Étude de l’expression de LAT-1 et de la fixation de la 18F-FDOPA dans les tumeurs cérébrales. Illustration par une série de cas

IntroductionPET imaging of amino acid analogues, in particular with ¹⁸F-FDOPA, is increasingly used for the diagnosis and post-therapeutic evaluation of brain tumors. The mechanism of ¹⁸F-FDOPA uptake in brain tumors is still debated in the literature, the main hypothesis being uptake via L-amino-transporter 1 (LAT-1).MethodWe present 4 cases of patients with primary or secondary brain lesions who underwent ¹⁸F-FDOPA PET/CT or PET/MRI for the evaluation of suspected tumor recurrence and who underwent surgical removal with immunostaining labeling of LAT-1 transporters within 3 months. For each of these patients, a correspondence between semi-quantitative PET parameters (SUVmax, TBRmax and TSRmax) and anatomopathological characteristics was performed.ResultsAll patients had a significant and intense tumor uptake on ¹⁸F-FDOPA PET. In contrast, the expression level of LAT-1 receptors was very variable from one patient to another (LAT-1 score ranging from 0 to 193).ConclusionThis article reflects the persistent questioning of the link between the LAT-1 receptor and the uptake intensity on ¹⁸F-FDOPA PET, especially in patients who have received a first line of treatment.     

Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study

Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [¹⁸F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [¹⁸F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [¹⁸F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [¹⁸F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.     

Myocardial Metastases on 6-[18F] fluoro-L-DOPA PET/CT: A Retrospective Analysis of 116 Serotonin Producing Neuroendocrine Tumour Patients

Purpose

This study evaluates the prevalence of cardiac metastases in patients with serotonin producing neuroendocrine tumours (NET), examined with ¹⁸F-FDOPA PET/CT, and the relationship of these metastases to the presence of carcinoid heart disease (CHD) based on echocardiography.

Background

CHD occurs in patients with serotonin producing NET. The diagnostic method of choice remains echocardiography. The precise prevalence of cardiac metastases is unknown given the limitations of standard technologies. Nuclear medicine modalities have the potential to visualize metastases of NET.

Methods

All patients who underwent ¹⁸F-FDOPA PET/CT because of serotonin producing NET between November 2009 and May 2012 were retrospectively analyzed. The presence of cardiac metastasis was defined as myocardial tracer accumulation higher than the surrounding physiological myocardial uptake. Laboratory tests and transthoracic echocardiography (TTE) results were digitally collected.

Results

116 patients (62 male) underwent ¹⁸F-FDOPA PET/CT, mean age was 61±13 years. TTE was performed in 79 patients. Cardiac metastases were present in 15 patients, of which 10 patients also underwent TTE. One patient had both cardiac metastasis (only on ¹⁸F-FDOPA PET/CT) and echocardiographic signs of CHD. There were no differences in echocardiographic parameters for CHD between patients with and without cardiac metastases. TTE in none of the 79 patients showed cardiac metastases.

Conclusion

The prevalence of cardiac metastases detected with ¹⁸F-FDOPA PET/CT in this study is 13%. ¹⁸F-FDOPA PET/CT can visualize cardiac metastases in serotonin producing NET patients. There appears to be no relationship between the presence of cardiac metastases and TTE parameters of CHD.     

Indications de la TEP-FDG en oncologie. Mise à jour selon les recommandations de prise en charge européennes et américaines

[18F]-Fluoro-2-Deoxy-D-Glucose-Positon Emission Tomography (PET) is a powerful tool which availability increases in France. The oncological PET indications are plentiful and are increasing. Yet, its cost is significant. Thus, it is important to use PET in validated indications and/or in situations in which it can improve the patient management. The first part of this work reviews the PET indications in oncology, according to the international clinical practice guidelines (European Society for Medical Oncology [ESMO] and National Comprehensive Cancer Network [NCCN]), and compares those with the French guidelines (Guide de bon usage [GBU] des examens d’imagerie médicale). The second part assesses the indication distribution of 400 consecutive PET-CT studies in an against cancer center, according to the cancer type and confronts those with the guidelines.     

The Sum of Tumour-to-Brain Ratios Improves the Accuracy of Diagnosing Gliomas Using 18F-FET PET

Gliomas are common brain tumours, but obtaining tissue for definitive diagnosis can be difficult. There is, therefore, interest in the use of non-invasive methods to diagnose and grade the disease. Although positron emission tomography (PET) with 18F-fluorethyltyrosine (18F-FET) can be used to differentiate between low-grade (LGG) and high-grade (HGG) gliomas, the optimal parameters to measure and their cut-points have yet to be established. We therefore assessed the value of single and dual time-point acquisition of 18F-FET PET parameters to differentiate between primary LGGs (n = 22) and HGGs (n = 24). PET examination was considered positive for glioma if the metabolic activity was 1.6-times higher than that of background (contralateral) brain, and maximum tissue-brain ratios (TBR_max) were calculated 10 and 60 min after isotope administration with their sums and differences calculated from individual time-point values. Using a threshold-based method, the overall sensitivity of PET was 97%. Several analysed parameters were significantly different between LGGs and HGGs. However, in a receiver operating characteristics analysis, TBR sum had the best diagnostic accuracy of 87% and sensitivity, specificity, and positive and negative predictive values of 100%, 72.7%, 80%, and 100%, respectively. 18F-FET PET is valuable for the non-invasive determination of glioma grade, especially when dual time-point metrics are used. TBR sum shows the greatest accuracy, sensitivity, and negative predictive value for tumour grade differentiation and is a simple method to implement. However, the cut-off may differ between institutions and calibration strategies would be useful.     

PET for diagnosis and therapy of brain tumors

Main contribution of PET in the management of brain tumors is at the therapeutic level. Specific reasons explain this role of molecular imaging in the therapeutic management of brain tumors, especially gliomas. Gliomas are by nature infiltrating neoplasms and the interface between tumor and normal brain tissue may not be accurately defined on CT and MRI. Also, gliomas are often histologically heterogeneous with anaplastic areas evolving within a low-grade tumor, and the contrast-enhancement on CT or MRI does not represent a good marker for anaplastic tissue detection. Finally, assessment of tumor residue, recurrence or progression may be altered by different signals related to inflammation or adjuvant therapies, even on contrast-enhanced CT and MRI. These limitations of the conventional neuroimaging in delineating tumor and detecting anaplastic tissue lead to potential inaccuracy in lesion targeting at different steps of the management (diagnostic, surgical, and post-therapeutic stages). Molecular information provided by PET has proved helpful to supplement morphological imaging data in this context. ¹⁸F-FDG (FDG) and amino-acid tracers such as ¹¹C-methionine (MET), provides complementary metabolic data that are independent from the anatomical MR information. These tracers help in the definition of glioma extension, in the detection of anaplastic areas and in the postoperative follow-up. Additionally, PET data have an independent prognostic value. To take advantage of PET data in glioma treatment, PET might be integrated in the planning of image-guided biopsies, radiosurgery and resection.     

Indications et performances de la TEP/TDM au fluorure de sodium (FNA)

18F-NAF PET/CT is a relatively uncommon imaging procedure in France, for which indications are similar to those for bone scan and that shows substantial advantages when compared to it. In this review article, we propose to introduce this poorly known radiotracer, its validated indications, performances and some tips for interpretation that will be illustrated by 6 case reports.     

Prescription et pratique de la recherche des microdélétions du chromosome Y en France: résultats de l’enquête nationale réalisée sous l’égide de la Société d’Andrologie de Langue Française

Screening for Y chromosome microdeletions is recommended in cases of severe impaired spermatogenesis. Improvement of molecular biology techniques has made this diagnosis more accessible in routine practice when evaluation of male infertility is necessary. However, the diagnosis of Y chromosome microdeletions is not proposed by all IVF centres. The aim of the present study was to specify the prescribing conditions (indication, financing) and practical conduct (methods, billing) for this analysis in France. We observed that microdeletion screening is a rapidly expanding activity. The development of a consensus on the indications for this screening and a standardised technique, with a national quality control, appears to be necessary. The funding of this analysis by French Social Security appears to be an essential step to ensure widespread use in routine practice. Lastly, the answers to our questionnaire revealed a strong demand for information concerning this analysis.     

Quantification in oncologic FDG-PET: A scientific overview

F18-Fluorodeoxyglose Positron Emission Tomography (FDG-PET) has gained wide acceptance in cancer patient management for initial diagnosis, staging, prognosis and patient monitoring. FDG-PET is also of interest for radiotherapy treatment planning. FDG-PET imaging has the potential to yield a quantitative assessment of glucose metabolism in tumours, which might be extremely helpful for differential diagnosis, patient monitoring and delineation of the biologically active tumour volume. The most accurate approach to assess the glucose metabolic rate (GMR) is by combining dynamic PET imaging and kinetic analysis. However, this requires a lengthy acquisition and an estimate of the arterial input function, which make the approach unpractical for clinical use. Several alternative strategies have thus been proposed to assess the GMR in tumours more easily. The presentation will review these different approaches, from the simplest one (using the Standardized uptake values [SUV] as done almost in all clinical centres) to more advanced approaches (for instance requiring at least one blood sample drawing).     

早期动态18F-FDG PET/CT成像在实体肿瘤评估中的应用

~(18)F-FDG PET/CT常规代谢成像反应肿瘤的葡萄糖代谢及乏氧情况,而~(18)F-FDG PET/CT早期动态成像能反映PET/CT成像早期肿瘤的灌注情况。由于肿瘤的异质性,在早期动态~(18)F-FDG PET/CT成像,即~(18)F-FDG PET/CT灌注成像中,存在独立于常规60 min~(18)F-FDG PET/CT代谢成像的SUVmax(最大标准摄取值)高摄取区。因此,在临床工作中应用~(18)F-FDG PET/CT早期动态成像,能够进一步对实体肿瘤的活性区域进行评估,能够更好评价患者预后、完善治疗方案。当前~(18)F-FDG早期动态成像已经应用在肝癌、肾癌以及膀胱癌等实体肿瘤诊断中。早期动态~(18)F-FDG PET/CT成像结合常规标准~(18)F-FDG PET/CT代谢成像,对实体肿块进行一站式成像方法,能够更好的对肿瘤进行评估。     

Intérêt de la TEP/TDM au FDG dans l’investigation étiologique des syndromes paranéoplasiques

Paraneoplastic syndromes (PNS) represent a rare and heterogeneous group of entities whose clinical symptoms may sometimes antedate the diagnosis of the causative tumor. In the context, the identification of the underlying tumor becomes very important for the patient's functional and sometimes vital prognosis, by allowing an earliest treatment of the tumor. ¹⁸FDG PET/CT has become indispensable in the diagnosis and follow-up of numerous cancers but its role in etiological investigation of isolated paraneoplastic syndromes for the research of an occult tumor is not defined yet. Nevertheless, requests of PET/CT in this indication are frequent in nuclear medicine departments, with an uncertain diagnostic yield. We have listed retrospectively 64 patients, sent to nuclear medicine department of Nancy university hospital between 2004 and 2010 for the research of an occult tumor because of a clinically suspected paraneoplastic syndrome, in order to estimate its diagnostic contribution in this indication. According to our results, ¹⁸FDG PET-CT would be interesting by its negative predictive value concerning the tumoral risk, in keeping with its known sensitivity PET-CT may also present an interest for the diagnosis and the characterization of non-tumoral conditions generating symptoms initially wrongly suspected to be paraneoplastic.     

Évaluation de la TEP au 18F-FDG dans la tuberculose extrapulmonaire : premiers résultats d’une étude pilote observationnelle

Aim

Extrapulmonary tuberculosis treatment is difficult to assess and there is a need for new tools. The aim of this observational pilot study is to evaluate the potential role of 18F-FDG PET/CT in the initial staging and treatment evaluation of extrapulmonary tuberculosis.

Methods

Twenty-eight patients were included between January 2009 and 2010. Twenty-three had a 18F-FDG PET/CT before treatment and/or during and/or after treatment. All patients will be followed for 18 months after the end of treatment. A control group of five patients with previous history of tuberculosis was also included and PET/CT was performed.

Results

Three cases of differential diagnosis were excluded of the study. The initial PET for staging showed additional lesions in 8/10 patients compared to conventional imaging. At the end of treatment, 6/11 patients had a negative PET, and 5/11 patients had a positive PET. PET had a significant clinical impact for 3/10 patients at initial staging (guiding biopsy or increase of planned treatment duration), and for 3/16 during follow up (extend or early interruption of the treatment). All PET scans in the control group were negative.

Conclusion

18F-FDG PET has an excellent sensitivity for the detection of extrapulmonary tuberculosis lesion and excellent negative predictive values. The impact of initial PET staging seems significant. The interest of 18F-FDG PET for the evaluation of response to treatment remains to be assessed and will be correlated with patients’ follow up in a second phase of this study.     

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using ¹⁸F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as ¹⁸F-Fluorocholine (¹⁸F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer ¹⁸F-FCH/¹⁸F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to ¹⁸F-FCH and ¹⁸F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The ¹⁸F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in ¹⁸F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by ¹⁸F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of ¹⁸F-FCH/ ¹⁸F-FDG-PET imaging in this study, while the false-positive caused by ¹⁸F-FCH can be eliminated. Dual tracer ¹⁸F-FCH/¹⁸F-FDG PET imaging has the potential to improve the visualization of low grade glioma. ¹⁸F-FCH delineates tumor areas and the tumor can be identified by subtracting the ¹⁸F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.     

The French experience of PSMA PET for the diagnosis of biological recurrence of prostate cancer

PSMA PET can only be performed in France in the context of a temporary authorization for use (ATU) granted by the ANSM only in the event of biological recurrence of prostate cancers with a normal or equivocal Fucyclovine or Choline PET scan. We present the experience of the Léon Bérard cancer centre and report on the experience of 3 other French centres that have published their results obtained within the framework of this ATU. Despite the absence of histological comparison of our results, the evidence of suspicious lesions on PSMA PET examination may induce changes in patient management in almost 2/3 of the patients. This is consistent with the already abundant results in the literature, which show a clear superiority of PSMA PET over Choline PET for the diagnosis of biological recurrence of prostate cancer.     

Role and Cost Effectiveness of PET/CT in Management of Patients with Cancer

PET/CT is a relatively new imaging technology, whose undoubted advantages are valuable in clinical oncology as well as in all fields of diagnosis, staging, and treatment. The hardware combination of anatomy and function has been the true evolution in imaging. PET using 18F-fluorodeoxyglucose (FDG) is increasingly used for the staging of solid malignancies, including colon, lung, etc., but anatomic information is limited. Integrated PET/CT enables optimal anatomic delineation of PET findings and identification of FDG-negative lesions on computed tomography (CT) images and might improve preoperative staging. However, controversy still exists in relation to the application of PET/CT in clinical practice, mainly because of its high cost. It is evident that apart from additional costs, potential savings also are associated with PET/CT as a result of avoiding additional imaging examinations or invasive procedures and by helping clinicians make the optimum treatment decisions. The authors review the literature on the role of PET/CT in management of various tumors and discuss the medicoeconomic usefulness.     

Synthesis and evaluation of 18F-hexafluorophosphate as a novel PET probe for imaging of sodium/iodide symporter in a murine C6-glioma tumor model

Noninvasive imaging of iodide uptake via the sodium/iodide symporter (NIS) has received great interest for evaluation of thyroid cancer and reporter imaging of NIS-expressing viral therapies. In this study, we investigate ¹⁸F-labeled hexafluorophosphate (HFP or PF₆^?) as a high-affinity iodide analog for NIS imaging. ¹⁸F-HFP was synthesized by radiofluorination of phosphorus pentafluoride·N-methylpyrrolidine complex and evaluated in human NIS (hNIS)-expressing C6 glioma cells and a C6 glioma xenograft mouse model. ¹⁸F-HFP was obtained in radiochemical yield of 10?±?5%, radiochemical purity of >96% and specific radioactivity of 604?±?18?MBq/µmol. Specific uptake of ¹⁸F-HFP and high affinity of ¹⁹F-HFP were observed in hNIS+ C6-glioma cells. PET imaging showed robust uptake of ¹⁸F-HFP in NIS-expressing tissues (thyroid, stomach, and hNIS+ C6 glioma xenografts), and the uptake of ¹⁸F-HFP was blocked by NaClO₄ pretreatment. Specific accumulation in hNIS-expressing xenograft (hNIS+) was observed relative to isogenic control tumor (hNIS?). Clearance of ¹⁸F-HFP was predominantly through renal excretion. The biodistribution showed consistent results with PET imaging. Minimal bone uptake was observed over 2?h period post-injection, indicating excellent in vivo stability of ¹⁸F-HFP. Although improvement in specific radioactivity is desirable, the results indicate that ¹⁸F-HFP is a promising candidate radiotracer for further evaluation for NIS imaging.     

Genetic analysis to complement histopathological diagnosis of brain tumors

Gliomas, the most frequent tumors originating in the human nervous system, are divided into various subtypes. Currently, microscopic examination alone is insufficient for classification and grading so that genetic profiles are increasingly being emphasized in recognition of the emerging role of molecular diagnostic approaches to glioma classification. Glioblastomas (WHO grade IV) may develop de novo (primary glioblastomas) or through progression from lower-grade astrocytomas (secondary glioblastomas), while both glioblastomas show similar histological features. In contrast, they do constitute distinct disease entities that evolve through different genetic pathways, and are likely to differ in prognosis and response to therapy. Oligodendrogliomas (WHO grade II) account for 2.7% of brain tumors and 5-18% of all gliomas. Since this tumor is recognized as a particular subtype of glioma that shows remarkable responses to chemotherapy, a correct diagnosis is of prime importance. The difficulty is that histological differentiation of oligodendrogliomas from diffuse astrocytomas is highly subjective in cases without typical morphological features and there is a lack of reliable immunohistochemical markers. While histological distinction of low-grade gliomas from reactive astrocytes is also often difficult, reactive astrocytes usually lack genetic alterations. More biological and molecular approaches to glioma classification thus appear warranted to provide improved means to achieve correct diagnoses.     

Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis

Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the {"type":"entrez-geo","attrs":{"text":"GSE16011","term_id":"16011"}}GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.     

Infection de prothèse vasculaire : TEP-FDG vs scintigraphie aux leucocytes marqués (planaires et TEMP/TDM)

Vascular prosthesis infection is an uncommon but life-threatening complication. Its diagnosis is difficult to establish especially due to the low specificity of computed tomography (CT). The aim of this preliminary study was to compare the diagnostic value of positron emission tomography with¹⁸FDG (¹⁸FDG-PET) and ^99mTc-HMPAO-labeled leukocytes scintigraphy in this indication. ¹⁸FDG-PET/CT and ^99mTc-HMPAO-labeled leukocytes scintigraphy (planar at 6th and 24th hours after injection + SPECT/CT at the 6th hour) were prospectively performed in 11 patients (total of 22 vascular prosthesis with 14 clinical suspicions of infection). Both scans were retrospectively and blindly assessed by two independent nuclear medicine physicians. Interpretation was based on visual analysis. The gold standard was bacteriology findings or clinical follow-up greater than 6 months. Eight prostheses were considered as infected. PET found eight true-positive and one false-positive. Scintigraphy found eight true-positive and no false-positive. A focal or heterogeneous FDG-uptake higher or equal than hepatic uptake was considered as positive in PET. A focal prosthetic activity, stable or increased at the 24th hour was considered as positive in labeled leukocyte scintigraphy. SPECT/CT gave accurate anatomic localization and differentiated clearly infections of soft tissues from those of prostheses. ¹⁸FDG-PET could be performed in first-line in suspicion of vascular prosthesis infection. In litigious cases, a^99mTc-HMPAO-labeled leukocytes scintigraphy in association with SPECT/CT could bring additional arguments for infection diagnosis.