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Accurate imaging is essential for staging prostate cancer and guiding management decisions. Conventional imaging modalities are hampered by a limited sensitivity for metastatic disease. Nearly all prostate cancers express prostate-specific membrane antigen (PSMA) and 18F-DCFPyL (piflufolastat F 18) is a new FDA-approved positron emission tomography (PET) agent that targets PSMA for improved staging of prostate cancer. This article provides an overview of PSMA, the mechanism of action of 18F-DCFPyL, and compares the performance of 18F-DCFPyL to conventional prostate imaging modalities. Current prostate cancer imaging guidelines are reviewed, as well as what changes can be expected in the future with increased access to PSMA-PET. The OSPREY and CONDOR clinical trials have demonstrated the superiority of 18F-DCFPyL over conventional imaging modalities for the staging and restaging of prostate cancer. The remarkable diagnostic accuracy of PSMA-PET is reshaping prostate cancer imaging and the modularity of these agents hint at exciting new diagnostic and therapeutic opportunities that have the potential to improve the care of patients with prostate cancer as a whole. [ABSTRACT FROM AUTHOR]

The phase 3 VISION trial demonstrated that [ 177 Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [ 177 Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [ 177 Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177 Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177 Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

G-quadruplex (G4) structures can form in guanine-rich DNA or RNA and have been found to modulate cellular processes including replication, transcription, and translation. Many studies on the cellular roles of G4s have focused on eukaryotic systems, with far fewer probing bacterial G4s. Using a chemical-genetic approach, we identified genes in Escherichia coli that are important for growth in G4-stabilizing conditions. Reducing levels of elongation factor Tu or slowing translation elongation with chloramphenicol suppress the effects of G4 stabilization. In contrast, reducing expression of certain translation termination or ribosome recycling proteins is detrimental to growth in G4-stabilizing conditions. Proteomic and transcriptomic analyses demonstrate that ribosome assembly factors and other proteins involved in translation are less abundant in G4-stabilizing conditions. Our integrated systems approach allowed us to propose a model for how RNA G4s can present barriers to E. coli growth and that reducing the rate of translation can compensate for G4-related stress., Competing Interests: Competing Interest Statement: There are no conflicts of interest with this study.

This study aimed to assess the accuracy of intraprostatic tumor volume measurements on prostate-specific membrane antigen-targeted 18 F-DCFPyL PET/CT made with various segmentation methods. An accurate understanding of tumor volumes versus segmentation techniques is critical for therapy planning, such as radiation dose volume determination and response assessment. Methods: Twenty-five men with clinically localized, high-risk prostate cancer were imaged with 18 F-DCFPyL PET/CT before radical prostatectomy. The tumor volumes and tumor-to-prostate ratios (TPRs) of dominant intraprostatic foci of uptake were determined using semiautomatic segmentation (applying SUV max percentage [SUV%] thresholds of SUV30%-SUV70%), adaptive segmentation (using adaptive segmentation percentage [A%] thresholds of A30%-A70%), and manual contouring. The histopathologic tumor volume (TV-Histo) served as the reference standard. The significance of differences between TV-Histo and PET-based tumor volume were assessed using the paired-sample Wilcoxon signed-rank test. The Spearman correlation coefficient was used to establish the strength of the association between TV-Histo and PET-derived tumor volume. Results: Median TV-Histo was 2.03 cm 3 (interquartile ratio [IQR], 1.16-3.36 cm 3 ), and median TPR was 10.16%. The adaptive method with an A40% threshold most closely determined the tumor volume, with a median difference of +0.19 (IQR, -0.71 to +2.01) and a median relative difference of +7.6%. The paired-sample Wilcoxon test showed no significant difference in PET-derived tumor volume and TV-Histo using A40%, A50%, SUV40%, and SUV50% threshold segmentation algorithms ( P > 0.05). For both threshold-based segmentation methods, use of higher thresholds (e.g., SUV60% or SUV70% and A50%-A70%) resulted in underestimation of tumor volumes, and use of lower thresholds (e.g., SUV30% or SUV40% and A30%) resulted in overestimation of tumor volumes relative to TV-Histo and TPR. Manual segmentation overestimated the tumor volume, with a median difference of +2.49 (IQR, 0.42-4.11) and a median relative difference of +130%. Conclusion: Segmentation of intraprostatic tumor volume and TPR with an adaptive segmentation approach most closely approximates TV-Histo. This information might be used to guide the primary treatment of men with clinically localized, high-risk prostate cancer., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) is rapidly becoming widely accepted as the standard-of-care for imaging of men with prostate cancer. Labeled indications for regulatoryapproved agents include primary staging and recurrent disease in men at risk of metastases. The first commercial PSMA PET agent to become available was 18F-DCFPyL (piflufolastat F 18), a radiofluorinated small molecule with high-affinity for PSMA. The regulatory approval of 18F-DCFPyL hinged upon two key, multi-center, registration trials, OSPREY (patient population: highrisk primary staging) and CONDOR (patient population: biochemical recurrence). In this manuscript, we will (1) review key findings from the OSPREY and CONDOR trials, (2) discuss the clinical acquisition protocol we use for 18F-DCFPyL PET scanning, (3) present information on important pearls and pitfalls, (4) provide an overview of the PSMA reporting and data system (PSMA-RADS) interpretive framework, and (5) posit important future directions for research in PSMA PET. Our overall goal is to provide a brief introduction for practices and academic groups that are adopting 18F-DCFPyL PET scans for use in their patients with prostate cancer.

Introduction: Accurate imaging is essential for staging prostate cancer and guiding management decisions. Conventional imaging modalities are hampered by a limited sensitivity for metastatic disease. Nearly all prostate cancers express prostate-specific membrane antigen (PSMA) and 18 F-DCFPyL (piflufolastat F 18) is a new FDA-approved positron emission tomography (PET) agent that targets PSMA for improved staging of prostate cancer., Areas Covered: This article provides an overview of PSMA, the mechanism of action of 18 F-DCFPyL, and compares the performance of 18 F-DCFPyL to conventional prostate imaging modalities. Current prostate cancer imaging guidelines are reviewed, as well as what changes can be expected in the future with increased access to PSMA-PET., Expert Opinion: The OSPREY and CONDOR clinical trials have demonstrated the superiority of 18 F-DCFPyL over conventional imaging modalities for the staging and restaging of prostate cancer. The remarkable diagnostic accuracy of PSMA-PET is reshaping prostate cancer imaging and the modularity of these agents hint at exciting new diagnostic and therapeutic opportunities that have the potential to improve the care of patients with prostate cancer as a whole. .

The bacterial single-stranded DNA-binding protein (SSB) uses an acidic C-terminal tail to interact with over a dozen proteins, acting as a genome maintenance hub. These SSB-protein interactions are essential, as mutations to the C-terminal tail that disrupt these interactions are lethal in Escherichia coli. While the roles of individual SSB-protein interactions have been dissected with mutational studies, small-molecule inhibitors of these interactions could serve as valuable research tools and have potential as novel antimicrobial agents. This chapter describes a high-throughput screening campaign used to identify inhibitors of SSB-protein interactions. A screen targeting the PriA-SSB interface from Klebsiella pneumoniae is presented as an example, but the methods may be adapted to target nearly any SSB interaction.

Protein-protein interaction (PPI) inhibitors are a rapidly expanding class of therapeutics. Recent advances in our understanding of PPIs and success of early examples of PPI inhibitors demonstrate the feasibility of targeting PPIs. This review summarizes the techniques used for the discovery and optimization of a diverse set PPI inhibitors, focusing on the development of PPI inhibitors as new antibacterial and antiviral agents. We close with a summary of the advances responsible for making PPI inhibitors realistic targets for therapeutic intervention and brief outlook of the field., (© 2018 Elsevier Inc. All rights reserved.)