Diagnostic Positron Emission Tomography Research Articles

Refined Chelator Spacer Moieties Ameliorate the Pharmacokinetics of PSMA-617.

Prostate-specific membrane antigen (PSMA) binding tracers are promising agents for the targeting of prostate tumors. To further optimize the clinically established radiopharmaceutical PSMA-617, novel PSMA ligands for prostate cancer endoradiotherapy were developed. A series of PSMA binding tracers that comprise a benzyl group at the chelator moiety were obtained by solid-phase synthesis. The compounds were labeled with 68Ga or 177Lu. Competitive cell-binding assays and internalization assays were performed using the cell line C4-2, a subline of the PSMA positive cell line LNCaP (human lymph node carcinoma of the prostate). Positron emission tomography (PET) imaging and biodistribution studies were conducted in a C4-2 tumor bearing BALB/c nu/nu mouse model. All 68Ga-labeled ligands were stable in human serum over 2 h; 177Lu-CA030 was stable over 72 h. The PSMA ligands revealed inhibition potencies [Ki] (equilibrium inhibition constants) between 4.8 and 33.8 nM. The percentage of internalization of the injected activity/106 cells of 68Ga-CA028, 68Ga-CA029, and 68Ga-CA030 was 41.2 ± 2.7, 44.3 ± 3.9, and 53.8 ± 5.4, respectively; for the comparator 68Ga-PSMA-617, 15.5 ± 3.1 was determined. Small animal PET imaging of the compounds showed a high tumor-to-background contrast. Organ distribution studies revealed high specific uptake in the tumor, that is, approximately 34.4 ± 9.8% of injected dose per gram (%ID/g) at 1 h post injection for 68Ga-CA028. At 1 h p.i., 68Ga-CA028 and 68Ga-CA030 demonstrated lower kidney uptake than 68Ga-PSMA-617, but at later time points, kidney time–activity curves converge. In line with the preclinical data, first diagnostic PET imaging using 68Ga-CA028 and 68Ga-CA030 revealed high-contrast detection of bone and lymph node lesions in patients with metastatic prostate cancer. The novel PSMA ligands, in particular CA028 and CA030, are promising agents for targeting PSMA-positive tumor lesions as shown in the preclinical evaluation and in a first patient, respectively. Thus, clinical translation of 68Ga-CA028 and 68Ga/177Lu-CA030 for diagnostics and endoradiotherapy of prostate cancer in larger cohorts of patients is warranted.

Automated Lung Cancer Segmentation Using a PET and CT Dual-Modality Deep Learning Neural Network

To develop an automated lung tumor segmentation method for radiation therapy planning based on deep learning and dual-modality positron emission tomography (PET) and computed tomography (CT) images. A 3-dimensional (3D) convolutional neural network using inputs from diagnostic PETs and simulation CTs was constructed with 2 parallel convolution paths for independent feature extraction at multiple resolution levels and a single deconvolution path. At each resolution level, the extracted features from the convolution arms were concatenated and fed through the skip connections into the deconvolution path that produced the tumor segmentation. Our network was trained/validated/tested by a 3:1:1 split on 290 pairs of PET and CT images from patients with lung cancer treated at our clinic, with manual physician contours as the ground truth. A stratified training strategy based on the magnitude of the gross tumor volume (GTV) was investigated to improve performance, especially for small tumors. Multiple radiation oncologists assessed the clinical acceptability of the network-produced segmentations. The mean Dice similarity coefficient, Hausdorff distance, and bidirectional local distance comparing manual versus automated contours were 0.79 ± 0.10, 5.8 ± 3.2 mm, and 2.8 ± 1.5 mm for the unstratified 3D dual-modality model. Stratification delivered the best results when the model for the large GTVs (>25 mL) was trained with all-size GTVs and the model for the small GTVs (<25 mL) was trained with small GTVs only. The best combined Dice similarity coefficient, Hausdorff distance, and bidirectional local distance from the 2 stratified models on their corresponding test data sets were 0.83 ± 0.07, 5.9 ± 2.5 mm, and 2.8 ± 1.4 mm, respectively. In the multiobserver review, 91.25% manual versus 88.75% automatic contours were accepted or accepted with modifications. By using an expansive clinical PET and CT image database and a dual-modality architecture, the proposed 3D network with a novel GTVbased stratification strategy generated clinically useful lung cancer contours that were highly acceptable on physician review.

Anion exchange and extraction chromatography tandem column isolation of zirconium-89 (89Zr) from cyclotron bombarded targets using an automated fluidic platform

The long-lived positron emitter 89Zr is a highly promising nuclide employed in diagnostic Positron Emission Tomography (PET) imaging. Methods of radiochemical processing to obtain 89Zr for clinical use are traditionally performed with a single hydroxamate resin column. Herein, we present a tandem column purification method for the preparation of high-purity 89Zr from cyclotron bombarded natural Y metal foils. The primary column is a macroporous, strongly basic anion exchange resin on styrene divinylbenzene co-polymer. The secondary microcolumn, with an internal volume of 33 μL, is packed with an extraction chromatography resin (ExCR) loaded with di-(2-ethylhexyl)phosphoric acid (HDEHP). A condition of “inverted selectivity” is presented, wherein the 89Zr elution from the primary column is synonymous with the load condition on the secondary column. The ability to transfer 89Zr from one column to the next allows two sequential purification steps to be performed prior to the final elution of the 89Zr product. This approach assures delivery of high purity 89Zr. The tandem column purification process has been implemented into a prototype automated fluidic system. Optimization of the method is presented, followed by evaluation of the process using seven cyclotron bombarded Y metal foil targets. Once optimized, we found that 93.7 ± 2.3% of the 89Zr present in the foils was recovered in the secondary column elution fraction (0.8 M oxalic acid). Radiochromatograms of the product elution peaks enabled determination of full width at half-maximum (FWHM) and 89Zr collection yields as a function of volume. Because of the small size of the secondary microcolumn, a 89Zr product volume of ∼0.28 mL is reported, which provides a substantially increased nuclide concentration over traditional methods. Finally, we evaluated the transchelation of the resulting 89Zr oxalate product to deferoxamine mesylate (DFOM) salt. We observed effective specific activities (ESA) and bindable metals concentrations ([MB]) that exceed those reported by the traditional single hydroxamate column method.

A prediction model for skeletal muscle evaluation and computed tomography-defined sarcopenia diagnosis in a predominantly overweight cohort of patients with head and neck cancer

PurposeThis study investigates the feasibility of computed tomography (CT)-defined sarcopenia assessment using a prediction model for estimating the cross-sectional area (CSA) of skeletal muscle (SM) in CT scans at the third lumbar vertebra (L3), using measures at the third cervical level (C3) in a predominantly overweight population with head and neck cancer (HNC).MethodsAnalysis was conducted on adult patients with newly diagnosed HNC who had a diagnostic positron emission tomography–CT scan. CSA of SM in CT images was measured at L3 and C3 in each patient, and a predictive formula developed using fivefold cross-validation and linear regression modelling. Correlation and agreement between measured CSA at L3 and predicted values were evaluated using intraclass correlation coefficients (ICC) and Bland–Altman plot. The model’s ability to identify sarcopenia was investigated using Cohen’s Kappa (k).ResultsA total of 109 patient scans were analysed, with 64% of the cohort being overweight or obese. The prediction model demonstrated high level of correlation between measured and predicted CSA measures (ICC 0.954, r = 0.916, p < 0.001), and skeletal muscle index (SMI) (ICC 0.939, r = 0.883, p < 0.001). Bland–Altman plot showed good agreement in SMI, with mean difference (bias) = 0.22% (SD 8.65, 95% CI − 3.35 to 3.79%), limits of agreement (− 16.74 to 17.17%). The model had a sensitivity of 80.0% and specificity of 85.0%, with moderate agreement on sarcopenia diagnosis (k = 0.565, p = 0.004).ConclusionThis model is effective in predicting lumbar SM CSA using measures at C3, and in identifying low SM in a predominately overweight group of patients with HNC.

The risk of increasing tumor malignancy after PET diagnosis

Abstract This manuscript reviews evidences underlying the estimation of risk of malignancy enhancement of advanced aggressive cancers as a result of the gamma radiation emitted by tracers used in PET diagnostics. We conclude that among many cancers, such a phenomenon likely occurs, particularly in tumor cells with an aggressive biology in the advanced stages of their development, e.g. prostate cancer, melanoma and colorectal cancer. Moreover, we surmise based on gathered evidence that fluorine -18 (18F) labeled pharmaceuticals (18F-deoxyglucose and 18F-choline), commonly used in positron emission tomography (PET) can lead to malignancy enhancement of diagnosed cancer, manifesting as accelerated infiltration of the neighboring tissue, accelerated metastasis and/or radio- and chemotherapy resistance. In this review, some suggestions on future studies verifying this concept are also proposed. If our concerns are justified, it might be appropriate in the future to consider this assumption at the stage of deciding whether to undertake PET monitoring in some patients with advanced aggressive cancer.

Development and Functional Characterization of a Versatile Radio-/Immunotheranostic Tool for Prostate Cancer Management.

Simple SummaryIn previous studies, we described a modular Chimeric Antigen Receptor (CAR) T cell platform which we termed UniCAR. In contrast to conventional CARs, the interaction of UniCAR T cells does not occur directly between the CAR T cell and the tumor cell but is mediated via bispecific adaptor molecules so-called target modules (TMs). Here we present the development and functional characterization of a novel IgG4-based TM, directed to the tumor-associated antigen (TAA) prostate stem cell antigen (PSCA), which is overexpressed in prostate cancer (PCa). We show that this anti-PSCA IgG4-TM cannot only be used for (i) redirection of UniCAR T cells to PCa cells but also for (ii) positron emission tomography (PET) imaging, and (iii) alpha particle-based endoradiotherapy. For radiolabeling, the anti-PSCA IgG4-TM was conjugated with the chelator DOTAGA. PET imaging was performed using the 64Cu-labeled anti-PSCA IgG4-TM. According to PET imaging, the anti-PSCA IgG4-TM accumulates with high contrast in the PSCA-positive tumors of experimental mice without visible uptake in other organs. For endoradiotherapy the anti-PSCA IgG4-TM-DOTAGA conjugate was labeled with 225Ac3+. Targeted alpha therapy resulted in tumor control over 60 days after a single injection of the 225Ac-labeled TM. The favorable pharmacological profile of the anti-PSCA IgG4-TM, and its usage for (i) imaging, (ii) targeted alpha therapy, and (iii) UniCAR T cell immunotherapy underlines the promising radio-/immunotheranostic capabilities for the diagnostic imaging and treatment of PCa.Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with 64Cu2+, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with 225Ac3+ and applied for targeted alpha therapy. A single injection of the 225Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy.

Charting the Chemical and Mechanistic Scope of Light-Triggered Protein Ligation.

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide (ArN3) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies (89Zr-mAbs) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers. Here, we report on the synthesis, 89Zr-radiochemistry, and light-triggered photoradiosynthesis of 89Zr-labeled human serum albumin (HSA) using a series of 14 different photoactivatable DFO derivatives. The photoactive groups explore a range of substituted, and isomeric ArN3 reagents, as well as derivatives of benzophenone, a para-substituted trifluoromethyl phenyl diazirine, and a tetrazole species. For the compounds studied, efficient photochemical activation occurs inside the UVA-to-visible region of the electromagnetic spectrum (∼365–450 nm) and the photochemical reactions with HSA in water were complete within 15 min under ambient conditions. Under standardized experimental conditions, photoradiosynthesis with compounds 1–14 produced the corresponding 89ZrDFO-PEG3-HSA conjugates with decay-corrected isolated radiochemical yields between 18.1 ± 1.8% and 62.3 ± 3.6%. Extensive density functional theory (DFT) calculations were used to explore the reaction mechanisms and chemoselectivity of the light-induced bimolecular conjugation of compounds 1–14 to protein. The photoactivatable DFO-derivatives operate by at least five distinct mechanisms, each producing a different type of bioconjugate bond. Overall, the experimental and computational work presented here confirms that photochemistry is a viable option for making diverse, functionalized protein conjugates.

Design, synthesis, biochemical evaluation, radiolabeling and in vivo imaging with high affinity class-IIa histone deacetylase inhibitor for molecular imaging and targeted therapy

Herein, we describe the design, synthesis and deciphering of the key characteristics of the structure activity relationship (SAR) of trifluoromethyloxadiazole (TFMO) bearing class-IIa HDAC inhibitors. Our medicinal chemistry campaign of 23 compounds identified compound 1 as a highly potent inhibitor with sub nM affinity to class-IIa HDAC4 isoform. Therefore, We radiolabeled compound 1 (named thereafter as NT160) with [18F]fluoride thus producing the identical [18F]-NT160 as a diagnostic tool for positron emission tomography (PET). [18F]-NT160 was produced in high radiochemical purity (>95%), moderate radiochemical yield (2–5%) and moderate molar activity in the range of 0.30–0.85 GBq/umol (8.0–23.0 mCi/umol). We also established that [18F]-NT160 can cross the blood brain barrier and bind to class-IIa HDACs in vivo. The combination of [18F]-NT160 and 1 represent a novel theranostic pair using the same molecule to enable diagnostic PET imaging with [18F]-NT160 followed by targeted therapy with NT160.

The Association Between Radiation to the Immune System and Overall Survival and Disease Progression in Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy

<h3>Purpose/Objective(s)</h3> Although the effects of effective radiation dose to the immune cells (EDRIC) in advanced stage non-small cell lung cancer (NSCLC) on overall survival (OS) and progression free survival (PFS) have been studied, no other study has shown its impact in early-stage NSCLC. In this retrospective cohort, we evaluated the role of EDRIC in this population. <h3>Materials/Methods</h3> The study cohort was generated using the cancer registry data including patients with early-stage NSCLC (T1-2, N0) who received stereotactic body radiation therapy (SBRT) in our institute since 2007. Patient were excluded if the dosimetric data were not available. EDRIC was calculated as a function of the number of radiation fractions and mean doses to the lung, heart, and the remaining body. Failure was defined as any type of failure including in-field, out-field, nodal and distant metastases. Variables that were included in the univariate and multivariate analysis were age, sex, positron emission tomography (PET) scan at diagnosis, Karnofsky Performance Status (KPS), Charlson Comorbidity Index (CCI), smoking history, histology, tumor location (central versus peripheral), TNM stage, Gross Tumor Volume (GTV) size, BED and EDRIC. <h3>Results</h3> 148 patients were included. 55% are female with a median age of 73 years. 23% had central lesions. 97% had diagnostic PET scan and all were treated with a mean dose of 50 Gy and Biological Effective Dose (BED) above 100 Gy. With a median follow up of 29 months, 34% of patients developed failure. The 2-year OS was 54%. In multivariate analysis, higher EDRIC (HR: 2.04) and lower KPS (HR: 0.35) continued to be associated with worse OS (<i>P</i> = 0.02 and <i>P</i> = 0.008). Considering each EDRIC quartile, there was a statistically significant difference in OS between 1st and 4^th and 1^st and 3^rd quartile (<i>P</i> = 0.01, <i>P</i> = 0.02). The median OS in each quartile is as followed: not reached, 47, 21, 21 months. There was no association between EDRIC and PFS. However, in multivariate analysis, KPS was associated with any type of failure (HR: 0.12, <i>P</i> = 0.013) <h3>Conclusion</h3> This study showed that EDRIC can affect OS in patients with early staged NSCLC treated with SBRT. However, it does not affect PFS and any type of failure after receiving SBRT.

Investigating Factors Predictive of Large Cell Transformation and Outcomes From Low Grade Lymphomas

<h3>Purpose/Objective(s)</h3> Relapses of low grade (indolent) lymphomas typically remain low grade, but there is a 1-3% annual risk of transformation to large B-cell lymphoma. Predictive factors at time of initial lymphoma diagnosis and clinical outcomes after transformation remain poorly characterized. In this study we aim to characterize clinical and positron emission tomography (PET) features of a cohort with transformed disease. <h3>Materials/Methods</h3> We performed a retrospective review of patients diagnosed with large cell transformation from initial low-grade lymphoma. Patients who did not experience transformation during follow up were referenced as a control. Standardized uptake unit (SUV) parameters from initial staging or low-grade disease follow up diagnostic PET scans were analyzed. Statistical analyses included t-test and Fisher's exact test for significance (SS) using alpha level of 0.05. Statistical analysis was performed using Python (version 3). <h3>Results</h3> We identified 50 patients with a mean age at initial diagnosis of 53 years (range: 16-73). The most common lymphoma types were follicular lymphoma (FL) in 40 (80%) patients, marginal zone (MZL) in 4 (8%), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in 3 (6%), 2 (4%) with Waldenstrom's (WM) and one (2%) with primary cutaneous follicle center (PCFCL). Initial lymphoma (non-WM) stages were 23% stage I, 8% stage II, 36% stage III and 33% stage IV. Mean time to transformation was 105 months (range: 5-373). Predominant transformed histology was diffuse large B-cell lymphoma (DLBCL) in 42 (84%) patients. Stage at transformation was 30% stage I-II and 70% stage III-IV. Median follow up from time of transformation was 52 months (range: 2-207). 1-year OS from transformation was 85%. 21 (42%) patients had PET-CT scans 7 months to 13 years prior to transformation with mean SUV-max of 12.2 (range: 3.8-30.0). Compared to 21 (1:1) non-transformed control patients with PET scans, a significant difference was found between the mean SUV-max values of 12.2 vs 6.3 (<i>P</i> < 0.001). Further, as an exploratory analysis, we generated a prognostic scoring model for post-transformation outcomes directly proportional to SUV-max squared and inverse to the time to transformation (in months). Among the 21 patients with pre-transformation PET imaging, the 17 who were alive at last follow up had a mean score of 2.4 vs. 64.2 among the 4 patients who died (<i>P</i> = 0.005). <h3>Conclusion</h3> We demonstrate the utility of PET-CT to identify patients with low grade lymphoma at high risk of transformation to large cell lymphoma. Specifically, we observe an increased risk of poor outcomes with increasing SUV-max and shorter time to transformation. If validated, our study may serve to risk stratify patients initially diagnosed with low grade lymphoma.

ASSESSMENT OF PATIENT'S RADIATION EXPOSURES RESULTED FROM PET/CT 18F-FCH AND 68GA-PSMA PROCEDURES.

This study has sought to evaluate patient exposures during the course of particular diagnostic positron emission tomography and computed tomography (PET/CT) techniques. A total of 73 patients were examined using two types of radiopharmaceutical: 18F-fluorocholine (FCH, 48 patients) and 68Ga-prostate-specific membrane antigen (PSMA, 25 patients). The mean and range of administered activity (AA) in MBq, and effective dose (mSv) for FCH were 314.4±61.6 (462.5-216.8) and 5.9±1.2 (8.8-4.11), respectively. Quoted in the same set of units, the mean and range of AA and effective dose for 68Ga-PSMA were 179.3±92.3 (603.1-115.1) and 17.9±9.2 (60.3-11.5). Patient effective doses from 18F-FCH being a factor of two greater than the dose resulting from 68Ga-PSMA PET/CT procedures. CT accounts for some 84 and 23% for 18F-FCH and 68Ga-PSMA procedures, accordingly CT acquisition parameter optimization is recommended. Patient doses have been found to be slightly greater than previous studies.

Effective doses and associated age-related risks for common paediatric diagnostic nuclear medicine and PET procedures at a large Australian paediatric hospital.

Effective dose alone cannot be used to specify and communicate the radiation risk for an individual as risks are dependent on many factors including age and gender. There are limited published data regarding age-specific effective doses and the associated lifetime risk of developing cancers for paediatrics. In this study, we have estimated the typical effective doses for six commonly performed paediatric nuclear medicine and positron emission tomography (PET) studies at the Royal Children's Hospital, Melbourne, Australia. Effective doses were used to estimate and categorise associated stochastic risks with commonly used risk terminology. Paediatric protocols for common nuclear medicine and PET studies and the World Health Organization (WHO) 50th percentile weight-for-age data for females and males aged up to 18 years were used to estimate typical organ and effective doses using ICRP dosimetric tables for radiopharmaceuticals and lifetime risk of cancer incidence using BEIR VII Phase 2 report data. Results were used to determine standardised levels of risk. Organ doses, effective doses, corresponding lifetime risk of cancer incidence and level of risk category from six common nuclear medicine and PET studies for paediatric patients were calculated and presented for ease of communication. Typical effective doses from common paediatric nuclear medicine and PET studies and the associated lifetime risk of cancer incidence and level of risk have been established for our institution. This can be used to convey risks to health professionals, patients and carers in ways that are easy to understand and compare with other everyday risks.

Imaging Somatostatin Positive Tumors with Tyr3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68.

Radiolabeled derivatives of Tyr3-octreotide and Tyr3-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (H3DFOSq) was used attach either Tyr3-octreotide or Tyr3-octreotate to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with H3DFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with H3DFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.

Comparison of Regularized Reconstruction and Ordered Subset Expectation Maximization Reconstruction in the Diagnostics of Prostate Cancer Using Digital Time-of-Flight 68Ga-PSMA-11 PET/CT Imaging.

In prostate cancer, the early detection of distant spread has been shown to be of importance. Prostate-specific membrane antigen (PSMA)-binding radionuclides in positron emission tomography (PET) is a promising method for precise disease staging. PET diagnostics depend on image reconstruction techniques, and ordered subset expectation maximization (OSEM) is the established standard. Block sequential regularized expectation maximization (BSREM) is a more recent reconstruction algorithm and may produce fewer equivocal findings and better lesion detection. Methods: 68Ga PSMA-11 PET/CT scans of patients with de novo or suspected recurrent prostate cancer were retrospectively reformatted using both the OSEM and BSREM algorithms. The lesions were counted and categorized by three radiologists. The intra-class correlation (ICC) and Cohen’s kappa for the inter-rater reliability were calculated. Results: Sixty-one patients were reviewed. BSREM identified slightly fewer lesions overall and fewer equivocal findings. ICC was excellent with regards to definitive lymph nodes and bone metastasis identification and poor with regards to equivocal metastasis irrespective of the reconstruction algorithm. The median Cohen’s kappa were 0.66, 0.74, 0.61 and 0.43 for OSEM and 0.61, 0.63, 0.66 and 0.53 for BSREM, with respect to the tumor, local lymph nodes, metastatic lymph nodes and bone metastasis detection, respectively. Conclusions: BSREM in the setting of 68Ga PMSA PET staging or restaging is comparable to OSEM.

A national cross-sectional survey investigating the use of endoscopic ultrasound in the diagnosis and treatment of oesophageal cancer in the UK

To evaluate variation in the pre-pandemic use of endoscopic ultrasound (EUS) for oesophageal cancer diagnosis and treatment planning up to 2019, and which factors contributed to this. A UK-wide online survey of oesophagogastric multidisciplinary team lead clinicians was undertaken to determine perceptions towards, and the use of, EUS to aid staging and treatment planning in oesophageal cancer. Thirty-five responses were received, representing 97 UK National Health Service Trusts/Health Boards. A majority of centres (n=21, 60%) did not have formal written guidance for EUS use. Although all respondents had access to EUS, a perceived lack of utility (n=7) and concerns about delaying treatment start dates (n=8) each restricted EUS use for a fifth of respondents. For most centres (n=24, 68.6%), EUS use is case-specific, whereas for 10 (28.6%) EUS is used for all patients with potentially curable disease. A majority of centres use diagnostic positron-emission tomography for radiotherapy target volume delineation (TVD), whereas 22 (62.9%) use EUS. The factors contributing to decisions to use EUS for staging, TVD and surgical planning varied between centres. The proportion of centre respondents who would request EUS in each of six clinical scenarios varied considerably. There were substantial differences in the patient and disease characteristics that are perceived to be indications for EUS use for both staging and treatment planning. Research to clarify in which patients with oesophageal cancer EUS affords benefit is required, as is urgent standardisation of its role in the diagnostic pathway.

Microfluidic Preparation of 89Zr-Radiolabelled Proteins by Flow Photochemistry.

89Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, 89Zr-labelled proteins are produced manually. Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare 89Zr-radiolabelled proteins. The light-induced functionalisation and 89Zr-radiolabelling of human serum albumin ([89Zr]ZrDFO-PEG3-Et-azepin-HSA) was achieved by flow photochemistry with a decay-corrected radiochemical yield (RCY) of 31.2 ± 1.3% (n = 3) and radiochemical purity >90%. In comparison, a manual batch photoreactor synthesis produced the same radiotracer in a decay-corrected RCY of 59.6 ± 3.6% (n = 3) with an equivalent RCP > 90%. The results indicate that photoradiolabelling in flow is a feasible platform for the automated production of protein-based 89Zr-radiotracers, but further refinement of the apparatus and optimisation of the method are required before the flow process is competitive with manual reactions.

18 F-labeled 1,2,3-triazole-linked Glu-urea-Lys-based PSMA ligands have good pharmacokinetic properties for positron emission tomography imaging of prostate cancer.

Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

Bivalent Inhibitors of Prostate-Specific Membrane Antigen Conjugated to Desferrioxamine B Squaramide Labeled with Zirconium-89 or Gallium-68 for Diagnostic Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.

Carbon Nanomaterials for Sorption of 68Ga for Potential Using in Positron Emission Tomography.

In present work, carbon nanomaterials (CNMs) are investigated as potential carriers of 68Ga, which is widely used in positron emission tomography (PET) in nuclear medicine. Sorption behavior of 68Ga was studied onto CNMs of various structures and chemical compositions: nanodiamonds (ND), reduced graphite oxide (rGiO) and multi-walled carbon nanotubes (MWCNT), as well as their oxidized (ND–COOH) or reduced (rGiO–H, MWCNT–H) forms. The physicochemical properties of the nanoparticles were determined by high resolution transmission electron microscopy, x-ray photoelectron spectroscopy, dynamic light scattering and potentiometric titration. The content of 68Ga in the solutions during the study of sorption was determined by gamma-ray spectrometry. The highest degree of 68Ga sorption was observed on ND and ND–COOH samples, and the optimal sorption conditions were determined: an aqueous solution with a pH of 5–7, m/V ratio of 50 μg/mL and a room temperature (25 °C). The 68Ga@ND and 68Ga@ND–COOH conjugates were found to be stable in a model blood solution—phosphate-buffered saline with a pH of 7.3, containing 40 g/L of bovine serum albumin: 68Ga desorption from these samples in 90 minutes was no more than 20% at 25 °C and up to 30% at 37 °C. Such a quantity of desorbed 68Ga does not harm the body and does not interfere with the PET imaging process. Thus, ND and ND–COOH are promising CNMs for using as carriers of 68Ga for PET diagnostics.

Light‐Activated Protein Conjugation and 89Zr‐Radiolabelling with Water‐Soluble Desferrioxamine Derivatives

Protein-conjugates are vital tools in biomedical research, drug discovery and imaging science. For example, functionalised monoclonal antibodies (mAbs) coupled to the desferrioxamine B (DFO) chelate and radiolabelled with 89 Zr4+ ions are used as radiopharmaceuticals for diagnostic positron emission tomography (PET). In this context, protein functionalisation requires the formation of a covalent bond that must be achieved without compromising the biological properties of the mAb. Photochemistry offers new synthetic routes toward protein conjugates like 89 Zr-mAbs but to harness the potential of light-induced conjugation reactions new photoactivatable reagents are required. Herein, we introduce two photoactivatable DFO-derivatives functionalised with an aryl azide (ArN3 ) for use in light-activated conjugation and radiosynthesis of 89 Zr-mAbs. Incorporation of a tris-polyethylene glycol (PEG)3 linker between DFO and the ArN3 group furnished water-soluble chelates that were used in the one-pot, photoradiosynthesis of different 89 Zr-radiolabelled protein conjugates with radiochemical yields up to 72.9±1.9 %. Notably, the DFO-PEG3 chelates can be readily synthesised in accordance with Good Laboratory Practice (GLP), which will facilitate clinical trials with photoradiolabelled 89 Zr-mAbs.