Synthesis and preclinical evaluation of BOLD-100 radiolabeled with ruthenium-97 and ruthenium-103.

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; ß-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.

Error mitigation enables PET radiomic cancer characterization on quantum computers.

BACKGROUND: Cancer is a leading cause of death worldwide. While routine diagnosis of cancer is performed mainly with biopsy sampling, it is suboptimal to accurately characterize tumor heterogeneity. Positron emission tomography (PET)-driven radiomic research has demonstrated promising results when predicting clinical endpoints. This study aimed to investigate the added value of quantum machine learning both in simulator and in real quantum computers utilizing error mitigation techniques to predict clinical endpoints in various PET cancer patients. METHODS: Previously published PET radiomics datasets including 11C-MET PET glioma, 68GA-PSMA-11 PET prostate and lung 18F-FDG PET with 3-year survival, low-vs-high Gleason risk and 2-year survival as clinical endpoints respectively were utilized in this study. Redundancy reduction with 0.7, 0.8, and 0.9 Spearman rank thresholds (SRT), followed by selecting 8 and 16 features from all cohorts, was performed, resulting in 18 dataset variants. Quantum advantage was estimated by Geometric Difference (GDQ) score in each dataset variant. Five classic machine learning (CML) and their quantum versions (QML) were trained and tested in simulator environments across the dataset variants. Quantum circuit optimization and error mitigation were performed, followed by training and testing selected QML methods on the 21-qubit IonQ Aria quantum computer. Predictive performances were estimated by test balanced accuracy (BACC) values. RESULTS: On average, QML outperformed CML in simulator environments with 16-features (BACC 70% and 69%, respectively), while with 8-features, CML outperformed QML with + 1%. The highest average QML advantage was + 4%. The GDQ scores were ≤ 1.0 in all the 8-feature cases, while they were > 1.0 when QML outperformed CML in 9 out of 11 cases. The test BACC of selected QML methods and datasets in the IonQ device without error mitigation (EM) were 69.94% BACC, while EM increased test BACC to 75.66% (76.77% in noiseless simulators). CONCLUSIONS: We demonstrated that with error mitigation, quantum advantage can be achieved in real existing quantum computers when predicting clinical endpoints in clinically relevant PET cancer cohorts. Quantum advantage can already be achieved in simulator environments in these cohorts when relying on QML.

SPECT and PET myocardial perfusion imaging in Austria, Germany, and Switzerland results of the first joint survey of 2021.

PURPOSE: This paper presents the results of the first joint survey on the use of SPECT and PET myocardial perfusion imaging (MPI) and cardiac amyloidosis imaging in Austria, Germany, and Switzerland of the year 2021. METHODS: A questionnaire was sent in 2022 to centres practicing nuclear medicine. RESULTS: Data from 14 Austrian (10,710 SPECT), 218 German (133,047 SPECT), and 16 Swiss centres (11,601 MPI (6,879 SPECT, 4722 PET)) were analysed. In Austria and Germany, the PET MPI numbers were close to zero and not considered. Official MPS numbers from 2015 to 2021 from Austria and Germany revealed a decline in Austria by about 40% in the pandemic years 2020 to 2021, but an increase in Germany by 9%. Ambulatory care cardiologists represented the major referral group (56-71%). Mostly, stress tests were performed pharmacologically (58-92%). Contrary to Germany, a 1-day protocol was predominant (58-97%) in Austria and Switzerland. The leading camera systems were SPECT-CT in Austria and Switzerland (57-79%) and multi-head systems in Germany (58%). Switzerland had the highest proportion of SPECT MPI with attenuation correction (84%), followed by Austria (43%), and Germany (33%). Electrocardiogram-gated SPECT MPI showed an overall high penetration of 87-99%. Scoring was most frequently applied in Germany (72%), followed by Austria (64%), and Switzerland (60%). Related to the population, the number of cardiac amyloidosis imaging was highest in Austria, followed by Switzerland and Germany. CONCLUSIONS: This first joint survey of 2021 shows considerable differences among the countries. The Swiss situation is outstanding due to the wide use of PET MPI. In terms of camera equipment, Switzerland is also leading, followed by Austria and Germany. Despite the differences in procedural issues, the results reveal an overall high standard of MPI imaging.

Machine learning predictive performance evaluation of conventional and fuzzy radiomics in clinical cancer imaging cohorts.

BACKGROUND: Hybrid imaging became an instrumental part of medical imaging, particularly cancer imaging processes in clinical routine. To date, several radiomic and machine learning studies investigated the feasibility of in vivo tumor characterization with variable outcomes. This study aims to investigate the effect of recently proposed fuzzy radiomics and compare its predictive performance to conventional radiomics in cancer imaging cohorts. In addition, lesion vs. lesion+surrounding fuzzy and conventional radiomic analysis was conducted. METHODS: Previously published 11C Methionine (MET) positron emission tomography (PET) glioma, 18F-FDG PET/computed tomography (CT) lung, and 68GA-PSMA-11 PET/magneto-resonance imaging (MRI) prostate cancer retrospective cohorts were included in the analysis to predict their respective clinical endpoints. Four delineation methods including manually defined reference binary (Ref-B), its smoothed, fuzzified version (Ref-F), as well as extended binary (Ext-B) and its fuzzified version (Ext-F) were incorporated to extract imaging biomarker standardization initiative (IBSI)-conform radiomic features from each cohort. Machine learning for the four delineation approaches was performed utilizing a Monte Carlo cross-validation scheme to estimate the predictive performance of the four delineation methods. RESULTS: Reference fuzzy (Ref-F) delineation outperformed its binary delineation (Ref-B) counterpart in all cohorts within a volume range of 938-354987 mm3 with relative cross-validation area under the receiver operator characteristics curve (AUC) of +4.7-10.4. Compared to Ref-B, the highest AUC performance difference was observed by the Ref-F delineation in the glioma cohort (Ref-F: 0.74 vs. Ref-B: 0.70) and in the prostate cohort by Ref-F and Ext-F (Ref-F: 0.84, Ext-F: 0.86 vs. Ref-B: 0.80). In addition, fuzzy radiomics decreased feature redundancy by approx. 20%. CONCLUSIONS: Fuzzy radiomics has the potential to increase predictive performance particularly in small lesion sizes compared to conventional binary radiomics in PET. We hypothesize that this effect is due to the ability of fuzzy radiomics to model partial volume effects and delineation uncertainties at small lesion boundaries. In addition, we consider that the lower redundancy of fuzzy radiomic features supports the identification of imaging biomarkers in future studies. Future studies shall consider systematically analyzing lesions and their surroundings with fuzzy and binary radiomics.

AI-enhanced simultaneous multiparametric 18F-FDG PET/MRI for accurate breast cancer diagnosis.

PURPOSE: To assess whether a radiomics and machine learning (ML) model combining quantitative parameters and radiomics features extracted from simultaneous multiparametric 18F-FDG PET/MRI can discriminate between benign and malignant breast lesions. METHODS: A population of 102 patients with 120 breast lesions (101 malignant and 19 benign) detected on ultrasound and/or mammography was prospectively enrolled. All patients underwent hybrid 18F-FDG PET/MRI for diagnostic purposes. Quantitative parameters were extracted from DCE (MTT, VD, PF), DW (mean ADC of breast lesions and contralateral breast parenchyma), PET (SUVmax, SUVmean, and SUVminimum of breast lesions, as well as SUVmean of the contralateral breast parenchyma), and T2-weighted images. Radiomics features were extracted from DCE, T2-weighted, ADC, and PET images. Different diagnostic models were developed using a fine Gaussian support vector machine algorithm which explored different combinations of quantitative parameters and radiomics features to obtain the highest accuracy in discriminating between benign and malignant breast lesions using fivefold cross-validation. The performance of the best radiomics and ML model was compared with that of expert reader review using McNemar's test. RESULTS: Eight radiomics models were developed. The integrated model combining MTT and ADC with radiomics features extracted from PET and ADC images obtained the highest accuracy for breast cancer diagnosis (AUC 0.983), although its accuracy was not significantly higher than that of expert reader review (AUC 0.868) (p = 0.508). CONCLUSION: A radiomics and ML model combining quantitative parameters and radiomics features extracted from simultaneous multiparametric 18F-FDG PET/MRI images can accurately discriminate between benign and malignant breast lesions.

Prognostic value of divergent pattern detection by 99mTc-sestamibi gated SPECT in patients with anterior acute myocardial infarction.

PURPOSE: In gated myocardial perfusion SPECT, apical remodeling may be identified by the presence of a divergent pattern (DP) of the left ventricle (LV). METHODS AND RESULTS: We examined 150 anterior ST-elevation myocardial infarction (STEMI) patients, all successfully treated with primary percutaneous coronary interventions (PCI). Perfusion gated-SPECT to measure infarct size, LV end-diastolic (ED) and end-systolic (ES) volumes and ejection fraction (EF) was acquired before hospital discharge and repeated at 6-month follow-up. DP was observed in 26 patients, who had larger infarct size (28 ± 19% vs. 15.7 ± 17%, P < 0.02), and lower EF (33 ± 7% vs. 41 ± 10%, P < 0.001) than patients without DP. At follow-up, DP patients had significantly larger EDV (156 ± 54 vs. 107 ± 44 mL, P < 0.0001), ESV (104 ± 47 vs. 59 ± 36 mL, P < 0.0001) and lower EF (35 ± 12% vs. 48 ± 13%, P < 0.0001). 54% of DP patients developed remodeling at follow-up vs. 12% of those without DP (P < 0.001). During follow up, 7 events in the DP group (27%) and 11 events in patients without DP (9%; P < 0.02) occurred. Kaplan-Meier survival curves showed a worse prognosis for DP patients. CONCLUSION: In patients with anterior AMI, early DP detection is related to subsequent LV dysfunction, larger infarct size, and worse severity. It is helpful for predicting LV remodeling at short-term follow-up and has prognostic implications.

Disrupted relationship between blood glucose and brain dopamine D2/3 receptor binding in patients with first-episode schizophrenia.

An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Persistence and clearance of high-risk human papillomavirus and cervical dysplasia at 1 year in women living with human immunodeficiency virus: a prospective cohort study.

OBJECTIVE: Evaluate 1-year outcomes of cervical cancer screening and treatment using primary high-risk human papillomavirus (HPV) testing in women living with human immunodeficiency virus (HIV). DESIGN: Prospective cohort study. SETTING: HIV treatment centre in Botswana. POPULATION: Women living with HIV. METHODS: Participants underwent cervical cancer screening with high-risk HPV testing and triage evaluation at baseline and 1-year follow up. Excisional treatment was offered as indicated. Histopathology was the reference standard. MAIN OUTCOME MEASURES: Persistence, clearance and incidence of high-risk HPV infection; and persistence, progression, regression, cure and incidence of cervical dysplasia. RESULTS: Among 300 women screened at baseline, 237 attended follow up (79%). High-risk HPV positivity significantly decreased from 28% at baseline to 20% at 1 year (P = 0.02). High-risk HPV persistence was 46% and clearance was 54%; incidence was high at 9%. Prevalence of cervical intraepithelial neoplasia Grade 2 (CIN2) or higher was most common in participants with incident high-risk HPV (53%). CIN2 or higher was also common in those with persistent high-risk HPV (32%) and even in those who cleared high-risk HPV (30%). Of the high-risk HPV-positive participants at baseline with

Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [68Ga]Ga-PSMA-11 PET/MRI.

PURPOSE: Risk classification of primary prostate cancer in clinical routine is mainly based on prostate-specific antigen (PSA) levels, Gleason scores from biopsy samples, and tumor-nodes-metastasis (TNM) staging. This study aimed to investigate the diagnostic performance of positron emission tomography/magnetic resonance imaging (PET/MRI) in vivo models for predicting low-vs-high lesion risk (LH) as well as biochemical recurrence (BCR) and overall patient risk (OPR) with machine learning. METHODS: Fifty-two patients who underwent multi-parametric dual-tracer [18F]FMC and [68Ga]Ga-PSMA-11 PET/MRI as well as radical prostatectomy between 2014 and 2015 were included as part of a single-center pilot to a randomized prospective trial (NCT02659527). Radiomics in combination with ensemble machine learning was applied including the [68Ga]Ga-PSMA-11 PET, the apparent diffusion coefficient, and the transverse relaxation time-weighted MRI scans of each patient to establish a low-vs-high risk lesion prediction model (MLH). Furthermore, MBCR and MOPR predictive model schemes were built by combining MLH, PSA, and clinical stage values of patients. Performance evaluation of the established models was performed with 1000-fold Monte Carlo (MC) cross-validation. Results were additionally compared to conventional [68Ga]Ga-PSMA-11 standardized uptake value (SUV) analyses. RESULTS: The area under the receiver operator characteristic curve (AUC) of the MLH model (0.86) was higher than the AUC of the [68Ga]Ga-PSMA-11 SUVmax analysis (0.80). MC cross-validation revealed 89% and 91% accuracies with 0.90 and 0.94 AUCs for the MBCR and MOPR models respectively, while standard routine analysis based on PSA, biopsy Gleason score, and TNM staging resulted in 69% and 70% accuracies to predict BCR and OPR respectively. CONCLUSION: Our results demonstrate the potential to enhance risk classification in primary prostate cancer patients built on PET/MRI radiomics and machine learning without biopsy sampling.

Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity-impulsivity symptoms in ADHD measured with PET.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a robust genetic influence. The norepinephrine transporter (NET) is of particular interest as it is one of the main targets in treatment of the disorder. As ADHD is a complex and polygenetic condition, the possible regulation by epigenetic processes has received increased attention. We sought to determine possible differences in NET promoter DNA methylation between patients with ADHD and healthy controls. DNA methylation levels in the promoter region of the NET were determined in 23 adult patients with ADHD and 23 healthy controls. A subgroup of 18 patients with ADHD and 18 healthy controls underwent positron emission tomography (PET) with the radioligand (S,S)-[18F]FMeNER-D2 to quantify the NET in several brain areas in vivo. Analyses revealed significant differences in NET methylation levels at several cytosine-phosphate-guanine (CpG) sites between groups. A defined segment of the NET promoter ("region 1") was hypermethylated in patients in comparison with controls. In ADHD patients, a negative correlation between methylation of a CpG site in this region and NET distribution in the thalamus, locus coeruleus, and the raphe nuclei was detected. Furthermore, methylation of several sites in region 1 was negatively associated with the severity of hyperactivity-impulsivity symptoms. Our results point to an epigenetic dysregulation in ADHD, possibly due to a compensatory mechanisms or additional factors involved in transcriptional processing.

Scavenging of Dickkopf-1 by macromer-based biomaterials covalently decorated with sulfated hyaluronan displays pro-osteogenic effects.

Dickkopf-1 (DKK1), a Wnt inhibitor secreted by bone marrow stromal cells (MSC), is known to play an important role in long-term non-union bone fracture defects and glucocorticoid induced osteoporosis. Mitigating its effects in early bone defects could improve osteogenesis and bone defect healing. Here, we applied a biomaterial strategy to deplete a defect environment from DKK1 by scavenging the protein via a macromer-based biomaterial covalently decorated with sulfated hyaluronan (sHA3). The material consisted of cross-copolymerized three-armed macromers with a small anchor molecule. Using the glycidyl anchor, polyetheramine (ED900) could be grafted to the material to which sHA3 was efficiently coupled in a separate step. For thorough investigation of material modification, flat material surfaces were generated by fabricating them on glass discs. The binding capability of sHA3 for DKK1 was demonstrated in this study by surface plasmon resonance measurements. Furthermore, the surfaces demonstrated the ability to scavenge and inactivate pathologic amounts of DKK1 from complex media. In a combinatory approach with Wnt3a, we were able to demonstrate that DKK1 is the preferred binding partner of our sHA3-functionalized surfaces. We validated our findings in a complex in vitro setting of differentiating SaOS-2 cells and primary hMSC. Here, endogenous DKK-1 was scavenged resulting in increased osteogenic differentiation indicating that this is a consistent biological effect irrespective of the model system used. Our study provides insights in the mechanisms and efficiency of sHA3 surface functionalization for DKK1 scavenging, which may be used in a clinical context in the future.

Correction to: Nuclear medicine services after COVID-19: gearing up back to normality.

The authors P. Orellana and N. El-Haj were inadvertently deleted in the original paper.

Machine learning classification of ADHD and HC by multimodal serotonergic data.

Serotonin neurotransmission may impact the etiology and pathology of attention-deficit and hyperactivity disorder (ADHD), partly mediated through single nucleotide polymorphisms (SNPs). We propose a multivariate, genetic and positron emission tomography (PET) imaging classification model for ADHD and healthy controls (HC). Sixteen patients with ADHD and 22 HC were scanned by PET to measure serotonin transporter (SERT') binding potential with [11C]DASB. All subjects were genotyped for thirty SNPs within the HTR1A, HTR1B, HTR2A and TPH2 genes. Cortical and subcortical regions of interest (ROI) were defined and random forest (RF) machine learning was used for feature selection and classification in a five-fold cross-validation model with ten repeats. Variable selection highlighted the ROI posterior cingulate gyrus, cuneus, precuneus, pre-, para- and postcentral gyri as well as the SNPs HTR2A rs1328684 and rs6311 and HTR1B rs130058 as most discriminative between ADHD and HC status. The mean accuracy for the validation sets across repeats was 0.82 (±0.09) with balanced sensitivity and specificity of 0.75 and 0.86, respectively. With a prediction accuracy above 0.8, the findings underlying the proposed model advocate the relevance of the SERT as well as the HTR1B and HTR2A genes in ADHD and hint towards disease-specific effects. Regarding the high rates of comorbidities and difficult differential diagnosis especially for ADHD, a reliable computer-aided diagnostic tool for disorders anchored in the serotonergic system will support clinical decisions.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Sex-differences in [68Ga]Ga-DOTANOC biodistribution.

INTRODUCTION: Still little is known about factors, influencing the organ uptake of somatostatin receptor (SSTR)-targeting radiopharmaceuticals. The aim of this study was to assess the influence of gender on [68Ga]Ga-DOTANOC uptake. Further on, we assessed other factors such as diabetes, proton pump inhibitors (PPIs) and oral antidiabetics (OADs). METHODS: In 118 studies of patients with a [68Ga]Ga-DOTANOC PET/CT (m = 60, f = 58; mean age: 61 ±â€¯15 yrs) SUVmax and SUVmean of the stomach, liver, spleen, kidneys, adrenal glands, and pancreas were assessed. Patients with history of splenectomy and significant tumor burden were excluded. Additionally, clinical information (gender, diabetes, age, pre-medications such as PPIs, OADs and somatostatin analogues (SSAs), were collected. RESULTS: [68Ga]Ga-DOTANOC uptake proved to be significantly lower in female patients compared to males for the SUVmax of the stomach (7.1, 9.1; P = 0.04), liver (8.3, 9.4; P = 0.0007), adrenal glands (15.9, 19.9; P = 0.05) kidneys (20.3, 18.9; P = 0.05) and the SUVmean of the pancreatic tail (2.9, 3.2; P = 0.03) and the kidneys (11.8, 10.6, P = 0.004). Additionally, patients with diabetes and below the age of 50 yrs. showed significantly higher SUVmax and SUVmean values of the stomach (diabetes: 9.1, 7.8; P = 0.01 and 6.0, 5.3; P = 0.004; age: 6.3, 8.3; P = 0.01 and 4.4, 5.5; P = 0.03). In contrast, intake of PPIs only affected the SUVmean of the liver (11.0, 9.0; P = 0.005), whereas OADs caused higher SUVmax values in the stomach (10.0, 7.8; P = 0.02), spleen (42.5, 32.6; P = 0.0005) adrenal glands (25.0, 16.9; P = 0.0003) and also higher SUVmean in the spleen (26.1, 21.4; P = 0.002) and adrenal glands (14.8, 12.4; P = 0.02). CONCLUSION: Factors such as gender, diabetes and age influence [68Ga]Ga-DOTANOC uptake, whereas ongoing medications such as PPIs and OADs exerted less influence.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

Preclinical In Vitro and In Vivo Evaluation of [18F]FE@SUPPY for Cancer PET Imaging: Limitations of a Xenograft Model for Colorectal Cancer.

Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of [18F]FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of [18F]FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of [18F]FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of [18F]FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using [18F]FE@SUPPY.

The patterns of in vitro cell-death and inflammatory cytokines induced by distinct BCG vaccine strains are differentially induced in human mononuclear cells.

Tuberculosis (TB) remains among the world's leading cause of mortality. For its control, studies of TB vaccines are needed. Since live-attenuated Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only TB vaccine currently in use, studies on the protective role of BCG are required. In this study, we analyzed host cells purified directly from whole blood of human immunodeficiency virus (HIV)-negative volunteers, comprising adult healthy donors (HD) and neonates (umbilical cord bloods, UCB), with the aim to directly compare in vitro immune responses with distinct BCG strains in human mononuclear cells. The Moreau, Pasteur, and Danish BCG strains were used to infect mononuclear cells in vitro for 48 h; bacilli viability and cell-death were subsequently detected by flow cytometry. In addition, cell culture supernatants were used in cytokine detection assays. Overall, the Moreau BCG strain induced higher levels of apoptosis than the Pasteur and Danish BCG strains in both the HD and UCB groups (p-value < 0.05), and a human monocytic cell-line mirrored those cell-death patterns after BCG infection. The Moreau BCG strain, exclusively, induced Th1 cytokines at the highest levels in cells from adults (p-value < 0.05) when compared with both Pasteur and Danish BCG strains, whereas TGF-ß1 levels were reduced significantly (p-value < 0.01) in the HD group when cells were infected with the Moreau BCG vaccine. As expected, eight out of 22 pro-inflammatory cytokines were secreted at significant levels (p-value < 0.05) above the baseline rates in all BCG-infected cell cultures, in the HD group only. When analyzing these results, we excluded confounding factors related to storage and viability of the BCG strains used. These findings suggest that Moreau BCG is a more potent immunostimulating agent than the Pasteur and Danish BCG strains. Clinical trials will be needed to confirm these findings.