificity 75%, AUC = 0.908 for oSVD and 0.917 for BAY, < 0.05 respectively; rBF: sensitivity 83%, specificity 65%, AUC = 0.825, < 0.05 for oSVD).

Conclusion: Advanced deconvolution DSC can reliably detect pathological perfusion alterations in FTD and MCI. Hence, this widely accessible technique has the potential to improve the diagnosis of dementia and MCI as part of an interdisciplinary multimodal imaging work-up. Advances in knowledge: Advanced DSC perfusion has a high potential in the work-up of suspected dementia and correlates with SPECT brain perfusion results in dementia and MCI.
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http://dx.doi.org/10.3390/jcm9061800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356248PMC
June 2020

Targeting Fibroblast Activation Protein: Radiosynthesis and Preclinical Evaluation of an F-Labeled FAP Inhibitor.

J Nucl Med 2020 12 24;61(12):1806-1813. Epub 2020 Apr 24.

Friedrich-Alexander University Erlangen-Nürnberg (FAU), Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Translational Research Center, Erlangen, Germany

Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. Ga-labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to PET imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an F-labeled glycosylated FAPI ([F]FGlc-FAPI). An alkyne-bearing precursor was synthesized and subjected to click chemistry-based radiosynthesis of [F]FGlc-FAPI by 2-step F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small-animal PET studies of [F]FGlc-FAPI compared with [Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. [F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of more than 99%. In HT1080hFAP cells, [F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared with FAPI-04 (half maximal inhibitory concentration [IC] = 32 nM), the glycoconjugate, FGlc-FAPI (IC = 167 nM), showed slightly lower affinity for FAP in vitro, whereas plasma protein binding was higher for [F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [F]FGlc-FAPI; however, small-animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [F]FGlc-FAPI (4.5 percentage injected dose per gram of tissue [%ID/g]) than of [Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor-bearing mice, both tracers showed similar tumor uptake, but [F]FGlc-FAPI showed a higher tumor retention. Interestingly, [F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. [F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of F. The availability of [F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis.
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http://dx.doi.org/10.2967/jnumed.120.242958DOI Listing
December 2020

Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from F-FDG-PET/CT and circulating tumor DNA.

Eur J Nucl Med Mol Imaging 2020 Jun;47(6):1613

Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

The author names and family names of the originally published article was inversed. Correct presentation is presented here.
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http://dx.doi.org/10.1007/s00259-019-04672-2DOI Listing
June 2020

Development of F-Fluoroglycosylated PSMA-Ligands with Improved Renal Clearance Behavior.

Mol Pharm 2020 03 17;17(3):933-943. Epub 2020 Feb 17.

Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich-Alexander University (FAU), Schwabachanlage 12, 91054 Erlangen, Germany.

The prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly expressed in the malignant human prostate epithelium. Therefore, PSMA has emerged as a very attractive target for developing radiopharmaceuticals for the diagnosis, e.g., by positron emission tomography (PET) imaging, and radiotherapy of prostate cancer. The aim of this study was to develop F-labeled PSMA ligands bearing different F-glycosyl moieties to study the effect on the clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based F-fluoroglcosylation using 2-deoxy-2-[F]fluoroglucosyl azide or 6-deoxy-6-[F]fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[F]FGlc-PSMA ([F]) and 6-[F]FGlc-PSMA ([F]). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using Tc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [F] (IC = 234 nM) and [F] (IC = 59 nM). Biodistribution and small-animal PET studies were performed using PSMA-positive PC-3 PIP and PSMA-negative PC-3 tumor-bearing nude mice. PSMA inhibitors [F] and [F] were obtained in high radioactivity yields of 19-22% (nondecay-corrected, referred to [F]fluoride) and with molar activities of 71-136 GBq/μmol. In the biodistribution studies, the uptake levels of [F] and [F] in PC-3 PIP tumors were 13 ± 3%ID/g and 6 ± 5%ID/g at 60 min p.i., respectively. PSMA-negative PC-3 tumors and all other tissues had negligible low uptake values. Interestingly, [F] had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [F] revealed a low uptake of 7.5%ID/g in the kidneys at 30 min p.i. and was rapidly cleared through the kidney (0.9%ID/g at 120 min p.i.). In direct comparison to a Ga-PSMA-11 PET scan of the same mouse, [F] and [F] showed 2- to 3-fold higher uptake values in PC-3 PIP tumors. Both radiotracers were solely cleared via the kidneys and not via the hepatobiliary pathway. The regional kidney distribution pattern of the tracers in the kidneys revealed that Ga-PSMA-11 and 2-[F]FGlc-PSMA([F]) mainly accumulated in the cortex of the kidneys, whereas 6-[F]FGlc-PSMA([F]) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [F], with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors This candidate could, therefore, be valuable for translation into the clinic.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01179DOI Listing
March 2020

99mTc-MIP-1404 SPECT/CT for Patients With Metastatic Prostate Cancer: Interobserver and Intraobserver Variability in Treatment-Related Longitudinal Tracer Uptake Assessments of Prostate-Specific Membrane Antigen-Positive Lesions.

Clin Nucl Med 2020 Feb;45(2):105-112

From the Department of Nuclear Medicine.

Background: Tc-MIP-1404 is a SPECT-suitable prostate-specific membrane antigen (PSMA) ligand for detection of prostate cancer. In patients with metastatic prostate cancer, there are no data as yet on interobserver and intraobserver variability when assessing PSMA-positive lesions for longitudinal changes of tracer uptake.

Methods: Tc-MIP-1404 SPECT/CT scans of 22 patients with metastatic prostate cancer were analyzed, and each subject was imaged at 2 separate points in time, before and after treatment. Mean interval between scans was 10 months. Three independent observers visually assessed a total of 96 PSMA-positive metastases (bone, 69; lymph node, 22; viscera, 3) or local recurrences (n = 2) for longitudinal changes in tracer uptake on planar scintigraphy and SPECT/CT. All lesions were categorized as regressive, stable, or progressive based on visual findings and on peak SUV (SUVpeak) of quantitative SPECT/CT (progressive, >30% SUVpeak increase; regressive, <30% SUVpeak decrease; or stable, all others).

Results: Quantitative analysis of PSMA-positive lesions yielded significantly higher interobserver agreement (90.6%; 95% confidence interval [CI], 0.83%-0.96%) than visual assessments by either SPECT/CT (76.0%; 95% CI, 0.66%-0.84%) or planar scintigraphy (56.3%; 95% CI, 0.46%-0.66%). Intermethod comparison of aggregated results yielded significantly higher agreement between quantitative and visual SPECT/CT (85.1%; 95% CI, 0.80%-0.89%), as opposed to quantitative SPECT/CT and planar scintigraphy (53.1%; 95% CI, 0.47%-0.59%) or visual SPECT/CT and planar scintigraphy (54.9%; 95% CI, 0.49%-0.61%). In visual and quantitative analysis of 96 PSMA-positive lesions, the number of discrepancies ranged from 9 (9.4%) for quantitative SPECT/CT to 42 (43.8%) for planar scintigraphy. Overall reader confidence was higher for SPECT/CT than for planar scintigraphy (P < 0.001). Intraobserver agreement was near-perfect for all methods, whether SPECT/CT (visual, all κ = 0.94-0.97; quantitative κ = 0.94-0.98) or planar scintigraphy (all κ = 0.90-0.94).

Conclusions: Quantitative evaluation of longitudinal change in tracer uptake by PSMA-positive lesions measured via SPECT/CT is superior to visual interpretation of images by planar scintigraphy or SPECT/CT. Compared with visual evaluation, quantitative SPECT/CT is highly reproducible, showing near-perfect agreement among observers and higher reader confidence.
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http://dx.doi.org/10.1097/RLU.0000000000002880DOI Listing
February 2020

Particle filter de-noising of voxel-specific time-activity-curves in personalized Lu therapy.

Z Med Phys 2020 May 17;30(2):116-134. Epub 2019 Dec 17.

Clinic of Nuclear Medicine, University Hospital Erlangen, 91054 Erlangen, Germany.

Background: Currently, there is a high interest in Lu targeted radionuclide therapies, which could be attributed to favorable results obtained from Lu compounds targeting neuro-endocrine and prostate tumors. SPECT based dosimetry could be used for deriving dose values for individual voxels, as is the standard in external-beam radiation-therapy (EBRT). For this a time-activity-curve (TAC) at voxel resolution and also a voxel-wise modeling of radiation energy deposition are necessary. But a voxel-wise determination of TACs is problematic, since several confounding factors exist, such as e.g. poor count-statistics or registration inaccuracies, which add noise to the observed activity states. A particle filter (PF) is a class of methods which applies regularization based on a model of the temporal evolution of activity states. The aim of this study is to introduce the application of PFs for de-noising of per-voxel time-activity curves.

Methods: We applied a PF for de-noising the TACs of 26 patients, who underwent Lu-DOTATOC or -PSMA therapy. The TACs were obtained from fully-quantitative, serial SPECT(/CT) data, acquired at 4h, 24h, 48h, 72h p.i. The model used in the PF was a mono-exponential decay and its free parameters were determined based on objective criteria. The time-integrated activities (TIA) resulting from the PF (PFF) were compared to the results of a mono-exponential fit (SF) of individual voxels in several volumes of interest (kidneys, spleen, tumors). Additionally, an organ-averaged TIA was derived from whole-organ VOIs and subsequent curve-fitting. This whole-organ TIA was also compared to the whole-organ TIAs obtained from summation of the voxel-wise TIAs from PFF and SF.

Results: The number of particles was set to 1000. Optimal values for noise of observations and noise of the model were 0.25 and 0.5, respectively. The deviation of whole-organ TIAs from conventional organ-based dosimetry and the summation of the voxel-wise TIAs was substantial for SF (kidneys -22.3%, spleen -49.6%, tumor -60.0%), as well as for PFF (kidneys -37.1%, spleen -57.9%, tumor -70.9%). The distribution of voxel-wise half-lives resulting from the PFF method was considerably closer to the organ-averaged value, and the number of implausibly long half-lives (>physical HL) was reduced.

Conclusion: The PFF leads to voxel-wise half-lives, which are more plausible than those resulting from SF. However, one has to admit that voxel-wise fitting generally leads to considerable deviations from the organ-averaged TIA as obtained by conventional whole-organ evaluation. Unfortunately, we did not have ground-truth TIA of our patient data and proper ground-truth could even be impossible to obtain. Nevertheless, there are strong indicators that particle filtering can be used for reducing voxel-wise TAC noise.
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http://dx.doi.org/10.1016/j.zemedi.2019.10.005DOI Listing
May 2020

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from F-FDG-PET/CT and circulating tumor DNA.

Eur J Nucl Med Mol Imaging 2020 06 18;47(6):1564-1575. Epub 2019 Dec 18.

Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Purpose: The purpose of this study was to perform a prospective integrated analysis of F-fluorodeoxyglucose (F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS).

Methods: A total of 20 patients with histologically confirmed EwS underwent multiple F-FDG-PET/CT, performed at the time of each patient's initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels.

Results: Twenty patients underwent a total of 87 F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8-104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%.

Conclusion: The combination of F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.
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http://dx.doi.org/10.1007/s00259-019-04649-1DOI Listing
June 2020

Changes over the years in radiopharmaceutical design.

Q J Nucl Med Mol Imaging 2019 Dec 13. Epub 2019 Dec 13.

Section Health and Development, Interuniversity Research Center for Sustainability (CIRPS), Napoli, Italy.

Of the many uses of radiopharmaceuticals, developing radiotracers that contribute significantly to diagnosis and therapy of patients has been a major focus. This requires a broad spectrum of expertise including that of the attending physician who lends insight to an unmet clinical need neither addressed by other imaging techniques nor by analysis of tissue, blood, and urine for diagnostics and addressed by pharmaceuticals for therapeutic applications. The design criteria have depended on radiochemistry, on matching the radiopharmaceutical with the imaging devices, and basing the design on current pharmaceuticals. The chelates of technetium-99m were based on radiochemistry rather than clinical need yet are still used today in >70% of the clinical studies. Targeted radiotracers in neurologic and psychiatric disorders, inflammation, cardiovascular disease, and oncology have all been studied with the goal of determining the change in the density of a target protein as a function of disease or treatment or, especially in oncology, detection of the total extent of disease. In latter approach PET in university settings leads the way; however, the use of SPECT/CT has increased the specificity of SPECT imaging to complement the cost- effective generator and instant kits already available. Remarkable advances has been achieved in radionuclide therapy using theragnostic agents, with the exclusive domain of oncology For this application the design of radionuclide therapy follows that used for diagnostics. The increased impact of the discipline depends on the opportunity to continue the search for the most appropriate radiopharmaceutical for each individual patient.
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http://dx.doi.org/10.23736/S1824-4785.19.03216-3DOI Listing
December 2019

Classification of three prognostically different groups of head and neck cancer patients based on their metabolic response to induction chemotherapy (IC-1).

Oral Oncol 2020 01 28;100:104479. Epub 2019 Nov 28.

Department of Radiation Oncology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany.

Objectives: There exist no uniform decision criteria for conservative organ preservation treatments in head and neck cancer patients. Even with F-FDG-PET/CT after induction chemotherapy patient selection is challenging. This study correlated metabolic tumor response with treatment types and recurrence patterns.

Materials And Methods: Decrease in SUVmax in F-FDG-PET/CT was measured 21-28 days after IC-1 in 102 patients and correlated to cancer-specific endpoints.

Results: Residual SUVmax (resSUVmax) values were uniformly distributed across five cut-off levels (0-0.2 vs. >0.2-0.4 vs. >0.4-0.6 vs. >0.6-0.8 vs. >0.8) containing 20%, 25% 25%, 15% and 15% of patients. Patients were stratified into three response categories according to residual SUVmax (Group A: 0-0.4 = high response Group B: >0.4-0.8 = moderate response, Group C > 0.8 = non-response), 5-year local control rates were 90.5% (Group A) vs. 78.9% (Group B; univariate p = 0.07, multivariate: HR: 3.6, p = 0.03) vs. 49.4% (Group C vs. B; univariate p = 0.04, multivariate: HR 5.5, p < 0.01). After IC-1, Group A received chemoradiotherapy (CRT) only. Group B received surgery plus either (chemo)radiotherapy (B_S + RT/CRT) or chemoradiotherapy (B_CRT), yielding local control rates of 100% and 74.2% (p = 0.11). Group C received surgery plus CRT or CRT alone; both achieved equally poor local control (p = 0.71). Group C had significantly worse distant metastasis-free survival and overall survival than Groups A and B (p < 0.05).

Conclusion: Metabolic response after IC-1 differentiates HNC patients into three subgroups predicting local tumor control. Non-response was associated with a poor outcome.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104479DOI Listing
January 2020

Growth rates of malignant and benign thyroid nodules in an ultrasound follow-up study: a retrospective cohort study.

BMC Cancer 2019 Nov 21;19(1):1139. Epub 2019 Nov 21.

Nuklearmedizinische Klinik, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

Background: Thyroid nodules are frequently detected by cervical ultrasound examinations. In follow-up studies, malignant as well as benign nodules may exhibit an increase in size. The objective of our investigation was to test whether histologically determined malignant and benign thyroid nodules show differences in growth rates above a defined significance level.

Methods: A retrospective ultrasound cohort follow-up study from 4 to 132 months included 26 patients with differentiated carcinomas and 26 patients with adenomas of the thyroid gland. Significance levels were determined by intra- and interobserver variations of volumetric measurements in 25 individuals.

Results: Intra- and interobserver volumetric measurements were highly correlated (r = 0.99 and r = 0.98, respectively), with variations of 28 and 40%, respectively. The growth rates of malignant and benign nodules did not show differences with respect to two sonographic measurements (d = - 0.04, 95%CI(P): 0.41-0.85, P = 0.83). Using shorter increments and multiple measurements, growth rates of malignant nodules revealed significantly higher values (d = 0.16, 95%CI(P): 0.02-0.04, P = 0.039).

Conclusions: The growth rates of benign and malignant thyroid nodules do not appear to differ using two sonographic volumetric measurements. However, due to temporal changes in cellular proliferation and arrest, malignant nodules may exhibit higher growth rates with multiple assessments and shorter increments.
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http://dx.doi.org/10.1186/s12885-019-6348-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873423PMC
November 2019

Single-cycle induction chemotherapy before chemoradiotherapy or surgery in functionally inoperable head and neck squamous cell carcinoma: 10-year results.

Eur Arch Otorhinolaryngol 2020 Jan 3;277(1):245-254. Epub 2019 Oct 3.

Department of Radiation Oncology, University Hospital, Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstrasse 27, 91054, Erlangen, Germany.

Introduction: The response to induction chemotherapy (IC) predicts local control after conservative treatment of laryngeal, meso- and hypopharyngeal head and neck squamous cell carcinoma (HNSCC) and can thus help to avoid surgery. Single-cycle induction chemotherapy may help to maintain a low local recurrence rate while keeping the overall toxicity manageable. However, long-term data on single-cycle IC response by tumor location is lacking.

Methods: N = 102 patients with functionally inoperable primary HNSCC of the larynx (n = 43), hypopharynx (n = 42) or mesopharynx/tongue (n = 17) received one cycle of docetaxel (75 mg/m, d1) plus cisplatin (30 mg/m, d1-3) or carboplatin (AUC 1.5, d1-3) and a response evaluation 3 weeks later. Responders (≥ 30% tumor size reduction and ≥ 20% SUVmax decrease in F-FDG PET/CT) were recommended chemoradiotherapy (CRT), and non-responders surgery.

Results: The overall response rate was 72.5%. All 74 responders and 10 non-responders received primary CRT, and 18 patients received primary surgery after single-cycle IC. Overall 10-year local recurrence-free survival (LRFS) was 73.7%. Three-year LRFS was 88.2% (mesopharynx/tongue), 88.2% (larynx), and 73.3% (hypopharynx); p = 0.17. 3-year distant metastasis-free survival (DMFS) was 94.1% (mesopharynx/tongue), 88.0% (larynx) and 76.4% (hypopharynx); p > 0.05. This influenced the 3-year cancer-specific survival (CSS) for larynx (91.2%) vs. hypopharynx tumors (60.8%); p = 0.003, but CSS was not different to tumors in the mesopharynx/tongue (81.4%); p > 0.05.

Conclusions: A single-cycle induction chemotherapy for HNSCC enables surgery plus adjuvant therapy as well as chemoradiotherapy. The long-term local and distant disease control was good but varied between tumors in the larynx and mesopharynx/tongue vs. hypopharynx.
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http://dx.doi.org/10.1007/s00405-019-05665-5DOI Listing
January 2020

F-labelled triazolyl-linked argininamides targeting the neuropeptide Y YR for PET imaging of mammary carcinoma.

Sci Rep 2019 09 10;9(1):12990. Epub 2019 Sep 10.

Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich-Alexander University (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.

Neuropeptide Y Y receptors (YR) have been found to be overexpressed in a number of different tumours, such as breast, ovarian or renal cell cancer. In mammary carcinoma the high YR density together with its high incidence of 85% in primary human breast cancers and 100% in breast cancer derived lymph node metastases attracted special attention. Therefore, the aim of this study was the development of radioligands for YR imaging by positron emission tomography (PET) with a special emphasis on imaging agents with reduced lipophilicity to provide a PET ligand with improved biodistribution in comparison with previously published tracers targeting the YR. Three new radioligands based on BIBP3226, bearing an F-fluoroethoxy linker (12), an F-PEG-linker (13) or an F-fluoroglycosyl moiety (11) were radiosynthesised in high radioactivity yields. The new radioligands displayed YR affinities of 2.8 nM (12), 29 nM (13) and 208 nM (11) and were characterised in vitro regarding binding to human breast cancer MCF-7-Y1 cells and slices of tumour xenografts. In vivo, small animal PET studies were conducted in nude mice bearing MCF-7-Y1 tumours. The binding to tumours, solid tumour slices and tumour cells correlated well with the YR affinities. Although 12 and 13 showed displaceable and specific binding to YR in vitro and in vivo, the radioligands still need to be optimised to achieve higher tumour-to-background ratios for YR imaging by PET. Yet the present study is another step towards an optimized PET radioligand for imaging of YR in vivo.
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http://dx.doi.org/10.1038/s41598-019-49399-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736837PMC
September 2019

PSMA SPECT/CT with Tc-MIP-1404 in biochemical recurrence of prostate cancer: predictive factors and efficacy for the detection of PSMA-positive lesions at low and very-low PSA levels.

Ann Nucl Med 2019 Dec 9;33(12):891-898. Epub 2019 Sep 9.

Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany.

Background: The in vivo expression of the prostate-specific membrane antigen (PSMA) can be investigated using the SPECT-suitable tracer Tc-MIP-1404. We investigated the performance of Tc-MIP-1404 PSMA SPECT/CT in the detection of PSMA-positive tumor lesions in patients suffering from biochemical recurrence of prostate cancer presenting with serum levels of the prostate-specific antigen (PSA) below 1 ng/mL.

Methods: We retrospectively analyzed Tc-MIP-1404-SPECT/CT scans of 50 patients (25 with low PSA levels between > 0.5 and 1 ng/mL and 25 with very low PSA levels between 0.2 and 0.5 ng/mL) that had undergone whole-body planar scintigraphy and SPECT/CT of the thorax, abdomen and pelvis 3-4 h p.i. of 691 ± 72 MBq Tc-MIP-1404. All datasets were evaluated for the presence and location of PSMA-positive tumor lesions, in which maximal standardized uptake values (SUV) were also measured. Based on the results of the quantitative evaluation as well as on biochemical and histological parameters, predictive factors for a positive Tc-MIP-1404 scan result were determined. The influence of Tc-MIP-1404 PSMA SPECT/CT on further therapy planning was assessed, based on the decision-making of the interdisciplinary tumor board.

Results: Pathological Tc-MIP-1404 uptake was detected in a total of 25 patients (50%). In the very low PSA subgroup, detection rates of PSMA-positive lesions suggestive of tumor recurrence were 44%, in the low-PSA subgroup 56%. Gleason scores ≥ 8 and the presence of antiandrogen deprivation therapy were further significant predictors of pathological Tc-MIP-1404 uptake. This was paralleled by significantly higher lesional SUV patients with PSA levels > 0.5 ng/mL and Gleason scores ≥ 8 compared to those without these two features. Changes in therapeutic strategy following MIP-1404 imaging were recommended by the interdisciplinary tumor board in 25/50 of patients.

Conclusion: Tc-MIP-1404 PSMA-SPECT/CT demonstrated a high performance in detecting PSMA-positive lesions suggestive of tumor recurrence in patients with biochemical recurrence of prostate cancer and low and very low serum PSA levels. Results from MIP-1404 PSMA SPECT/CT have therapeutic impact in one-half of the patients examined by this technology.
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http://dx.doi.org/10.1007/s12149-019-01400-6DOI Listing
December 2019

68Ga-PSMA-11 PET/CT derived quantitative volumetric tumor parameters for classification and evaluation of therapeutic response of bone metastases in prostate cancer patients.

Ann Nucl Med 2019 Oct 23;33(10):766-775. Epub 2019 Jul 23.

Institute of Radiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: To evaluate the role of Gallium prostate-specific membrane antigen-positron emission tomography/computed tomography (Ga-PSMA-11 PET/CT) derived quantitative volumetric tumor parameters in comparison with fully diagnostic conventional CT and serum-PSA levels for classification and evaluation of therapeutic response of bone metastases in patients with metastasized prostate cancer (PC).

Methods: A total of 177 men with biochemical recurrence of prostate cancer suffering from bone metastases underwent PET/CT with [Ga] Ga-PSMA-HBED-CC (Ga-PSMA-11). To calculate Ga-PSMA-11 PET quantitative volumetric tumor parameters including whole-body total-lesion PSMA (TL-PSMA), whole-body PSMA-tumor volume (PSMA-TV), as well as the established maximum standard uptake values (SUVmax) and mean standard uptake values (SUVmean), all 443 Ga-PSMA-11-positive bone lesions in the field of view were assessed quantitatively. Quantitative volumetric tumor parameters were correlated with CT-derived volume and bone density measurements of metastatic bone lesions, serum prostate-specific antigen (PSA) levels, and Gleason Scores. In the 20 patients suffering from bone metastases who underwent Ga-PSMA-11 PET/CT before and after therapy, CT-derived volume and bone density measurements of metastatic lesions were compared to biochemical response determined by serum-PSA levels.

Results: In 177 patients, a total of 443 Ga-PSMA-11 PET-positive bone lesions were detected. Of these, 50 lesions (11%) were only detectable on PET but not on conventional CT. PET-positive/CT-negative bone metastases demonstrated a significantly lower PSMA uptake compared to PET-positive/CT-positive bone lesions (p < 0.05). SUVmax, SUVmean, PSMA-TV, and TL-PSMA of bone metastases were significantly higher (p < 0.05) in patients with Gleason Scores > 7 compared to those with Gleason Scores ≤ 7. In the linear regression analysis, an association was determined between SUVmean, Gleason Scores, lesion classification, and serum-PSA levels but not for CT-derived bone density measurements. No significant correlation could be found between changes of bone density and CT-derived volume measurements of metastatic bone lesions and changes of serum-PSA levels (p > 0.05) before and after therapy, while a highly significant correlation was observed for changes of PSMA-TV, TL-PSMA, and serum-PSA levels (p < 0.001).

Conclusion: Our results suggest that Ga-PSMA-11 PET/CT might be a valuable tool for the detection and follow-up of bone metastases in patients with metastasized prostate cancer. Ga-PSMA-11 PET-derived quantitative volumetric parameters demonstrated a highly significant correlation with changes of serum-PSA levels during the course of therapy. No such correlation could be determined for bone density measurements of metastatic bone lesions. Compared to the fully diagnostic CT scan, a significantly higher proportion of bone metastases was detected on Ga-PSMA-11 PET.
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http://dx.doi.org/10.1007/s12149-019-01387-0DOI Listing
October 2019

Quantitative radionuclide imaging of bone metastases.

Q J Nucl Med Mol Imaging 2019 Jun 11;63(2):129-135. Epub 2019 Jul 11.

Clinic of Nuclear Medicine, University-Hospital Erlangen-Nürnberg, Erlangen, Germany -

By improving the localization of foci of pathological tracer uptake and offering information on their computed tomography (CT) morphology, single photon emission computed tomography (SPECT)/CT hybrid imaging has considerably improved the diagnostic accuracy of skeletal scintigraphy. SPECT/CT also has the potential to measure tracer uptake in vivo in absolute units. The present article reviews the methodology for and the potential clinical impact of quantitative skeletal scintigraphy.
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http://dx.doi.org/10.23736/S1824-4785.19.03204-7DOI Listing
June 2019
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