11C Acetate Research Articles

406-P: Spatial Metabolomics of Human Kidney Tissues Reveal Impaired Tricarboxylic Acid (TCA) Cycle Turnover in Type 1 Diabetes (T1D)

In abstract 2023-A-3497-Diabetes, we show impaired TCA cycle turnover using 11C acetate PET and lower proximal tubular transcripts of TCA cycle enzymes by single-cell RNA sequencing of kidney biopsies in young adults with T1D vs. healthy controls (HC). Spatial metabolomics analyses of the kidney tissue were conducted to further explore perturbations in kidney oxidative metabolism in T1D. Matrix-assisted laser desorption/ionization-mass spectrometry imaging-based spatial metabolomics was used to analyze metabolites in situ (spatial resolution: 20 μm) in kidney tissues from 8 participants with T1D and preserved kidney function and 5 HC. Univariate analysis (t-test or Wilcoxon Mann Whitney test) demonstrated that 36 of 456 METASPACE annotated metabolites were altered (P<0.05) in T1D vs. HC. Partial least squares-discriminant analysis (PLS-DA) and heatmaps showed clearly separated clusters of metabolites. To identify the most significant discriminators for T1D, a variable importance in projection (VIP) plot from PLS-DA model was applied. Of the top 15 metabolites, two TCA cycle intermediates, succinic acid (m/z 117.0193, -H; P = 0.016) and malic acid (m/z 133.0142, -H; P = 0.026), were reduced in kidney tissues of participants with T1D. Pathway analysis revealed that the TCA cycle, mitochondrial electron transport chain, glutamate metabolism, malate-aspartate shuttle, and purine pathway were the dominant metabolic pathways perturbed in T1D kidney tissue. Spatial metabolomics comparing T1D kidney biopsies vs. HC reveal alterations of TCA cycle intermediates indicating mitochondrial dysfunction in the subclinical stages of diabetic kidney disease. The spatial metabolomics data are consistent with the data from transcriptomics and stable isotope tracing analysis in a subset of same participants. Further analysis with pathologic features will identify potential pathways linked to disease development. Disclosure G.Zhang: None. C.Birznieks: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. J.A.Schaub: None. K.J.Nadeau: None. V.Nair: None. F.Alakwaa: None. P.J.Mccown: None. A.Naik: Advisory Panel; CareDx. L.Pyle: None. D.Blondin: None. L.Liu: None. G.Richard: None. M.Kretzler: Research Support; Lilly, Boehringer Ingelheim Inc., Traveere Pharmaceuticals, Novo Nordisk, certa, Chinook Therapeutics Inc., Janssen Research & Development, LLC, AstraZeneca, Moderna, Inc., Gilead Sciences, Inc., Regeneron, Ionis Pharmaceuticals, Angioin, Renalytix. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. I.M.Tamayo: None. N.Garcia ponce de leon: None. T.B.Vigers: None. K.L.Tommerdahl: None. R.G.Nelson: None. P.E.Ladd: None. T.Alexandrov: None. Funding National Institutes of Health (UH3DK114920); JDRF (2-SRA-2019-845-S-B); Diabetes Research Center (P30DK116073)

Abstract 2326: Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor

Abstract ACSS2 is a nucleo-cytoplasmic enzyme that converts acetate into Acetyl-CoA. In many tumor types ACSS2 is dramatically upregulated in response to the hypoxic and lipid-depleted conditions often encountered in the tumor microenvironment. In these conditions, ACSS2 allows tumor cells to switch to acetate as key carbon source to meet their anabolic and energetic needs and thereby they become dependent on both acetate and ACSS2. MTB-9655 is a novel, potent and selective ACSS2 inhibitor discovered at Metabomed. It is currently in Phase I clinical investigation on patients with tumors with high levels of ACSS2. The antitumor effect of MTB-9655 was characterized in a number of PDX models across various tumor types. PDX tumors that exhibit over 50 TPM copies of ACSS2 mRNA showed significant sensitivity to ACSS2 inhibition in vivo. TCGA analyses suggests that most GU tumors, such as hepatocellular, gastric, colorectal show high frequency of ACSS2 upregulation and therefore present an opportunity for treatment with MTB-9655. In addition, PDX studies revealed a significant combination effect with cisplatin and gemcitabine. This opens opportunities for combination treatments of several GU cancers expressing high levels of ACSS2, such as ovarian and breast cancers.As a potential PD biomarker assay, 11C acetate PET imaging was explored preclinically in tumor-bearing mice as a way to assess inhibition of acetate flux in the presence of ACSS2 inhibitor. MTB-9655 resulted in robust inhibition of 11C acetate uptake in tumors in a dose-dependent manner opening the possibility of using 11C acetate PET as a clinical PD biomarker. Citation Format: Andreas Goutopoulos, Iris Amanati, Ali Fattaey, Avital Hay-Koren, Philippe Nakache, Omri Erez, Dimitri Kovalerchik, Dikla Paz, Simone Botti, Hannah Oppenheimer, Irit Fainer. Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2326.

MRI and 11C Acetate PET/CT for Prediction of Regional Lymph Node Metastasis in Newly Diagnosed Prostate Cancer.

BackgroundThe aim of the study was to examine the value of quantitative and qualitative MRI and 11C acetate PET/CT parameters in predicting regional lymph node (LN) metastasis of newly diagnosed prostate cancer (PCa).Patients and methodsPatients with intermediate (n = 6) and high risk (n = 47) PCa underwent 3T MRI (40 patients) and 11C acetate PET/CT (53 patients) before extended pelvic LN dissection. For each patient the visually most suspicious LN was assessed for mean apparent diffusion coefficient (ADCmean), maximal standardized uptake value (SUVmax), size and shape and the primary tumour for T stage on MRI and ADCmean and SUVmax in the index lesion. The variables were analysed in simple and multiple logistic regression analysis.ResultsAll variables, except ADCmean and SUVmax of the primary tumor, were independent predictors of LN metastasis. In multiple logistic regression analysis the best model was ADCmean in combintion with MRI T-stage where both were independent predictors of LN metastasis, this combination had an AUC of 0.81 which was higher than the AUC of 0.65 for LN ADCmean alone and the AUC of 0.69 for MRI T-stage alone.ConclusionsSeveral quantitative and qualitative imaging parameters are predictive of regional LN metastasis in PCa. The combination of ADCmean in lymph nodes and T-stage on MRI was the best model in multiple logistic regression with increased predictive value compared to lymph node ADCmean and T-stage on MRI alone.

Bottom up design of nanoparticles for anti-cancer diapeutics: “put the drug in the cancer’s food”

The story starts in Basel at CLINAM in 2013, when I asked Pieter about making nanoparticles and he advised me to “try this solvent-exchange method we have developed for making limit sized particles”. We are particularly interested in what are “limit size materials” because we want to test the feasibility of an idea: could we design, make, develop, and test the concept for treating metastatic cancer by, “Putting the Drug in the Cancer’s Food? “Limit size” is the size of the cancer‘s food, ? the common Low Density Lipoprotein, (LDL) ~20 nm diameter. In this contribution to Pieter’s LTAA we focus on the “bottom” (nucleation) and the “up” (growth) of “bottom-up design” as it applies to homogeneous nucleation of especially, hydrophobic drugs and the 8 physico-chemical stages and associated parameters that determine the initial size, and any subsequent coarsening, of a nanoparticle suspension. We show that, when made by the rapid solvent-exchange method, the same sized particles can be obtained without phospholipid. Furthermore, the obtained size follows the predictions of classic nucleation theory when the appropriate values for the parameters (surface tension and supersaturation) at nucleation are included. Calculations on dissolution time for nanoparticles reveal that a typical fewmicromolar-solubility, hydrophobic, anti-cancer drug (like Lapatinib, Niclosamide, Abiraterone, and Fulvestrant) of 500 nm diameter would take between 3?7 s to dissolve in an infinite sink like the blood stream; and a 50 nm particle would dissolve in less than a second! And so the nanoparticle design requires a highly water-insoluble drug, and a tight, encapsulating, impermeable lipid:cholesterol monolayer. While the “Y” junction can be used to mix an ethanolic solution with anti-solvent, we find that a “no-junction” can give equally good results. A series of nanoparticles (DiI-fluorescently labeled Triolein-cored and drug-cored nanoparticles of Orlistat) were then tested in well-characterized cell lines for uptake and efficacy as well as a PET-imageable nanoparticle in initial PET-imaging studies in animals for EPR uptake and tumor detection. We show that, while free-drug cannot be optimally administered in vivo, a nanoparticle formulation of orlistat could in principle represent a stable parenteral delivery system. The article ends with a brief discussion of what we see as the way forward in Individualized Medicine from the Diagnostic-Therapeutic (“Diapeutic”) side, requiring 18FDG detection of metastatic lesions, functional imaging of a protein target (e.g. Fatty Acid Synthase) using 11C acetate, then a PET (or other)-imageable nanoparticle to demonstrate EPR accumulation, and then the administration of the pure-drug nanoparticle taken in by the most aggressive cancer cells in the perivascular space, as they would their “food”.

Role of nuclear medicine methods in prostate cancer management

There is limited role of nuclear medicine in imaging of primary prostate cancer – the only method used more frequent is bone scan for staging of disease. Situation is different in the case of prostate cancer recurrence. Radiological methods are often inadequate for visualization of changes, despite to biochemical markers of recurrence. SPECT-CT Indium 111In-capromab pendetide (ProstaScint®), is a radiolabeled monoclonal antibody to prostate-specific membrane antigen, which offers a potential means of localizing sites of soft tissue metastasis in prostate cancer patients. PET-CT and PET MRI 1. 11C choline, 18F fluorocholine – Choline is an essential component of phospholipids in the cell membrane. Increase in cell proliferation and the enzyme activity is associated with an increase in choline uptake. 2. 11C acetate – is quickly and selectively taken up by PCa tumour cells located in the gland, prostate bed, lymph nodes or distant organs. 3. PMSA – 68Ga-PSMA - in PSA levels as low as ⩽0.5 ng/ml, 68Ga-PSMA PET/CT is able to show pathological accumulation outside the prostate bed. Both primary and metastatic prostate carcinomas show rapid uptake of 68Ga PSMA. 4. 68Ga-PSMA PET/CT can detect PC relapses and metastases with significantly improved contrast when compared to choline-based PET/CT, especially at low PSA levels. 5. 68Ga-PSMA PET/MRI – The novel technology shows similar accuracy and reliability in the depiction of LN and metastases to PET/CT. Because MRI is the method of choice for the assessment of the prostate gland and its combination with 68Ga-PSMA seems highly promising.

A Comparison of Different Imaging Techniques for Localisation of Cancers in the Prostate

The diagnostic accuracy of standard transrectal ultrasound-guided (TRUL) biopsy is limited due to the finite number of cores that can be obtained. It has been shown that the technique is not sufficiently reliable in defining the location and extent of prostatic cancer. The main aim of this study was to investigate the effectiveness of magnetic resonance imaging (MRI), and positron emission tomography (PET/CT) imaging techniques in pinpointing potential tumour lesions prior to prostate biopsy.Material and methodsThe study cohort consisted of 45 men with a raised prostate specific-antigen (PSA) level and/or suspected prostate cancer (PCa) at digital rectal examinations (DRE). Of the 45 patients, 23 had PCa detected with core needle biopsy (CNB). All had 11C acetate PET/CT imaging. Ten of those 23 patients underwent radical prostatectomy (RP), of those ten patients, eight patients had MR spectroscopic imaging (MRSI) with 3 T and six had diffusion weighted imaging (DWI) with apparent diffusion coefficient calculation (MRI DWI ADC). CNB, PET/CT, 2D MRSI and ADC map results were compared with postoperative specimen histopathology.Results The sensitivity of CNB, PET/CT, MRSI and DWI ADC were 0.53, 0.55, 0.79 and 0.95, whereas the specificity of was 0.88, 0.87, 0.46 and 0.73, respectively.Conclusion MRI improves the PCa detection by defining the areas of interest for targeted CNB of the prostate and can reduce the number of biopsies required

Abstract 2661: C11 Acetate and 18F FDG PET/CT imaging of MDR2-/- mouse model of hepatocellular carcinoma.

Abstract Our previous research reveals a link between the enzyme autotaxin (ATX) and its product lysophosphatidic acid (LPA) in hepatocellular carcinoma (HCC). We have shown a shift in ATX levels and LPA variant biosynthesis associated with HCC in patients that was corrected by liver transplantation. Moreover we have demonstrated a reduction in hepatic tumor burden in the MDR2-/- mouse model of HCC by treatment with commercial ATX inhibitors. The purpose of this study was to establish the relevance of FDG PET versus 11C acetate imaging to monitor response to ATX inhibition in the in-vivo MDR2 /- mouse model of HCC whereby we would be able to test the impact of novel inhibitors on both the initiation and progression of HCC. Methods: Dynamic high-resolution Positron Emission Tomography (PET) images of 12 month MDR-/- mice and FVB controls were acquired using 18F-FDG or 11C-Acetate (N=3 per group). At the end of the PET imaging session whole body CT images were acquired. Image segmentation for discrete volumes of interests (VOI) was manually constructed from parametric images for the liver for 18F-FDG images while for 11C-Acetate VOIs were submitted to kinetic modeling, using a 3-compartment, 4-parameter model. Results. MDR2-/- mice had significant hepatic tumors at 12 month (7.9±1.8mm) whereas no tumors were observed in FVB controls. MDR2-/- mice had significantly higher hepatic 11C-Acetate uptake and metabolic rates when compared to FVB controls (0.6±0.04 vs 0.49±0.02ml/g/min P=0.038). In contrast there was no significant difference in 18F-FDG metabolism or uptake in the livers of MDR2-/- mice when compared to wild type FVB controls (1.1±0.23 v 1.32±0.2 and 3.61±0.97 vs. 4.3±0.6SUV respectively p=ns). Conclusion: The biology of HCC formation in MDR2-/- is better suited to 11C acetate PET/CT imaging than 18F FDG. 11C acetate is the most effective imaging method available to test response to treatment in an in-vivo model of HCC. Citation Format: Nicholas J. Skill, Paul R. Territo, Amanda A. Riley, Brian P. McCarthy, Mary A. Maluccio. C11 Acetate and 18F FDG PET/CT imaging of MDR2-/- mouse model of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2661. doi:10.1158/1538-7445.AM2013-2661 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

509 THERAPEUTIC FATTY ACID SYNTHASE INHIBITION IN PROSTATE CANCER AND THE USE OF 11C-ACETATE TO MONITOR THERAPEUTIC EFFECTS

You have accessJournal of UrologyProstate Cancer: Basic Research (III)1 Apr 2013509 THERAPEUTIC FATTY ACID SYNTHASE INHIBITION IN PROSTATE CANCER AND THE USE OF 11C-ACETATE TO MONITOR THERAPEUTIC EFFECTS Greg Shaw, David Lewis, Joan Boren, Antonio Ramos-Montoya, Robert Bielik, Dmitry Soloviev, Brindle Kevin, and Neal David Greg ShawGreg Shaw Cambridge, United Kingdom More articles by this author , David LewisDavid Lewis Cambridge, United Kingdom More articles by this author , Joan BorenJoan Boren Cambridge, United Kingdom More articles by this author , Antonio Ramos-MontoyaAntonio Ramos-Montoya Cambridge, United Kingdom More articles by this author , Robert BielikRobert Bielik Cambridge, United Kingdom More articles by this author , Dmitry SolovievDmitry Soloviev Cambridge, United Kingdom More articles by this author , Brindle KevinBrindle Kevin Cambridge, United Kingdom More articles by this author , and Neal DavidNeal David Cambridge, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1903AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Fatty acid synthase(FAS) is upregulated in prostate cancer at mRNA and protein levels and is linked to prognosis. Clinical FAS inhibition is a rational therapeutic target and the development of a biomarker by which to monitor therapeutic effect is attractive. METHODS Prostate cancer C42b cell xenografts were generated in Nod-SCID-gamma mice. The mice were dosed daily by oral gavage with 3mg/kg GSK2194069, a novel FAS inhibitor or vehicle. Mice bearing xenografts were injected with 11C acetate and imaged using PET CT before and after oral administration of GSK2194069 3mg/kg. Similar animals were administered 14C acetate before and after GSK2194069 administration. Gas chromatography/Mass spectrometry was used to quantify fatty acid content of tumours before and after GSK2194069 administration. RESULTS Tumour growth was inhibited in those mice dosed with GSK2194069. Mean tumour size after 5 weeks growth was 595.0 ± 171.2mm3 (N=6) in the vehicle group (and 106.2 ± 26.23mm3 (N=5) in the GSK2194069 treated group (p=0.037 two-tailed unpaired t-test). There was no significant weight loss in the GSK2194069 treated cohort and no adverse effects noted. The effect of GSK2194069 in decreasing acetate uptake was seen with scintillation detection of 14C-acetate in the lipid phase of C42b xenograft tumours by 56% 2 hours after dosing with GSK2194069. Inhibition of FAS by GSK2194069 resulted in a decrease in acetate signal in all animals (n=7) and by a median of 43 percent (p<0.05, paired t-test). CONCLUSIONS PC xenograft growth can be inhibited with GSK2194069 a novel FAS inhibitor. The effects of GSK2194069 on FAS activity can be monitored non-invasively by imaging with 11C acetate PET. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e208-e209 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Greg Shaw Cambridge, United Kingdom More articles by this author David Lewis Cambridge, United Kingdom More articles by this author Joan Boren Cambridge, United Kingdom More articles by this author Antonio Ramos-Montoya Cambridge, United Kingdom More articles by this author Robert Bielik Cambridge, United Kingdom More articles by this author Dmitry Soloviev Cambridge, United Kingdom More articles by this author Brindle Kevin Cambridge, United Kingdom More articles by this author Neal David Cambridge, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

The Role of PET/CT and SPECT/CT in Oncology Drug Development

Understanding the hallmarks of cancer is valuable in advancing drug development to fight the disease. With the advent of molecular imaging, non-invasive in vivo visualization of physiology and functional pathways allow for multiple levels of disease and therapy assessment beyond tumor size measurements offered by conventional anatomic scans. Radiolabeling targeted molecules can provide insight into tumor interactions within the body and may help guide therapeutic constructs. Traditionally, radiolabeled probes have been useful for staging and diagnosis but they can also be created to monitor and identify drug targets and pharmaceutical biodistribution among other novel approaches. Radiotracers can be imaged either through single photon emission computed tomography (SPECT) or positron emission tomography (PET), with advantages and limitations to both. Adding CT to either modality is an added benefit for anatomic localization and attenuation correction. In this review, we will briefly discuss several molecular imaging agents, which target metabolism (18F-FDG, 18F-FACBC, 11C acetate), proliferation (18F-FLT, 18F-5FU, 18F-FdCyd), and cancer specific drug receptors (111In-morab009, 111In-trastuzumab, 89Zr-panutumumab). Molecular imaging is a powerful tool that one day, may be employed to personalize treatment and dosing strategies and predict anticancer therapy outcomes. Keywords: Molecular Imaging, oncology, PET/CT, prostate cancer, radioimmunoscintigraphy, SPECT/CT, 18 F-FDG, 18 F-FACBC, 8 F-FLT, 18 F-5FU, Drug Development

EFFECTS OF INTENSIFIED PULMONARY HYPERTENSION SPECIFIC VASODILATOR THERAPY ON MYOCARDIAL OXIDATIVE METABOLISM AASSESSED USING C-11 ACETATE PET IN PATIENTS WITH PULMONARY HYPERTENSION

Background: Elevated pulmonary arterial pressure may increase right ventricular (RV) oxidative metabolism in patients with pulmonary hypertension (PH). A pulmonary hypertension (PH)-speciic vasodilator decreases pulmonary arterial pressure. However, it is not clear whether such a treatment favorably affects RV myocardial oxidative metabolism. The purpose of this study was to investigate the possible impacts of the intensiied PH-speciic vasodilator therapy on myocardial energetics using 11C acetate PET.

833 Monitoring the effects of therapeutic fatty acid synthase inhibition in prostate canecr using 11C acetate PET

833 Monitoring the effects of therapeutic fatty acid synthase inhibition in prostate canecr using 11C acetate PET

Thyroid Replacement Therapy and Heart Failure

Heart failure (HF) is a major public health and economic problem in Western countries and is one of the most common causes of hospitalization and death. Coronary artery disease is the underlying cause in more than two thirds of chronic HF patients. By 2020, the World Health Organization projects that ischemic heart disease alone will be the most important global cause of morbidity and mortality. The estimated increases in HF-related morbidity and mortality suggest that our understanding of the pathophysiological mechanisms of this syndrome is inadequate. Interest in the role of thyroid hormones (THs) in HF has increased in recent years. The driving considerations can be summarized as follows: (1) the known effects of THs on contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis that TH signaling is critical in preserving cardiac structure and performance under normal conditions and after cardiac injury; and (3) evidence that mildly altered TH function is strongly associated with a worsening prognosis in cardiac patients in general and in HF patients in particular. Diastolic function and systolic function are clearly influenced by THs.1 Ventricular contractile function is also influenced by changes in hemodynamic conditions secondary to TH effects on peripheral vascular tone.1 TH homeostasis preserves positive ventricular-arterial coupling, leading to a favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4 (thyroxine).3–6 This review highlights a growing body of evidence from animal studies and small-scale clinical trials suggesting that low cellular thyroid activity at the cardiac tissue level may adversely affect HF …

Normal organ standard uptake values in carbon-11 acetate PET imaging

The goal of this study was to determine normal standard uptake values of carbon-11 (11C) acetate in healthy organs. By accurately determining the range of physiologic activity, abnormal focal or diffuse 11C-acetate activity can be more accurately assessed and thus improve the sensitivity and specificity of this emerging diagnostic PET agent. We reviewed all 55 patients (mean age+/-SD 64.8+/-10.8, age range 35-88 years) who underwent 11C-acetate PET/computed tomography at our institution from 2005 to 2007. Regions of interest were drawn in organs that were devoid of clinical or imaging evidence of disease. The maximum standard uptake value for each region was calculated and analyzed for mean, standard deviation, and 95% confidence intervals. The results are presented as average maximum standard uptake value+/-1 SD with the pancreas, liver, spleen and salivary glands showing the greatest 11C-acetate avidity. A review of the literature shows our results to be similar to those published earlier. Accurate knowledge of normal biodistribution and standardized uptake values will provide the foundation for assessing focal or diffuse organ disease while using this PET agent.

Quel bilan d’imagerie avant une radiothérapie de rattrapage après prostatectomie radicale pour adénocarcinome prostatique ?

Prostatectomy is one of the most widely used methods for treatment of adenocarcinoma of the prostate. According to anatomopathological criteria, between 10 and 40% of patients will display biochemical relapse in the absence of adjuvant radiotherapy. Anatomopathological and biochemical criteria are powerful tools for selecting patients for salvage radiotherapy. The aim of this article is to review literature on the latest progress in radiological and nuclear medicine techniques and their performance levels, in order to determine local, regional and metastatic relapses associated with the techniques and specify the radiotherapy target volume. Magnetic resonance imaging (MRI) displays the best sensitivity and specificity for examination of the prostate bed and enables simultaneous assessment of the pelvic region – thus diminishing the utility of computed tomography. The performance levels of MRI will probably continue to improve, with the use of dynamic MRI and MR spectroscopy. Despite the development of new markers like 11C and 18F choline and acetate, the sensitivity of positron emission tomography is still low. Prospective studies with an appropriate methodology are necessary for specifying the technique's value in this context.

Myocardial Metabolic Imaging in the Clinical Setting

Glucose and free fatty acids are a major energy source in the myocardium. Metabolic imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) have been widely used for the evaluation of the pathophysiology of coronary artery disease (CAD) and heart failure. 18F fluorodeoxyglucose (FDG) is a glucose analogue that is used to measure myocardial glucose utilisation. The myocardial uptake of a modified branched fatty acid, 15-(p-[iodine-123] iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP), reflects the activation of fatty-acid metabolism by co-enzyme A (CoA) and indirectly reflects cellular adenosine triphosphate (ATP) production. The turnover rate of the tricarboxylic acid (TCA) cycle reflects the rate of overall myocardial oxidative metabolism. 11C acetate is readily metabolised to CO2 almost exclusively through the TCA cycle. These three major agents have been most commonly used for probing myocardial energy metabolism in vivo. Such metabolic imaging has been used for assessing myocardial viability on the basis of persistent glucose utilisation in ischaemic but viable myocardium. BMIPP and FDG have been identified for locating a recent history of myocardial ischaemia. Furthermore, metabolic imaging is promising for the assessment of the pathophysiology of heart failure and the treatment effect of various drugs, as well as mechanical treatments. In this article we will provide an overview of the application of myocardial metabolic imaging in a clinical setting.

Positive Imaging of Thymoma by 11C-Acetate Positron Emission Tomography

Several studies have shown that fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is not useful for the diagnosis of thymoma. We describe 3 patients with thymoma who underwent both FDG-PET and carbon-11 (11C) acetate (AC)-PET. Although all three thymomas were successfully imaged by AC-PET, one of the thymomas was not imaged by FDG-PET. These results suggest that AC-PET may have a potentially important role in the diagnosis of thymoma. This is the first report of the use of AC-PET for diagnostic imaging of thymoma.

Positron emission tomography for prostate, bladder, and renal cancer

Prostate cancer, renal cancer, bladder, and other urothelial malignancies make up the common tumors of the male genitourinary tract. For prostate cancer, common clinical scenarios include managing the patient presenting with 1) low-risk primary cancer; 2) high-risk primary cancer; 3) prostate-specific antigen (PSA) recurrence after apparently successful primary therapy; 4) progressive metastatic disease in the noncastrate state; and 5) progressive metastatic disease in the castrate state. These clinical states dictate the appropriate choice of diagnostic imaging modalities. The role of positron emission tomography (PET) is still evolving but is likely to be most important in determining early spread of disease in patients with aggressive tumors and for monitoring response to therapy in more advanced patients. Available PET tracers for assessment of prostate cancer include FDG, 11C or 18F choline and acetate, 11C methionine, 18F fluoride, and fluorodihydrotestosterone. Proper staging of prostate cancer is particularly important in high-risk primary disease before embarking on radical prostatectomy or radiation therapy. PET with 11C choline or acetate, but not with FDG, appears promising for the assessment of nodal metastases. PSA relapse frequently is the first sign of recurrent or metastatic disease after radical prostatectomy or radiation therapy. PET with FDG can identify local recurrence and distant metastases, and the probability for a positive test increases with PSA. However, essentially all studies have shown that the sensitivity for recurrent disease detection is higher with either acetate or choline as compared with FDG. Although more data need to be gathered, it is likely that these two agents will become the PET tracers of choice for staging prostate cancer once metastatic disease is strongly suspected or documented. 18F fluoride may provide a more sensitive bone scan and will probably be most valuable when PSA is greater than 20 ng/mL in patients with high suspicion or documented osseous metastases. Several studies suggest that FDG uptake in metastatic prostate cancer lesions reflects the biologic activity of the disease. Accordingly, FDG can be used to monitor the response to chemotherapy and hormonal therapy. Androgen receptor imaging agents like fluorodihydrotestosterone are being explored to predict the biology of treatment response for progressive tumor in late stage disease in castrated patients. The assessment of renal masses and primary staging of renal cell carcinoma are the domain of helical CT. PET with FDG may be helpful in the evaluation of "equivocal findings" on conventional studies, including bone scan, and also in the differentiation between recurrence and posttreatment changes. The value of other PET tracers in renal cell carcinoma is under investigation. Few studies have addressed the role of PET in bladder cancer. Because of its renal excretion, FDG is not a useful tracer for the detection of primary bladder tumors. The few studies that investigated its role in the detection of lymph node metastases at the time of primary staging were largely disappointing. Bladder cancer imaging with 11C choline, 11C methionine, or 11C- acetate deserves further study.

Comparison of myocardial oxygen consumption using 11C acetate positron emission tomography scanning in a working and non-working heart transplant model.

In acute cardiac rejection, changes in myocardial oxygen consumption occur; non-invasive detection of these metabolic changes would have obvious clinical utility. In the classic cervical, heterotopic, canine, transplant model, the heart is non-working. It has a low myocardial oxygen consumption. Creation of a working model with normal myocardial oxygen consumption would enhance validity of non-human studies. Clearance of 11C acetate was determined by positron emission tomography (PET) scanning and compared with myocardial oxygen consumption in normal and transplanted canine hearts. Donor hearts from mongrel dogs (2.5-3 kg; n=4) were transplanted into the neck of adult beagles (12-15 kg; n=4), no immunosuppression was given. Two non-working hearts were modified to eject only coronary flow via the right ventricle. In two hearts, a novel working model was created with aortic regurgitation to load the left ventricle. Working and non-working hearts underwent PET scanning on post-operative days 2 and 4. Normal dog hearts (n=2) and native hearts of transplanted dogs (n=3) were used to validate the scanning technique. Coronary sinus and aortic oxygen saturation data along with myocardial blood flow (radiolabeled microspheres) confirmed that clearance of 11C acetate in normal and transplanted hearts followed a bi-exponential model. Myocardial oxygen consumption was correlated with the rate constant of 11C acetate rapid phase clearance (r=0.91) in normal and transplanted hearts. The working hearts had increased myocardial oxygen consumption compared to non-working hearts. This study (1) introduces a model of a working heterotopic cardiac transplantation with near-normal oxygen consumption; and (2) demonstrates that regional myocardial oxygen consumption in transplanted hearts can be detected by 11C acetate PET.

Extent of myocardial damage in regions with reverse redistribution at 3 h and at 24 h on 201Tl SPET: evaluation based on regional myocardial oxidative metabolism.

Reverse redistribution (RRD) of 201Tl is often observed in patients with recent myocardial infarction. However, the difference in the extent of myocardial damage between regions with 3-h RRD and those with 24-h RRD remains unknown. Accordingly, we investigated RRD from the standpoint of myocardial oxidative metabolism. Carbon-11 (11C) acetate dynamic myocardial PET scanning was performed at rest in 14 patients with recent myocardial infarction, and the clearance rate constant (Kmono) of 11C-acetate was calculated in 6-7 ROIs on the transaxial image in each patient using a monoexponential fit as an index of myocardial oxidative metabolism. Exercise 201Tl myocardial SPET was also performed. Ninety-two regions corresponding to the PET study were then classified based on the findings of transaxial 201Tl SPET imaging; that is, regions with reverse redistribution, regions with severely decreased 201Tl activity or no 201Tl activity on the 24-h delayed images, and regions with normal 201Tl activity throughout the study. Kmono in regions with reverse redistribution (0.051 +/- 0.009 min-1) was significantly lower than that in regions with normal 201Tl activity throughout the study (0.066 +/- 0.011 min-1) (P < 0.001) but significantly higher than that in regions with severely decreased or no 201Tl activity on the 24-h delayed images (0.037 +/- 0.003 min-1) (P < 0.001). Percent Kmono (i.e. Kmono in region with RRD/the mean of Kmono in all regions with a normal 201Tl SPET result) was significantly lower in the 3-h RRD regions (81.3 +/- 6.3%) than in the 24-h RRD regions (87.6 +/- 6.1%) (P < 0.05). Impairment of myocardial oxidative metabolism is observed in regions with RRD, suggesting that RRD corresponds to mild myocardial damage. Reverse redistribution on 24-h delayed images may indicate much milder myocardial damage compared with RRD on 3-h delayed images.

Imaging of myocardial metabolism by positron emission tomography

Tracer techniques have provided new insight in cardiology by allowing noninvasive studies of myocardial perfusion, function, metabolism, and, more recently, ligand-receptor interaction. Positron emission tomography allows accurate quantification and the use of natural substrates labelled with 11C, 13N, or 15O. Myocardial metabolism is complex and utilizes a number of substrates, primarily fatty acids. Fatty acids utilization can be studied with 11C palmitate, while 11C acetate more selectively traces TCA cycle activity and reflects myocardial oxygen utilization. Glucose uptake can be traced using 18F deoxyglucose, a glucose analog that is a substrate for hexokinase but is not further metabolized. Flow and oxidative glucose metabolism are usually coupled, and thereby the uptake of FDG and perfusion tracers are usually similar. In myocardial ischemia, however, glucose utilization can persist due to anaerobic glycolysis, and its uptake is frequently enhanced. Clinical applications of the use of metabolic studies in patients with ischemic heart disease are presented.