Intra-arterial PSMA injection using hepatic arterial infusion pump in intrahepatic cholangiocarcinoma: a proof-of-concept study.

Prostate-specific membrane antigen (PSMA) targeted tracers show increased uptake in several malignancies, indicating a potential for peptide radioligand therapy. Intra-arterial injection of radiotracers can increase the therapeutic window. This study aimed to evaluate the feasibility of intra-arterial injection of [68Ga]Ga-PSMA-11 for intrahepatic cholangiocarcinoma and compare tracer uptake after intrahepatic arterial injection and intravenous injection. Three patients with intrahepatic cholangiocarcinoma received [68Ga]Ga-PSMA-11 through a hepatic arterial infusion pump, followed by positron emission tomography/computed tomography (PET/CT). Two-three days later, patients underwent PET/CT after intravenous [68Ga]Ga-PSMA-11 injection. All tumours showed higher uptake on the intra-arterial scan compared with the intravenous scan: the intra-arterial / intravenous standardised uptake value normalised by lean body mass ratios were 1.40, 1.46, and 1.54. Local intra-arterial PSMA injection is possible in patients with intrahepatic cholangiocarcinoma. Local injection increases tumour-to-normal tissue ratios, increasing the therapeutic window for theranostic applications. RELEVANCE STATEMENT: Intra-arterial Prostate specific membrane antigen (PSMA) injection increases the therapeutic window for potential theranostic application in intrahepatic cholangiocarcinoma. KEY POINTS: Three patients with intrahepatic cholangiocarcinoma underwent PET/CT after intra-arterial and intravenous injection of [68Ga]Ga-PSMA-11. Intra-arterial injection showed higher uptake than intravenous injection. PSMA-targeted imaging could be valuable for a subset of intrahepatic cholangiocarcinoma patients.

Biodistribution of Native and Nanoformulated Innate Defense Regulator Peptide 1002.

Innate defense regulator-1002 (IDR-1002) is a synthetic peptide with promising immunomodulatory and antibiofilm properties. An appreciable body of work exists around its mechanism of action at the cellular and molecular level, along with its efficacy across several infection and inflammation models. However, little is known about its absorption, distribution, and excretion in live organisms. Here, we performed a comprehensive biodistribution assessment with a gallium-67 radiolabeled derivative of IDR-1002 using nuclear tracing techniques. Various dose levels of the radiotracer (2-40 mg/kg) were administered into the blood, peritoneal cavity, and subcutaneous tissue, or instilled into the lungs. The peptide was well tolerated at all subcutaneous and intraperitoneal doses, although higher levels were associated with delayed absorption kinetics and precipitation of the peptide within the tissues. Low intratracheal doses were rapidly absorbed systemically, and small increases in the dose level were lethal. Intravenous doses were rapidly cleared from the blood at lower levels, and upon escalation, were toxic with a high proportion of the dose accumulating within the lung tissue. To improve biocompatibility and prolong its circulation within the blood, IDR-1002 was further formulated onto high molecular weight hyperbranched polyglycerol (HPG) polymers. Constructs prepared at 5:1 and 10:1 peptide-to-polymer ratios were colloidally stable, maintained the biological profile of the peptide payload and helped reduce red blood cell lysis. The 5:1 construct circulated well in the blood, but higher peptide loading was associated with rapid clearance by the reticuloendothelial system. Many peptides face pharmacokinetic and biocompatibility challenges, but formulations such as those with HPG have the potential to overcome these limitations.

68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography Maximum Standardized Uptake Value as a Predictor of Gleason Pattern 4 and Pathological Upgrading in Intermediate-Risk Prostate Cancer.

PURPOSE: Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA PET/CT) and the maximum standardized uptake value (SUVmax) may improve risk stratification within this population. MATERIALS AND METHODS: We reviewed men with International Society for Urological Pathology Grade Group (GG) 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per segment at surgery at 3 thresholds: >/<50% GP4, >/<20% GP4, and >/<10% GP4. SUVmax was compared by GP4, and multivariable logistic regression examined the relationship between SUVmax and GP4. Secondary outcome was association between SUVmax and pathological upgrading (GG 1/2 to GG ≥3 from biopsy to surgery). RESULTS: Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/<50% GP4 (p <0.001); 4.77 (3.31-7.00) vs 3.13 (2.64-4.41) >/<20% GP4 (p <0.001); and 4.54 (6.10-3.13) vs 3.03 (2.45-3.70) >/<10% GP4 (p <0.001). SUVmax remained an independent predictor of >50% (OR=1.39 [95%CI 1.18-1.65], p <0.001) and >20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathological upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value 75% and negative predictive value 72%. Threshold 5.4 predicted pathological upgrading with 91% specificity and negative predictive value 94%. CONCLUSIONS: SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

In vitro and in vivo comparative study of a novel 68Ga-labeled PSMA-targeted inhibitor and 68Ga-PSMA-11.

68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.

Biodistribution and internal radiation dosimetry of a companion diagnostic radiopharmaceutical, [68Ga]PSMA-11, in subcutaneous prostate cancer xenograft model mice.

[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with 68Ga-labeled PD-L1 targeted nanobody.

Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a 68Ga-labeled single-domain antibody tracer, 68Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that 68Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. 68Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti-PD-1 treatment activates tumor-reactive CD103+ CD39+ CD8+T cells (TILs) in tumor microenvironment.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. PROCEDURE: Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 µg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. RESULTS: Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). CONCLUSIONS: Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Early differences in dynamic uptake of 68Ga-PSMA-11 in primary prostate cancer: A test-retest study.

INTRODUCTION: Dynamic PET/CT allows visualization of pharmacokinetics over the time, in contrast to static whole body PET/CT. The objective of this study was to assess 68Ga-PSMA-11 uptake in pathological lesions and benign tissue, within 30 minutes after injection in primary prostate cancer (PCa) patients in test-retest setting. MATERIALS AND METHODS: Five patients, with biopsy proven PCa, were scanned dynamically in list mode for 30 minutes on a digital PET/CT-scanner directly after an intravenous bolus injection of 100 MBq 68Ga-PSMA-11. Approximately 45 minutes after injection a static whole body scan was acquired, followed by a one bed position scan of the pelvic region. The scans were repeated approximately four weeks later, without any intervention in between. Semi-quantitative assessment was performed using regions-of-interest in the prostate tumor, bladder, gluteal muscle and iliac artery. Time-activity curves were extracted from the counts in these regions and the intra-patient variability between both scans was assessed. RESULTS: The uptake of the iliac artery and gluteal muscle reached a plateau after 5 and 3 minutes, respectively. The population fell apart in two groups with respect to tumor uptake: in some patients the tumor uptake reached a plateau after 5 minutes, whereas in other patients the uptake kept increasing, which correlated with larger tumor volumes on PET/CT scan. Median intra-patient variation between both scans was 12.2% for artery, 9.7% for tumor, 32.7% for the bladder and 14.1% for the gluteal muscle. CONCLUSION: Dynamic 68Ga-PSMA-11 PET/CT scans, with a time interval of four weeks, are reproducible with a 10% variation in uptake in the primary prostate tumor. An uptake plateau was reached for the iliac artery and gluteal muscle within 5 minutes post-injection. A larger tumor volume seems to be related to continued tumor uptake. This information might be relevant for both response monitoring and PSMA-based radionuclide therapies.

Recent Breakthrough in 68Ga-Radiopharmaceuticals Cold Kits for Convenient PET Radiopharmacy.

68Ga-PET has emerged as an important diagnostic tool for precise detection and monitoring of oncological situations. Availability, cost, and radiosynthesis procedure are determining steps for success of a radioisotope/radiopharmaceutical in nuclear medicine. Availability of 68Ga from a 68Ge/68Ga generator containing a long-lived parent radioisotope (68Ge: t1/2 = 271 days) and an inexpensive, simplified production of 68Ga-radiopharmaceuticals through kit methodology has allowed smooth accommodation of 68Ga-PET in clinics. The uncomplicated formulation of 68Ga-radiopharmaceuticals from a lyophilized, cold kit is an impending breakthrough in clinical PET. The huge success of 68Ga in neuroendocrine tumor and prostate cancer imaging along with the regulatory approval of respective cold kits has opened a pathway for development of kits for other evolving radiotracers. There is a definite scope for increased participation of commercial manufacturers and distributors of cold kits to spread the potential of 68Ga worldwide across all the geographical locations and satellite centers.

Usefulness of 68Ga-DOTATOC PET/CT to localize the culprit tumor inducing osteomalacia.

Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome presenting with sustained hypophosphatemia. Treatment of choice is removal of the tumor causing the TIO, but identification of the culprit tumor by routine imaging is challenging. This study aimed to assess the usefulness of somatostatin receptor imaging, called 68Ga-DOTATOC PET/CT, in the management of patients with TIO. Twelve patients who were suspected of having TIO underwent 68Ga-DOTATOC PET/CT. Lesion detectability and maximum standardized uptake value (SUVmax) were determined and retrospectively compared with the clinical/imaging surveillance and histopathologic diagnosis. The median duration of suspected TIO with hypophosphatemia was 7.8 years (range 2.1-21.0). Conventional radiologic and/or nuclear medicine images failed to identify the culprit tumors. However, 68Ga-DOTATOC PET/CT scans showed that 8 of the 12 patients had positive lesions, suggesting the presence of focal culprit tumors. The SUVmax of positive tumors was 1.9-45.7 (median: 11.5). Six skeletal lesions and two extra-skeletal lesions were identified. Seven of the lesions were pathologically confirmed as potential culprits of TIO. Hypophosphatemia was resolved in five patients who underwent lesion excision. The 68Ga-DOTATOC PET/CT is a useful whole-body imaging modality for the detection of causative tumors in patients with suspected TIO.

Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

Development and validation of a kit formulation of [68Ga]Ga-P15-041 as a bone imaging agent.

One of the commonly performed studies in nuclear medicine are bone scans with [99mTc]Tc-methylene diphosphonate (MDP) for detecting various bone lesions, including cancer metastasis. The recent emergence of commercially available 68Ge/68Ga radionuclide generators makes it possible to provide 68Ga-labelled bisphosphonates as positron emission tomography (PET) tracers for bone imaging. Preliminary human studies suggested that [68Ga]Ga-HBED-CC-BP ([68Ga]Ga-P15-041) in conjunction with PET/computed tomography (CT) showed accumulation in known bone lesions, fast clearance from blood and soft tissue, and an ability to provide high contrast images. A simple and efficient lyophilized P15-041 kit formulation for the rapid production of [68Ga]Ga-P15-041 with excellent radiochemical purity (RCP) under ambient temperature without the need for purification is described. It is demonstrated that clinical doses of [68Ga]Ga-P15-041 can be prepared manually within minutes with an excellent purity (> 90%) and readily meet the dose release criteria. When [68Ga]Ga-P15-041 was evaluated in a patient with cancer, the imaging agent clearly showed accumulations in multiple lesions. In conclusion, [68Ga]Ga-P15-041, prepared by a lyophilized kit, might be an excellent bone imaging agent for widespread clinical application.

Pancreatic serous cystoadenoma (CSA) showing increased tracer uptake at 68-GaDOTA-peptide Positron Emission Tomography (68Ga-DOTA-peptide PET-CT): a case report.

BACKGROUND: Serous cysto-adenoma (SCA) is a rare benign neoplasm of the pancreas. SCA can mimic other pancreatic lesions, such as neuroendocrine tumours. 68Gallium-DOTA-peptide Positron Emission Tomography (PET) is able to image in vivo the over-expression of the somatostatin receptors, playing an important role for the identification of neuroendocrine neoplasms. CASE PRESENTATION: We reported a case of 63-year-old man, with a solid lesion of 7 cm of diameter of the body-tail of the pancreas. Two fine-needle-aspirations (FNA) were inconclusive. A 68Ga-DOTA-peptide PET-CT revealed a pathological uptake of the pancreatic lesion. The diagnosis of a pancreatic neuroendocrine neoplasm was established and a laparoscopic distal splenopancreatectomy and cholecystectomy was performed. Final histopathological report revealed the presence of a micro-cystic SCA. CONCLUSIONS: The current case firstly reports a pancreatic SCA showing increased radiopharmaceutical uptake at 68Ga-DOTA-peptide PET-CT images. This unexpected finding should be taken into account during the diagnostic algorithm of a pancreatic lesion, in order to minimize the risk of misdiagnosis and overtreatment of SCA.

Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours.

Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.

A Prospective Trial of 68Ga-PSMA and 18F-FDG PET/CT in Nonmetastatic Prostate Cancer Patients with an Early PSA Progression During Castration.

PURPOSE: Tumor heterogeneity and burden, which impact treatment outcome in prostate cancer, are rarely evaluated using next-generation imaging. EXPERIMENTAL DESIGN: The trial prospectively included 37 patients who had an early PSA progression (≤2 ng/mL) during castration and high-risk (PSA doubling time ≤10 months) nonmetastatic disease by conventional imaging. All patients underwent both 68Ga-PSMA and 18F-FDG PET/CT. Lesions were classified into PSMA+FDG± lesions and PSMA-FDG+ lesions. The primary endpoint was the prevalence of PSMA-FDG+ disease. Tumor burden, predictors for positive imaging, and suitability for oligometastases-directed therapy (OMDT) were also evaluated. RESULTS: All patients were treated with RP and the median duration of castration was 23 months. The median PSA at imaging was 0.57 ng/mL. Overall, 114 lesions were detected in 29 of the 37 patients. A high prevalence (73%) of N+/M+ disease was observed. Of the 114 lesions, 81 were PSMA+FDG± and 33 were PSMA-FDG+. Per patient level, 9 men (24%; 95% confidence interval: 10%-39%) showed at least one new PSMA-FDG+ lesions. A short PSA doubling time (P = 0.009, OR = 8.000) was associated with PSMA+FDG± disease, while a high Gleason grade group (P = 0.022, OR = 13.091) with PSMA-FDG+ disease. Nineteen patients (51%) with 51 lesions, including 10 PSMA-FDG+ lesions, could be enrolled for OMDT. Among different disease stages, PSMA-FDG+ disease was rarely detected in the hormone-sensitive cohort, but frequently found in the castration-resistant cohort. CONCLUSIONS: Using 68Ga-PSMA and 18F-FDG PET, we observed a high prevalence of N+/M+ disease and a significant proportion of PSMA-FDG+ disease in patients with an early PSA progression during castration (ChiCTR1900022634).

In vivo biodistribution of calcium phosphate nanoparticles after intravascular, intramuscular, intratumoral, and soft tissue administration in mice investigated by small animal PET/CT.

Calcium phosphate nanoparticles were covalently surface-functionalized with the ligand DOTA and loaded with the radioisotope 68Ga. The biodistribution of such 68Ga-labelled nanoparticles was followed in vivo in mice by positron emission tomography in combination with computer tomography (PET-CT). The biodistribution of 68Ga-labelled nanoparticles was compared for different application routes: intravenous, intramuscular, intratumoral, and into soft tissue. The particle distribution was measured in vivo by PET-CT after 5 min, 15 min, 30 min, 1 h, 2 h, and 4 h, and ex vivo after 5 h. After intravenous injection (tail vein), the nanoparticles rapidly entered the lungs with later redistribution into liver and spleen. The nanoparticles remained mostly at the injection site following intramuscular, intratumoral, or soft tissue application, with less than 10 percent being mobilized into the blood stream. STATEMENT OF SIGNIFICANCE: The in vivo biodistribution of DOTA-terminated calcium phosphate nanoparticles was followed by PET/CT. To our knowledge, this is the first study of this kind. Four different application routes of clinical relevance were pursued: Intravascular, intramuscular, intratumoral, and into soft tissue. Given the high importance of calcium phosphate as biomaterial and for nanoparticular drug delivery and immunization, this is most important to assess the biofate of calcium phosphate nanoparticles for therapeutic application and also judge biodistribution of nanoscopic calcium phosphate ceramics, including debris from endoprostheses and related implants.

Preparation, radiolabeling with 99mTc and 67Ga and biodistribution studies of albumin nanoparticles covered with polymers. / Preparación, radiomarcaje con 99mTc y 67Ga y estudios de biodistribución de nanopartículas de albúmina con recubrimientos poliméricos.

OBJECTIVE: To optimize radiolabeling with 99mTc and 67Ga of albumin nanoparticles coated with 4 differents synthetic polymers and to evaluate their stability in vivo and in vitro, as well as their biodistribution in vivo after intravenous administration. MATERIAL AND METHODS: The nanoparticles were prepared using albumin and NOTA-modified albumin by the desolvation method and coated with 4 different polymers; HPMC, GMN2, GPM2 and GTM2. They were purified, lyophilized and characterized. Radiolabelling with 99mTc was perfomed with 74 MBq of 99mTc sodium pertechnetate, previously reduced with and acid solution of tin chloride at different concentrations (0.003, 0.005, 0.007, 0.01, 0.05 and 0.1mg/ml) and at different times (5, 10, 15, 30 and 60minutes) and temperatures (room temperature, 40°C and 60°C). Radiolabelling with 67Ga was perfomed by incubation of the nanoparticles with 37 MBq of 67Gallium chloride (obtained from commercial gallium-67 citrate) at different times (10 and 30minutes) and temperatures (room temperature, 30°C and 60°C), and posterior purification with microconcentrators. The radiochemical purity was evaluated by TLC. Stability studies of radiolabeled nanoparticles in physiological serum and blood plasma were perfomed. Biodistribution studies of nanoparticles coated with GPM2 polymer were carried out in Wistar rats after intravenous administration of the nanoparticles. Control animals were carried out with 99mTc sodium pertechnetate and 67Ga chloride. To do so, the animals were killed and activity in organs was measured in a gamma counter. RESULTS: 99mTc labeling was carried out optimally with a tin concentration of 0.007mg/ ml for the GPM2 nanoparticles and 0.005mg / ml for the rest of the formulations, with a radiolabelling time of 10minutes at room temperature. In the case of 67Ga the label was optimized at 30° C temperature and 30minutes of incubation. In both cases the radiochemical purity obtained was greater than 97%. The nanoparticles showed high stability in vitro after 48hours of labeling (70% nanoparticles labeled with 99mTc and 90% those labeled with 67Ga). Biodistribution studies of nanoparticles 99mTc -GPM2 and 67Ga -NOTA-GPM2 showed a high accumulation of activity in the liver at 2 and 24hours after intravenous administration. CONCLUSION: The labeling procedure with 99mTc and 67Ga of albumin and albumin modified with NOTA nanoparticles allows obtaining nanoparticles with high labeling yields and adequate in vitro stability, allowing their use for in vivo studies.

Topical Sensor for the Assessment of Injection Quality for 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE Positron Emission Tomography.

INTRODUCTION: Calculation of the standard uptake value (SUV) and image quality in positron emission tomography (PET) hinges on accurate dose delivery. Extravasation or partial extravasation of the radiopharmaceutical dose can undermine SUV and image quality, and contribute to unnecessary imaging (time and CT dose). Topical sensor characterisation of injections has been reported, with extravasation rates ranging from 9% to 23% for 18F-FDG after manual injection. METHOD: A single site, single PET/CT scanner was used to characterise injections using an autoinjector with standardised apparatus, flush volume and infusion rate using 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE; more reflective of Australian PET facilities. 296 patients with topical application of LARA sensors were retrospectively analysed. RESULTS: Only 1.1% of studies showed evidence of partial dose extravasation. In total, 9.1% were identified to have an injection anomaly (including venous retention). No statistically significant differences were noted across the radiopharmaceuticals for demographic data. Although not demonstrating a statistically significant correlation, there was more extravasated doses associated with female patients (P = .334), right side (P = .372), and hand injections (P = .539). Extravasation was independent of dose administered (P = .495), the radiopharmaceutical (P = .887), who injected the dose (P = .343), height (P = .438), weight (P = .607) or age (P = .716). Extravasation was associated with higher glucose levels (P < .001), higher t-half (P = .019) and higher aUCR10, tc50, aUCR1 and c1 (all P < .001). CONCLUSION: Topical monitoring and characterisation of PET dose administration is possible and practical with the LARA device. Extravasation and partial extravasation of PET doses are not only readily detected but they are also preventable. The LARA device can provide the insights into variables that could eliminate extravasation as a cause of image quality or SUV accuracy issues.

68Ga-PSMA-11 dose reduction for dedicated pelvic imaging with simultaneous PET/MR using TOF BSREM reconstructions.

OBJECTIVES: When increasing the PET acquisition time to match the longer MRI protocol in simultaneous PET/MR, the injected PET tracer dose can possibly be lowered to reduce radiation exposure. Moreover, applying new commercially available time-of-flight (TOF) block sequential regularized expectation maximization (BSREM)-based reconstruction algorithms could allow for further dose reductions. The purpose of this study was to find the minimal dose of the tracer targeting the prostate specific membrane antigen (68Ga-PSMA-11) for a dedicated 15-min pelvic PET/MR scan that still matches the image quality of a reference 3-min scan at 100% (150 MBq) dose. METHODS: In this retrospective analysis, 25 patients were included. PET emission datasets were edited to simulate stepwise reductions of injected tracer dose. Reference TOF ordered subset expectation maximum (OSEM) and new TOF BSREM reconstructions were performed and differences in the resulting PET images were visually and quantitatively assessed. RESULTS: Visually, TOF BSREM reconstructions with relatively high regularization parameter (ß) values are preferred. Quantitatively, however, high ß-values result in lower lesion maximum standardized uptake values (SUVmax) compared to the reference. A ß-value of 550 was considered the optimal compromise for the lowest possible 10% dose reconstructions, resulting in comparable visual assessment and lesion SUVmax. CONCLUSIONS: This study indicates that the injected 68Ga-PSMA-11 tracer dose for a standard 3-min PET scan can be reduced to approximately 10% (15 MBq) when the PET acquisition time is matched to the 15-min pelvic MRI protocol, and when reconstructed with TOF BSREM using ß = 550. This decreases the effective dose from 3.54 to 0.35 mSv. KEY POINTS: • Low-dose dedicated pelvic68Ga-PSMA-11 PET/MR reduces radiation exposure for patients. • Retrospective study investigating the minimal dose needed for adequate image quality for 15-min PET frames over the pelvis showed using quantitative and qualitative analysis that a substantial dose reduction is possible without significant loss of image quality when using the TOF BSREM reconstruction algorithm. • With the introduction of low-dose pelvic68Ga-PSMA-11 PET/MR, new potential applications of68Ga-PSMA-11 PET for local staging or investigation of equivocal MRI findings could become applicable, even for patients without confirmed prostate cancer.

Accuracy of Oral 67Gallium Citrate Scintigraphy in assessment of inflammatory activity of Crohn's disease.

AIM: The main goal in Crohn´s disease (CD) is a sustained suppression of inflammatory activity associated with mucosa healing in endoscopic evaluation. During clinical routine, there are small numbers of good markers to monitor inflammatory activity under treatment. We postulated that Oral 67Gallium Citrate Scintigraphy is able to mark inflammatory disease in mucosa and deep inflammation in CD, when used in oral form. OBJECTIVE: Measure the accuracy of Oral 67Gallium Citrate Scintigraphy in intestinal inflammatory activity of Crohn´s disease. PATIENTS AND METHODS: In a prospective consecutive cross-sectional study from January 2018 to June 2019, the ileocolonic region of 32 patients with CD were studied by dividing into four regions of interest (ROI) from the ileum to the rectum. A total of 128 intestinal segments were analyzed in cluster data. Accuracy values of Oral 67Gallium Scintigraphy and colonoscopy tests were evaluated with the histological reference test. Values of the respective receiver operating characteristic (ROC) curves were obtained  and compared. The reliability between the tests was evaluated by Kappa statistical with the segment-level analyses using variance adjustments. All statistical analyses were performed with a test significance level of 0.05. RESULTS: The study population included 32 patients with CD (10 men, 22 women; average age 39 years). Disease time was five years on average. Anti-TNFs treatment was found in 71%. The most found phenotype of the Montreal classification was L3. Differences in ROC curves for colonoscopy (0.94) and Oral 67Ga Scintigraphy (0.96) did not show significant value (p = 0.32). The sensitivity of scintigraphy to detect intestinal inflammatory activity in CD was 64%, specificity of 96% and accuracy of 84%. A high agreement was found between oral scintigraphy and histological measurements with kappa = 0.64. CONCLUSIONS: Oral 67Ga Scintigraphy had similar accuracy and agreement compared to colonoscopy in the identification of inflammatory activity in Crohn´s Disease. This new approach may be useful and less invasive for long term follow-ups.