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1.
Nat Commun ; 10(1): 4627, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604917

RESUMO

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

2.
ACS Nano ; 13(9): 10161-10178, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31503450

RESUMO

Polyelectrolyte complex (PEC) nanoparticles assembled from plasmid DNA (pDNA) and polycations such as linear polyethylenimine (lPEI) represent a major nonviral delivery vehicle for gene therapy tested thus far. Efforts to control the size, shape, and surface properties of pDNA/polycation nanoparticles have been primarily focused on fine-tuning the molecular structures of the polycationic carriers and on assembly conditions such as medium polarity, pH, and temperature. However, reproducible production of these nanoparticles hinges on the ability to control the assembly kinetics, given the nonequilibrium nature of the assembly process and nanoparticle composition. Here we adopt a kinetically controlled mixing process, termed flash nanocomplexation (FNC), that accelerates the mixing of pDNA solution with polycation lPEI solution to match the PEC assembly kinetics through turbulent mixing in a microchamber. This achieves explicit control of the kinetic conditions for pDNA/lPEI nanoparticle assembly, as demonstrated by the tunability of nanoparticle size, composition, and pDNA payload. Through a combined experimental and simulation approach, we prepared pDNA/lPEI nanoparticles having an average of 1.3 to 21.8 copies of pDNA per nanoparticle and average size of 35 to 130 nm in a more uniform and scalable manner than bulk mixing methods. Using these nanoparticles with defined compositions and sizes, we showed the correlation of pDNA payload and nanoparticle formulation composition with the transfection efficiencies and toxicity in vivo. These nanoparticles exhibited long-term stability at -20 °C for at least 9 months in a lyophilized formulation, validating scalable manufacture of an off-the-shelf nanoparticle product with well-defined characteristics as a gene medicine.

3.
J Neuropsychiatry Clin Neurosci ; : appineuropsych18110274, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31394988

RESUMO

OBJECTIVE: The primary objective of this preliminary study was to examine the impact of NFL play on interregional functional connectivity between two brain regions, the supramarginal gyrus (SMG) and the thalamus, identified as having higher binding of [11C]DPA-713 in NFL players. The authors' secondary objective was to examine the effect of years since play on the interregional connectivity. METHODS: Resting-state functional MRI was used to examine functional brain changes between regions with evidence of past injury in active or recently retired NFL players (defined as ≤12 years since NFL play) and distantly retired players (defined as >12 years since NFL play). Age-comparable individuals without a history of concussion or participation in collegiate or professional collision sports were included as a control group. RESULTS: Compared with healthy control subjects, NFL players showed a loss of anticorrelation between the left SMG and bilateral thalami (mean z score=-2.434, p=0.015). No difference was observed when examining right SMG connectivity. The pattern of connectivity in active and recently retired players mimicked the pattern observed in distantly retired players and older control subjects. CONCLUSIONS: Further study of the clinical significance of this altered pattern of interregional connectivity in active and recently retired NFL players is needed.

4.
Eur J Nucl Med Mol Imaging ; 46(12): 2545-2557, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31399803

RESUMO

PURPOSE: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the ß-particle radiation of 177Lu. METHODS: We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1-177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice. RESULTS: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent. CONCLUSIONS: 177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

5.
J Nucl Med ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420499

RESUMO

Emerging evidence supports a hypothesized role of the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease (AD). 18F-ASEM is a radioligand for estimating availability of the α7-nAChR in the brain in vivo with positron emission tomography (PET). Methods: In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed 18F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Results: Higher 18F-ASEM binding was observed in MCI compared to controls across all regions, supporting higher availability of the α7-nAChR in MCI. 18F-ASEM binding was not associated with verbal memory in this small MCI sample. Conclusion: These data support use of 18F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.

6.
J Nucl Med ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451492

RESUMO

Purpose: Bone metastases in prostate cancer (PCa) have important prognostic significance and imaging modalities used for PCa staging should have high sensitivity for detecting such lesions. Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracers are promising new agents for imaging PCa. We undertook a head-to-head comparison of PSMA-targeted 18F-DCFPyL PET to Na18F PET to determine which modality was more sensitive for the detection of lesions suspicious for bone metastases in a group of patients with metastatic PCa. Materials and Methods: Patients with progressive, metastatic PCa were prospectively imaged with both 18F-DCFPyL and Na18F PET/CT, with both scans occurring within 24 hours of each other. A consensus, 2-reader central review was carried out to identify all bone lesions suspicious for sites of PCa involvement on both scans and maximized standardized uptake values corrected for weight (SUVmax) and lean body mass (SULmax) were recorded. Soft tissue lesions were also noted on both scans and SUVmax, SULmax, and PSMA-RADS version 1.0 scores were recorded. Data from the two scans was compared using a generalized estimating equation. Results: In total, 16 patients meeting all inclusion criteria were enrolled in this study and 15/16 (93.8%) were imaged with both PET radiotracers. A total of 405 bone lesions suspicious for sites of PCa were identified on at least one scan. On 18F-DCFPyL PET/CT, 391 (96.5%) were definitively positive, 4 (1.0%) were equivocally positive, and 10 (2.5%) were negative. On Na18F PETCT, the corresponding values were 388 (95.8%), 4 (1.0%), and 13 (3.2%). Of the definitively negative lesions on 18F-DCFPyL PET, 8/10 (80.0%) were sclerotic and 2/10 (20.0%) were infiltrative/marrow-based. Additionally, 12/13 (92.3%) of the definitively negative lesions on Na18F PET were infiltrative/marrow-based and 1/13 (7.7%) was lytic. 78 PSMA-RADS-4, 17 PSMA-RADS-5, and 1 PSMA-RADS-3C soft tissue lesions were also identified. Conclusion: PET/CT imaging using 18F-DCFPyL and Na18F PET had nearly identical sensitivities for the detection of bone lesions in patients with metastatic PCa. As would be expected, PSMA-targeted PET provides more information on soft tissue disease. There may be little additional value to imaging patients with PCa with Na18F after a PSMA-targeted PET scan has already been performed.

7.
J Digit Imaging ; 32(6): 1071-1080, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31388864

RESUMO

Extensive research is currently being conducted into dynamic positron emission tomography (PET) acquisitions (including dynamic whole-body imaging) as well as extraction of radiomic features from imaging modalities. We describe a new PET viewing software known as Imager-4D that provides a facile means of viewing and analyzing dynamic PET data and obtaining associated quantitative metrics including radiomic parameters. The Imager-4D was programmed in the Java language utilizing the FX extensions. It is executable on any system for which a Java w/FX compliant virtual machine is available. The software incorporates the ability to view and analyze dynamic data acquired with different types of dynamic protocols. For image display, the program maintains a built-in library of 62 different lookup tables with monochromatic and full-color distributions. The Imager-4D provides multiple display layouts and can display fused images. Multiple methods of volume-of-interest (VOI) selection are available. Dynamic analysis features, such as image summation and full Patlak analysis, are also available. The user interface includes window width and level, blending, and zoom functionality. VOI sizes are adjustable and data from VOIs can either be displayed numerically or graphically within the software or exported. An example case of a 50-year-old woman with metastatic colorectal cancer and thyroiditis is included and demonstrates the steps for a user to obtain standard PET parameters, dynamic data, and radiomic features using selected VOIs. The Imager-4D represents a novel PET viewer that allows the user to view dynamic PET data, to derive dynamic and radiomic parameters from that data, and to combine dynamic data with radiomics ("dynomics"). The Imager-4D is available as a free download. This software has the potential to speed the adoption of advanced analysis of dynamic PET data into routine clinical use.

8.
Lancet Oncol ; 20(8): e443-e451, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364596

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy is one of the most remarkable advances in cancer therapy in the last several decades. More than 300 adoptive T-cell therapy trials are ongoing, which is a testament to the early success and hope engendered by this line of investigation. Despite the enthusiasm, application of CAR T-cell therapy to solid tumours has had little success, although positive outcomes are increasingly being reported for these diseases. In this Series paper, we discuss the short-term strategies to improve CAR T-cell therapy responses, particularly for solid tumours, by combining CAR T-cell therapy with radiotherapy through the use of careful monitoring and non-invasive imaging. Through the use of imaging, we can gain greater mechanistic insights into the cascade of events that must unfold to enable tumour eradication by CAR T-cell therapy.

9.
Prostate ; 79(14): 1597-1603, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361358

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies. METHODS: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory. RESULTS: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with 177 Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased. CONCLUSIONS: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.

10.
Neuron ; 103(4): 627-641.e7, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31255487

RESUMO

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).


Assuntos
Transporte Axonal , Transtornos Parkinsonianos/etiologia , Agregados Proteicos , Nervo Vago/metabolismo , alfa-Sinucleína/farmacocinética , Animais , Química Encefálica , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Duodeno/inervação , Duodeno/metabolismo , Humanos , Injeções Intramusculares , Corpos de Lewy/metabolismo , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Neurológicos , Músculo Liso/inervação , Músculo Liso/metabolismo , Comportamento de Nidação/fisiologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Transtornos Parkinsonianos/psicologia , Fosforilação , Processamento de Proteína Pós-Traducional , Piloro/inervação , Piloro/metabolismo , Teste de Desempenho do Rota-Rod , Vagotomia , alfa-Sinucleína/administração & dosagem , alfa-Sinucleína/deficiência , alfa-Sinucleína/toxicidade
11.
Sci Adv ; 5(7): eaaw5096, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31281894

RESUMO

Chimeric antigen receptor (CAR) T cell therapy for hematologic malignancies is fraught with several unknowns, including number of functional T cells that engage target tumor, durability and subsequent expansion and contraction of that engagement, and whether toxicity can be managed. Non-invasive, serial imaging of CAR T cell therapy using a reporter transgene can address those issues quantitatively. We have transduced anti-CD19 CAR T cells with the prostate-specific membrane antigen (PSMA) because it is a human protein with restricted normal tissue expression and has an expanding array of positron emission tomography (PET) and therapeutic radioligands. We demonstrate that CD19-tPSMA(N9del) CAR T cells can be tracked with [18F]DCFPyL PET in a Nalm6 model of acute lymphoblastic leukemia. Divergence between the number of CD19-tPSMA(N9del) CAR T cells in peripheral blood and bone marrow and those in tumor was evident. These findings underscore the need for non-invasive repeatable monitoring of CAR T cell disposition clinically.

12.
Mol Imaging ; 18: 1536012119852189, 2019 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31187691

RESUMO

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [18F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, 19FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC50], 26-32 nM). The radiotracer, [18F]FPy-WL12, was prepared by conjugating 2,3,5,6-tetrafluorophenyl 6-[18F]fluoronicotinate ([18F]FPy-TFP) to WL12 and assessed for specificity in vitro in 6 cancer cell lines with varying PD-L1 expression. The uptake of the radiotracer reflected the PD-L1 expression assessed by flow cytometry. Next, we performed the in vivo evaluation of [18F]FPy-WL12 in mice bearing cancer xenografts by PET imaging, ex vivo biodistribution, and blocking studies. In vivo data demonstrated a PD-L1-specific uptake of [18F]FPy-WL12 in tumors that is reduced in mice receiving a blocking dose. The majority of [18F]FPy-WL12 radioactivity was localized in the tumors, liver, and kidneys indicating the need for optimization of the labeling strategy to improve the in vivo pharmacokinetics of the radiotracer.

13.
Semin Nucl Med ; 49(4): 255-270, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31227049

RESUMO

The continuing adoption of prostate specific membrane antigen (PSMA)-targeted PET for prostate cancer molecular imaging requires imagers and clinicians alike to be aware of the increasing number of potential interpretive pitfalls that have been reported. This review summarizes and illustrates the spectrum of benign and malignant nonprostatic conditions with high PSMA-radiotracer uptake that may be mistaken for sites of prostate cancer and also discusses potential false negatives. We discuss the recent literature on the effect of androgen deprivation therapy on lesion detection. Furthermore, we briefly review the recently proposed structured reporting systems for the standardized interpretation of PSMA-targeted PET that can guide both imaging specialists and referring clinicians in the appropriate interpretation and work-up of pitfalls.

14.
J Nucl Med ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253744

RESUMO

Targeted radiopharmaceutical therapy (TRT) employing α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)-targeted low-molecular-weight (LMW) agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. Methods: Five rationally designed LMW ligands (L1-L5) were synthesized using the lysine-urea-glutamate (Lys-urea-Glu) scaffold and PSMA inhibition constants (Ki) were determined. Tissue biodistribution and SPECT/CT imaging of 203Pb-L1-203Pb-L5 were performed in mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. Radiation absorbed dose of the corresponding 212Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(-) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.1-17 nM. 203Pb-L1-203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearances of 203Pb-L1-203Pb-L5 were fast, the absorbed dose coefficients [mGy/kBq], of the tumor and kidneys were highest for 203Pb-L5 (31.0, 15.2), and lowest for 203Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203Pb-L3 (3.2) and 203Pb-L4 (3.6) compared to the other agents, however, with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h post-injection. A proof-of-concept therapy study with a single administration of 212Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared to 177Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: 203Pb-L1-203Pb-L5 demonstrated favorable pharmacokinetics for 212Pb-based TRT. Antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

15.
Eur J Nucl Med Mol Imaging ; 46(9): 1940-1951, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31161257

RESUMO

INTRODUCTION: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers. METHODS: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO)2. Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO)3(Bdiol)110. Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood-brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution. RESULTS: Intravenous administration of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89ZrNB(DFO)2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89ZrG4(DFO)3(Bdiol)110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT. CONCLUSIONS: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

16.
J Nucl Med ; 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201249

RESUMO

Purpose: To provide the results of a prospective study evaluating PSMA-targeted 18F-DCFPyL PET/CT in patients with biochemical failure following radical prostatectomy for prostate cancer (PCa). Procedures: 31 patients with post-prostatectomy serum PSA levels ≥ 0.2 ng/mL and negative conventional imaging were enrolled in this study and imaged with 18F-DCFPyL PET/CT. A consensus central review identified foci of radiotracer uptake consistent with sites of PCa. Descriptive statistics were utilized. Results: 21/31 (67.7%) patients had at least one finding on 18F-DCFPyL PET/CT consistent with a site of PCa. Imaging was positive in 59.1% of patients with PSA < 1.0 ng/ml and in 88.9% of patients with PSA > 1.0 ng/mL. The median SUVmax across all lesions was 11.6 (range 1.5 to 57.6). Conclusion: In this prospective study utilizing the PSMA-targeted PET agent 18F-DCFPyL, most patients with biochemical failure following radical prostatectomy had foci of suspicious uptake, even at low serum PSA levels.

17.
Ann Nucl Med ; 33(8): 617-623, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147927

RESUMO

OBJECTIVE: Complete surgical resection of metastatic sites has been shown to prolong survival in select patients with oligometastatic RCC. This treatment strategy is dependent upon the accurate characterization of a patient's extent of disease. The objective of this study was to explore the utility of PSMA-targeted 18F-DCFPyL PET/CT in patients with presumed oligometastatic clear cell RCC. METHODS: This is a subset analysis of a prospective study in which patients with RCC were imaged with 18F-DCFPyL PET/CT (ClinicalTrials.gov identifier NCT02687139). In the present analysis, patients with oligometastatic clear cell RCC, defined as ≤ 3 metastatic lesions on conventional imaging, were evaluated. 18F-DCFPyL PET/CT scans were reviewed for sites of disease and compared to conventional imaging. RESULTS: The final cohort included 14 patients with oligometastatic clear cell RCC. Conventional imaging revealed 21 metastatic lesions and 3 primary tumors. 18F-DCFPyL PET/CT detected 29 sites of metastatic disease and 3 primary tumors. Of the 21 metastatic lesions detected on conventional imaging, 17 (81.0%) had radiotracer uptake. Additionally, all 3 primary tumors had radiotracer uptake. In 4 (28.6%) patients a total of 12 more lesions were identified on 18F-DCFPyL PET/CT than conventional imaging. Notably, 3 (21.4%) patients were no longer considered oligometastatic. The detection rates of conventional imaging and 18F-DCFPyL PET/CT for identifying sites of disease were 66.7% and 88.9%, respectively. CONCLUSIONS: PSMA-targeted PET/CT appears to aid in the identification of patients with oligometastatic clear cell RCC. If borne out in future studies, this suggests that PSMA-targeted imaging has the potential to help select candidates for metastasis-directed therapy.

18.
Eur J Nucl Med Mol Imaging ; 46(9): 1773-1786, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144061

RESUMO

Although single-photon-emitting radiotracers have long been the standard for renal functional molecular imaging, recent years have seen the development of positron emission tomography (PET) agents for this application. We provide an overview of renal radionuclide PET radiotracers, in particular focusing on novel 18F-labelled and 68Ga-labelled agents. Several reported PET imaging probes allow assessment of glomerular filtration rate, such as [68Ga]ethylenediaminetetraacetic acid ([68Ga]EDTA), [68Ga]IRDye800-tilmanocept and 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS)). The diagnostic performance of [68Ga]EDTA has already been demonstrated in a clinical trial. [68Ga]IRDye800-tilmanocept shows receptor-mediated binding to glomerular mesangial cells, which in turn may allow the monitoring of progression of diabetic nephropathy. [18F]FDS shows excellent kidney extraction and excretion in rats and, as has been shown in the first study in humans. Further, due to its simple one-step radiosynthesis via the most frequently used PET radiotracer 2-deoxy-2-[18F]fluoro-D-glucose, [18F]FDS could be available at nearly every PET centre. A new PET radiotracer has also been introduced for the effective assessment of plasma flow in the kidneys: Re(CO)3-N-([18F]fluoroethyl)iminodiacetic acid (Re(CO)3([18F]FEDA)). This compound demonstrates similar pharmacokinetic properties to its 99mTc-labelled analogue [99mTc](CO)3(FEDA). Thus, if there is a shortage of molybdenum-99, Re(CO)3([18F]FEDA would allow direct comparison with previous studies with 99mTc. The PET radiotracers for renal imaging reviewed here allow thorough evaluation of kidney function, with the tremendous advantage of precise anatomical coregistration with simultaneously acquired CT images and rapid three-dimensional imaging capability.

19.
J Am Coll Radiol ; 16(11): 1612-1617, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31132333

RESUMO

Recent years have witnessed an expanded use of single-photon emission CT and PET for a wide range of clinical applications, including imaging of brain abnormalities. As a result, molecular brain imaging is now being more extensively utilized in criminal cases, in particular in the sentencing phase of a trial. This perspective aims to provide a brief overview for the practicing radiologist of this expanded use of single-photon emission CT and PET in criminal cases and will discuss the role of radiology in this field.

20.
Mol Imaging Biol ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31115751

RESUMO

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has impacted the management of patients with prostate cancer (PCa) in many parts of the world. PSMA-targeted endoradiotherapies are also being increasingly utilized and for these applications, the radiopharmaceutical distribution in normal organs is particularly important because it may limit the dose that can be delivered to tumors. In this study, we measured both interpatient and intrapatient variability of [18F]DCFPyL uptake in the most relevant normal organs. PROCEDURES: Baseline and 6-month follow-up PSMA-targeted [18F]DCFPyL PET/computed tomography (CT) scans from 39 patients with PCa were reviewed. Volumes of interest were manually drawn using the best visual approximation of the organ edge for both lacrimal glands, all four major salivary glands, the liver, the spleen, and both kidneys for all patients. The average SUVmean, the COVs, and intraclass correlation coefficients (ICCs) across scans were calculated. Bland-Altman analyses were performed for all organs to derive repeatability coefficients (RCs). RESULTS: The liver demonstrated the lowest interpatient variability (13.0 and 16.6 % at baseline and follow-up, respectively), while the spleen demonstrated the largest interpatient variability (44.6 and 51.0 % at baseline and follow-up, respectively). The lowest intrapatient variability was found in the spleen (ICC 0.86) while the highest intrapatient variability was in the kidneys (ICCs 0.40-0.50). Bland-Altman analyses showed 95 % repeatability coefficients for mean uptake > 40 % for multiple organs and were highest for the lacrimal glands, kidneys, and spleen. CONCLUSIONS: Normal organs demonstrate significant variability in uptake of the PSMA-targeted radiotracer [18F]DCFPyL. Depending on the organ, different contributions of interpatient and intrapatient factors affect the intrinsic variability. The RCs also vary significantly among the different organs were highest for the lacrimal glands, kidneys, and spleen. These findings may have important implications for the design of clinical protocols and personalized dosimetry for PSMA-targeted endoradiotherapies.

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