Ultrasmall superparamagnetic particles of iron oxide USPIOs imaged with magnetic resonance imaging MRI have been proposed as an experimental method for visualizing lymph node LN metastases. The method does not require ionizing radiation, yet can detect small nodes that are involved with metastases. USPIOs are naturally taken up by macrophages that deposit in the normal LN creating a low signal region in normal areas; areas within the node that do not show this loss of signal are likely involved by tumor although there can be other causes fibrosis or inflammation. However, the lack of approved USPIOs that are clinically available hinders adoption and larger studies. Detection of lymph node LN metastasis is an important prognostic marker and has a strong impact on prostate cancer PCa management.
However, Uspio prostate prostate cancer Uspio prostate beyond the gland to the lymphatic tissues, the opportunity for cure with a local therapy is lost in most cases and significantly diminished in others[ 1 ]. Objectives There is a crucial need to develop prostate cancer specific imaging contrast agent CA for early and accurate detection and staging of prostate cancer in patients. Radiat Oncol. Nanoparticle uptake was also seen in the kidney, liver, lung, pancreases and spleen for the nanoparticle probe with a diameter of 50 nm. Metastatic lymph nodes retain signal and therefore stay white. Eur Urol. Copyright Translational Andrology and Urology. Eros rammazoti nodal staging at the time of diagnosis of prostate cancer is crucial in determining a treatment plan for the patient. The FDA prosate approved the use of ferumoxytol for the treatment of iron deficiency anemia in adult patients with chronic kidney disease CKD. DWI can be performed proetate without the need of a contrast medium.
Phatest butts in the world. Introduction
It is a very straightforward legal issue. Harriet C. Innis, W. The excised organs and tumors were weighed prior to dissolving them in 3 mL aqua regia by sonication. Prostate Cancer International. Imaging is the key — the US needs to catch up. Barile, M. Udpio, A. News and information provided on this site Uspio prostate not be used for diagnosing or treating any health problem or disease. ENW EndNote.
Objectives There is a crucial need to develop prostate cancer specific imaging contrast agent CA for early and accurate detection and staging of prostate cancer in patients.
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Study record managers: refer to the Data Element Definitions if submitting registration or results information. Postcontrast MR imaging will be performed hours after contrast medium injection. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.
For general information, Learn About Clinical Studies. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.
Search for terms x. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Last Update Posted : October 12, Study Description. However, current morphological assessment of lymph nodes based on size and shape is unable to detect smaller metastases or liable to give false positive results on lymph nodes with reactive hyperplasia.
FDA Resources. Arms and Interventions. Diffusion-weighted MRI of the entire pelvis to detect lymph node metastases. Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Inclusion Criteria: Patients with histologically proven prostate cancer TN0M0 Gleason score scheduled for radical prostatectomy or patients with histologically proven bladder cancer TbN0M0G3 scheduled for cystectomy Written informed consent to participate in this trial.
Patients in a critical cardiovascular state, with risk of decompensation after administration of the USPIO contrast agent. Patients with hemochromatosis or an allergy to dextran or iron compounds. Pregnant or breast-feeding women.
Patients who have received gadolinium complexes within 2 days or iron oxide particles within 7 days before MRI. Patients who underwent chemotherapy or radiotherapy before surgery. Patients whose degree of cooperation is incompatible with carrying out the study. Patients with contraindications to Glucagon administration. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. Layout table for location information Switzerland Inselspital Bern, Switzerland, More Information. Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients.
Eur Urol. Epub Jan 7. Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer. Epub Jul Eur J Cancer. Epub Oct National Library of Medicine U.
National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Prostate Cancer Bladder Cancer. Phase 3. Study Type :. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. A Diffusion-weighted MRI.
Although the specificity of uptake was proven for both cell types, the exact uptake mechanism is still unclear. Our own FDAs opioid crisis is a present-day example. Nanoparticles are known to interact with plasma proteins in the blood and are subsequently surrounded by a protein corona that significantly alters their size, charge, and biological behavior. You are commenting using your WordPress. Subsequently, the FMN-covered nanoparticles were washed with water under the influence of highgradient magnetophoresis and then sonicated with 50 mM GMP for 1 h.
Uspio prostate. Forum Information
Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms x. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details.
Last Update Posted : October 12, Study Description. However, current morphological assessment of lymph nodes based on size and shape is unable to detect smaller metastases or liable to give false positive results on lymph nodes with reactive hyperplasia. FDA Resources. Arms and Interventions. Diffusion-weighted MRI of the entire pelvis to detect lymph node metastases.
Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Inclusion Criteria: Patients with histologically proven prostate cancer TN0M0 Gleason score scheduled for radical prostatectomy or patients with histologically proven bladder cancer TbN0M0G3 scheduled for cystectomy Written informed consent to participate in this trial.
Patients in a critical cardiovascular state, with risk of decompensation after administration of the USPIO contrast agent. Patients with hemochromatosis or an allergy to dextran or iron compounds. Pregnant or breast-feeding women. Patients who have received gadolinium complexes within 2 days or iron oxide particles within 7 days before MRI. Patients who underwent chemotherapy or radiotherapy before surgery.
Patients whose degree of cooperation is incompatible with carrying out the study. Patients with contraindications to Glucagon administration. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. Trypsinization was stopped by adding respective cell growth media and the cell suspension was centrifuged at 1, rpm Multifuge, Thermo scientific, Germany for 5 min.
The pellet was washed thrice by centrifugation with saline. Cells 0. All animal experiments were approved by the government review committee on animal care.
Subsequently, different LnCap tumor sections were stained for macrophages using a primary rat anti-mouse CD68 antibody AbD Serotec, Duesseldorf, Germany for 2 h room temperature combined with a Cy3-labeled anti-rat IgG secondary antibody for 45 min room temperature. Compound, Sakura Finetek Europe B. The Prussian blue staining protocol was performed as described in section 2. Cover slips were mounted on the sections using Vitro-Clud R. The excised organs and tumors were weighed prior to dissolving them in 3 mL aqua regia by sonication.
Subsequently, 1 mL sample solution was diluted in water and and mixed with phosphate buffer, 4 M NaOH, and 0. The absorbance of the iron-tiron complex was measured at nm. USPIO nanoparticles prepared in water are prone to oxidative degradation at their surface in the absence of a protective coating. In addition, without surface functionalization, USPIO uptake by most tissues and cells is low, except for those of the reticuloendothelial system RES , which rapidly remove the particles from the blood.
Therefore, we selected FMN as a specific, fluorescent, non-polymeric coating molecule, which adsorptively binds to the iron oxide cores via phosphate groups Fig. Protecting the surface of USPIO nanoparticles with FMN only led to partial sedimentation of the particles visual observation resulting in less-stable suspensions.
Therefore, to achieve colloidal stability and sustain FMN fluorescence without quenching under aqueous conditions, the surface of USPIO nanoparticles was additionally covered with non-toxic and biocompatible GMP. We previously demonstrated that a ratio of 0. Nanoparticles are known to interact with plasma proteins in the blood and are subsequently surrounded by a protein corona that significantly alters their size, charge, and biological behavior.
Free FMN suspended in different physiological solutions at varied concentrations revealed intense emission at nm. S3 a and S3 b in the ESM. The partial reduction of fluorescence in protein solutions could be due to non-specific association between FMN and serum proteins [ 26 ].
S3 c and S3 d in the ESM. These stable fluorescent properties are highly beneficial, in particular, when considering FLUSPIO for longitudinal cell-labeling studies and for fluorescence-based histological analysis. Comparison of the elemental surface composition obtained by XPS measurements Fig.
One of the other physiological solutions evaluated in this study will be selected for further study, via systemic administration of FLUSPIO in vivo. As shown in Figs. S4 a —S4 d in the ESM, trypan blue staining indicated no significant reduction in cell viability of both cell types until 24 h, at labeling concentrations of up to 0.
Consistent with these results, another previous study showed that even high FLUSPIO concentrations do not negatively affect cellular proliferation and integrity or induce major oxidative stress [ 27 ]. This trend persisted and was also visible when the incubation time was increased to 3 h Figs.
S5 a —S5 f in the ESM. The higher uptake by HUVEC than LnCap cells might be due to cell type-specific characteristics and increased metabolic activity linked to elevated Rf-transporter expression [ 28 ]. Thus, we speculate that in vivo , FLUSPIO mostly labels the endothelial layer of angiogenic blood vessels prior to their entry into the tumor tissue. For these experiments, LnCap cells were used, which are more uniform and easy to handle than primary cultures of endothelial cells.
Furthermore, LnCap cells have been described to display the highest RCP levels among all prostate cancer cells tested so far [ 15 ]. Although the specificity of uptake was proven for both cell types, the exact uptake mechanism is still unclear. There is a hypothesis that uptake of the latter occurs via clathrin-mediated endocytosis, which is one of the fastest and most efficient internalization pathways for nanoparticles [ 16 ].
In vivo accumulation and competitive binding experiments using LnCap tumor xenografts, as analyzed by MRI and immunohistochemistry. Significantly less accumulation g is observed in the competitive binding group e and f. Together, these results clearly show accumulation of FLUSPIO nanoparticles in endothelial cells, tumor associated macrophages, and tumor cells as well as their in vivo specificity for RCP. In summary, we showed that Rf receptor-mediated targeting is an efficient way to accumulate nanoparticles in prostate cancer cells.
High levels of FLUSPIO accumulation in the tumors can be explained by its ability to target both, the tumor cell and the stromal compartment, of macrophages and angiogenic endothelial cells. Furthermore, our bio-distribution data indicate that besides the expected nanoparticle uptake by organs of the RES, the skin shows enhanced accumulation that can be related to high Rf receptor expression. Nevertheless, further and more detailed studies will be required to better understand the regulation of the Rf receptor expression in healthy and pathologically altered tissues before it can be considered as a target for diagnostic and therapeutic probes.
The authors would like to thank Mr. Yang Shi, department of pharmaceutical science, Universiteit Utrecht, The Netherlands for performing zeta potential measurements and Dr. The authors would like to thank Prof. Twan Lammers for reading the manuscript.
Skip to main content Skip to sections. Advertisement Hide. Download PDF. In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts.
Open Access. First Online: 29 September Introduction Vitamins have been studied in the context of diagnostic and therapeutic agents because they are biocompatible, endogenously accessible, act as carriers, strongly bind to respective receptors, and mediate important cellular metabolic functions [ 1 , 2 , 3 ].
S2 a and S2 b in the ESM. Open image in new window. The higher mass peaks shown in Fig. The chosen experimental time points were early since FLUSPIO nanoparticles display a short circulation time of only 30 min unpublished data. Figure 4 In vivo accumulation and competitive binding experiments using LnCap tumor xenografts, as analyzed by MRI and immunohistochemistry.
Further, its accumulation in the lung can be explained by macrophage uptake. The presence of particles in the colon is the consequence of the mainly hepatobiliary elimination. High accumulation of Rfreceptor targeted particles in the skin was found for all Rf-based probes that we tested so far and is most probably related to the known high expression of Rf receptors in this organ [ 35 ].
Thus, targeting this organ can be considered as a further indication for RFT-targeted nanoparticles and drugs. On the other hand, in safety evaluations of RFT-targeted probes particular care has to be taken not to oversee adverse side effects in the skin. Mamede, A. The role of vitamins in cancer: A review. Cancer , 63 , — CrossRef Google Scholar. Russell-Jones, G. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours.
Giancaspero, T. FAD synthesis and degradation in the nucleus create a local flavin cofactor pool. Becker, K. Flavins and flavoenzymes in diagnosis and therapy. In Flavoprotein Protocols ; Chapman, S.
Rao, P. Elevation of serum riboflavin carrier protein in breast cancer. Cancer Epidemiol. Biomarkers Prev. Google Scholar. Bareford, L. Endocytic mechanisms for targeted drug delivery. Drug Deliv. Riboflavin-targeted polymer conjugates for breast tumor delivery.
Huang, S. Involvement of endocytic organelles in the subcellular trafficking and localization of riboflavin. Pedrolli, D. Riboflavin analogs as antiinfectives: Occurrence, mode of action, metabolism and resistance. Chen, C. Structural basis for molecular recognition of folic acid by folate receptors.
Nature , , — Wang, S. Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. Release , 53 , 39—
Accurate nodal staging at the time of diagnosis of prostate cancer is crucial in determining a treatment plan for the patient. Pelvic lymph node dissection is the most reliable method, but is less than perfect and has increased morbidity. Cross sectional imaging with computed tomography CT and magnetic resonance imaging MRI are non-invasive tools that rely on morphologic characteristics such as shape and size of the lymph nodes.
However, lymph nodes harboring metastatic disease may be normal sized and non-metastatic lymph nodes may be enlarged due to reactive hyperplasia. The optimal strategy for preoperative staging remains a topic of ongoing research. Advanced imaging techniques to assess lymph nodes in the setting of prostate cancer utilizing novel MRI contrast agents as well as positron emission tomography PET tracers have been developed and continue to be studied. Magnetic resonance lymphography utilizing ultra-small super paramagnetic iron oxide has shown promising results in detection of metastatic lymph nodes.
Combining MRL with diffusion-weighted imaging may also improve accuracy. PET tracers that will be reviewed in this article include [ 18 F]fluoro-D-glucose, sodium [ 18 F]fluoride, [ 18 F]choline, [ 11 C]choline, prostate specific membrane antigen binding ligands, [ 11 C]acetate, [ 18 F]fluciclovine, gastrin releasing peptide receptor ligands, and androgen binding receptors.
This article will review these advanced imaging modalities and ability to detect prostate cancer metastasis to lymph nodes. While more research is needed, these novel techniques to image lymph nodes in the setting of prostate cancer show a promising future in improving initial lymph node staging.
Core tip: Accurate nodal staging at time of prostate cancer diagnosis is crucial in determining a treatment plan for the patient. This review article highlights the newest imaging techniques that have been and are being developed for imaging of lymph nodes in the initial staging of prostate cancer. Magnetic resonance lymphography utilizing ultra-small super paramagnetic iron oxide has shown to detect metastatic disease in normal sized lymph nodes. Considerable efforts are being made in molecular imaging to develop effective positron emission tomography radiotracers that may be combined with computed tomography or magnetic resonance to detect prostate metastasis as well as potential therapeutic applications.
Prostate cancer is the most common cancer in American men and is associated with a significant likelihood of cure when patients have organ-confined disease through the use of local definitive therapy such as radical prostatectomy or radiation therapy[ 1 ].
However, once prostate cancer spreads beyond the gland to the lymphatic tissues, the opportunity for cure with a local therapy is lost in most cases and significantly diminished in others[ 1 ]. Due to the adverse prognostic implications associated with lymph node metastasis, detection of clinically occult lymph node metastasis is of extreme importance[ 2 ].
Risk assessment tools are used to predict patients who are at risk for higher pathologic stage and use inputs such as PSA, biopsy Gleason sum, percent positive biopsies, and magnetic resonance imaging MRI findings[ 3 - 5 ]. Patients determined to be at higher risk for systemic disease need to undergo nodal staging. The most reliable method is pelvic lymph node dissection; however, this is invasive and may be associated with increased morbidity and risk of complications[ 1 ]. Furthermore, pelvic lymph node dissection is less than perfect as several studies have reported positive lymph nodes outside the routine dissection template[ 8 - 11 ].
Cross sectional imaging is a non-invasive tool utilized for nodal staging and largely relies on morphologic characteristics such as size and shape. A threshold of 1. However, more than half of lymph nodes involved with metastatic prostate cancer may be less than 1 cm[ 14 ]. Moreover, non-metastatic nodes may be enlarged due to reactive hyperplasia. Herein, we will discuss these modalities for improved prostate cancer lymph node staging. High resolution MRI utilizing ultra-small super paramagnetic iron oxide USPIO has been utilized to improve sensitivity for detection of metastatic lymph nodes[ 15 , 16 ].
Lymphotropic superparamagnetic nanoparticles are avidly taken up by lymph nodes where they are internalized by macrophages[ 17 ].
Malignant nodes have a relatively paucity of macrophages compared to benign lymph nodes. This evaluation of macrophage function does not rely on nodal size to detect metastasis[ 19 ]. Moreover, it does not depend on the functional activity of cancer in the lymph nodes as it labels normal macrophages in the lymph nodes[ 20 ].
Given the high spatial resolution of MRI, more lymph nodes at smaller sizes can be detected and accurately characterized as benign or malignant with macrophage replacement by metastatic cancer cells[ 20 ]. USPIO particles have been used extensively as a lymphotropic contrast agent for detection of metastatic prostate cancer in numerous clinical trials[ 16 , 21 - 26 ].
In an initial study that utilized USPIO ferumoxtran , nodes were considered malignant when one of the following three criteria are present: 1 A decrease in signal intensity of less than 30 percent on T2-weighted fast spin-echo or gradient-echo sequences after the administration of USPIO; 2 a heterogeneous signal giving the entire node a mottled appearance , discrete focal defects isolated islands of high signal intensity , or both on gradient echo imaging; and 3 nodes with a central area of hyperintensity excluding a fatty hilum but a peripheral decrease in signal intensity[ 15 ].
This initial study utilizing ferumoxtran demonstrated a sensitivity for detection of malignant lymph nodes with short axis diameter of mm was increased with use of USPIO compared to MRI alone Additionally, the potential for MRL to detect metastatic lymph nodes outside of the routine dissection margin has potential for great clinical value including surgical and radiation therapy planning.
Salvage radiation therapy is associated with some toxicity[ 33 ], and improved selection of patients and detection of nodal targets can decrease morbidity and improve cure rates[ 25 ]. However, despite these promising results, ferumoxtran failed to achieve Food and Drug Administration FDA approval and production was halted[ 34 ]. Ferumoxytol is a newly released USPIO agent that has been more recently utilized in detection of malignant lymph nodes[ 35 ].
Ferumoxytol is a compound closely related to ferumoxtran that is FDA approved as iron replacement therapy in patients with chronic kidney failure with the recommended clinical dose of mg two doses of mg administered intravenously d apart [ 35 , 36 ].
In phase I and II clinical trials, ferumoxytol was associated with low adverse event rate which the most common events including nausea, dizziness, and diarrhea[ 37 ], although more serious reactions such as hypotension and anaphylaxis have been reported[ 38 , 39 ]. This has led to the FDA releasing a safety communication recommending modifications to give ferumoxytol as a dilute infusion[ 40 ]. Due to its large size, ferumoxytol remains in a relatively steady concentration within the intravascular space for several hours circulating half-life is h and then is gradually cleared by macrophages from the blood pool over several days[ 41 ].
Following macrophage breakdown, the iron oxide particles are taken up by the reticuloendothelial system[ 41 ]. In a recent phase I dose escalation trial, it was shown that the signal intensity of normal lymph nodes drop in a dose dependent manner with the optimal dose determined to be 7.
A pilot study quantitatively compared the ability of ferumoxytol and ferumoxtran to suppress signal intensity in normal lymph nodes in patients with high risk prostate cancer and showed that signal suppression was weaker for ferumoxytol MRL than for ferumoxtran MRL[ 42 ]. This study was limited in that only 4 patients received ferumoxytol and the dose was 6. Ferumoxytol MRL has also been preliminarily evaluated in non-human primates for use as an intraprostatic injection to directly map lymph nodes draining the prostate gland, with a potential of guiding lymphatic drainage patterns for specific gland segments[ 43 ].
MRL may have false positive results in the setting of reactive nodal hyperplasia or granulomatous diseases in which there are decreased number of macrophages in otherwise benign lymph nodes that may lead to mischaracterization of lymph nodes as malignant suspicion on imaging[ 44 ] Figure 2.
In diffusion-weighted imaging DWI , the Brownian motion of water molecules within a voxel of tissue is imaged and can be quantitatively expressed using the apparent diffusion coefficient ADC value. DWI can be performed quickly without the need of a contrast medium. Malignant tissue tends to have increased cellularity with enlarged nuclei and an abundance of macromolecular proteins, resulting in restricted diffusion[ 45 ]. Malignant lymph nodes have been shown to have a lower ADC value when compared to benign lymph nodes[ 46 , 47 ], but show less promising results in normal sized lymph nodes with a wide range of ADC values[ 45 , 48 ].
In a study of 29 patients with prostate cancer and a total of lymph nodes evaluated by DWI-MRI, a cut off value of 1. ADC values can be elevated in necrotic nodes due to the free diffusion of water, which can lead to misclassification[ 49 ]. While some authors have reporting the combination of nodal size and the relative ADC value nodes is more useful in detecting pelvic lymph node metastasis[ 50 ], others have found less promising results[ 45 ].
Nevertheless, there can be an overlap of ADC values in benign and malignant lymph nodes[ 51 ]. Evaluating additional morphologic features at MR imaging such as round shape, irregular border, low T2 signal may improve specificity than relying only on diffusion weighted imaging[ 51 ].
Further advances in DWI-MRI technique will require standardization of the technique, image acquisition and sequence parameters of different scanner platforms[ 53 ]. Considerable efforts are currently being made to develop effective radiotracers to image prostate cancer in both the setting of primary staging as well as biochemical recurrence.
Although not the focus of this paper, there is substantial evidence supporting the use of PET tracers for biochemical recurrence, and two PET tracers [ 11 C choline and 18 F fluciclovine] have been approved by the FDA for the detection and staging of biochemical recurrence.
However, there has been less investigation regarding the use of PET in the initial nodal staging of prostate cancer. A wide range of PET tracers have been developed and investigated for prostate cancer imaging, and this section summarizes PET tracers that have demonstrated utility for detecting lymph node metastases from prostate cancer. These tracers and their key properties are summarized in Table 1.
In PET imaging, a positron emitting radiotracer is administered to the patient, which then emits keV gamma rays through annihilation of the positron with an electron in the tissue which can be localized through coincidence detection[ 55 ].
One of the limitations of PET is resolution, with decreased sensitivity of the detection and characterization of PET tracer uptake in lesions less than 8 mm. Carbon and fluorine are produced using cyclotrons while gallium is produced using a generator system.
Fluorine is widely available, and its long half-life facilitates production of large batches of PET tracers and distribution to sites that do not have onsite production capabilities. The most commonly used radiotracer for clinical oncologic imaging is 2-deoxy 18 F fluoro-D-glucose FDG , but this tracer is of limited utility for the initial staging of prostate cancer due to the low metabolic activity in the early phase of the disease which results in poor sensitivity[ 56 ].
Another disadvantage of FDG is urinary excretion, potentially decreasing sensitivity for pelvic lymph nodes[ 57 ].
For the evaluation of bony metastases, sodium 18 F fluoride NaF has been used for skeletal scintigraphy which takes advantage of higher spatial resolution when compared with conventional planar 99m Tc methyldiphosphinate MDP. The uptake of 18 F fluoride is based on bone turnover with increased binding to newly deposited mineralize bone matrix that occurs in bone metastases, particularly osteoblastic metastases.
Choline is a naturally-occurring small molecule that is incorporated into tumor cells after phosphorylation by choline kinase, which is up regulated in prostate cancer[ 59 ]. This PET tracer has been used for prostate cancer with a pooled sensitivity of Results are better for larger nodes, but sensitivity is limited in lymph nodes smaller than 7 mm[ 20 ].
Fluorinated analogues of choline have been developed to take advantage of the longer half-life of fluorine [ e. Additionally, 18 F-labeled analogues of choline are eliminated via the kidney and urinary tract activity, which is undesirable for pelvic imaging. Acetate is a naturally occurring metabolic substrate that can enter the fatty acid metabolic pathway which is overexpressed in prostate cancer cells[ 68 ].
Prostate specific membrane antigen PSMA is a protein expressed by the prostate and overexpressed in prostate cancer[ 70 ]. While initial results showed improvement over conventional techniques, there was limited sensitivity and specificity[ 71 , 72 ]. However with the additional of MRI, sensitivity and specificity were increased[ 73 ]. The main disadvantage of In indium capromab pendetide is that it targets an intracellular protein making imaging only a possibility upon apoptosis or necrosis and not in viable tissue[ 55 , 70 , 74 ].
Additionally, the slow kinetics of In indium capromab pendetide requires imaging d after injection. More recently, a great deal of research has been focused on small molecule ligands that bind to the extracellular portion of PSMA[ 75 , 76 ].
Amino acid radiotracers can accumulate in prostate cancer cells through the upregulation of transmembrane amino acid transport in prostate cancer[ 81 ]. The most work with a synthetic amino acid PET radiotracer for prostate cancer has been with 18 F fluciclovine for detection of recurrent disease, and this PET tracer was approved by the FDA for use in biochemically recurrent prostate cancer in Figure 4.
Preliminary studies have reported results for initial staging[ 81 , 82 ]. Overall accuracies were similar An additional molecular target that is currently under investigation is the gastrin-releasing peptide receptor GRPR which is overexpressed in prostate but has lower levels in benign prostate tissue including benign prostatic hyperplasia[ 84 ].
A number of peptide based ligands for GRPR have been developed including the 14 amino acid peptide bombesin, as well as analogues of the amino acid gastrin releasing peptide GRP [ 86 ]. A single human trial utilizing a 68 Ga-labeled GRPR antagonist for pre-operative staging has been completed[ 87 ]. Androgen sensitivity and receptor expression remain a mainstay in the diagnosis and treatment of prostate carcinoma.
The role, if any, of 18 F FDHT in the pre-operative evaluation of prostate cancer is not yet defined. An interesting future in targeted molecular imaging of metastatic prostate carcinoma is the use of PSMA and bombesin agents for targeted therapy with alpha-emitters or beta-emitters including 90 Y and Lu.
These agents are currently being utilized in clinical trials for patients with biochemical recurrence, but are not currently approved for use in the United States[ 90 , 91 ]. These compounds may play a future role in adjuvant therapy post prostatectomy as the previously described molecular targeted PET agents become established for initial staging. Conventional imaging CT and MRI cannot depict small metastases in normal sized and normal appearing lymph nodes.
The optimal strategy for the preoperative staging of prostate cancer remains a topic of ongoing research.