111Ag phantom images with Cerenkov Luminescence Imaging and digital autoradiography within the ISOLPHARM project.

Targeted Radionuclide Therapy (TRT) is a medical technique exploiting radionuclides to combat cancer growth and spread. TRT requires a supply of radionuclides that are currently produced by either cyclotrons or nuclear research reactors. In this context, the ISOLPHARM project investigates the production of innovative radionuclides for medical applications. This production will be based on the forthcoming SPES facility at the Legnaro National Laboratories (LNL) of the National Institute for Nuclear Physics (INFN), an ISOL facility where high-purity radioactive beams will be used to produce carrier-free radiopharmaceuticals. Previous studies demonstrated that a significant amount of 111Ag, an innovative ß/γ emitter suitable for TRT with theranostic applications, can be obtained at the SPES facility. The present work describes the first imaging study on phantoms with 111Ag performed by the ISOLPHARM collaboration. This is a fundamental step to pave the way for the upcoming in vivo studies on the 111Ag-based radiopharmaceutical currently being developed. The imaging potential of this radionuclide was investigated by acquiring phantom images with Cerenkov Luminescence Imaging (CLI) and digital autoradiography (ARG).

[Clinical Value of Dual Tracer PET Imaging With 68Ga-PSMA and 18F-FDG in Patients With Metastatic Prostate Cancer]. / 68Ga-PSMA联合18F-FDG PET/CTæ˜¾åƒåœ¨è½¬ç§»æ€§å‰åˆ—è ºç™Œæ‚£è€ ä¸­çš„åº”ç”¨æŽ¢è®¨.

Objective: In this study, we retrospectively analyzed the imaging characteristics of dual-tracer 68Ga-prostate specific membrane antigen (PSMA) and 18F-flurodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in metastatic prostate cancer (mPCa) patients. We analyzed the uptake modes of the dual tracers, explored clinical pathological parameters affecting the 18F-FDG uptake in the lesions, and evaluated their prognostic implications for prostate specific antigen progression-free survival (PSA-PFS). Methods: A total of 41 mPCa patients who underwent dual-tracer PET/CT (68Ga-PSMA and 18F-FDG) scans between September 2021 and January 2024 were retrospectively enrolled. One patient had negative uptake of both PSMA and FDG. According to the uptake patterns of the 2 tracers, the other patients, 40 in total, were categorized in 2 groups, including group A consisting of 33 cases who showed PSMA and FDG dual and those who showed FDG only avidity, and group B consisting of 7 cases who showed PSMA avidity only. Comparative analyses of clinical pathological characteristics between group A and group B were conducted. The relationship between various parameters and PSA-PFS was analyzed by the Kaplan-Meier method. Results: A total of 26 patients (63.4%) were diagnosed with metastatic castration-resistant prostate cancer (mCRPC), and 38 cases (92.7%) had a Gleason score of 8-9. Bone metastasis, the predominant type of distant metastasis, occurred in 36 cases (87.8%). The skeletal and distant lymph node metastases mostly showed a dual positive uptake pattern for both PSMA and FDG (85.7% [24/28] and 81.8% [9/11]). 37.5% (3/8) of the metastases to organs showed FDG only positive uptake pattern. The serum levels of prostate specific antigen (PSA) in group A were significantly higher than those in group B (P=0.013). A total of 13 patients of special pathological classification (intraductal carcinoma and neuroendocrine differentiation) were all found to be in group A. Among the 41 cases, 16 were lost to follow-up. Of the 25 patients who completed follow-up, 9 patients, with a median PSA value of 104 ng/mL, experienced PSA progression, while the 16 other patients, with a median PSA of 0.34 ng/mL, did not incur any PSA progression. There was significant difference in the median PSA between patients showing PSA progression and those who did not show PSA progression (P<0.001). Kaplan-Meier survival analysis revealed that the median PSA-PFS of patients of specific pathological classifications was 7 months, which was shorter than the 16 months of the patients with typical prostate cancer, with the difference between the two groups being statistically meaningful (P=0.043). The median PSA-PFS for group A was 30 months. With more than half of the patients in the group not experiencing any PSA progression, group B did not reach the median PSA-PFS (P=0.645). Conclusion: Dual-tracer PET/CT imaging with 68Ga-PSMA and 18F-FDG commonly exhibits avidity for both tracers in mPCa. Serum PSA level is a reliable biomarker for predicting FDG-positive lesions. mPCa presented with intraductal carcinoma and neuroendocrine differentiation tends to exhibit FDG avidity and is more susceptible to PSA progression.

Antimicrobial peptide LyeTx I mn∆K labeled with 68Ga is a potential PET radiopharmaceutical for molecular imaging of infections.

BACKGROUND: Antimicrobial peptides have been radiolabeled and investigated as molecular diagnostic probes due to their propensity to accumulate in infectious sites rather than aseptic inflammatory lesions. LyeTx I is a cationic peptide from the venom of Lycosa erythrognatha, exhibiting significant antimicrobial activity. LyeTx I mn∆K is a shortened derivative of LyeTx I, with an optimized balance between antimicrobial and hemolytic activities. This study reports the first 68Ga-radiolabeling of the DOTA-modified LyeTx I mn∆K and primarily preclinical evaluations of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for infection imaging. METHODS: DOTA(K)-LyeTx I mn∆K was radiolabeled with freshly eluted 68Ga. Radiochemical yield (RCY), radiochemical purity (RCP), and radiochemical stability (in saline and serum) were evaluated using ascending thin-layer chromatography (TLC) and reversed-phase high-performance liquid chromatography (RP-HPLC). The radiopeptide's lipophilicity was assessed by determining the logarithm of the partition coefficient (Log P). Serum protein binding (SBP) and binding to Staphylococcus aureus (S. aureus) cells were determined in vitro. Ex vivo biodistribution studies and PET/CT imaging were conducted in healthy mice (control) and mice with infection and aseptic inflammation to evaluate the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a specific PET radiopharmaceutical for infections. RESULTS: [68Ga]Ga-DOTA(K)-LyeTx I mn∆K was obtained with a high RCY (>90 %), and after purification through a Sep-Pak C18 cartridge, the RCP exceeded 99 %. Ascending TLC and RP-HPLC showed that the radiopeptide remained stable for up to 3.0 h in saline solution and up to 1.5 h in murine serum. [68Ga]Ga-DOTA(K)-LyeTx I mn∆K exhibited hydrophilic characteristics (Log P = -2.4 ± 0.1) and low SPB (ranging from 23.3 ± 0.4 % at 5 min of incubation to 10.5 ± 1.1 % at 60 min of incubation). The binding of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K to S. aureus cells was proportional to bacterial concentration, with binding percentages of 8.8 ± 0.5 % (0.5 × 109 CFU.mL-1), 16.2 ± 1.4 % (1.0 × 109 CFU.mL-1), and 62.2 ± 0.6 % (5.0 × 109 CFU.mL-1). Ex vivo biodistribution studies and PET/CT images showed higher radiopeptide uptake at the infection site compared to the aseptic inflammation site; the latter was similar to the control group. Target-to-non-target (T/NT) ratios obtained by ex vivo biodistribution data were approximately 1.0, 1.3, and 3.0 at all investigated time intervals for the control, aseptic inflammation, and infection groups, respectively. Furthermore, T/NT ratios obtained from PET/CT images were 1.1 ± 0.1 for the control group and 1.4 ± 0.1 for the aseptic inflammation group. For the infection group, T/NT ratio was 5.0 ± 0.3, approximately 5 times greater compared to the former groups. CONCLUSIONS: The results suggest the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for molecular imaging of infections.

[68Ga]Ga-LNC1007 versus 2-[18F]FDG in the evaluation of patients with metastatic differentiated thyroid cancer: a head-to-head comparative study.

PURPOSE: This head-to-head comparison study aimed to compare the performance of [68Ga]Ga-FAPI-RGD (LNC1007) and 2-[18F]FDG PET/CT in the evaluation of patients with metastatic differentiated thyroid cancer (mDTC). METHODS: Ten unexplained hyperthyroglobulinemia (UHTg) patients and 20 patients with definite metastatic lesions of thyroid cancer (DmDTC) were enrolled in the study. All patients underwent both [68Ga]Ga-LNC1007 and 2-[18F]FDG PET/CT within 1 week. The final diagnosis was based on histopathological results and a comprehensive evaluation of laboratory tests and multimodal imaging characteristics. RESULTS: In patients with UHTg, [68Ga]Ga-LNC1007 PET/CT detected more metastatic lymph nodes (LNs) (17 vs. 15, P = 0.317) and lung lesions (2 vs. 0) than 2-[18F]FDG. In patients with DmDTC, [68Ga]Ga-LNC1007 PET/CT also detected more true positive lesions than 2-[18F]FDG (Total: 133 vs. 103, LN: 20 vs. 15, lung: 18 vs. 10, bone: 87 vs.73). [68Ga]Ga-LNC1007 PET/CT demonstrated significantly higher SUVmax (Total: 6.30 vs. 3.84, LN: 8.28 vs. 4.82, Lung: 3.31 vs. 1.49, Bone: 5.73 vs. 3.87, all P < 0.05) and TBR (Total: 6.92 vs. 4.93, LN: 6.48 vs. 4.16, Lung: 5.16 vs. 2.57, Bone: 7.22 vs. 5.41, all P < 0.05) in true positive lesions compared to 2-[18F]FDG. Specifically, the sensitivity of [68Ga]Ga-LNC1007 PET/CT was higher than that of 2-[18F]FDG in detecting lung and bone metastases (94.7% vs. 52.6% and 100% vs. 83.9%, all P < 0.05). [68Ga]Ga-LNC1007 PET/CT exhibited better specificity and accuracy in diagnosing LNs (96.9% vs. 66.7% and 96.3% vs. 68.5%, all P < 0.05). However, the specificity of [68Ga]Ga-LNC1007 for bone metastasis was inferior to 2-[18F]FDG (15.4% vs. 88.5%, P < 0.05). CONCLUSION: Compared with 2-[18F]FDG, [68Ga]Ga-LNC1007 PET/CT could detect more metastatic lesions, with higher SUVmax and TBR, in patients with mDTC. [68Ga]Ga-LNC1007 had better accuracy in the diagnosis of LN and lung metastasis. Trial registration ClinicalTrials.gov NCT05515783. Registered 01 May 2022. URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05515783.

Validation of a radiosynthesis method and a novel quality control system for [68 Ga]Ga-MAA: is TLC enough to assess radiopharmaceutical quality?

BACKGROUND: Technetium-99 m-labelled macroaggregated human serum albumin ([99mTc]Tc-MAA) is commonly used for lung perfusion scintigraphy. The European Pharmacopoeia (Eu.Ph.) specifies thin-layer chromatography (TLC) as the only method to assess its radiochemical purity (RCP). Similarly, TLC is the sole method reported in the literature to evaluate the RCP of Gallium-68-labelled MAA [68 Ga]Ga-MAA, recently introduced for lung perfusion PET/CT imaging. Since [68 Ga]Ga-MAA is prepared from commercial kits originally designed for the preparation of [99mTc]Tc-MAA, it is essential to optimize and validate the preparation methods for [68 Ga]Ga-MAA. RESULTS: We tested a novel, simplified method for the preparation of [68 Ga]Ga-MAA that does not require organic solvents, prewash or final purification steps to remove radioactive impurities. We assessed the final product using radio-TLC, radio-UV-HPLC, and radio SDS-PAGE. Overall, our quality control (QC) method successfully detected [68 Ga]Ga-MAA along with all potential impurities, including free Ga-68, [68 Ga]Ga-HSA, unlabeled HSA, which may occur during labelling process and HEPES residual, a non-toxic but non-human-approved contaminant, used as buffer solution. We then applied our QC system to [68 Ga]Ga-MAA prepared under different conditions (25°-40°-75°-95 °C), thus defining the optimal temperature for labelling. Scanning Electron Microscopy (SEM) analysis of the products obtained through our novel method confirmed that most [68 Ga]Ga-MAA particles preserved the morphological structure and size distribution of unlabeled MAA, with a particle diameter range of 25-50 µm, assuring diagnostic efficacy. CONCLUSIONS: We optimized a novel method to prepare [68 Ga]Ga-MAA through a QC system capable of monitoring all impurities of the final products.

Cutting the Gordian Knot: Rare Presentation of Nodular Fasciitis as Supraclavicular Swelling with Muscular Involvement in 68Ga-FAPI-PET/CT.

Background: Nodular fasciitis is a benign, singularly occurring nodular fibroblastic/myofibroblastic neoplasia. Due to the rapid growth and cellular atypia, this rare differential diagnosis in the head and neck region can be mistaken for malignant sarcomas. Methods: We present a 40-year-old female patient with an unclear, rough, and poorly displaceable supraclavicular swelling on the right as part of a medical check-up. Sonographically, the lump was poorly circumscribed with little vascularization. A consecutive core needle biopsy of the lesion yielded inconclusive results showing spindle-shaped tumor cells. 68Ga-FAPI-PET/CT showed an intensive uptake of the right supraclavicular lesion in addition to postoperative changes in the right tonsil. Subsequent operative partial excision of the lesion confirmed the histopathological diagnosis of nodular fasciitis. Results: Nodular fasciitis is the most prevalent pseudosarcoma found in soft tissues. This case is the first description of 68Ga-FAPI-PET/CT in nodular fasciitis. Surgical removal is advised; nevertheless, the tumor frequently diminishes on its own, and recurrence is rare. Extensive surgical therapy is not necessary. Conlcusions: The recognition of nodular fasciitis and its benign characteristics is crucial to prevent diagnostic errors and the subsequent unnecessary operative treatment of the patient.

Rapid Concentration of Ga-68 and Proof-of-Concept Microscale Labeling of [68Ga]Ga-PSMA-11 in a Droplet Reactor.

The radiometal gallium-68 (Ga-68) has garnered significant interest due to its convenient production via compact and widely available generators and the high performance of 68Ga-labeled compounds for positron-emission tomography (PET) imaging for cancer diagnosis and management of patients undergoing targeted radionuclide therapy. Given the short half life of Ga-68 (68 min), microfluidic-based radiosynthesis is a promising avenue to establish very rapid, efficient, and routine radiolabeling with Ga-68; however, the typical elution volume of Ga-68 from a generator (4-10 mL) is incompatible with the microliter reaction volumes of microfluidic devices. To bridge this gap, we developed a microscale cartridge-based approach to concentrate Ga-68. By optimizing cartridge design, resin type, resin mass, and eluent composition, Ga-68 was reliably concentrated from ~6 mL to ~80 µL with high recovery efficiency (>97%, n = 14). Furthermore, this method is suitable for both single- and dual-generator setups. To demonstrate suitability of the concentrated radiometal for radiolabeling, we performed microdroplet synthesis of [68Ga]Ga-PSMA-11, achieving high radiochemical yield (83 ± 11%, n = 3), excellent radiochemical purity (>99%), and high apparent specific activity (255-320 MBq/µg). The entire process, including Ga-68 concentration, radiosynthesis, purification, and formulation, was completed in 12 min. Starting with activity of 0.81-0.84 GBq, 0.51-0.64 GBq of product was produced, sufficient for multiple patient doses. This work paves the way to clinical-scale production of other 68Ga-labeled compounds using droplet microreactor methods, or high-throughput labeling optimization or compound screening of 68Ga-labeled probes using droplet reaction arrays.

Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter's sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

18F-FDG PET/CT and 68Ga-DOTATATE PET/CT Findings of Polycystic Kidney-derived Paraganglioma.

Paragangliomas (PGLs) are neuroendocrine tumors originating from the neural crest. They usually arise from the adrenal medulla and sympathetic or parasympathetic ganglions. Approximately 10% of PGLs are located in the extra-adrenal gland. Renal PGL is a rare condition. In this case report, we present the 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) and 68Ga-DOTATATE PET/CT findings of polycystic kidney-derived PGL.

Distinguishing Bronchial Carcinoid from Benign Bronchocele using 68Ga-DOTATOC PET/CT Imaging.

Bronchial carcinoids are low-grade neuroendocrine tumors with slow growth rates and the potential to spread to nearby lymph nodes. Here we present a challenging case of bronchial carcinoid visualized alongside an adjacent benign bronchocele. Chest computed tomography (CT) identified the endobronchial mass with unclear morphological and diagnostic insights. A differential diagnosis of several benign and malignant etiologies was made. Subsequently, an endobronchial biopsy confirmed lung carcinoid. For better evaluation, a 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/CT scan was performed. The scan revealed a locally confined endobronchial mass with intense 68Ga-DOTATOC expression. Adjacent benign bronchocele was visualized with insignificant 68Ga-DOTATOC expression. Histopathological examination of the resected upper lobe confirmed these findings. This case highlights the importance of somatostatin receptor imaging in accurately identifying the extent of carcinoid tumors in the primary, nodal, and metastatic domains.

Prostate-specific membrane antigen PET versus [99mTc]Tc-MDP bone scan for diagnosing bone metastasis in prostate cancer: a head-to-head comparative meta-analysis.

Purpose: To evaluate the diagnostic performance of PSMA PET/CT, including [68Ga]Ga-PSMA-11 and [18F]DCFPyL, in comparison with the [99mTc]Tc-MDP bone scan (BS) in identifying bone metastases among prostate cancer patients. Methods: A search was performed in the PubMed and Embase databases to locate pertinent publications from inception to February 12, 2024. The studies included were those that examined the diagnostic effectiveness of PSMA PET/CT (covering [68Ga]Ga-PSMA-11 and [18F]DCFPyL) compared to [99mTc]Tc-MDP BS in identifying bone metastases among prostate cancer patients. The quality of the selected studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) checklist. Results: The meta-analysis included nine articles involving 702 patients. The sensitivity of PSMA PET/CT was higher compared to [99mTc]Tc-MDP BS (0.98 vs. 0.85, P < 0.01), while the specificity of PSMA PET/CT was also higher than [99mTc]Tc-MDP BS (0.97 vs. 0.70,P < 0.01). In subgroup analysis, the sensitivity of [68Ga]Ga-PSMA-11 PET/CT was higher compared to [99mTc]Tc-MDP BS (0.98 vs. 0.86), while the specificity of [68Ga]Ga-PSMA-11 PET/CT was also higher than [99mTc]Tc-MDP BS (0.98 vs. 0.65). Conclusion: Our meta-analysis demonstrates that PSMA PET/CT exhibits superior sensitivity and specificity in comparison with [99mTc]Tc-MDP BS for identifying bone metastases in prostate cancer patients. Further research with head-to-head design is necessary to validate these results and evaluate the clinical effectiveness of these imaging methods. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO CRD42024545112.

Prognostic value of PSMA PET in predicting long-term biochemical control following curative intent treatment for prostate cancer.

INTRODUCTION: The aim of this study is to investigate the prognostic value of 68Ga-labelled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) metrics in predicting long-term biochemical failure-free survival (BFFS) following curative intent treatment for prostate cancer. METHODS: We completed a prospective study that followed men who had PSMA PET for staging of newly diagnosed prostate cancer between 2015 and 2017 who went on to have curative intent treatment with radiotherapy (RT) or radical prostatectomy (RP). PSMA PET CT imaging was reported and the intraprostatic maximum standardised uptake value (SUVmax) was recorded. The primary outcome was BFFS. Statistical analysis included descriptive statistics, Cox proportional hazards (PH) models, Kaplan-Meier survival analysis and a regression tree structured method. RESULTS: A total of 183 men were included in the analysis with a median age of 66 years and the majority of patients (55.2%) had ISUP grade 1-3 disease. All patients had PSMA PET staging prior to curative intent treatment with RP (66.1%) or external beam radiotherapy (33.9%). PSMA-avid pelvic nodes were present in 26 patients but were not associated with worse biochemical control. A PSMA SUVmax of the prostate primary greater than the median (>5.6) was associated with a lower BFFS (HR: 4.4, 95% CI 1.42-3.72, P = 0.01). A multivariate Cox model incorporating initial biopsy grade, age and PSMA SUVmax showed that PSMA SUVmax was an independent predictor of BFFS. The RT-structured method identified an optimal threshold of 6.8 for PSMA SUVmax, above which patients with ISUP 1-3 disease had a significantly worse BFFS. CONCLUSION: PSMA SUVmax is a strong predictor of BFFS in patients with non-metastatic prostate cancer who underwent curative intent treatment. Patients with low-risk disease on biopsy (ISUP 1-3) but high PSMA SUVmax may have biochemical failure risk analogous to higher-risk disease (ISUP 4-5). These findings allow for further risk stratification and prognosis of patients with newly diagnosed prostate cancer planned for definitive treatment.

Cardiac Neuroendocrine Tumor Metastases on 68Ga-DOTATATE PET/CT: Identification and Prognostic Significance.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%-4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on 68Ga-DOTATATE PET/CT. Methods: 68Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUVmax with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent 68Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1-2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1-2 gastroenteropancreatic NETs. On Kaplan-Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUVmax (P = 0.027) and SUVmax-to-myocardial background ratio (P = 0.021). Conclusion: Routine 68Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

Ectopic ACTH-Dependent Cushing's Syndrome Emerging at a Late Stage of a Mixed Histology Neuroendocrine Neoplasm: A Case Report.

Introduction: Neuroendocrine neoplasms encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (neuroendocrine carcinomas [NECs]), which are distinguished by their clinical behavior and molecular characteristics. They can cause paraneoplastic syndromes, such as ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), necessitating prompt recognition and management due to severe hypercortisolism. Case Presentation: A 66-year-old patient with a 3-year history of metastatic mixed neuroendocrine-non-neuroendocrine neoplasm with a NEC and adenocarcinoma component originating from the vulva presented to the emergency department with dyspnea and fatigue. Upon clinical examination, we found widespread hyperpigmentation, a moon-face appearance, hirsutism, buffalo hump, and muscle atrophy. Laboratory investigations revealed severe hypokalemia (2.3 mmol/L), elevated serum cortisol (1,726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol measurement was 21-fold the upper limit of the reference range (3,614.0 nmol/24 h), and cortisol concentration did not decrease after 1mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L), confirming the ACTH-dependent CS. Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and lungs. Brain magnetic resonance imaging indicated multifocal metastatic infiltration but no evidence of pituitary adenoma. Interestingly, despite a previously negative 68Ga-DOTATATE positron emission tomography (PET)/CT performed 1 year prior, there was moderate somatostatin receptor (SSTR) expression in lymphatic, pulmonary, peritoneal, and bone tissues, suggesting the presence of a component with redifferentiation and re-expression of the SSTR. After the workup, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin analogs. Unfortunately, the patient was too frail to benefit from peptide receptor radionuclide therapy (PRRT). Conclusion: This redifferentiation phenomenon in neuroendocrine tumors should be further investigated as patients might be, under certain conditions, eligible for PRRT. Therefore, we suggest that newly occurring paraneoplastic syndromes in patients with NEC should always be evaluated using 68Ga-DOTATATE PET/CT.

Head-to-Head Comparison of [68Ga]Ga-NOTA-RM26 and [18F]FDG PET/CT in Patients with Gastrointestinal Stromal Tumors: A Prospective Study.

Gastrointestinal stromal tumors (GISTs) are the most common stromal tumors in the gastrointestinal tract. This study was designed to evaluate a gastrin-releasing peptide receptor antagonist PET tracer, [68Ga]Ga-NOTA-RM26, and compare it with [18F]FDG PET/CT in the assessment of patients with GISTs. Methods: With institutional review board approval and informed consent, 30 patients with suspected or proven GISTs based on abdominal CT or gastroscopy were recruited. All patients underwent [68Ga]Ga-NOTA-RM26 and [18F]FDG PET/CT scans. Pathology and other patient information were collected. Results: No radiopharmaceutical-related adverse events were observed in the patients. In total, 18 lesions in 16 patients were diagnosed as GIST, 3 patients were diagnosed with schwannoma, and 4 patients were diagnosed with leiomyoma. In 18 GISTs, the mean SUVmax of [68Ga]Ga-NOTA-RM26 PET was significantly higher than that of [18F]FDG PET (17.07 ± 19.57 vs. 2.28 ± 1.65; P < 0.01), and [68Ga]Ga-NOTA-RM26 PET/CT had a higher tumor detection rate than did [18F]FDG PET/CT (88.9% vs. 50%; P < 0.01). The uptake of [68Ga]Ga-NOTA-RM26 in GISTs was significantly higher than that in 2 other benign tumors (leiomyoma or schwannoma) (17.07 ± 19.57 vs. 4.23 ± 1.77; P = 0.014). With the SUVmax cutoff value of 6.0, the sensitivity of 68Ga-NOTA-RM26 PET/CT in diagnosing GISTs is 72% and the specificity is 85.7%. Conclusion: Compared with [18F]FDG PET/CT, [68Ga]Ga-NOTA-RM26 PET/CT is a promising and effective imaging modality for the detection of GISTs.

A Long Way to Find a Small Tumor: The Hunt for an Insulinoma.

We report a case of a 35-year-old woman with recurrent episodes of hypoglycemia. Biochemical investigation was suggestive of hyperinsulinemic hypoglycemia, and hence a provisional diagnosis of insulinoma was made. Despite extensive investigation using magnetic resonance imaging, endoscopic ultrasound, and 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scanning, the tumor could not be localized. Long-distance travel allowed her to undergo a 68Ga-Exendin-4 PET/CT scan that identified a lesion in the uncinate process of the pancreas, subsequently confirmed by intraoperative ultrasound. Enucleation of the 1.5-cm lesion was performed, and histopathology confirmed a well-differentiated pancreatic neuroendocrine tumor. Postoperatively, the patient has remained free of hypoglycemic episodes and has shown normalization of glucose levels. This case underscores the efficacy of 68Ga-Exendin-4 PET/CT in the localization of an occult insulinoma, facilitating timely and curative surgical intervention, and the importance of patients having access to such a facility when not locally available.

PET imaging of pheochromocytoma and paraganglioma - 18F-FDOPA vs. somatostatin analogues.

CONTEXT: Functional imaging with positron emission tomography (PET) scans is an essential part of the diagnostic workup for pheochromocytoma and paraganglioma (PPGL). The purpose of this review is a) to provide a brief overview of functional imaging for PPGL, b) summarize selected present and older guideline and review recommendations, and c) conduct a literature review on the diagnostic performance of the most used PET tracers for PPGL. EVIDENCE ACQUISITION: We conducted a systematic literature search in PubMed from January 2004 to August 2024 with the search string: ("Pheochromocytoma" OR "Paraganglioma") AND ("Positron-Emission Tomography" OR "Radionuclide Imaging" OR ("PET" AND ("FDG" OR "DOTATOC" OR "DOTANOC" OR "DOTATATE" OR "DOPA" OR "FDOPA"))). Studies involving PET scans of at least 20 individuals with PPGL, or at least five individuals in a rare, well-defined subgroup of PPGL (e.g. sympathetic or head-neck paragangliomas, and specific pathogenic variants) were included. EVIDENCE SYNTHESIS: Seventy studies were identified of which 21 were head-to-head comparisons of at least two different PET tracers (18F-fluorodihydroxyphenylalanine, 18F-FDOPA; 68Ga-DOTA-conjugated somatostatin analogues, 68Ga-SSA; and 18F-fluorodeoxyglucose, 18F-FDG). 18F-FDOPA had higher sensitivity for pheochromocytoma compared to 68Ga-SSA and equal sensitivity for metastatic pheochromocytoma. 18F-FDOPA and 68Ga-SSA had similar sensitivity for primary non-SDHx sympathetic and head-neck paraganglioma. However, 68Ga-SSA had higher sensitivity for metastatic sympathetic and head-neck paraganglioma and for SDHx-related paraganglioma. CONCLUSION: 18F-FDOPA and 68Ga-SSA PET are both sensitive for localizing PPGL. However, 18F-FDOPA is the most sensitive for detecting pheochromocytoma, while 68Ga-SSA is superior to 18F-FDOPA for metastatic sympathetic and head-neck paraganglioma and SDHx-related paraganglioma.

[68Ga]Ga-FAPI04 Outperforms [18F]FDG PET/CT for Detecting Nodal Metastasis of Head and Neck Squamous Cell Carcinoma: A Single-Center Experience.

This study assesses fibroblast activated protein inhibitor (FAPI) targeted PET/CT imaging against [18F]FDG PET/CT (FDG PET) for detecting nodal involvement in head and neck squamous cell carcinoma (HNSCC), intending to improve diagnostic precision for metastatic lymph nodes and lay the groundwork for future investigations. Methods: Patients diagnosed with HNSCC were retrospectively enrolled. All patients underwent [68Ga]Ga-FAPI04 PET/CT (FAPI PET) and FDG PET within 6 d. Primary tumor, lymph nodes, and tracer uptake were visually and quantitatively compared. The metastatic lymph nodes were evaluated using patient-and lesion-based analyses, with biopsy or postoperative histopathological examination as the reference. Results: The cohort includes 24 patients (17 men, 7 women; mean age 60 ± 11.8 years) who underwent FDG and FAPI PET for preoperative diagnostic workup or restaging due to known recurrence of HNSCC. Lesions included 24 primary tumors, 54 cervical lymph nodes, and 5 metastases. Primary tumors exhibited significant uptake on both PET modalities (median maximum standardized uptake value [SUVmax]: FDG 19.4 ± 11.6, FAPI 16.9 ± 4.6), with no statistically significant difference (p > 0.5). For lymph nodes, FAPI and FDG PET showed median SUVmax of 9.18 ± 6.77 and 9.67 ± 6.5, respectively. The patient-based analysis found FDG PET sensitivity at 88.2% and FAPI PET at 94.1%, with FAPI PET specificity significantly higher (85.7% vs. 42.8% for FDG PET). Lesion-based analysis revealed FAPI PET sensitivity and specificity at 84.2% and 93.7%, respectively, contrasting FDG PET's at 81.5% and 25%, respectively. Conclusion: This study underscores the efficacy of FAPI PET in detecting primary tumors in HNSCC. Furthermore, FAPI PET shows improved specificity over FDG PET for metastatic lymph nodes advocating further investigations for integrating FAPI PET into HNSCC clinical protocols for its enhanced precision in detecting metastatic lymph nodes.

Same-Day Positron Emission Tomography/Computed Tomography with 68Ga-Radiolabeled Fibroblast Activation Protein Inhibitors and 18F-Fluorodeoxyglucose Imaging for Gastrointestinal Cancers.

Objective: We investigated the clinical practicability of same-day 68Ga-radiolabeled fibroblast activation protein inhibitors (68Ga-FAPI)-first and 18F-fluorodeoxyglucose (18F-FDG) imaging and compared it with same-day 18F-FDG-first or 2-day procedures in diagnosing gastrointestinal cancers. Materials and Methods: Sixty-five patients with confirmed gastrointestinal cancers were divided into same-day 68Ga-FAPI-first group (Group A), same-day 18F-FDG-first group (Group B), and 2-day group (Group C). Low-dose CT and low injection activity were performed on 68Ga-FAPI positron emission tomography/computed tomography (PET/CT). Interval times, radiation dose, diagnostic performance, and detectability were assessed among groups. Additionally, the uptake, tumor-to-liver ratio (TLR), diagnostic efficacy, and TNM stage were compared between the two modalities. Results: The total waiting time for Group C was significantly longer than that for Group A or B (both p < 0.001). The total dose-length product and effective dose decreased in all groups. There were comparable detectability and diagnostic performance among groups (all p > 0.05). The within-group analysis in Group B indicated that 68Ga-FAPI PET/CT had higher uptake in the primary and recurrent lesions than 18F-FDG without differences in TLR, due to higher liver background on 68Ga-FAPI PET than Group A or C (both p < 0.001).68Ga-FAPI PET/CT possessed higher accuracy than 18F-FDG and changed staging in 14 patients (14/65, 21.54%). Conclusions: The same-day 68Ga-FAPI-first and 18F-FDG imaging reduced examination waiting time without increased radiation dose, simultaneously achieving excellent diagnostic performance and improving clinical staging in diagnosing gastrointestinal cancers.

Head-to-head comparison of 68 Ga-FAPI-46 PET/CT, 18F-FDG PET/CT, and contrast-enhanced CT for the detection of various tumors.

OBJECTIVE: FAPI-PET/CT exhibits high tumor uptake and low background accumulation, enabling high-sensitivity tumor detection. We compared the diagnostic performance of 68 Ga-FAPI-46 PET/CT plus contrast-enhanced CT (CE-CT), 18F-FDG PET/CT plus CE-CT, and standalone CE-CT in patients with various malignancies. METHODS: 232 patients underwent 68 Ga-FAPI-46 PET/CT,18F-FDG PET/CT, and CE-CT each within 4 weeks. Detection rates were assessed by a blinded reader, with ≥ 2 weeks between scans of the same patient to avoid recall bias. A sub-analysis of diagnostic performance was performed for 490 histopathologically validated lesions. Detection rates were compared using McNemar's test. RESULTS: Lesion-based detection rates in 68 Ga-FAPI-46 PET/CT plus CE-CT, 18F-FDG PET/CT plus CE-CT, and CE-CT alone were 91.2% (1540/1688), 82.5% (1393/1688) and 60.2% (1016/1688). The detection rates were significantly higher for 68 Ga-FAPI-46 PET/CT plus CE-CT than for 18F-FDG PET/CT plus CE-CT (p < 0.02 for primary lesions and p < 0.001 for total, abdominopelvic nodal, liver and other visceral lesions) and CE-CT (p < 0.0001 for total, primary, cervicothoracic nodal, abdominopelvic nodal, liver, other visceral, and bone lesions). In the sub-analysis, sensitivity, specificity, positive and negative predictive value, and accuracy were 61.3%, 96.7%, 81.4%, 91.4% and 90.0% for 68 Ga-FAPI-46 PET/CT plus CE-CT, 57.0%, 95.7%, 75.7%, 90.5% and 88.4% for 18F-FDG PET/CT plus CE-CT, and 51.6%, 97.2%, 81.4%, 89.6% and 88.6% for CECT, respectively. CONCLUSIONS: 68 Ga-FAPI-46 PET/CT plus CE-CT demonstrates a higher tumor detection rate than 18F-FDG PET/CT plus CE-CT and CE-CT in a diverse spectrum of malignancies, especially for primary, abdominopelvic nodal, liver, and other visceral lesions. Further studies on which entities draw particular benefit from 68 Ga-FAPI-46 PET/CT are warranted to aid appropriate diagnostic workup. TRIAL REGISTRATION: A total of N = 232 patients were analyzed. Of these, N = 50 patients were included in a prospective interventional trial (NCT05160051), and N = 175 in a prospective observational trial (NCT04571086) for correlation and clinical follow-up of PET findings; N = 7 patients were analyzed retrospectively.