Publications by authors named "Martin G Pomper"

407 Publications

Imaging infections in patients using pathogen-specific positron emission tomography.

Sci Transl Med 2021 04;13(589)

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[F]fluoro-d-sorbitol (F-FDS) can selectively detect infections in murine models. Here, we demonstrate that uptake of F-FDS by bacteria occurs via a metabolically conserved sorbitol-specific pathway with rapid in vitro F-FDS uptake noted in clinical strains, including MDR isolates. Whole-body F-FDS PET/computerized tomography (CT) in 26 prospectively enrolled patients with either microbiologically confirmed infection or other pathologies demonstrated that F-FDS PET/CT was safe, could rapidly detect and localize infections due to drug-susceptible or MDR strains, and differentiated them from sterile inflammation or cancerous lesions. Repeat imaging in the same patients monitored antibiotic efficacy with decreases in PET signal correlating with clinical improvement. To facilitate the use of F-FDS, we developed a self-contained, solid-phase cartridge to rapidly (<10 min) formulate ready-to-use F-FDS from commercially available 2-deoxy-2-[F]fluoro-d-glucose (F-FDG) at room temperature. In a hamster model, F-FDS PET/CT also differentiated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia from secondary pneumonia-a leading cause of complications in hospitalized patients with COVID-19. These data support F-FDS as an innovative and readily available, pathogen-specific PET technology with clinical applications.
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http://dx.doi.org/10.1126/scitranslmed.abe9805DOI Listing
April 2021

A Systematic Review and Meta-analysis of the Effectiveness and Toxicities of Lutetium-177-labeled Prostate-specific Membrane Antigen-targeted Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

Eur Urol 2021 Apr 8. Epub 2021 Apr 8.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Context: Castration-resistant prostate cancer (CRPC) treatment is an evolving challenge. Prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) with small-molecule, urea-based agents labeled with the β-particle-emitting radionuclide lutetium-177 (Lu) is a promising new approach.

Objective: In this systematic review and meta-analysis, we evaluated the efficacy and toxicity of PRLT.

Evidence Acquisition: A systematic search was performed in PubMed/Medline (last updated February 18, 2019). A total of 250 studies were reviewed, and 24 studies with 1192 patients were included in the analysis. Proportions of patients with ≥50% serum prostate-specific antigen (PSA) decrease, any PSA decrease, and any PSA increase were extracted. Proportions of patients showing any grade toxicity and those with grade 3/4 toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) grading were extracted from manuscripts. Overall survival and progression-free survival were evaluated. A meta-analysis of single proportions was carried out. Furthermore, we compared the two most common PRLT agents, Lu-PSMA with Lu-PSMA-I&T, for effectiveness and toxicity.

Evidence Synthesis: Among the 24 included studies, 20 included data on Lu-PSMA-617, three included data on Lu-PSMA-I&T, and one study had aggregated data for Lu-PSMA-617 and Lu-PSMA-I&T. The estimated proportion of Lu-PSMA-617-treated patients who showed a serum PSA decrease of ≥50% with at least an 8-wk interval between therapy and PSA measurement was 0.44 (0.39; 0.50). Therapy with Lu-PSMA-I&T demonstrated an estimated proportion of patients with ≥50% PSA reduction to be 0.36 (0.26; 0.47). The aggregate results for men treated with more than one cycle of any kind of PRLT showed an estimated proportion of 0.46 (0.41; 0.51) for PSA response ≥50%. Regarding aggregate data from all of the PRLT agents, we found that grade 3 and 4 toxicities were uncommon, with estimated proportions from 0.01 (0.00;0.04) for nausea, fatigue, diarrhea, and elevated aspartate transaminase up to 0.08 (0.05; 0.12) for anemia. There was considerable heterogeneity among the studies in the "any-grade toxicity" groups. Meta-regression showed that more than one cycle of PRLT is associated with a greater proportion of patients with ≥50% PSA reduction. Overall survival according to pooled hazard ratios (HRs) for any PSA decline was 0.29 (0.18; 0.46), and for >50% PSA reduction was 0.67 (0.43; 1.07). Progression-free survival according to a pooled HR of >50% PSA reduction was 0.53 (0.32; 0.86).

Conclusions: The relatively high number of PSA responders alongside the low rate of severe toxicity reflects the potentially promising role of PRLT in treating CRPC. The ultimate utility of this treatment modality will become clearer as multiple prospective studies continue to accrue. In the interim, this systematic review and meta-analysis can serve as a compendium of effectiveness and adverse events associated with PRLT for treating clinicians.

Patient Summary: Prostate-specific membrane antigen-targeted endoradiotherapy/radioligand therapy (PRLT) is associated with ≥50% reduction in prostate-specific antigen level in a large number of patients and a low rate of toxicity, reflecting its potential in treating castration-resistant prostate cancer. This systematic review and meta-analysis presents as a compendium of the effectiveness and adverse events related to PRLT for treating clinicians.
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http://dx.doi.org/10.1016/j.eururo.2021.03.004DOI Listing
April 2021

CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas.

Diagnostics (Basel) 2021 Mar 29;11(4). Epub 2021 Mar 29.

European Neuroendocrine Tumor Society (ENETS) Center of Excellence, NET Zentrum, University Hospital Würzburg, 97080 Würzburg, Germany.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. Ga-Pentixafor visualized tumor lesions in 10/11 subjects, whileF-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, = 107; < 0.001). Semi-quantitative analysis revealed markedly higher F-FDG uptake as compared to Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUV: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUV: 7.4 ± 5.4 vs. 3.1 ± 3.2, < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard F-FDG PET/CT.
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http://dx.doi.org/10.3390/diagnostics11040605DOI Listing
March 2021

A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile.

Sci Rep 2021 Mar 29;11(1):7114. Epub 2021 Mar 29.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success. We developed a non-radioactive prodrug, SBPD-1, composed of a small-molecule PSMA-targeting moiety, a cancer-selective cleavable linker, and the microtubule inhibitor monomethyl auristatin E (MMAE). SBPD-1 demonstrated high binding affinity to PSMA (K = 8.84 nM) and selective cytotoxicity to PSMA-expressing PC cell lines (IC = 3.90 nM). SBPD-1 demonstrated a significant survival benefit in two murine models of human PC relative to controls. The highest dose tested did not induce toxicity in immunocompetent mice. The high specific targeting ability of SBPD-1 to PSMA-expressing tumors and its favorable toxicity profile warrant its further development.
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http://dx.doi.org/10.1038/s41598-021-86551-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007718PMC
March 2021

Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

J Med Chem 2021 Apr 17;64(7):4059-4070. Epub 2021 Mar 17.

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States.

Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, and [In], using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity . and [In] demonstrated nanomolar inhibition of FAP at values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically . [In] showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02171DOI Listing
April 2021

Prospective, Single-Arm Trial Evaluating Changes in Uptake Patterns on Prostate-Specific Membrane Antigen (PSMA)-Targeted F-DCFPyL PET/CT in Patients with Castration-Resistant Prostate Cancer Starting Abiraterone or Enzalutamide.

J Nucl Med 2021 Feb 19. Epub 2021 Feb 19.

Johns Hopkins University School of Medicine, United States.

Positron emission tomography (PET) with small molecules targeting prostate-specific membrane antigen (PSMA) is being adopted as a clinical standard for prostate cancer (PCa) imaging. In this study, we evaluated changes in uptake on PSMA-targeted PET in men starting abiraterone or enzalutamide. This prospective, single-arm, two-center, exploratory clinical trial enrolled men with metastatic castration-resistant prostate cancer (CRPC) initiating abiraterone or enzalutamide. Each patient was imaged with F-DCFPyL at baseline and within 2-4 months after starting therapy. Patients were followed for up to 48 months from enrollment. A central review evaluated baseline and follow-up PET scans recording change in maximum standardized uptake value (SUV) at all disease sites and classifying the pattern of change. Two parameters: the delta percent SUV (DPSM) of all lesions and the delta absolute SUV (DASM) of all lesions were derived. Kaplan-Meier curves were used to estimate time to therapy change (TTTC) and overall survival (OS). Sixteen evaluable patients were accrued to the study. Median TTTC was 9.6 months (95% confidence interval (CI), 6.9-14.2) and median OS was 28.6 months (95% CI 18.3-not available (N/A)). Patients with a mixed-but-predominantly-increased pattern of radiotracer uptake had shorter TTTC and OS. Men with low DPSM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS 37.2 months (95% CI 28.9-N/A), while those with high DPSM had median TTTC 6.5 months (95% CI 4.6-N/A, = 0.0001) and median OS 17.8 months (95% CI 13.9-N/A, = 0.02). Men with low DASM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS N/A (95% CI 37.2 months-N/A), while those with high DASM had median TTTC 6.9 months (95% CI 6.1-N/A, = 0.003) and median OS 17.8 months (95% CI 13.9-N/A, = 0.002). Findings on PSMA-targeted PET 2-4 months after initiation of abiraterone or enzalutamide are associated with TTTC and OS. Development of new lesions and/or increasing intensity of radiotracer uptake at sites of baseline disease are poor prognostic findings suggesting shorter TTTC and OS.
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http://dx.doi.org/10.2967/jnumed.120.259069DOI Listing
February 2021

Synthesis and preliminary evaluation of At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Nucl Med Biol 2021 Mar-Apr;94-95:67-80. Epub 2021 Jan 23.

Department of Radiology, Duke University Medical Center, Durham, NC, USA. Electronic address:

Introduction: The high potency and short tissue range of α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of At-labeled prostate-specific membrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment.

Methods: Four novel Glu-urea based PSMA ligands containing a trialkyl stannyl group were synthesized and labeled with At, and for comparative purposes, I, via halodestannylation reactions with N-chlorosuccinimide as the oxidant. A PSMA inhibitory assay was performed to evaluate PSMA binding of the unlabeled, iodinated compounds. A series of paired-label biodistribution experiments were performed to compare each At-labeled PSMA ligand to its I-labeled counterpart in mice bearing subcutaneous PC3 PSMA+ PIP xenografts.

Results: Radiochemical yields ranged from 32% to 65% for the At-labeled PSMA inhibitors and were consistently lower than those obtained with the corresponding I-labeled analogue. Good localization in PC3 PSMA+ PIP but not control xenografts was observed for all labeled molecules studied, which exhibited a variable degree of in vivo dehalogenation as reflected by thyroid and stomach activity levels. Normal tissue uptake and in vivo stability for several of the compounds was markedly improved compared with the previously evaluated compounds, [At]DCABzL and [*I]DCIBzL.

Conclusions And Implications For Patient Care: Compared with the first generation compound [At]DCABzL, several of the novel At-labeled PSMA ligands exhibited markedly improved stability in vivo and higher tumor-to-normal tissue ratios. [At]GV-620 has the most promising characteristics and warrants further evaluation as a targeted radiotherapeutic for prostate cancer.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987787PMC
January 2021

First-in-human neuroimaging of soluble epoxide hydrolase using [F]FNDP PET.

Eur J Nucl Med Mol Imaging 2021 Feb 13. Epub 2021 Feb 13.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Purpose: Soluble epoxide hydrolase (sEH) is an enzyme with putative effect on neuroinflammation through its influence on the homeostasis of polyunsaturated fatty acids and related byproducts. sEH is an enzyme that metabolizes anti-inflammatory epoxy fatty acids to the corresponding, relatively inert 1,2-diols. A high availability or activity of sEH promotes vasoconstriction and inflammation in local tissues that may be linked to neuropsychiatric diseases. We developed [F]FNDP to study sEH in vivo with positron emission tomography (PET).

Methods: Brain PET using bolus injection of [F]FNDP followed by emission imaging lasting 90 or 180 min was completed in healthy adults (5 males, 2 females, ages 40-53 years). The kinetic behavior of [F]FNDP was evaluated using a radiometabolite-corrected arterial plasma input function with compartmental or graphical modeling approaches.

Results: [F]FNDP PET was without adverse effects. Akaike information criterion favored the two-tissue compartment model (2TCM) in all ten regions of interest. Regional total distribution volume (V) values from each compartmental model and Logan analysis were generally well identified except for corpus callosum V using the 2TCM. Logan analysis was assessed as the choice model due to stability of regional V values from 90-min data and due to high correlation of Logan-derived regional V values with those from the 2TCM. [F]FNDP binding was higher in human cerebellar cortex and thalamus relative to supratentorial cortical regions, which aligns with reported expression patterns of the epoxide hydrolase 2 gene in human brain.

Conclusion: These data support further use of [F]FNDP PET to study sEH in human brain.
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http://dx.doi.org/10.1007/s00259-021-05231-4DOI Listing
February 2021

Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [ In]In-XYIMSR-01 for phase I regulatory approval.

J Labelled Comp Radiopharm 2021 Feb 12. Epub 2021 Feb 12.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

[ In]In-XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [ In]In-XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212. Toxicity was evaluated by using nonradioactive [ In]In-XYIMSR-01 according to 21 CFR Part 58 guidelines. Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was used to calculate the maximum single dose for human studies. Three process validation runs at starting radioactivities of ~800 MBq were completed with a minimum concentration of 407 MBq/ml and radiochemical purity of >99% at the end of synthesis. A single intravenous dose of 55 μg/ml of [ In]In-XYIMSR-01 was well tolerated in male and female Sprague-Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [ In]In-XYIMSR-01. We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [ In]In-XYIMSR-01 in a phase I clinical trial.
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http://dx.doi.org/10.1002/jlcr.3906DOI Listing
February 2021

Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors.

Nanotheranostics 2021 19;5(2):182-196. Epub 2021 Jan 19.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Enhanced vascular permeability in tumors plays an essential role in nanoparticle delivery. Prostate-specific membrane antigen (PSMA) is overexpressed on the epithelium of aggressive prostate cancers (PCs). Here, we evaluated the feasibility of increasing the delivery of PSMA-targeted magnetic nanoparticles (MNPs) to tumors by enhancing vascular permeability in PSMA(+) PC tumors with PSMA-targeted photodynamic therapy (PDT). PSMA(+) PC3 PIP tumor-bearing mice were given a low-molecular-weight PSMA-targeted photosensitizer and treated with fluorescence image-guided PDT, 4 h after. The mice were then given a PSMA-targeted MNP immediately after PDT and monitored with fluorescence imaging and T-weighted magnetic resonance imaging (T-W MRI) 18 h, 42 h, and 66 h after MNP administration. Untreated PSMA(+) PC3 PIP tumor-bearing mice were used as negative controls. An 8-fold increase in the delivery of the PSMA-targeted MNPs was detected using T-W MRI in the pretreated tumors 42 h after PDT, compared to untreated tumors. Additionally, T-W MRIs revealed enhanced peripheral intra-tumoral delivery of the PSMA-targeted MNPs. That finding is in keeping with two-photon microscopy, which revealed higher vascular densities at the tumor periphery. These results suggest that PSMA-targeted PDT enhances the delivery of PSMA-targeted MNPs to PSMA(+) tumors by enhancing the vascular permeability of the tumors.
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http://dx.doi.org/10.7150/ntno.52361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868004PMC
January 2021

Detection of Early Progression with F-DCFPyL PET/CT in Men with Metastatic Castration-Resistant Prostate Cancer Receiving Bipolar Androgen Therapy.

J Nucl Med 2021 Jan 15. Epub 2021 Jan 15.

Johns Hopkins University, United States.

Bipolar androgen therapy (BAT) is an emerging treatment for metastatic castration resistant prostate cancer (mCRPC). F-DCFPyL is a small-molecule positron emission tomography (PET) radiotracer targeting prostate-specific membrane antigen (PSMA). We analyzed the utility of F-DCFPyL PET/CT in determining clinical response to BAT. Six men with mCRPC receiving BAT were imaged with F-DCFPyL PET/CT at baseline and after 3 months of treatment. Progression by PSMA-targeted PET/CT was defined as the appearance of any new F-DCFPyL-avid lesion. Three of 6 (50%) patients had progression on F-DCFPyL PET/CT. All three had stable disease or better on contemporaneous conventional imaging. Radiographic progression on CT and/or bone scan was observed within 3 months of progression on F-DCFPyL PET/CT. For the 3 patients that did not have progression on F-DCFPyL PET/CT, radiographic progression was not observed for > 6 months. New radiotracer-avid lesions on F-DCFPyL PET/CT in men with mCRPC undergoing BAT can indicate early progression.
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http://dx.doi.org/10.2967/jnumed.120.259226DOI Listing
January 2021

A Learned Reconstruction Network for SPECT Imaging.

IEEE Trans Radiat Plasma Med Sci 2021 Jan 12;5(1):26-34. Epub 2020 May 12.

Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.

A neural network designed specifically for SPECT image reconstruction was developed. The network reconstructed activity images from SPECT projection data directly. Training was performed through a corpus of training data including that derived from digital phantoms generated from custom software and the corresponding projection data obtained from simulation. When using the network to reconstruct images, input projection data were initially fed to two fully connected (FC) layers to perform a basic reconstruction. Then the output of the FC layers and an attenuation map were delivered to five convolutional layers for signal-decay compensation and image optimization. To validate the system, data not used in training, simulated data from the Zubal human brain phantom, and clinical patient data were used to test reconstruction performance. Reconstructed images from the developed network proved closer to the truth with higher resolution and quantitative accuracy than those from conventional OS-EM reconstruction. To understand better the operation of the network for reconstruction, intermediate results from hidden layers were investigated for each step of the processing. The network system was also retrained with noisy projection data and compared with that developed with noise-free data. The retrained network proved even more robust after having learned to filter noise. Finally, we showed that the network still provided sharp images when using reduced view projection data (retrained with reduced view data).
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http://dx.doi.org/10.1109/trpms.2020.2994041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781067PMC
January 2021

Enhancement of Radiotherapy with Human Mesenchymal Stem Cells Containing Gold Nanoparticles.

Tomography 2020 12;6(4):373-378

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD; and.

Radiotherapy is a common approach for the treatment of a wide variety of cancer types. Available data indicate that nanoparticles can enhance the effect of radiotherapy. We report the use of human mesenchymal stem cells to selectively deliver gold nanoparticles (GNPs) to MDA-MB-231 breast tumor xenografts in mice for the purpose of enhancing the effect of radiation therapy. Targeted delivery of GNPs to the tumor site, followed by irradiation of the tumor, enabled control of tumor growth. The results indicate that tumor-selective GNP delivery by human mesenchymal stem cells may represent a viable way to enhance the effectiveness of radiotherapy.
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http://dx.doi.org/10.18383/j.tom.2020.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744188PMC
December 2020

Subtherapeutic Photodynamic Treatment Facilitates Tumor Nanomedicine Delivery and Overcomes Desmoplasia.

Nano Lett 2021 01 10;21(1):344-352. Epub 2020 Dec 10.

Princess Margaret Cancer Centre, University Health Network, 101 College Street, PMCRT 5-354, Toronto, Ontario M5G 1L7, Canada.

Limited tumor nanoparticle accumulation remains one of the main challenges in cancer nanomedicine. Here, we demonstrate that subtherapeutic photodynamic priming (PDP) enhances the accumulation of nanoparticles in subcutaneous murine prostate tumors ∼3-5-times without inducing cell death, vascular destruction, or tumor growth delay. We also found that PDP resulted in an ∼2-times decrease in tumor collagen content as well as a significant reduction of extracellular matrix density in the subendothelial zone. Enhanced nanoparticle accumulation combined with the reduced extravascular barriers improved therapeutic efficacy in the absence of off-target toxicity, wherein 5 mg/kg of Doxil with PDP was equally effective in delaying tumor growth as 15 mg/kg of Doxil. Overall, this study demonstrates the potential of PDP to enhance tumor nanomedicine accumulation and alleviate tumor desmoplasia without causing cell death or vascular destruction, highlighting the utility of PDP as a minimally invasive priming strategy that can improve therapeutic outcomes in desmoplastic tumors.
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http://dx.doi.org/10.1021/acs.nanolett.0c03731DOI Listing
January 2021

F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography.

Eur J Med Chem 2021 Mar 25;213:113047. Epub 2020 Nov 25.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. Electronic address:

Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with F for a longer isotope half-life. A series of non-radioactive fluorinated analogs of clozapine with a wide range of in vitro binding affinities for the hM3Dq and hM4Di DREADD receptors has been synthesized for PET. Compound [F]7b was radiolabeled via a modified F-deoxyfluorination protocol with a commercial ruthenium reagent. [F]7b demonstrated encouraging PET imaging properties in a DREADD hM3Dq transgenic mouse model, whereas the radiotracer uptake in the wild type mouse brain was low. [F]7b is a promising long-lived alternative to the DREADD radiotracers [C]clozapine ([C]CLZ) and [C]deschloroclozapine ([C]DCZ).
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http://dx.doi.org/10.1016/j.ejmech.2020.113047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925357PMC
March 2021

Preclinical evaluation of Bi-/Ac-labeled low-molecular-weight compounds for radiopharmaceutical therapy of prostate cancer.

J Nucl Med 2020 Nov 27. Epub 2020 Nov 27.

Johns Hopkins Medical Institutions.

Prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical therapy is a new treatment option for patients with advanced prostate cancer refractory to other treatments. Previously we synthesized a β-particle-emitting low-molecular-weight compound, Lu-L1, which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, Bi-L1, and Ac-L1 to evaluate their safety and cell kill effect in PSMA+ xenograft models. Radiochemical synthesis, cell uptake, cell kill effect, and biodistribution of Bi-L1 and Ac-L1 were evaluated. The efficacy of Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 weeks and chronic toxicity at one year after administration were evaluated for Ac-L1. Radiation absorbed dose of Ac-L1 was determined using the biodistribution data and α-camera imaging. Bi-/Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. Biodistribution of Bi-L1 and Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. Ac-L1 also showed an increased survival benefit in the micrometastatic model compared to Lu-L1. Activity-escalated acute and chronic toxicity studies of Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was ~1 MBq/kg. α-camera imaging of Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity issues. Ac-L1 is a promising therapeutic for further clinical evaluation.
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http://dx.doi.org/10.2967/jnumed.120.256388DOI Listing
November 2020

Triptolide: reflections on two decades of research and prospects for the future.

Nat Prod Rep 2020 Nov 4. Epub 2020 Nov 4.

Department of Pharmacology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Hunterian Building, Room 516, Baltimore, MD 21205, USA.

Covering: 2000 to 2020 Triptolide is a bioactive diterpene triepoxide isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries. Although triptolide and its analogs exhibit potent bioactivities against various cancers, and inflammatory and autoimmune diseases, none of them has been approved to be used in the clinic. This review highlights advances in material sourcing, molecular mechanisms, clinical progress and new drug design strategies for triptolide over the past two decades, along with some prospects for the future course of development of triptolide.
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http://dx.doi.org/10.1039/d0np00054jDOI Listing
November 2020

A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia.

iScience 2020 Sep 5;23(9):101536. Epub 2020 Sep 5.

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity and . Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.
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http://dx.doi.org/10.1016/j.isci.2020.101536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509213PMC
September 2020

A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia.

Mol Psychiatry 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.
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http://dx.doi.org/10.1038/s41380-020-00901-5DOI Listing
October 2020

Measurement of PET Quantitative Bias In Vivo.

J Nucl Med 2020 Oct 9. Epub 2020 Oct 9.

Johns Hopkins Medical Institutions.

Quantitative imaging biomarkers are widely used in PET for both research and clinical applications, yet bias in the underlying image data has not been well-characterized. In the absence of a readily available reference standard for in vivo quantification, bias in PET images has been inferred using physical phantoms, even though arrangements of this sort provide only a poor approximation of the imaging environment in real patient examinations. In this study we used data acquired in patient volunteers to assess PET quantitative bias in vivo. Image-derived radioactivity concentrations in the descending aorta were compared with blood samples counted on a calibrated gamma counter. Ten patients with prostate cancer were studied using F-DCFPyL PET/CT. For each patient, 3 whole-body PET/CT image series were acquired following a single administration of the radiotracer: shortly after injection as well as approximately 1 and 4 hours later. Venous blood samples were obtained at 8 time points over an 8 hour period and whole-blood was counted on a NaI gamma counter. A 10 mm diameter, 20 mm long cylindrical volume-of-interest was positioned in the descending thoracic aorta to estimate the PET-derived radioactivity concentration in blood (CPET). A tri-exponential function was fit to the gamma counter blood data and used to estimate the radioactivity concentration (Cgamma) at the time of each PET acquisition. CPET and Cgamma were linearly related with R2 = 0.985 over a range of relevant radioactivity concentrations. The mean difference between the PET and gamma counter data corresponded to 4.8 ± 8.6 % with the PET measurements tending to be greater. Human image data acquired on a conventional whole-body PET/CT system with a typical clinical protocol differed by an average of around 5 % compared to blood samples counted on a calibrated gamma counter. This bias may be partly attributable to residual uncorrected scatter or attenuation correction error. These data offer an opportunity for the assessment of PET bias in vivo and provide additional support for the use of quantitative imaging biomarkers.
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http://dx.doi.org/10.2967/jnumed.120.251397DOI Listing
October 2020

The prostate-specific membrane antigen (PSMA)-targeted radiotracer F-DCFPyL detects tumor neovasculature in metastatic, advanced, radioiodine-refractory, differentiated thyroid cancer.

Med Oncol 2020 Oct 9;37(11):98. Epub 2020 Oct 9.

Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Prostate-specific membrane antigen (PSMA; also termed glutamate carboxypeptidase II (GCP II)) is abundantly expressed in prostate cancer. It has been shown recently that PSMA is expressed in neovasculature of differentiated thyroid cancer. In this study, we show that F-DCFPyl might detect neovasculature in advanced, metastatic differentiated thyroid cancer (DTC). We first stained the preserved lymph node samples of three patients with DTC who had undergone total thyroidectomy and neck dissection for cervical lymph node metastatic disease to identify PSMA expression, with the PSMA antibody (DAKO Monoclonal). Then, we performed F-DCFPyl imaging in two other advanced DTC patients with elevated serum thyroglobulin (Tg), indicative of residual disease. We compared the findings with contemporaneous FDG PET/CT scan, conventional Imaging (CT,MRI) and whole-body scan performed with I/I. All the three lymph node samples stained positive for PSMA expression in the neovasculature. In the first imaged patient, F-DCFPyl detected activity within the retropharyngeal CT contrast-enhancing lymph node. Compared to FDG PET/CT, the F-DCFPyl scan showed a greater SUV (3.1 vs 1.8). In the second imaged patient, F-DCFPyl showed intense uptake in the L3 vertebra (not seen on the post treatment I scan or the F-FDG PET/CT). MRI of the lumbar spine confirmed the presence of sclerotic-lytic lesion at the location, consistent with metastatic disease. Our exploratory study is proof of principle, that the prostate cancer imaging agent F-DCFPyl may prove useful for the localization of metastases, in patients with metastatic RAI-refractory DTC by detecting neoangiogenesis within the tumor.
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http://dx.doi.org/10.1007/s12032-020-01427-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759157PMC
October 2020

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection.

J Neuroinflammation 2020 Sep 17;17(1):273. Epub 2020 Sep 17.

Department of Neurology and Neuroscience, Baltimore, USA.

Background: Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood.

Methods: Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals.

Results: In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra.

Conclusions: In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection.
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http://dx.doi.org/10.1186/s12974-020-01949-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499959PMC
September 2020

Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization.

Int J Mol Sci 2020 Sep 12;21(18). Epub 2020 Sep 12.

Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic.

Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use.
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http://dx.doi.org/10.3390/ijms21186672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555429PMC
September 2020

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting.

Prostate 2020 11 31;80(15):1273-1296. Epub 2020 Aug 31.

Science Department, Prostate Cancer Foundation, Santa Monica, California.

Introduction: The Prostate Cancer Foundation (PCF) convened a PCF prostate-specific membrane antigen (PSMA) Theranostics State of the Science Meeting on 18 November 2019, at Weill Cornell Medicine, New York, NY.

Methods: The meeting was attended by 22 basic, translational, and clinical researchers from around the globe, with expertise in PSMA biology, development and use of PSMA theranostics agents, and clinical trials. The goal of this meeting was to discuss the current state of knowledge, the most important biological and clinical questions, and critical next steps for the clinical development of PSMA positron emission tomography (PET) imaging agents and PSMA-targeted radionuclide agents for patients with prostate cancer.

Results: Several major topic areas were discussed including the biology of PSMA, the role of PSMA-targeted PET imaging in prostate cancer, the physics and performance of different PSMA-targeted PET imaging agents, the current state of clinical development of PSMA-targeted radionuclide therapy (RNT) agents, the role of dosimetry in PSMA RNT treatment planning, barriers and challenges in PSMA RNT clinical development, optimization of patient selection for PSMA RNT trials, and promising combination treatment approaches with PSMA RNT.

Discussion: This article summarizes the presentations from the meeting for the purpose of globally disseminating this knowledge to advance the use of PSMA-targeted theranostic agents for imaging and treatment of patients with prostate cancer.
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http://dx.doi.org/10.1002/pros.24056DOI Listing
November 2020

High Interobserver Agreement for the Standardized Reporting System SSTR-RADS 1.0 on Somatostatin Receptor PET/CT.

J Nucl Med 2021 Apr 28;62(4):514-520. Epub 2020 Aug 28.

Nuclear Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany.

Recently, a standardized framework system for interpreting somatostatin receptor (SSTR)-targeted PET/CT, termed the SSTR reporting and data system (RADS) 1.0, was introduced, providing reliable standards and criteria for SSTR-targeted imaging. We determined the interobserver reliability of SSTR-RADS for interpretation of Ga-DOTATOC PET/CT scans in a multicentric, randomized setting. A set of 51 randomized Ga-DOTATOC PET/CT scans was independently assessed by 4 masked readers with different levels of experience (2 experienced readers and 2 inexperienced readers) trained on the SSTR-RADS 1.0 criteria (based on a 5-point scale from 1 [definitively benign] to 5 [high certainty that neuroendocrine neoplasia is present]). For each scan, SSTR-RADS scores were assigned to a maximum of 5 target lesions (TLs). An overall scan impression based on SSTR-RADS was indicated, and interobserver agreement rates on a TL-based, on an organ-based, and on an overall SSTR-RADS score-based level were computed. The readers were also asked to decide whether peptide receptor radionuclide therapy (PRRT) should be considered on the basis of the assigned RADS scores. Among the selected TLs, 153 were chosen by at least 2 readers (all 4 readers selected the same TLs in 58 of 153 [37.9%] instances). The interobserver agreement for SSTR-RADS scoring among identical TLs was good (intraclass correlation coefficient [ICC] ≥ 0.73 for 4, 3, and 2 identical TLs). For lymph node and liver lesions, excellent interobserver agreement rates were derived (ICC, 0.91 and 0.77, respectively). Moreover, the interobserver agreement for an overall scan impression based on SSTR-RADS was excellent (ICC, 0.88). The SSTR-RADS-based decision to use PRRT also demonstrated excellent agreement, with an ICC of 0.80. No significant differences between experienced and inexperienced readers for an overall scan impression and TL-based SSTR-RADS scoring were observed ( ≥ 0.18), thereby suggesting that SSTR-RADS seems to be readily applicable even for less experienced readers. SSTR-RADS-guided assessment demonstrated a high concordance rate, even among readers with different levels of experience, supporting the adoption of SSTR-RADS for trials, clinical routine, or outcome studies.
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http://dx.doi.org/10.2967/jnumed.120.245464DOI Listing
April 2021

Development of 5D3-DM1: A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive Prostate Cancer Therapy.

Mol Pharm 2020 09 17;17(9):3392-3402. Epub 2020 Aug 17.

The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, United States.

Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it for binding affinity, internalization, and cytotoxicity. The therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957835PMC
September 2020

Prospective Evaluation of F-DCFPyL PET/CT in Detection of High-Risk Localized Prostate Cancer: Comparison With mpMRI.

AJR Am J Roentgenol 2020 09 8;215(3):652-659. Epub 2020 Jul 8.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, 10 Center Dr, Rm B3B85, Bethesda, MD 20814.

The purpose of this study was to assess the utility of PET with (2)-2-[[(1)-1-carboxy-5-[(6-(F)fluoranylpyridine-3-carbonyl)amino]pentyl]carbamoylamino]pentanedioic acid (F-DCFPyL), a prostate-specific membrane antigen (PSMA)-targeted radiotracer, in the detection of high-risk localized prostate cancer as compared with multiparametric MRI (mpMRI). This HIPAA-compliant prospective study included 26 consecutive patients with localized high-risk prostate cancer (median age, 69.5 years [range, 53-81 years]; median prostate-specific antigen [PSA] level, 18.88 ng/mL [range, 1.03-20.00 ng/mL]) imaged with F-DCFPyL PET/CT and mpMRI. Images from PET/CT and mpMRI were evaluated separately, and suspicious areas underwent targeted biopsy. Lesion-based sensitivity and tumor detection rate were compared for PSMA PET and mpMRI. Standardized uptake value (SUV) and PSMA PET parameters were correlated with histopathology score, and uptake in tumor was compared with that in nonmalignant tissue. On a patient level, SUV and PSMA tumor volume were correlated with PSA density. Forty-four tumors (one in Gleason grade [GG] group 1, 12 in GG group 2, seven in GG group 3, nine in GG group 4, and 15 in GG group 5) were identified at histopathology. Sensitivity and tumor detection rate of F-DCFPyL PET/CT and mpMRI were similar (PET/CT, 90.9% and 80%; mpMRI, 86.4% and 88.4%; = 0.58/0.17). Total lesion PSMA and PSMA tumor volume showed a relationship with GG (τ = 0.27 and = 0.08, τ = 0.30 and = 0.06, respectively). Maximum SUV in tumor was significantly higher than that in nonmalignant tissue ( < 0.05). Tumor burden density moderately correlated with PSA density ( = 0.47, = 0.01). Five true-positive tumors identified on F-DCFPyL PET/CT were not identified on mpMRI. In patients with high-risk prostate cancer, F-DCFPyL PET/CT is highly sensitive in detecting intraprostatic tumors and can detect tumors missed on mpMRI. Measured uptake is significantly higher in tumor tissue, and PSMA-derived tumor burden is associated with severity of disease.
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http://dx.doi.org/10.2214/AJR.19.22042DOI Listing
September 2020

Meta-analysis of the Glial Marker TSPO in Psychosis Revisited: Reconciling Inconclusive Findings of Patient-Control Differences.

Biol Psychiatry 2021 Feb 15;89(3):e5-e8. Epub 2020 Jul 15.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899168PMC
February 2021

Evaluation of Musculoskeletal and Pulmonary Bacterial Infections With [I]FIAU PET/CT.

Mol Imaging 2020 Jan-Dec;19:1536012120936876

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Imaging is limited in the evaluation of bacterial infection. Direct imaging of in situ bacteria holds promise for noninvasive diagnosis. We investigated the ability of a bacterial thymidine kinase inhibitor ([I]FIAU) to image pulmonary and musculoskeletal infections.

Methods: Thirty-three patients were prospectively accrued: 16 with suspected musculoskeletal infection, 14 with suspected pulmonary infection, and 3 with known rheumatoid arthritis without infection. Thirty-one patients were imaged with [I]FIAU PET/CT and 28 with [F]FDG PET/CT. Patient histories were reviewed by an experienced clinician with subspecialty training in infectious diseases and were determined to be positive, equivocal, or negative for infection.

Results: Sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of [I]FIAU PET/CT for diagnosing infection were estimated as 7.7% to 25.0%, 0.0%, 50%, 0.0%, and 20.0% to 71.4% for musculoskeletal infections and incalculable-100.0%, 51.7% to 72.7%, 0.0% to 50.0%, 100.0%, and 57.1% to 78.6% for pulmonary infections, respectively. The parameters for [F]FDG PET/CT were 75.0% to 92.3%, 0.0%, 23.1% to 92.3%, 0.0%, and 21.4% to 85.7%, respectively, for musculoskeletal infections and incalculable to 100.0%, 0.0%, 0.0% to 18.2%, incalculable, and 0.0% to 18.2% for pulmonary infections, respectively.

Conclusions: The high number of patients with equivocal clinical findings prevented definitive conclusions from being made regarding the diagnostic efficacy of [I]FIAU. Future studies using microbiology to rigorously define infection in patients and PET radiotracers optimized for image quality are needed.
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http://dx.doi.org/10.1177/1536012120936876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325456PMC
June 2020