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Background
Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment.
Methods
To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT).
Results
SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%).
Conclusion
SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.
This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.
BACKGROUND:
We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL).
METHODS:
We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed.
RESULTS:
18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10% (range, 10% to 20%) in FL and 70% (40% to 80%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90% (range, 80 to 100), 90% (80 to 100) and 100% (80 to 100) in FL versus 90% (60 to 100), 90% (60 to 100) and 100% (80 to 100) in DLBCL, respectively.
CONCLUSIONS:
This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.
Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies.
Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.
[\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018).
[\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
\(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions
(2017)
\(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG).
78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available.
MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases.
MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72).
This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers \(^{11}\)C-Methionine (paraprotein-biosynthesis) and \(^{18}\)F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138\(^{+}\) plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM. 1S tumors underwent MET- and FDG-\(\mu\)PET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET-but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.
Background
\(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.
Results
\(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.
Conclusions
The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.
\(^{11}\)C-methionine (\(^{11}\)C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of \(^{11}\)C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to \(^{18}\)F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone \(^{11}\)C-MET and \(^{18}\)F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion \(^{11}\)C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), \(^{11}\)C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in \(^{11}\)C-MET than in \(^{18}\)F-FDG (p < 0.05, respectively). \(^{11}\)C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that \(^{11}\)C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than \(^{18}\)F-FDG. Its implications for prognosis evaluation need further investigation.
Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with \(^{68}\)Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from \(^{68}\)Ga- to \(^{18}\)F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite \(^{68}\)Ge/\(^{68}\)Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, \(^{18}\)F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, \(^{18}\)F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging \(^{18}\)F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available \(^{18}\)F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.
Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor.
15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples.
\(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression.
In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.
Background
Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin.
Case presentation
Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred.
Conclusion
Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer.
Purpose
Patient-specific dosimetry is required to ensure the safety of molecular radiotherapy and to predict response. Dosimetry involves several steps, the first of which is the determination of the activity of the radiopharmaceutical taken up by an organ/lesion over time. As uncertainties propagate along each of the subsequent steps (integration of the time–activity curve, absorbed dose calculation), establishing a reliable activity quantification is essential. The MRTDosimetry project was a European initiative to bring together expertise in metrology and nuclear medicine research, with one main goal of standardizing quantitative \(^{177}\)Lu SPECT/CT imaging based on a calibration protocol developed and tested in a multicentre inter-comparison. This study presents the setup and results of this comparison exercise.
Methods
The inter-comparison included nine SPECT/CT systems. Each site performed a set of three measurements with the same setup (system, acquisition and reconstruction): (1) Determination of an image calibration for conversion from counts to activity concentration (large cylinder phantom), (2) determination of recovery coefficients for partial volume correction (IEC NEMA PET body phantom with sphere inserts), (3) validation of the established quantitative imaging setup using a 3D printed two-organ phantom (ICRP110-based kidney and spleen). In contrast to previous efforts, traceability of the activity measurement was required for each participant, and all participants were asked to calculate uncertainties for their SPECT-based activities.
Results
Similar combinations of imaging system and reconstruction lead to similar image calibration factors. The activity ratio results of the anthropomorphic phantom validation demonstrate significant harmonization of quantitative imaging performance between the sites with all sites falling within one standard deviation of the mean values for all inserts. Activity recovery was underestimated for total kidney, spleen, and kidney cortex, while it was overestimated for the medulla.
Conclusion
This international comparison exercise demonstrates that harmonization of quantitative SPECT/CT is feasible when following very specific instructions of a dedicated calibration protocol, as developed within the MRTDosimetry project. While quantitative imaging performance demonstrates significant harmonization, an over- and underestimation of the activity recovery highlights the limitations of any partial volume correction in the presence of spill-in and spill-out between two adjacent volumes of interests.
Background
The GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this “plug ‘n’ synthesize” principle to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of N-methyl-[\(^{11}\)C]choline, L-S-methyl-[\(^{11}\)C]methionine and [11C]acetate.
Results
The target gas purification of cyclotron produced [\(^{11}\)C]CO\(_2\) and subsequent conversion to [\(^{11}\)C]MeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce N-methyl-[\(^{11}\)C]choline and L-S-methyl-[\(^{11}\)C]methionine by loading a reaction loop with neat N,N'-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and L-homocysteine (L-HC), respectively and a subsequent reaction with [\(^{11}\)C]MeI. After 18 min N-methyl-[\(^{11}\)C]choline was isolated with 52% decay corrected yield and a radiochemical purity of > 99%. For L-S-methyl-[\(^{11}\)C]methionine the total reaction time was 19 min reaction, yielding 25% of pure product (> 97%). The reactor design was used as an exemplary model for the technically challenging [\(^{11}\)C]acetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore [\(^{11}\)C]CO\(_2\) was passed through. After complete release of [\(^{11}\)C]CO\(_2\) the reaction mixture was quenched with water and guided through a series of ion exchangers (H\(^+\), Ag\(^+\) and OH\(^−\)). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess [\(^{11}\)C]CO\(_2\) before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure [\(^{11}\)C]acetate (n = 10) was isolated with a decay corrected yield of 51 ± 5%.
Conclusion
Herein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of N-methyl-[\(^{11}\)C]choline, L-S-methyl-[\(^{11}\)C]methionine and [11C]acetate.
The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4–5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.
Importance
Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis.
Objective
To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases.
Design, Setting, and Participants
This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients’ tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled.
Exposures
All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection.
Main Outcomes and Measures
The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference.
Results
Of the 150 patients enrolled, 135 patients (74 [54.8%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3% sensitivity (95% CI, 71.2%-95.5%) and 84.8% specificity (95% CI, 77.8%-91.9%) and had a negative predictive value of 93.3% (95% CI, 88.2%-98.5%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0%; 95% CI, 57.4%-76.7%; P < .01) and cervical magnetic resonance imaging (62.6%; 95% CI, 52.7%-72.6%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6% sensitivity (95% CI, 63.4%-93.8%) and 83.1% specificity (95% CI, 75.1%-91.2%), and contralateral metastatic involvement was detected with 66.7% sensitivity (95% CI, 28.9%-100.0%) and 98.6% specificity (95% CI, 95.9%-100.0%). No distant metastases were observed.
Conclusions and Relevance
In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients.
Background
In recent years, a lot of effort has been put in the enhancement of medical imaging using artificial intelligence. However, limited patient data in combination with the unavailability of a ground truth often pose a challenge to a systematic validation of such methodologies. The goal of this work was to investigate a recently proposed method for an artificial intelligence-based generation of synthetic SPECT projections, for acceleration of the image acquisition process based on a large dataset of realistic SPECT simulations.
Methods
A database of 10,000 SPECT projection datasets of heterogeneous activity distributions of randomly placed random shapes was simulated for a clinical SPECT/CT system using the SIMIND Monte Carlo program. Synthetic projections at fixed angular increments from a set of input projections at evenly distributed angles were generated by different u-shaped convolutional neural networks (u-nets). These u-nets differed in noise realization used for the training data, number of input projections, projection angle increment, and number of training/validation datasets. Synthetic projections were generated for 500 test projection datasets for each u-net, and a quantitative analysis was performed using statistical hypothesis tests based on structural similarity index measure and normalized root-mean-squared error. Additional simulations with varying detector orbits were performed on a subset of the dataset to study the effect of the detector orbit on the performance of the methodology. For verification of the results, the u-nets were applied to Jaszczak and NEMA physical phantom data obtained on a clinical SPECT/CT system.
Results
No statistically significant differences were observed between u-nets trained with different noise realizations. In contrast, a statistically significant deterioration was found for training with a small subset (400 datasets) of the 10,000 simulated projection datasets in comparison with using a large subset (9500 datasets) for training. A good agreement between synthetic (i.e., u-net generated) and simulated projections before adding noise demonstrates a denoising effect. Finally, the physical phantom measurements show that our findings also apply for projections measured on a clinical SPECT/CT system.
Conclusion
Our study shows the large potential of u-nets for accelerating SPECT/CT imaging. In addition, our analysis numerically reveals a denoising effect when generating synthetic projections with a u-net. Clinically interesting, the methodology has proven robust against camera orbit deviations in a clinically realistic range. Lastly, we found that a small number of training samples (e.g., ~ 400 datasets) may not be sufficient for reliable generalization of the u-net.
Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days
(2023)
Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([\(^{18}\)F]FDG) was evaluated in different brain regions in 14 male Sprague–Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [\(^{18}\)F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [\(^{18}\)F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [\(^{18}\)F]FDG-PET study provides important insights into glucose metabolism alterations following SAH—for the first time in different brain regions and up to day 7 during course of disease.
Background
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS).
Materials and Methods
In this bicentric analysis, we included 184 mCRPC patients treated with \(^{177}\)Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan–Meier curves and log-rank comparison.
Results
A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44–0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25–0.60; p < 0.001).
Conclusions
In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued.
Background: The American Thyroid Association (ATA) uses criteria to assess the risk for persistent disease in differentiated thyroid carcinoma (DTC) after radioiodine therapy (RAI). There are no data available showing that this classification can be adopted unadjusted by Germany. Aim: The aim of our study is to investigate whether the ATA classification can be applied to a German population for short-term prognosis. Furthermore, we investigated the influence of an age cutoff value. Methods: We retrospectively analyzed 121 patients who were referred to our tertiary referral center. Patients were classified into risk categories, and the therapy response was determined according to ATA. Results: A total of 73/83 (88%) ATA low-risk patients and 12/19 (63%) intermediate-risk patients showed an excellent response; 2/19 (11%) high-risk patients had a biochemical, and 6 (31%) had a structural incomplete response. Of all 39 patients ≥55 years, 84% had an excellent response. Using a cut off of 50 years, 50/62 (81%) of the older patients showed an excellent response. Conclusion: The ATA risk classification is able to estimate the response to RAI therapy in a German population. A shift from 55 to 50 years as an age cutoff value does not result in any relevant change in the treatment response.
DD is a cardiac disturbance, which has gained increasing importance in recent years due to its important role in different cardiac disease and cardiomyopathies including ischemic cardiomyopathy, arterial hypertension and diabetic cardiomyopathy.
ECG-gated 18F-FDG PET is an imaging technique, that can distinguish between districts of myocardial viability and myocardial scars and further provides information of great interest on the efficacy of experimental approaches designed to improve the cardiac function and/or myocardial metabolism in experimental small animal models. However, ECG-gated 18F-FDG PET is a technique whose feasibility in the assessment of the LV diastolic function in small animals has not been a subject of study.
In this thesis, the ability of the ECG-gated 18F-FDG PET for the assessment of both the systolic and diastolic function in eight control rats and in seven ZDF rats, which are an experimental animal model mimicking T2DM conditions and diabetic related complications in humans including DCM, has been investigated The ECG-gated 18F-FDG PET imaging was performed under hyperinsulinemic-euglycemic clamping and the data were stored in list mode files and retrospectively reconstructed. The systolic and diastolic parameters were achieved from the time/volume and the time/filling curve calculated from the software HFV. Additionally, the influence of the number of gates per cardiac cycle on the LV volumes and function parameters has been studied.
Hyperinsulinemic-euglycemic clamp procedure and blood glucose measurement did confirm the development of a manifest diabetes in the ZDF rats at the timepoint of the experiments.
Regarding the systolic parameters, no significant difference could be detected between the ZDF and ZL rats. The values for the CO were similar in both groups, which demonstrates a similar LV systolic function in the ZDF and the ZL rats at the age of 13 weeks. Values for the systolic parameters are in good line with previous PET, MRI and cardiac catheterization-based studies in diabetic rats.
The main finding of this study was that by using in vivo ECG-gated 18F-FDG PET and the software HFV, reliable diastolic parameters could be calculated. Moreover, it was possible to detect the presence of a mild impaired diastolic filling in the ZDF rats in absence of any systolic alteration. This impaired diastolic function in an early stage of diabetes could also be detected by other investigators, who used echocardiography or cardiac catheterization. Therefore, this is the first study showing, that the assessment of the diastolic function in rats can be carried out by ECG-gated 18F-FDG PET imaging.
In conclusion, additionally to calculating LV volumes and LV EF, ECG-gated 18F-FDG PET can evaluate the diastolic function of healthy and diabetic rats and is able to detect a DD in ZDF rats.
The use of prostate-specific membrane antigen targeted PET imaging for the evaluation of prostate cancer has increased significantly in the last couple of decades. When evaluating these imaging findings based on the PSMA reporting and data system version 1.0, which categorize lesions based on their likelihood of prostate cancer involvement, PSMA-RADS-3A lesions are commonly seen, which are indeterminate for the presence of disease. A total of 28 patients with 171 PSMA-RADS-3A lesions on \(^{18}\)F-DCFPyL PET/CT scans from June 2016 to May 2017 who had follow-up cross-sectional imaging over time were included in this study. The PSA levels of patients with PSMA-RADS-3A lesions were categorized into four groups, 0–0.2, 0.2–1, 1–2, and >2 ng/mL. The pre-operative Gleason score of these patients was categorized into two groups, Gleason score < 7 or ≥7. The median age for these patients was 72.5 years (range 59–81). The median PSA value for patients with positive lesions was significantly higher than those with negative lesions (5.8 ng/mL vs. 0.2 ng/mL, p < 0.0001). The lesion positivity rate was significantly higher in patients with PSA > 1 ng/mL (18.2% vs. 81.9%, p < 0.001). On ROC analysis, the highest classification accuracy was seen at PSA ≥ 0.6 ng/mL of 80.12% (95% CI = 73.69–86.16%), and the area under the curve was 71.32% (95% CI = 61.9–80.7%, p < 0.0001). A total of 96.4% (108/112) of patients with positive lesions and 86.4% (51/59) of patients with negative lesions had a PSMA-RADS-4/5 lymph node on the initial \(^{18}\)F-DCFPyL PET/CT scan (p = 0.02). In patients with a Gleason score ≥ 7, the presence of positive PSMA-RADS-3A lesions was higher, compared to negative PSMA-RADS-3A lesions (p = 0.049). Higher PSA levels in patients with PSMA-RADS-3A lesions can point towards the presence of true positivity. PSA levels may be considered in deciding whether to call an indeterminate lesion on PSMA PET.
(1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.
Background
Radioligand therapy (RLT) with \(^{177}\)Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [\(^{177}\)Lu]Lu-PSMA I&T RLT in a long-term follow-up.
Materials and methods
Ninety-two mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (interval\(_{Diagnosis-RLT}\), per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan–Meier analyses.
Results
Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02–1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01–1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06–1.26; P = 0.001), and interval\(_{Diagnosis-RLT}\) (HR, 0.95, 95% CI 0.91–0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and interval\(_{Diagnosis-RLT}\), 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan–Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval\(_{Diagnosis-RLT}\) (P ≤ 0.01, respectively).
Conclusion
In mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [\(^{177}\)Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.
Purpose
The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE.NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals.
Methods
A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting.
Results
Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago.
Conclusion
It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained.
Background:
Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing \(^{99m}\)Tc-MAG3 renal scans based on a retrospective analysis of existing patient data. Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing \(^{99m}\)Tc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool.
Results:
The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of \(^{99m}\)Tc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified).
Conclusion:
In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with \(^{99m}\)Tc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the \(^{99m}\)Tc-MAG3 scans is very low in comparison to the general population risk for developing cancer.
Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism.
Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case–control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial “misdiagnosis.”
DNA double strand break (DSB) formation induced by ionizing radiation exposure is indicated by the DSB biomarkers \(\gamma\)-H2AX and 53BP1. Knowledge about DSB foci formation in-vitro after internal irradiation of whole blood samples with radionuclides in solution will help us to gain detailed insights about dose-response relationships in patients after molecular radiotherapy (MRT). Therefore, we studied the induction of radiation-induced co-localizing \(\gamma\)-H2AX and 53BP1 foci as surrogate markers for DSBs in-vitro, and correlated the obtained foci per cell values with the in-vitro absorbed doses to the blood for the two most frequently used radionuclides in MRT (I-131 and Lu-177). This approach led to an in-vitro calibration curve. Overall, 55 blood samples of three healthy volunteers were analyzed. For each experiment several vials containing a mixture of whole blood and radioactive solutions with different concentrations of isotonic NaCl-diluted radionuclides with known activities were prepared. Leukocytes were recovered by density centrifugation after incubation and constant blending for 1 h at 37°C. After ethanol fixation they were subjected to two-color immunofluorescence staining and the average frequencies of the co-localizing \(\gamma\)-H2AX and 53BP1 foci/nucleus were determined using a fluorescence microscope equipped with a red/green double band pass filter. The exact activity was determined in parallel in each blood sample by calibrated germanium detector measurements. The absorbed dose rates to the blood per nuclear disintegrations occurring in 1 ml of blood were calculated for both isotopes by a Monte Carlo simulation. The measured blood doses in our samples ranged from 6 to 95 mGy. A linear relationship was found between the number of DSB-marking foci/nucleus and the absorbed dose to the blood for both radionuclides studied. There were only minor nuclide-specific intra-and inter-subject deviations.
Molecular imaging of rats is of great importance for basic and translational research. As a powerful tool in nuclear medicine, SPECT can be used to visualize specific functional processes in the body, such as myocardial perfusion or bone metabolism. Typical applications in laboratory animals are imaging diagnostics or the development of new tracers for clinical use. Innovations have enabled resolutions of up to a quarter of a millimeter with acceptable sensitivity. These advances have recently led to significantly more interest in SPECT both clinically and preclinically.
The objective of this thesis was to evaluate the performance of the new U-SPECT5/CT E-Class by MILabs with a dedicated ultra-high resolution multi-pinhole collimator for rats and its potential for in vivo imaging of rats. The unique features of the U-SPECT are the large stationary detectors and the new iterative reconstruction algorithm. In addition, compared to the conventional system, the "E-Class" uses only two detectors instead of three.
First, the sensitivity, maximum resolution, and uniformity were determined as performance parameters. Thereafter, CNRs for different activity levels comparable to those of typical in vivo activities were examined. Finally, two example protocols were carried out for imaging with 99mTc-MIBI and 99mTc-HMDP in healthy rats to evaluate the in vivo capabilities. For this purpose, CNR calculations and an image quality assessment were performed. The focus was on image quality as a function of scan time and post-reconstruction filter across a wide range of realistically achievable in vivo conditions.
Performance was reasonable compared to other systems in the literature, with a sensitivity of 567 cps/MBq, a maximum resolution of 1.20 mm, and a uniformity of 55.5%. At the lower activities, resolution in phantom studies decreased to ≥1.80 mm while maintaining good image quality. High-quality bone and myocardial perfusion SPECTs were obtained in rats with a resolution of ≥1.80 mm and ≥2.20 mm, respectively. Although limited sensitivity remains a weakness of SPECT, the U-SPECT5/CT E-Class with the UHR-RM collimator can achieve in vivo results of the highest standard despite the missing third detector. Currently, it is one of the best options for high-resolution radionuclide imaging in rats.
We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available \(^{99m}\)Tc-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with \(^{99m}\)Tc-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with similar to 100 MBq [\(^{99m}\)TcTc-MIBI or similar to 150 MBq [\(^{99m}\)Tc]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1="very poor" to 5="very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time.
Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.
Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.
The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.
Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with \(^{18}\)F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV\(_{max}\), SUV\(_{peak}\), SUV\(_{mean}\)) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories (p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV\(_{max}\) and SUV\(_{peak}\) compared to the entire PSMA-RADS-4 or -5 cohort (p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort (p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV\(_{max}\), p = 0.07; SUV\(_{peak}\), p = 0.08). SUV\(_{mean}\) (p = 0.30) and TL-PSMA (p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT (p = 0.0066), which was driven by lymph nodes (p = 0.0239), but not bone lesions (p = 0.15). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in \(^{18}\)F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV\(_{mean}\) and TL-PSMA in contrast to PSMA-TV.
Objective: To investigate the association between levodopa‐induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease.
Methods: This study included 13 Parkinson's disease patients with peak‐of‐dose levodopa‐induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5‐[\(^{123}\)I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single‐photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [\(^{123}\)I]N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane single‐photon emission computed tomography, to measure dopamine reuptake transporter density and 2‐[\(^{18}\)F]fluoro‐2‐deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed.
Results: Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side.
Interpretation: Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic‐depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.
Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable.
Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.
The risk of developing thyroid cancer increases considerably after exposure to external or internal radiation, especially in children below the age of 10. After the Chernobyl reactor accident, the yearly incidence of childhood thyroid cancer in Belarus increased to approximately 40 per 1.000.000 in girls and to roughly 20 per 1.000.000 in boys compared to approximately 0.5 cases per 1.000.000 prior to the accident. Typically, young children with thyroid cancer after radiation exposure present in ≈95% of the cases as papillary cancers, in ≈50% as invasive tumors growing outside the thyroid capsule, in ≈65% with lymph node metastases and in ≈15% with distant metastases. A joint Belarusian-German project starting in April 1993 that combined treatment with surgery and radioiodine was organized in 237 selected children from Belarus who were exposed to the Chernobyl fallout and had advanced stages of thyroid cancer. The study group included 141 girls and 96 boys. Their median age at the time of the accident was 1.7 years; whereas the median age at the time of diagnosis was 12.4 years. With the exception of two cases with follicular histology, the majority of the patients had been diagnosed with papillary thyroid cancers. In 63%, the tumor had grown outside the thyroid capsule and invaded the tissue of the neck (pT4). Nearly all of the selected cases (96%) showed-up with lymph node metastases (pN1) and 43% of the patients with distant metastases mainly to the lungs (pM1). In 58% of the children, complete remissions of thyroid cancer could be achieved until December 31st 2010 and in 34% of the children, stable partial remissions; in the remaining 8% of the patients, partial remissions were observed. The risk of radiation-induced thyroid cancer increased considerably in children and adolescents who were affected by the Chernobyl reactor accident. In spite of the fact, that thyroid cancers in young children seem to behave more aggressively than in older patients, the results of combined treatment with thyroidectomy, radioiodine therapy and thyroid hormone replacement are excellent.
Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer. Different radionuclides that emit β-rays such as 153Samarium and 89Strontium and achieve palliation are commercially available. In contrast to β-emitters, 223Radium as a α-emitter has a short path-length. The advantage of the α-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms. Due to the limited range of the α-particles the bone surface to red bone marrow dose ratio is also lower for 223Radium which is expressed in a lower myelotoxicity. The α emitter 223Radium dichloride is the first radiopharmaceutical that significantly prolongs life in castrate resistant prostate cancer patients with wide-spread bone metastatic disease. In a phase III, randomized, double-blind, placebo-controlled study 921 patients with castration-resistant prostate cancer and bone metastases were randomly assigned. The analysis confirmed the 223Radium survival benefit compared to the placebo (median, 14.9 mo vs 11.3 mo; P < 0.001). In addition, the treatment results in pain palliation and thus, improved quality of life and a delay of skeletal related events. At the same time the toxicity profile of 223Radium was favourable. Since May 2013, 223Radium dichloride (Xofigo®) is approved by the US Food and Drug Administration.
Core tip: The incidence rate of prostate cancer worldwide is high. Ninety percent of patients dying of prostate cancer have bone metastases with varying symptoms which are significantly impairing their quality of life. 223Radium is the first therapeutic that results in a survival benefit for patients with bone metastatic, castrate resistant prostate cancer. 223Radium was also associated with low myelosuppression rates and fewer adverse events.This article provides an overview of the pre-clinical and clinical trials with 223Radium.
Background
Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.
Methods
A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.
Results
Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging.
Conclusions
[\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.
[\(^{223}\)Ra]RaCl\(_2\) and [\(^{224}\)Ra]RaCl\(_2\) are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (\(^{223}\)Ra: ≈28 MeV, \(^{224}\)Ra: ≈26 MeV). [\(^{224}\)Ra]RaCl\(_2\) has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [\(^{224}\)Ra]RaCl\(_2\). In 2013 [\(^{223}\)Ra]RaCl\(_2\) obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (\(^{224}\)Ra:\(^{223}\)Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [\(^{224}\)Ra]RaCl\(_2\). Two epidemiological studies followed two patient groups treated with [\(^{224}\)Ra]RaCl\(_2\) for more than 25 years. One of them was the “Spiess study”, a cohort of 899 juvenile patients who received several injections of [\(^{224}\)Ra]RaCl\(_2\) with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [\(^{224}\)Ra]RaCl\(_2\), 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the “Wick study”. In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [\(^{223}\)Ra]RaCl\(_2\) as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [\(^{223}\)Ra]RaCl\(_2\).
Background
Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis.
Case presentation
We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment.
Conclusions
E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.
Background:
Irradiation with α-particles creates densely packed damage tracks along particle trajectories in exposed cells, including complex DNA damage and closely spaced double-strand breaks (DSBs) in hit nuclei. Here, we investigated the correlation of the absorbed dose to the blood and the number of α-induced DNA damage tracks elicited in human blood leukocytes after ex-vivo in-solution exposure with Ra-224. The aim was to compare the data to previously published data on Ra-223 and to investigate differences in DNA damage induction between the two radium isotopes.
Results:
Blood samples from three healthy volunteers were exposed ex-vivo to six different concentrations of Ra-224 dichloride. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the Ra-224 decay chain, ranging from 0 to 127 mGy. γ-H2AX + 53BP1 DNA damage co-staining and analysis was performed on ethanol-fixed leukocytes isolated from the irradiated blood samples. For damage quantification, α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci were enumerated in the exposed leukocytes. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values.
Conclusions:
Our data provide a first estimation of the DNA damage induced by Ra-224 in peripheral blood mononuclear cells. A comparison with our previously published Ra-223 data suggests that there is no difference in the induction of radiation-induced DNA damage between the two radium isotopes due to their similar decay properties.
In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C-11, Ga-68, and F-18 have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology.
C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM).
Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival.
ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive.
CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.
Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms.
Methods: Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [\(^{68}\)Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV\(_{max}\)) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [\(^{68}\)Ga]Pentixafor findings were further compared to immunohistochemistry and [\(^{18}\)F]FDG PET/CT.
Results: On [\(^{68}\)Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUVmax of 5.4 (range, 1.7–16.0) and a median TBR of 2.6 (range, 0.8–7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUVmax, 16.0; TBR, 7.4). The relatively low uptake on [\(^{68}\)Ga]Pentixafor was also noted in metastases, exhibiting a median SUVmax of 4.5 (range, 2.3–8.8; TBR, 1.7; range, 1.0–4.1). A good correlation between uptake on [\(^{68}\)Ga]Pentixafor and histological derived CXCR4 expression was noted (R = 0.62, P < 0.05). In the 3 patients in whom [\(^{18}\)F]FDG PET/CT was available, [\(^{68}\)Ga]Pentixafor exhibited lower uptake in all lesions.
Conclusions: In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [\(^{68}\)Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients.
We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.
Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy
(2021)
Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [\(^{123}\)I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical workup including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [\(^{123}\)I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [\(^{123}\)I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 +/- 0.63 vs. 2.91 +/- 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 +/- 0.51 vs. 2.74 +/- 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.
Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of \(^{68}\)Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and 68Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All \(^{68}\)Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7% vs. 72.6%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA (p < 0.01) and PSMA-derived tumor volume (p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.
AimIn PET imaging, the different types of radiotracers and accumulations, as well as the diversity of disease patterns, make the analysis of molecular imaging data acquired in vivo challenging. Here, we evaluate and validate a semi-automated MRI template-based data analysis tool that allows preclinical PET images to be aligned to a self-created PET template. Based on the user-defined volume-of-interest (VOI), image data can then be evaluated using three different semi-quantitative parameters: normalized activity, standardized uptake value, and uptake ratio.
Materials and MethodsThe nuclear medicine Data Processing Analysis tool (NU_DPA) was implemented in Matlab. Testing and validation of the tool was performed using two types of radiotracers in different kinds of stroke-related brain diseases in rat models. The radiotracers used are 2-[\(^{18}\)F]fluoro-2-deoxyglucose ([\(^{18}\)F]FDG), a metabol\(^{68}\)Ga]Ga-Fucoidan, a target-selective radioligand specifically binding to p-selectin. After manual image import, the NU_DPA tool automatically creates an averaged PET template out of the acquired PET images, to which all PET images are then aligned onto. The added MRI template-based information, resized to the lower PET resolution, defines the VOI and also allows a precise subdivision of the VOI into individual sub-regions. The aligned PET images can then be evaluated semi-quantitatively for all regions defined in the MRI atlas. In addition, a statistical analysis and evaluation of the semi-quantitative parameters can then be performed in the NU_DPA tool.
ResultsUsing ischemic stroke data in Wistar rats as an example, the statistical analysis of the tool should be demonstrated. In this [\(^{18}\)F]FDG-PET experiment, three different experimental states were compared: healthy control state, ischemic stroke without electrical stimulation, ischemic stroke with electrical stimulation. Thereby, statistical data evaluation using the NU_DPA tool showed that the glucose metabolism in a photothrombotic lesion can be influenced by electrical stimulation.
ConclusionOur NU_DPA tool allows a very flexible data evaluation of small animal PET data in vivo including statistical data evaluation. Using the radiotracers [\(^{18}\)F]FDG and [\(^{68}\)Ga]Ga-Fucoidan, it was shown that the semi-automatic MRI-template based data analysis of the NU_DPA tool is potentially suitable for both metabolic radiotracers as well as target-selective radiotracers.
Simple Summary
Discordant FDG-positive but PSMA-negative (FDG+/PSMA−) metastases constitute a negative prognostic marker of overall survival in patients undergoing PSMA radioligand therapy (RLT). The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA− lesions, which occur during or after PSMA RLT. In a retrospective bicentric analysis of 32 patients undergoing PSMA RLT and follow-up dual tracer staging with PSMA and FDG PET/CT, FDG+/PSMA− lesions occurred in a limited number of patients. However, the presence of FDG+/PSMA− lesions appears not to have a significant impact on the OS, but further studies are needed to establish the clinical relevance of such lesions.
Abstract
Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate-specific membrane antigen (PSMA) is crucial for the assessment of adequate PSMA expression in patients with metastatic castration-resistant prostate cancer (mCRPC) prior to PSMA radioligand therapy (PSMA RLT). Moreover, initial dual tracer staging using combined PSMA and [\(^{18}\)F]fluorodeoxyglucose (FDG) PET/CT provides relevant information, since discordant FDG-positive but PSMA-negative (FDG+/PSMA−) lesions constitute a negative prognostic marker of overall survival (OS) after PSMA RLT. However, little is known about the prognostic implications of dual tracer imaging for restaging at follow-up. The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA− lesions during or after PSMA RLT. Methods: This bicentric analysis included 32 patients with mCRPC who underwent both FDG and PSMA PET/CT imaging after two or four cycles of PSMA RLT. Patients with FDG+/PSMA− lesions prior to PSMA RLT were not considered. The presence of FDG+/PSMA− lesions was assessed with follow-up dual tracer imaging of patients after two or four cycles of PSMA RLT. Patients with at least one new FDG+/PSMA− lesion were compared to patients without any FDG+/PSMA− lesions at the respective time points. A log-rank analysis was used to assess the difference in OS between subgroups. Results: After two cycles of PSMA RLT, four of 32 patients (13%) had FDG+/PSMA− metastases. No significant difference in OS was observed (p = 0.807), as compared to patients without FDG+/PSMA− lesions. Follow-up dual tracer imaging after the 4th cycle of PSMA RLT was available in 18 patients. Of these, four patients presented with FDG+/PSMA− findings (n = 2 already after two cycles). After the fourth cycle of PSMA RLT, no significant difference in OS was observed between patients with and without FDG+/PSMA− lesions (p = 0.442). Conclusion: This study shows that FDG+/PSMA− lesions develop in a limited number of patients undergoing PSMA RLT. Further studies are needed to establish the clinical relevance of such lesions.
Background: Use of FDG-PET/CT for staging and restaging of lymphoma patients is widely incorporated into current practice guidelines. Our aim was to prospectively evaluate the diagnostic performance of FDG-PET/MRI and WB-DW-MRI compared with FDG-FDG-PET/CT using a tri-modality PET/CT-MRI system.
Methods: From 04/12 to 01/14, a total of 82 FDG-PET/CT examinations including an additional scientific MRI on a tri-modality setup were performed in 61 patients. FDG-PET/CT, FDG-PET/MRI, and WB-DW-MRI were independently analyzed. A lesion with a mean ADC below a threshold of 1.2 x 10\(^{-3}\) mm\(^2\)/s was defined as positive for restricted diffusion. FDG-PET/CT and FDG-PET/MRI were evaluated for the detection of lesions corresponding to lymphoma manifestations according to the German Hodgkin Study Group. Imaging findings were validated by biopsy (n = 21), by follow-up imaging comprising CT, FDG-PET/CT, and/or FDG-PET/MRI (n = 32), or clinically (n = 25) (mean follow-up: 9.1 months).
Results: FDG-PET/MRI and FDG-PET/CT accurately detected 188 lesions in 27 patients. Another 54 examinations in 35 patients were negative. WB-DW-MRI detected 524 lesions, of which 125 (66.5 % of the aforementioned 188 lesions) were true positive. Among the 188 lesions positive for lymphoma, FDG-PET/MRI detected all 170 instances of nodal disease and also all 18 extranodal lymphoma manifestations; by comparison, WB-DW-MRI characterized 115 (67.6 %) and 10 (55.6 %) lesions as positive for nodal and extranodal disease, respectively. FDG-PET/MRI was superior to WB-DW-MRI in detecting lymphoma manifestations in patients included for staging (113 vs. 73), for restaging (75 vs. 52), for evaluation of high-(127 vs. 81) and low-grade lymphomas (61 vs. 46), and for definition of Ann Arbor stage (WB-DW-MRI resulted in upstaging in 60 cases, including 45 patients free of disease, and downstaging in 4).
Conclusion: Our results indicate that FDG-PET/CT and FDG-PET/MRI probably have a similar performance in the clinical work-up of lymphomas. The performance of WB-DW-MRI was generally inferior to that of both FDG-PET-based methods but the technique might be used in specific scenarios, e.g., in low-grade lymphomas and during surveillance.
Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy
(2020)
[\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator #1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater #1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.
Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging
(2015)
Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [\(^{68}\)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [\(^{68}\)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [\(^{68}\)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [\(^{68}\)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.
Aim
The aim of this study was to provide a systematic approach to characterize DNA damage induction and repair in isolated peripheral blood mononuclear cells (PBMCs) after internal ex vivo irradiation with [\(^{131}\)I]NaI. In this approach, we tried to mimic ex vivo the irradiation of patient blood in the first hours after radioiodine therapy.
Material and methods
Blood of 33 patients of two centres was collected immediately before radioiodine therapy of differentiated thyroid cancer (DTC) and split into two samples. One sample served as non-irradiated control. The second sample was exposed to ionizing radiation by adding 1 ml of [\(^{131}\)I]NaI solution to 7 ml of blood, followed by incubation at 37 °C for 1 h. PBMCs of both samples were isolated, split in three parts each and (i) fixed in 70% ethanol and stored at − 20 °C directly (0 h) after irradiation, (ii) after 4 h and (iii) 24 h after irradiation and culture in RPMI medium. After immunofluorescence staining microscopically visible co-localizing γ-H2AX + 53BP1 foci were scored in 100 cells per sample as biomarkers for radiation-induced double-strand breaks (DSBs).
Results
Thirty-two of 33 blood samples could be analysed. The mean absorbed dose to the blood in all irradiated samples was 50.1 ± 2.3 mGy. For all time points (0 h, 4 h, 24 h), the average number of γ-H2AX + 53BP1 foci per cell was significantly different when compared to baseline and the other time points. The average number of radiation-induced foci (RIF) per cell after irradiation was 0.72 ± 0.16 at t = 0 h, 0.26 ± 0.09 at t = 4 h and 0.04 ± 0.09 at t = 24 h. A monoexponential fit of the mean values of the three time points provided a decay rate of 0.25 ± 0.05 h\(^{−1}\), which is in good agreement with data obtained from external irradiation with γ- or X-rays.
Conclusion
This study provides novel data about the ex vivo DSB repair in internally irradiated PBMCs of patients before radionuclide therapy. Our findings show, in a large patient sample, that efficient repair occurs after internal irradiation with 50 mGy absorbed dose, and that the induction and repair rate after \(^{131}\)I exposure is comparable to that of external irradiation with γ- or X-rays.
The aim was to investigate the induction and repair of radiation-induced DNA double-strand breaks (DSBs) as a function of the absorbed dose to the blood of patients undergoing PET/CT examinations with [68Ga]Ga-PSMA. Blood samples were collected from 15 patients before and at four time points after [68Ga]Ga-PSMA administration, both before and after the PET/CT scan. Absorbed doses to the blood were calculated. In addition, blood samples with/without contrast agent from five volunteers were irradiated ex vivo by CT while measuring the absorbed dose. Leukocytes were isolated, fixed, and stained for co-localizing γ-H2AX+53BP1 DSB foci that were enumerated manually. In vivo, a significant increase in γ-H2AX+53BP1 foci compared to baseline was observed at all time points after administration, although the absorbed dose to the blood by 68Ga was below 4 mGy. Ex vivo, the increase in radiation-induced foci depended on the absorbed dose and the presence of contrast agent, which could have caused a dose enhancement. The CT-dose contribution for the patients was estimated at about 12 mGy using the ex vivo calibration. The additional number of DSB foci induced by CT, however, was comparable to the one induced by 68Ga. The significantly increased foci numbers after [68Ga]Ga-PSMA administration may suggest a possible low-dose hypersensitivity.
DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223
(2018)
Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.
Simple Summary
Prostate cancer often relapses after initial radical prostatectomy, and salvage radiotherapy offers a second chance of cure for relapsed patients. Modern imaging techniques, especially prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), enable radiation oncologists to target radiotherapy at the involved sites of disease. In a group of patients, PSMA PET/CT imaging can detect a macroscopic local recurrence with or without locoregional lymph node metastasis. In these cases, an escalation of the radiotherapy dose is often considered for controlling the visible tumor mass. As the evidence for dose-escalated salvage radiotherapy for macroscopic recurrent prostate cancer after PSMA PET/CT imaging is still limited, we address this topic in the current analysis. We found that the outcome of patients with dose-escalated salvage radiotherapy for macroscopic prostate cancer recurrence is encouragingly favorable, while the toxicity is very limited.
Abstract
Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3–72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1–97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2–100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.
In 2006, 0.18 Mio pediatric nuclear medicine diagnostic exams were performed worldwide. However, for most of the radiopharmaceuticals used data on biokinetics and, as a consequence on dosimetry, are missing or have not been made publicly available. Therefore, most of the dosimetry assessments presented today for diagnostic agents in children and adolescents rely on the biokinetics data of adults. Even for one of the most common nuclear medicine exams for this patient group, renal scintigraphy with 99mTc-MAG3 for assessing renal function measured data on biokinetics is available only from a study performed on four children of different ages. In particular, renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a risk group with a higher probability of developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study is to reassess the dosimetry and the associated radiation risk for a larger number of infants undergoing 99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data.
Data were collected retrospectively from 34 patients younger than 20 months with normal (20 patients) and abnormal renal function (14 patients) undergoing 99mTc-MAG3 scans. The patient-specific organ activity was estimated based on a retrospective calibration which was performed based on a set of two 3D-printed infant kidneys (newborns: 8.6 ml; 1-year-old: 23.4 ml) filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old phantom. Based on absorbed dose values, the radiation risk estimation was performed individually for each of the 34 patients with the National Cancer Institute’s Radiation Risk Assessment Tool.
The patients’ organ-specific mean absorbed dose coefficients for the patients with normal renal function were 0.04±0.03 mGy/MBq for the kidneys and 0.27±0.24 mGy/MBq for the bladder. This resulted in a mean effective dose coefficient of 0.02±0.02 mSv/MBq. Based on the dosimetry results, the evaluation of the excess lifetime risk (ELR) for the development of radiation-induced cancer showed that the group of newborns has an ELR of 16.8 per 100,000 persons, which is higher in comparison with the 1-year-old group with an ELR of 14.7 per 100,000 persons. With regard to the 14 patients with abnormal renal function, the mean values for the organ absorbed dose coefficients for the patients were: 0.40±0.34 mGy/MBq for the kidneys and 0.46±0.37 mGy/MBq for the bladder. The corresponding effective dose coefficients (mSv/MBq) was: 0.05±0.02 mSv/MBq. The mean ELR (per 100,000 persons) for developing cancer from radiation exposure for patients with abnormal renal function was 29.2±18.7 per 100,000 persons.
As a result, the radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the 99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.
Furthermore, due to the increasing demand for PET-scans in children and adolescents with 68Ga-labelled peptides, in this work published data sets for those compounds were analyzed to derive recommendations for the administered activities in children and adolescents. The recommendation for the activities to be administered were based on the weight-independent effective dose model, proposed by the EANM Pediatric Dosage Card for application in pediatric nuclear medicine. The aim was to derive recommendations on administered activities for obtaining age-independent effective doses. Consequently, the corresponding weight-dependent effective dose coefficients were rescaled according to the formalism of the EANM dosage card, to determine the radiopharmaceutical class of 68Ga-labeled peptides (“multiples”), and to calculate the baseline activities based on the biokinetics of these compounds and an upper limit of the administered activity of 185 MBq for an adult. Analogous to 18F-fluoride, a minimum activity of 14 MBq is recommended. As a result, for those pediatric nuclear medicine applications involving 68Ga-labeled peptides, new values for the EANM dosage card were proposed and implemented based on the results derived in this work.
Overall, despite the low additional radiation-related cancer risk, all efforts should be undertaken to optimize administered activities in children and adolescents for obtaining sufficient diagnostic information with minimal associated radiation risk.
The EC Directive 2013/59/Euratom states in article 56 that exposures of target volumes in nuclear medicine treatments shall be individually planned and their delivery appropriately verified. The Directive also mentions that medical physics experts should always be appropriately involved in those treatments. Although it is obvious that, in nuclear medicine practice, every nuclear medicine physician and physicist should follow national rules and legislation, the EANM considered it necessary to provide guidance on how to interpret the Directive statements for nuclear medicine treatments.
For this purpose, the EANM proposes to distinguish three levels in compliance to the optimization principle in the directive, inspired by the indication of levels in prescribing, recording and reporting of absorbed doses after radiotherapy defined by the International Commission on Radiation Units and Measurements (ICRU):
Most nuclear medicine treatments currently applied in Europe are standardized. The minimum requirement for those treatments is ICRU level 1 (“activity-based prescription and patient-averaged dosimetry”), which is defined by administering the activity within 10% of the intended activity, typically according to the package insert or to the respective EANM guidelines, followed by verification of the therapy delivery, if applicable.
Non-standardized treatments are essentially those in developmental phase or approved radiopharmaceuticals being used off-label with significantly (> 25% more than in the label) higher activities. These treatments should comply with ICRU level 2 (“activity-based prescription and patient-specific dosimetry”), which implies recording and reporting of the absorbed dose to organs at risk and optionally the absorbed dose to treatment regions.
The EANM strongly encourages to foster research that eventually leads to treatment planning according to ICRU level 3 (“dosimetry-guided patient-specific prescription and verification”), whenever possible and relevant.
Evidence for superiority of therapy prescription on basis of patient-specific dosimetry has not been obtained. However, the authors believe that a better understanding of therapy dosimetry, i.e. how much and where the energy is delivered, and radiobiology, i.e. radiation-related processes in tissues, are keys to the long-term improvement of our treatments.
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
Background The precise definition of the post-operative resection status in high-grade gliomas (HGG) is crucial for further management. We aimed to assess the feasibility of assessment of the resection status with early post-operative positron emission tomography (PET) using [\(^{18}\)F]O-(2-[\(^{18}\)F]-fluoroethyl)-L-tyrosine ([\(^{18}\)F]FET). Methods 25 patients with the suspicion of primary HGG were enrolled. All patients underwent preoperative [\(^{18}\)F]FET-PET and magnetic resonance imaging (MRI). Intra-operatively, resection status was assessed using 5-aminolevulinic acid (5-ALA). Imaging was repeated within 72h after neurosurgery. Post-operative [\(^{18}\)F]FET-PET was compared with MRI, intra-operative assessment and clinical follow-up. Results [\(^{18}\)F]FET-PET, MRI and intra-operative assessment consistently revealed complete resection in 12/25 (48%) patients and incomplete resection in 6/25 cases (24%). In 7 patients, PET revealed discordant findings. One patient was re-resected. 3/7 experienced tumor recurrence, 3/7 died shortly after brain surgery. Conclusion Early assessment of the resection status in HGG with [\(^{18}\)F]FET-PET seems to be feasible.
As a scintigraphic approach evaluating cardiac nerve integrity, \(^{123}\)I-metaiodobenzylguanidine (123I-mIBG) has been recently Food and Drug Administration approved. A great deal of progress has been made by the prospective ADMIRE-HF trial, which primarily demonstrated the association of denervated myocardium assessed by \(^{123}\)I-mIBG and cardiac events. However, apart from risk stratification, myocardial nerve function evaluated by molecular imaging should also be expanded to other clinical contexts, in particular to guide the referring cardiologist in selecting appropriate candidates for specific therapeutic interventions. In the present issue of the Journal of Nuclear Cardiology, the use of 123I-mIBG for identifying cardiomyopathy patients, which would most likely not benefit from ICD due low risk of arrhythmias, is described. If we aim to deliver on the promise of cardiac innervation imaging as a powerful tool for risk stratification in a manner similar to nuclear oncology, studies such as the one reviewed here may imply an important step to lay the proper groundwork for a more widespread adoption in clinical practice.
Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is emerging as an important modality for imaging patients with prostate cancer (PCa). As with any imaging modality, indeterminate findings will arise. The PSMA reporting and data system (PSMA-RADS) version 1.0 codifies indeterminate soft tissue findings with the PSMA-RADS-3A moniker. We investigated the role of point-spread function (PSF) reconstructions on categorization of PSMA-RADS-3A lesions. Methods: This was a post hoc analysis of an institutional review board approved prospective trial. Around 60 min after the administration of 333 MBq (9 mCi) of PSMA-targeted \(^{18}\)F-DCFPyL, patients underwent PET/computed tomography (CT) acquisitions from the mid-thighs to the skull vertex. The PET data were reconstructed with and without PSF. Scans were categorized according to PSMA-RADS version 1.0, and all PSMA-RADS-3A lesions on non-PSF images were re-evaluated to determine if any could be re-categorized as PSMA-RADS-4. The maximum standardized uptake values (SUVs) of the lesions, mean SUVs of blood pool, and the ratios of those values were determined. Results: A total of 171 PSMA-RADS-3A lesions were identified in 30 patients for whom both PSF reconstructions and cross-sectional imaging follow-up were available. A total of 13/171 (7.6%) were re-categorized as PSMA-RADS-4 lesions with PSF reconstructions. A total of 112/171 (65.5%) were found on follow-up to be true positive for PCa, with all 13 of the re-categorized lesions being true positive on follow-up. The lesions that were re-categorized trended towards having higher SUV\(_{max}\)-lesion and SUV\(_{max}\)-lesion/SUV\(_{mean}\)-blood-pool metrics, although these relationships were not statistically significant. Conclusions: The use of PSF reconstructions for \(^{18}\)F-DCFPyL PET can allow the appropriate re-categorization of a small number of indeterminate PSMA-RADS-3A soft tissue lesions as more definitive PSMA-RADS-4 lesions. The routine use of PSF reconstructions for PSMA-targeted PET may be of value at those sites that utilize this technology.
The objective of this prospective observational controlled study was to evaluate potential effects and dose-response relationship of LT4 administration on BMD, parameters of bone and muscle strength, and biochemical variables of calcium homoeostasis and bone turnover.Ninety-seven men and pre-menopausal women after near total thyroidectomy and ¹³¹I remnant ablation for well-differentiated thyroid carcinoma or after strumectomy for non-toxic goitre were stratified by degree of TSH suppression and by gender in three subgroups: 28 men and 46 women on LT4 suppressive treatment and 23 women on LT4 replacement therapy. Patients were matched for age, gender and BMI to 89 healthy controls with a negative history of thyroid disease. Patients and controls were followed and studied for a mean time of 1.1±0.2 years. Peripheral volumetric total and trabecular BMD as well as bone strength (pQCT) were determined at the ultra-distal radius. Central areal BMD (DXA) was measured at the lumbar spine, left and right femoral neck as well as left and right total hip. Maximum grip strength (dynamometer) of the non-dominant forearm and serum markers of calcium and bone metabolism were assessed. BMD at the axial skeleton and muscle strength were not impaired by LT4 medication irrespective of gender, underlying diagnosis or treatment regimen. By contrast, a general trend of inversely affected total and trabecular BMD and of decreased bone strength was detected at the ultra-distal radius. Only in women on LT4 suppressive treatment, loss of total BMD at the ultra-distal radius reached a level of high significance. In women on LT4 replacement therapy, a significant decline of maximum grip strength appeared in comparison with female controls, while appendicular total and trabecular BMD as well as bone strength remained unchanged and did not differ from respective controls. In men on LT4 suppressive treatment, greater reduction of bone strength as compared to female thyroid cancer patients was marginally significant. Calcium balance was stable and serum concentrations of bone metabolism markers levelled off or rather decreased contradicting (high turnover) bone loss. The study did not reveal any dose-related differential influence of LT4 administration either on primary or secondary study endpoints in female patients. A gender-related difference of bone strength in response to LT4 suppressive treatment might not be excluded, as male thyroid cancer patients showed greater decline of bone strength despite unaffected peripheral BMD and muscle strength. In conclusion, there was only little evidence of adverse LT4 effects. For the most part, LT4 administration irrespective of degree of TSH suppression was not associated with low or accelerated loss of BMD at the peripheral and central skeleton and loss of bone and muscle strength, a finding also confirmed biochemically. The ultra-distal radius as a non-weight bearing skeletal site might be at risk for BMD reduction. According to the results, pre-menopausal women on LT4 suppressive therapy might be at risk of bone loss. The more complex approach of this study also took into account biomechanical qualities of bone material as well as structural and geometrical characteristics of bone architecture implying a causal muscle-bone interrelationship.
Purpose
Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse.
Methods
A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated.
Results
Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24-48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%.
Conclusion
These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.
In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole-body counts were collected at 2, 24, 72, and 120 h after I-131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I-131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th-hour uptake and time-integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion-based dosimetry.
Background: Sorbents have been shown to adsorb iodinated radiocontrast media. Objective: In this study we describe a simple method to compare various sorbents in terms of capacity to adsorb radiocontrast media. Methods: Iodixanol solution was injected into columns filled with three types of sorbent at filtration velocities of increasing magnitude. Two variables of interest – contrast removal rate and matched iodine retention (MIR) – were calculated to measure the adsorption efficiency and the mass of contrast iodine adsorbed versus sorbent used, respectively. Results: The highest contrast removal and MIR for Porapak Q, CST 401 and Amberlite XAD4 were 41, 38 and 16% (p = 0.22 and 0.0005 for comparisons between Porapak Q-CST 401 and CST 401-Amberlite XAD4) and 0.060, 0.055 and 0.024, respectively (p = 0.18 and 0.0008). Extrapolation to a clinical scenario may suggest that removal of 8 ml iodixanol could be achieved by masses of sorbents of 43, 47 and 107 g, respectively. Conclusion: In this study we set a benchmark for comparing the radiocontrast-adsorbing efficiency of polymer sorbents during first-pass experiments, using a readily available methodology.
Purpose
T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals.
Methods
A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal.
Results
The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz.
Conclusion
This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization.
Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has become commonly utilized in patients with prostate cancer (PCa). The PSMA reporting and data system version 1.0 (PSMA-RADS version 1.0) categorizes lesions on the basis of the likelihood of PCa involvement, with PSMA-RADS-3A (soft tissue) and PSMA-RADS-3B (bone) lesions being indeterminate for the presence of disease. We retrospectively reviewed the imaging follow-up of such lesions to determine the rate at which they underwent changes suggestive of underlying PCa.
Methods: PET/CT imaging with \(^{18}\)F-DCFPyL was carried out in 110 patients with PCa and lesions were categorized according to PSMA-RADS Version 1.0. 56/110 (50.9%) patients were determined to have indeterminate PSMA-RADS-3A or PSMA-RADS-3B lesions and 22/56 (39.3%) patients had adequate follow-up to be included in the analysis. The maximum standardized uptake values (SUV\(_{max}\)) of the lesions were obtained and the ratios of SUV\(_{max}\) of the lesions to SUV\(_{mean}\) of blood pool (SUV\(_{max}\)-lesion/SUV\(_{mean}\)-bloodpool) were calculated. Pre-determined criteria were used to evaluate the PSMA-RADS-3A and PSMA-RADS-3B lesions on follow-up imaging to determine if they demonstrated evidence of underlying malignancy.
Results: A total of 46 lesions in 22 patients were considered indeterminate for PCa (i.e. PSMA-RADS-3A (32 lesions) or PSMA-RADS-3B (14 lesions)) and were evaluable on follow-up imaging. 27/46 (58.7%) lesions demonstrated changes on follow-up imaging consistent with the presence of underlying PCa at baseline. These lesions included 24/32 (75.0%) PSMA-RADS-3A lesions and 3/14 (21.4%) lesions categorized as PSMA-RADS-3B. The ranges of SUVmax and SUVmax-lesion/SUVmean-bloodpool overlapped between those lesions demonstrating changes consistent with malignancy on follow-up imaging and those lesions that remained unchanged on follow-up.
Conclusion: PSMA-RADS-3A and PSMA-RADS-3B lesions are truly indeterminate in that proportions of findings in both categories demonstrate evidence of malignancy on follow-up imaging. Overall, PSMA-RADS-3A lesions are more likely than PSMA-RADS-3B lesions to represent sites of PCa and this information should be taken into when guiding patient therapy.
Purpose
The aim of this study was to compare the wave‐CAIPI (controlled aliasing in parallel imaging) trajectory to the Cartesian sampling for accelerated free‐breathing 4D lung MRI.
Methods
The wave‐CAIPI k‐space trajectory was implemented in a respiratory self‐gated 3D spoiled gradient echo pulse sequence. Trajectory correction applying the gradient system transfer function was used, and images were reconstructed using an iterative conjugate gradient SENSE (CG SENSE) algorithm. Five healthy volunteers and one patient with squamous cell carcinoma in the lung were examined on a clinical 3T scanner, using both sampling schemes. For quantitative comparison of wave‐CAIPI and standard Cartesian imaging, the normalized mutual information and the RMS error between retrospectively accelerated acquisitions and their respective references were calculated. The SNR ratios were investigated in a phantom study.
Results
The obtained normalized mutual information values indicate a lower information loss due to acceleration for the wave‐CAIPI approach. Average normalized mutual information values of the wave‐CAIPI acquisitions were 10% higher, compared with Cartesian sampling. Furthermore, the RMS error of the wave‐CAIPI technique was lower by 19% and the SNR was higher by 14%. Especially for short acquisition times (down to 1 minute), the undersampled Cartesian images showed an increased artifact level, compared with wave‐CAIPI.
Conclusion
The application of the wave‐CAIPI technique to 4D lung MRI reduces undersampling artifacts, in comparison to a Cartesian acquisition of the same scan time. The benefit of wave‐CAIPI sampling can therefore be traded for shorter examinations, or enhancing image quality of undersampled 4D lung acquisitions, keeping the scan time constant.
Background: Precise regional quantitative assessment of renal function is limited with conventional \(^{99m}\)Tc-labeled renal radiotracers. A recent study reported that the positron emission tomography (PET) radiotracer 2-deoxy-2-(\(^{18}\)F-fluorosorbitol (\(^{18}\)F-FDS) has ideal pharmacokinetics for functional renal imaging. Furthermore, (\(^{18}\)F-FDS is available via simple reduction from routinely used 2-deoxy-2-(\(^{18}\)F-fluoro-D-glucose ((\(^{18}\)F-FDG). We aimed to further investigate the potential of (\(^{18}\)F-FDS PET as a functional renal imaging agent using rat models of kidney diseases.
Methods: Two different rat models of renal impairment were investigated: Glycerol induced acute renal failure (ARF) by intramuscular administration of glycerol in hind legs and unilateral ureteral obstruction (UUO) by ligation of the left ureter. 24h after these treatments, dynamic 30 min 18F-FDS PET data were acquired using a dedicated small animal PET system. Urine 18F-FDS radioactivity 30 min after radiotracer injection was measured together with co-injected \(^{99m}\)Tc-diethylenetriaminepentaacetic acid (\(^{99m}\)Tc-DTPA) urine activity. Results: Dynamic PET imaging demonstrated rapid (\(^{18}\)F-FDS accumulation in the renal cortex and rapid radiotracer excretion via kidneys in control healthy rats. On the other hand, significantly delayed renal radiotracer uptake (continuous slow uptake) was observed in ARF rats and UUO-treated kidneys. Measured urine radiotracer concentrations of (\(^{18}\)F-FDS and \(^{99m}\)Tc-DTPA were well correlated (R=0.84, P<0.05).
Conclusions: (\(^{18}\)F-FDS PET demonstrated favorable kinetics for functional renal imaging in rat models of kidney diseases. Advantages of high spatiotemporal resolution of PET imaging and simple tracer production could potentially complement or replace conventional renal scintigraphy in select cases and significantly improve the diagnostic performance of renal functional imaging.
Gait Initiation in Parkinson’s Disease: Impact of Dopamine Depletion and Initial Stance Condition
(2020)
Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson’s disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment.
Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [\(^{68}\)Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [\(^{68}\)Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [\(^{68}\)Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [\(^{68}\)Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [\(^{68}\)Ga]KISS1-54 cell uptake amounted to 0.6–4.4% per 100,000 cells. Moreover, the accumulation of [\(^{68}\)Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [\(^{68}\)Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [\(^{68}\)Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.
Deep convolutional generative adversarial networks (GAN) allow for creating images from existing databases. We applied a modified light-weight GAN (FastGAN) algorithm to cerebral blood flow SPECTs and aimed to evaluate whether this technology can generate created images close to real patients. Investigating three anatomical levels (cerebellum, CER; basal ganglia, BG; cortex, COR), 551 normal (248 CER, 174 BG, 129 COR) and 387 pathological brain SPECTs using N-isopropyl p-I-123-iodoamphetamine (123I-IMP) were included. For the latter scans, cerebral ischemic disease comprised 291 uni- (66 CER, 116 BG, 109 COR) and 96 bilateral defect patterns (44 BG, 52 COR). Our model was trained using a three-compartment anatomical input (dataset ‘A’; including CER, BG, and COR), while for dataset ‘B’, only one anatomical region (COR) was included. Quantitative analyses provided mean counts (MC) and left/right (LR) hemisphere ratios, which were then compared to quantification from real images. For MC, ‘B’ was significantly different for normal and bilateral defect patterns (P < 0.0001, respectively), but not for unilateral ischemia (P = 0.77). Comparable results were recorded for LR, as normal and ischemia scans were significantly different relative to images acquired from real patients (P ≤ 0.01, respectively). Images provided by ‘A’, however, revealed comparable quantitative results when compared to real images, including normal (P = 0.8) and pathological scans (unilateral, P = 0.99; bilateral, P = 0.68) for MC. For LR, only uni- (P = 0.03), but not normal or bilateral defect scans (P ≥ 0.08) reached significance relative to images of real patients. With a minimum of only three anatomical compartments serving as stimuli, created cerebral SPECTs are indistinguishable to images from real patients. The applied FastGAN algorithm may allow to provide sufficient scan numbers in various clinical scenarios, e.g., for “data-hungry” deep learning technologies or in the context of orphan diseases.
Even as medical data sets become more publicly accessible, most are restricted to specific medical conditions. Thus, data collection for machine learning approaches remains challenging, and synthetic data augmentation, such as generative adversarial networks (GAN), may overcome this hurdle. In the present quality control study, deep convolutional GAN (DCGAN)-based human brain magnetic resonance (MR) images were validated by blinded radiologists. In total, 96 T1-weighted brain images from 30 healthy individuals and 33 patients with cerebrovascular accident were included. A training data set was generated from the T1-weighted images and DCGAN was applied to generate additional artificial brain images. The likelihood that images were DCGAN-created versus acquired was evaluated by 5 radiologists (2 neuroradiologists [NRs], vs 3 non-neuroradiologists [NNRs]) in a binary fashion to identify real vs created images. Images were selected randomly from the data set (variation of created images, 40%-60%). None of the investigated images was rated as unknown. Of the created images, the NRs rated 45% and 71% as real magnetic resonance imaging images (NNRs, 24%, 40%, and 44%). In contradistinction, 44% and 70% of the real images were rated as generated images by NRs (NNRs, 10%, 17%, and 27%). The accuracy for the NRs was 0.55 and 0.30 (NNRs, 0.83, 0.72, and 0.64). DCGAN-created brain MR images are similar enough to acquired MR images so as to be indistinguishable in some cases. Such an artificial intelligence algorithm may contribute to synthetic data augmentation for "data-hungry" technologies, such as supervised machine learning approaches, in various clinical applications.
Purpose
FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of \(^{68}\)Ga-FAPI versus standard-of-care \(^{18}\)F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers.
Material and Methods
This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ).
Results
A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. \(^{68}\)Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for \(^{68}\)Ga-FAPI than \(^{18}\)F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, \(^{68}\)Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases.
Conclusion
Quantitative tumor uptake is comparable between \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for \(^{68}\)Ga-FAPI. Thus, \(^{68}\)Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological \(^{18}\)F-FDG uptake.
This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6% at 5 years and 75.9% at 10 years. Local control (LC) at 5 and 10 years was 82.4% and 73.4%, respectively. Local recurrence was observed in 22 patients (18.5%). Higher grade acute and chronic toxicities were observed in seven patients (5.9%) and five patients (4.2%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.
PURPOSE:
To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis.
METHODS:
Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis.
RESULTS:
Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9\(\pm\)0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0\(\pm\)0.2% ID/g), control sham group+ simvastatin (1.2\(\pm\)0.3% ID/g) and control sham group (1.3\(\pm\)0.2% ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups.
CONCLUSIONS:
Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins.
(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.
The EANM 2015 Annual Congress, held from October 10th to 14th in Hamburg, Germany, was outstanding in many respects. With 5550 participants, this was by far the largest European congress concerning nuclear medicine. More than 1750 scientific presentations were submitted, with more than 250 abstracts from young scientists, indicating that the future success of our discipline is fuelled by a high number of young individuals becoming involved in a multitude of scientific activities. Significant improvements have been made in molecular imaging of cancer, particularly in prostate cancer. PSMA-directed PET/CT appears to become a new gold standard for staging and restaging purposes. Novel tumour specific compounds have shown their potential for target identification also in other solid neoplasms and further our understanding of tumour biology and heterogeneity. In addition, a variety of nuclear imaging techniques guiding surgical interventions have been introduced. A particular focus of the congress was put on targeted, radionuclide based therapies. Novel theranostic concepts addressing also tumour entities with high incidence rates such as prostate cancer, melanoma, and lymphoma, have shown effective anti-tumour activity. Strategies have been presented to improve further already established therapeutic regimens such as somatostatin receptor based radio receptor therapy for treating advanced neuroendocrine tumours. Significant contributions were presented also in the neurosciences track. An increasing number of target structures of high interest in neurology and psychiatry are now available for PET and SPECT imaging, facilitating specific imaging of different subtypes of dementia and movement disorders as well as neuroinflammation. Major contributions in the cardiovascular track focused on further optimization of cardiac perfusion imaging by reducing radiation exposure, reducing scanning time, and improving motion correction. Besides coronary artery disease, many contributions focused on cardiac inflammation, cardiac sarcoidosis, and specific imaging of large vessel vasculitis. The physics and instrumentation track included many highlights such as novel, high resolution scanners. The most noteworthy news and developments of this meeting were summarized in the highlights lecture. Only 55 scientific contributions were mentioned, and hence they represent only a brief summary, which is outlined in this article. For a more detailed view, all presentations can be accessed by the online version of the European Journal of Nuclear Medicine and Molecular Imaging (Volume 42, Supplement 1).
Background
Rhabdomyosarcoma is the most frequent malignant intraorbital tumour in paediatric patients. Differentiation of tumour recurrence or metastases from post-therapeutic signal alteration can be challenging, using standard MR imaging techniques. Diffusion-weighted MRI (DWI) is increasingly considered a helpful supplementary imaging tool for differentiation of orbital masses.
Case presentation
We report on a 15-year-old female adolescent of Caucasian ethnicity who developed isolated bilateral thickening of extraocular eye muscles about two years after successful multimodal treatment of orbital alveolar rhabdomyosarcoma. Intramuscular restricted diffusion was the first diagnostic indicator suggestive of metastatic disease to the eye muscles. DWI subsequently showed signal changes consistent with tumour progression, complete remission under chemoradiotherapy and tumour recurrence.
Conclusions
Restricted diffusivity is a strong early indicator of malignancy in orbital tumours. DWI can be the key to correct diagnosis in unusual tumour manifestations and can provide additional diagnostic information beyond standard MRI and PET/CT. Diffusion-weighted MRI is useful for monitoring therapy response and for detecting tumour recurrence.
Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future.
The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10–20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 “internal radiation therapy” of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3–5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.
The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell–Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a “critical distance” dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit—a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.
Background
The heart-to-mediastinum (H/M) ratio is a commonly used parameter to measure cardiac I-123 metaiodobenzylguanidine (MIBG) uptake. Since the H/M ratio is substantially influenced by the collimator type, we investigated whether an empirical linear conversion of H/M ratios between camera systems with low-energy (LE) and medium-energy (ME) collimator is possible.
Methods
We included 18 patients with parkinsonism who were referred to one of the two participating molecular imaging facilities for the evaluation of cardiac sympathetic innervation by MIBG scintigraphy. Two consecutive planar image datasets were acquired with LE and ME collimators at 4 h after MIBG administration. Linear regression analyses were performed to describe the association between the H/M ratios gained with both collimator settings, and the accuracy of a linear transfer of the H/M ratio between collimators and across centers was assessed using a leave-one-out procedure.
Results
H/M ratios acquired with LE and ME collimators showed a strong linear relationship both within each imaging facility (R\(^2\) = 0.99, p < 0.001 and R\(^2\) = 0.90, p < 0.001) and across centers (H/M-LE = 0.41 × H/M-ME + 0.63, R\(^2\) = 0.97, p < 0.001). A linear conversion of H/M ratios between collimators and across centers was estimated to be very accurate (mean absolute error 0.05 ± 0.04; mean relative absolute error 3.2 ± 2.6%).
Conclusions
The present study demonstrates that a simple linear conversion of H/M ratios acquired with different collimators is possible with high accuracy. This should greatly facilitate the exchange of normative data between settings and pooling of data from different institutions.
C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.
Background
Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced \(^{68}\)Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning.
Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent \(^{68}\)Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of \(^{68}\)Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity.
Results
Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months.
Conclusions
\(^{68}\)Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.
Background: \(^{123}\)I-metaiodobenzylguanidine (mIBG) provides independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not impact its quantitative information. We aimed to evaluate the four most-prescribed antidepressants currently used as a first‑line treatment for patients with major depressive disorder (MDD) and their potential on altering mIBG imaging results.
Methods: The inhibition effect of four different types of antidepressants (desipramine, escitalopram, venlafaxine and bupropion) for MDD treatment on \(^{131}\)I-mIBG uptake was assessed by in-vitro cell uptake assays using human neuroblastoma SK-N-SH cells. The half maximal inhibitory concentration (IC50) of tracer uptake was determined from dose-response curves. To evaluate the effects of IV pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5, 15 mg/kg) on mIBG cardiac uptake, in-vivo planar 123I-mIBG scans in healthy New Zealand White Rabbits were conducted. Results: The IC50 values of desipramine, escitalopram, venlafaxine and bupropion on \(^{131}\)I-mIBG cellular uptake were 11.9 nM, 7.5 μM, 4.92 μM, and 12.9 μM, respectively. At the maximum serum concentration (Cmax, as derived by previous clinical trials), the inhibition rates of 131I-mIBG uptake were 90.6 % for desipramine, 25.5 % for venlafaxine, 11.7 % for bupropion and 0.72 % for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in-vivo rabbit model: with dosage considerably higher than clinical practice, the non-inhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine led to a marked reduction of cardiac 123I-mIBG uptake.
Conclusions: In the present in-vitro binding assay and in-vivo rabbit study, the selective-serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac mIBG uptake within therapeutic dose ranges, while other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac mIBG imaging, in particular, if the patient’s neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine interfering antidepressant.
Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma
(2020)
Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=−0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
Purpose: As has been previously reported, the somatostatin receptor (SSTR) imaging agent [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotate ([\(^{68}\)Ga]DOTATATE) demonstrates lower uptake in normal organs in patients with a high neuroendocrine tumor (NET) burden. Given the higher SSTR affinity of [\(^{68}\)Ga]DOTATATE, we aimed to quantitatively investigate the biodistribution of [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ([68Ga]DOTATOC) to determine a potential correlation between uptake in normal organs and NET burden.
Procedures: Of the 44 included patients, 36/44 (82%) patients demonstrated suspicious radiotracer uptake on [\(^{68}\)Ga]DOTATOC positron emission tomography (PET)/x-ray computed tomography (CT). Volumes of Interest (VOIs) were defined for tumor lesions and normal organs (spleen, liver, kidneys, adrenals). Mean body weight corrected standardized uptake value (SUV\(_{mean}\)) for normal organs was assessed and was used to calculate the corresponding mean specific activity uptake (Upt: fraction of injected activity per kg of tissue). For the entire tumor burden, SUV\(_{mean}\), maximum standardized uptake value (SUV\(_{max}\)), and the total mass (TBM) was calculated and the decay corrected tumor fractional uptake (TBU) was assessed. A Spearman’s rank correlation coefficient was used to determine the correlations between normal organ uptake and tumor burden.
Results: The median SUV\(_{mean}\) was 18.7 for the spleen (kidneys, 9.2; adrenals, 6.8; liver, 5.6). For tumor burden, the median values were SUV\(_{mean}\) 6.9, SUV\(_{max}\) 35.5, TBM 42.6g, and TBU 1.2%. With increasing volume of distribution, represented by lean body mass and body surface area (BSA), Upt decreased in kidneys, liver, and adrenal glands and SUV\(_{mean}\) increased in the spleen. Correlation improved only for both kidneys and adrenals when the influence of the tumor uptake on the activity available for organ uptake was taken into account by the factor 1/(1-TBU). TBU was neither predictive for SUV\(_{mean}\) nor for Upt in any of the organs. The distribution of organ Upt vs. BSA/(1-TBU) were not different for patients with minor TBU (<3%) vs. higher TBU (>7%), indicating that the correlations observed in the present study are explainable by the body size effect. High tumor mass and uptake mitigated against G1 NET.
Conclusions: There is no significant impact on normal organ biodistribution with increasing tumor burden on [\(^{68}\)Ga]DOTATOC PET/CT. Potential implications include increased normal organ dose with [\(^{177}\)Lu-DOTA]\(^0\)-D-Phe\(^1\)-Tyr\(^3\)-Octreotide and decreased absolute lesion detection with [\(^{68}\)Ga]DOTATOC in high NET burden.