More effective treatments for metastatic prostate cancer (mPC) are needed as disease progression remains universal. 177Lu-PSMA-617 radiopharmaceutical therapy (RPT)—Pluvicto (Novartis)—was first approved for the treatment of castration-resistant prostate cancer (PC) based on the landmark VISION

Heat shock protein 90 (Hsp90) is essential for maintaining cellular proteostasis and may play an important role in the development of neurodegenerative proteinopathies. Therefore, we aimed to develop an Hsp90-specific PET brain tracer to quantify Hsp90 expression in the brain invivo in order to explore its potential as a biomarker for neurodegenerative disease characterization and to support Hsp90-targeted drug development. Methods: We developed the radiosynthesis of (R)-2-amino-7-(4-fluoro-2-(6-(methoxy-11C)pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, [11C]HSP990, and validated the tracer using invitro autoradiography, invitro brain homogenate saturation binding, ex vivo biodistribution, and invivo PET imaging in rodent models of Alzheimer disease (AD) and Parkinson disease versus healthy age-matched and young controls. Human brain samples from AD patients and healthy subjects were included in our invitro binding studies. A nonhuman primate PET brain study with arterial blood sampling was conducted under baseline and blocking conditions. Results: In vitro and invivo [11C]HSP990 studies in rodents and a nonhuman primate revealed saturable Hsp90 binding pools in natural killer lymphocytes, bone marrow, and notably the brain, where the highest binding was observed, particularly in gray matter. Blocking studies indicated that saturable Hsp90 in natural killer lymphocytes considerably influences the pharmacokinetics of Hsp90-targeting probes, which is critical for Hsp90 drug development. In vitro [3H]HSP990 brain homogenate saturation binding assays suggested that the tracer binds a distinct subfraction of the total Hsp90 pool, which is significantly diminished in both rodent and human AD brain tissue compared with age-matched controls. In vivo PET imaging confirmed reduced [11C]HSP990 brain binding on aging and an even stronger decrease in AD mice, suggesting that Hsp90 depletion may impair protein quality control and accelerate proteinopathies. Conclusion: [11C]HSP990 is a promising Hsp90-specific tracer and reveals strong Hsp90 binding in the brain. Uniformly reduced tracer binding was observed in AD brain tissue compared with age-matched controls. [11C]HSP990 holds potential as a biomarker for neurodegenerative disease characterization and progression, and it may aid in patient stratification and therapy monitoring. Human [11C]HSP990 PET neuroimaging studies are under way to investigate whether these findings translate to humans.

A joint task force of subject-matter experts from the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently released a revised and updated guideline/procedure standard for indications and protocols for hybrid [18F]FDG imaging in

Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined BRAF/MEK inhibition for BRAF-mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved. The role of immune checkpoint inhibition has since expanded to the neoadjuvant and adjuvant settings with multiple regimens in routine use. Personalized therapies, including tumor-infiltrating lymphocytes that are extracted from a patient’s melanoma and eventually reinfused into the patient, and messenger RNA vaccines used to target neoantigens unique to a patient’s tumor, show promise. Improvements in accompanying imaging modalities, particularly within the field of nuclear medicine, have allowed for more accurate staging of disease and assessment of treatment response. Continued growth in the role of nuclear medicine in the evaluation of melanoma, including the incorporation of artificial intelligence into image interpretation and use of radiolabeled tracers allowing for intricate imaging of the tumor immune microenvironment, is expected in the coming years.

Targeted radionuclide therapy, as described by Goldsmith using Ehrlich’s words, is a magic bullet capable of delivering energy to a specific target to destroy it ([1][1]). Many new radiotracers have been rising, useful both for diagnosis and for therapy. Patients undergoing radiopharmaceutical

The current study aimed to compare 68Ga-NODAGA-Cpa-cyclo(d-Cys-amino-Phe-hydroorotic acid-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)-d-Tyr-NH2 (JR11) and 68Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. Methods: A prospective bicenter study aimed at enrolling 100 patients with histologically proven, metastatic or unresectable, well-differentiated neuroendocrine tumors was conducted. The first 48 patients represented the study cohort. Each patient received 68Ga-DOTATATE on the first day and 68Ga-NODAGA-JR11 on the second day. Whole-body PET/CT scans were performed at 40-60 min after injection. Normal-organ uptake, lesion numbers, lesion uptake, and sensitivity were compared. The potential impact on clinical management was also determined. Results: Overall, 68Ga-NODAGA-JR11 demonstrated lower background uptake in normal organs. Compared with 68Ga-DOTATATE, 68Ga-NODAGA-JR11 detected significantly more liver lesions (673 vs. 584, P = 0.002). The target-to-background ratio of liver lesions was significantly higher on 68Ga-NODAGA-JR11 (6.4 ± 8.7 vs. 3.1 ±2.6, P = 0.000). Comparable uptake was observed for primary tumors, bone lesions, and lymph node metastases. In total, 180 lesions were detected on conventional imaging in 15 patients; 165 and 139 lesions of them were positive on 68Ga-NODAGA-JR11 and 68Ga-DOTATATE, leading to a sensitivity of 91.7% and 77.2%, respectively. In 14.5% (7/48) of patients, 68Ga-NODAGA-JR11 PET might have a potential impact on clinical management. Conclusion: 68Ga-NODAGA-JR11 shows better sensitivity and a higher target-to-background ratio than 68Ga-DOTATATE. The detection of more lesions by the antagonist may have a potential impact on clinical management in a subgroup of patients.

We investigated the effects of blood glucose levels on the performance of 18F-FDG PET/CT for detecting an infection focus in patients with bacteremia. Methods: A total of 322 consecutive patients with bacteremia who underwent 18F-FDG PET/CT between 2010 and 2021 were included. Logistic regression analysis was performed to evaluate the association between finding a true-positive infection focus on 18F-FDG PET/CT and blood glucose level, type of diabetes, and use of hypoglycemic medication. C-reactive protein, leukocyte count, duration of antibiotic treatment, and type of isolated bacteria were considered as well. Results: Blood glucose level (odds ratio, 0.76 per unit increase; P = <0.001) was significantly and independently associated with 18F-FDG PET/CT outcome. In patients with a blood glucose level between 3.0 and 7.9 mmol/L (54-142 mg/dL), the true-positive detection rate of 18F-FDG PET/CT varied between 61% and 65%, whereas in patients with a blood glucose level between 8.0 and 10.9 mmol/L (144-196 mg/dL), the true-positive detection rate decreased to 30%-38%. In patients with a blood glucose level greater than 11.0 mmol/L (200 mg/dL), the true-positive detection rate was 17%. In addition to C-reactive protein (odds ratio, 1.004 per point increase; P = 0.009), no other variables were independently associated with 18F-FDG PET/CT outcome. Conclusion: In patients with moderate to severe hyperglycemia, 18F-FDG PET/CT was much less likely to identify the focus of infection than in normoglycemic patients. Although current guidelines recommend postponing 18F-FDG PET/CT only in cases of severe hyperglycemia with glucose levels greater than 11 mmol/L (200 mg/dL), a lower blood glucose threshold seems to be more appropriate in patients with bacteremia of unknown origin and other infectious diseases.

223Ra, a targeted α-therapy, is approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have bone metastases. In the phase 3 ALSYMPCA study, 223Ra prolonged survival and improved quality of life versus placebo. Our real-world study, PARABO, investigated pain and bone pain-related quality of life in patients with mCRPC and symptomatic bone metastases receiving 223Ra in clinical practice. Methods: PARABO was a prospective, observational, noninterventional single-arm study conducted in nuclear medicine centers across Germany (NCT02398526). The primary endpoint was a clinically meaningful pain response (≥2-point improvement from baseline for the worst-pain item score in the Brief Pain Inventory-Short Form). Results: The analysis included 354 patients, who received a median of 6 223Ra injections (range, 1-6). Sixty-seven percent (236/354) received 5-6 injections, and 33% (118/354) received 1-4 injections. Of 216 patients with a baseline worst-pain score of more than 1, 59% (128) had a clinically meaningful pain response during treatment. Corresponding rates were 67% (range, 98/146) with 5-6 223Ra injections versus 43% (range, 30/70) with 1-4 injections, 60% (range, 60/100) in patients with no more than 20 lesions versus 59% (range, 65/111) in those with more than 20 lesions, and 65% (range, 69/106) in patients without prior or concomitant opioid use versus 54% (range, 59/110) in those with prior or concomitant opioid use. Mean subscale scores (pain severity and pain interference) on the Brief Pain Inventory-Short Form improved during treatment. Conclusion: 223Ra reduced pain in patients with mCRPC and symptomatic bone metastases, particularly in patients who received 5-6 injections. The extent of metastatic disease did not impact pain response.

REPLY: We very much would like to thank Dr. Bailey for his valuable comments, which give us the opportunity to further explain our definition of theranostics. Dr. Bailey writes that a meaningful definition of theranostics requires that the targeting moiety be the same or very similar for the

Correct and timely diagnosis of pancreatic cancer (PC) is essential for treatment selection but is still clinically challenging. Standard-of-care imaging methods can sometimes not differentiate malignancies from inflammatory lesions or detect malignant transformation in premalignant lesions. This interim analysis of a prospective clinical trial aimed to evaluate the diagnostic accuracy of [68Ga]fibroblast activation protein inhibitor (FAPI)-46 PET/CT for PC and determine the sample size needed to demonstrate whether this imaging technique improves the characterization of equivocal lesions detected by standard-of-care imaging methods. Methods: [68Ga]FAPI-46 PET/CT imaging was performed on 30 patients scheduled for surgical resection of suspected PC. Target lesions were delineated, SUVmax and SUVmean were determined, and the results were compared with those of standard-of-care imaging. Receiver operating characteristics were calculated for the whole cohort and a subcohort of 11 patients with an equivocal clinical imaging work-up preoperatively. Postoperative histopathologic findings served as a reference standard, and the statistical power was determined. Results: Histopathologic examination revealed malignancy in 20 patients and benign lesions in 10 patients. Significantly elevated [68Ga]FAPI-46 uptake was observed in malignant tumors compared with benign lesions (P < 0.001). Receiver-operating-characteristic analyses established optimal cutoffs for both SUVs for differentiation of malignant from nonmalignant pancreatic tumors. The optimal SUVmax cutoff was 10.2 and showed 95% sensitivity and 80% specificity for the whole cohort, as well as 100% diagnostic accuracy when considering the subcohort with equivocal imaging work-up only. For sufficient statistical power, 38 equivocal observations are needed. Conclusion: We conclude that [68Ga]FAPI-46 PET/CT can accurately differentiate malignant from benign pancreatic lesions deemed equivocal by standard-of-care imaging. This trial will therefore continue to recruit a total of 120 patients to reach those 38 equivocal observations needed for sufficient statistical power. On the basis of our findings, we propose that [68Ga]FAPI-46 PET/CT not only can be clinically applied as a complement but also could become a necessary tool when standard-of-care imaging is inconclusive.