Elisabetta Giovannini

The role of positron emission tomography using carbon-11 and fluorine-18 choline in tumors other than prostate cancer: a systematic review

To systematically review published data on the role of positron emission tomography (PET) or PET/computed tomography (PET/CT) using either Carbon-11 (11C) or Fluorine-18 (18F) choline tracer in tumors other than prostatic cancer. A comprehensive literature search of studies published in PubMed/MEDLINE and Embase databases through January 2012 and regarding 11C-choline or 18F-choline PET or PET/CT in patients with tumors other than prostatic cancer was carried out. Fifty-two studies comprising 1800 patients were included and discussed. Brain tumors were evaluated in 15 articles, head and neck tumors in 6, thoracic tumors (including lung and mediastinal neoplasms) in 14, liver tumors (including hepatocellular carcinoma) in 5, gynecologic malignancies (including breast tumors) in 5, bladder and upper urinary tract tumors in 5, and musculoskeletal tumors in 7. Radiolabeled choline PET or PET/CT is useful to differentiate high-grade from low-grade gliomas and malignant from benign brain lesions, to early detect brain tumor recurrences and to guide the stereotactic biopsy sampling. The diagnostic accuracy of radiolabeled choline PET is superior compared to Fluorine-18 fluorodeoxyglucose (18F-FDG) PET in this setting. Radiolabeled choline PET or PET/CT seems to be accurate in differential diagnosis between malignant and benign thoracic lesions and in staging lung tumors; nevertheless, a superiority of radiolabeled choline compared to 18F-FDG has not been demonstrated in this setting, except for the detection of brain metastases. Few but significant studies on radiolabeled choline PET and PET/CT in patients with hepatocellular carcinoma (HCC) and musculoskeletal tumors are reported in the literature. The combination of radiolabeled choline and 18F-FDG PET increases the detection rate of HCC. The diagnostic accuracy of radiolabeled choline PET or PET/CT seems to be superior compared to 18F-FDG PET or PET/CT and conventional imaging methods in patients with bone and soft tissue tumors. Limited experience exists about the role of radiolabeled choline PET and PET/CT in patients with head and neck tumors, bladder cancer and gynecologic malignancies including breast cancer.

Clinical evidence on PET/CT for radiation therapy planning in prostate cancer

The present chapter is focused on the role of positron emission tomography/computed tomography (PET/CT) and [11C]-labelled Choline ([11C]Choline) for the management of prostate cancer patients for radiation therapy planning. Although still a matter of debate, PET/CT with [11C]Choline is not routinely recommended for selecting patients for prostate cancer primary radiation treatment. However, due to its high accuracy in detecting and localizing recurrences when a biochemical failure occurs, [11C]Choline PET/CT may play a role in the re-staging phase to distinguish patients with local versus distant relapse, thus influencing patient management (curative versus palliative therapy). Limited data are currently available on the role of [11C]Choline PET/CT in target volume selection and delineation. According to available literature, [11C]Choline PET/CT is not clinically recommendable to plan target volume both for primary prostate treatment and for local recurrence. Nevertheless, promising data suggested a potential role of [11C]Choline PET/CT as an image guide tool for the irradiation of prostate cancer relapse.

The role of PET/computed tomography scan in the management of prostate cancer

Purpose of review To evaluate the role of PET/computed tomography (CT) imaging in patients with prostate cancer and to provide clinical recommendations, both in pretreatment and in post-treatment phase. Recent findings The potential role of PET/CT for evaluating intraprostatic disease, staging and restaging prostate cancer patients has been largely investigated. In particular, among the different PET tracers evaluated, choline, acetate and fluoride are showing the most promising results for imaging prostate cancer and its metastases. However, although choline PET/CT is an established diagnostic tool for imaging prostate cancer patients, as documented by a large amount of literature, further studies are still necessary to establish the final clinical role of PET/CT with acetate and fluoride. Summary Choline PET/CT is clinically indicated to noninvasively restage, in one single session, prostate cancer patients presenting a progressive increase of prostate-specific antigen, after radical treatment. Conversely, choline PET/CT does not allow the accurate assessment of intraprostatic tumor and of small lymph nodal involvement, thus not being currently recommended as a first-line method for initial diagnosis and staging. The current use of PET/CT with acetate and fluoride in clinical practice still needs further confirmations.

PET and PET/CT with radiolabeled choline in prostate cancer: a critical reappraisal of 20 years of clinical studies

We here aim to provide a comprehensive and critical review of the literature concerning the clinical applications of positron emission tomography/computed tomography (PET/CT) with radiolabeled choline in patients with prostate cancer (PCa). We will initially briefly summarize the historical context that brought to the synthesis of [11C]choline, which occurred exactly 20 years ago. We have arbitrarily grouped the clinical studies in three different periods, according to the year in which they were published and according to their relation with their applications in urology, radiotherapy and oncology. Studies at initial staging and, more extensively, studies in patients with biochemical failure, as well as factors predicting positive PET/CT will be reviewed. The capability of PET/CT with radiolabeled choline to provide prognostic information on PCa-specific survival will also be examined. The last sections will be devoted to the use of radiolabeled choline for monitoring the response to androgen deprivation therapy, radiotherapy, and chemotherapy. The accuracy and the limits of the technique will be discussed according to the information available from standard validation processes, including biopsy or histology. The clinical impact of the technique will be discussed on the basis of changes induced in the management of patients and in the evaluation of the response to therapy. Current indications to PET/CT, as officially endorsed by guidelines, or as routinely performed in the clinical practice will be illustrated. Emphasis will be made on methodological factors that might have influenced the results of the studies or their interpretation. Finally, we will briefly highlight the potential role of positron emission tomography/magnetic resonance and of new radiotracers for PCa imaging.

A thyroid incidentaloma detected by 18F-choline PET/CT.

We report a case of thyroid incidentaloma detected by 18F-choline PET/CT. A 66-year-old male patient with a history of prostate cancer underwent a 18F-choline PET/CT for restaging. PET/CT revealed a focal area of increased 18F-choline uptake corresponding to a hypodense nodule in the right lobe of the thyroid. Based on PET/CT findings, the patient underwent a ultrasonography guided fine-needle aspiration biopsy which demonstrated the presence of a benign thyroid nodule.

Role of PET/CT in the clinical management of locally advanced pancreatic cancer.

AIM To evaluate the role of 18F-fluorodeoxyglucose (FDG) PET/CT in: a) the selection of patients with locally advanced pancreatic cancer for helical tomotherapy with concurrent chemotherapy (HTT-ChT); b) monitoring HTT-ChT treatment efficacy in comparison with contrast-enhanced CT (c.e.CT). METHODS Forty-two consecutive patients with unresectable locally advanced pancreatic cancer referred for HTT-ChT were enrolled in the study. All patients were pretreated with induction ChT. Before the beginning of HTT-ChT treatment patients underwent diagnostic c.e.CT (CT0) and FDG PET/CT (PET/CT0) for staging. After staging, patients received HTT-ChT. Three months after the end of HTT-ChT a control c.e.CT (CT1) was done. FDG PET/CT (PET/CT1) was repeated only in patients with positive PET/CT0. PET/CT1 and CT1 were compared with baseline imaging results to assess treatment efficacy. RESULTS In 31/42 cases (74%) PET/CT0 documented pathological uptake in pancreatic lesions, while in the remaining 11/42 cases it showed no uptake. In 7/42 (17%) patients, PET/CT0 also detected distant metastases, prompting a change in the therapeutic approach. Compared to PET/CT0, PET/CT1 (n = 18) documented 3 complete metabolic responses, 9 partial metabolic responses, 2 instances of stable metabolic disease, and 4 instances of progressive metabolic disease. In the same group of 18 patients, CT1 showed 0 complete responses, 3 partial responses, 8 instances of stable disease, and 7 instances of progressive disease compared to CT0. Concordance between PET/CT and CT response was seen in 33% of cases. In 50% of cases, PET/CT1 documented a response to therapy that was not evident on CT. CONCLUSIONS PET/CT influenced the treatment strategy by detecting distant metastases not documented by CT, thus accurately selecting patients for HTT-ChT after induction ChT. In monitoring treatment efficacy, PET/CT can detect a metabolic response to treatment not identified by CT.

Molecular Imaging of Huntington's Disease†

The onset and the clinical progression of Huntington Disease (HD) is influenced by several events prompted by a genetic mutation that affects several organs tissues including different regions of the brain. In the last decades years, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) helped to deepen the knowledge of neurodegenerative mechanisms that guide to clinical symptoms. Brain imaging with PET represents a tool to investigate the physiopathology occurring in the brain and it has been used to predict the age of onset of the disease and to evaluate the therapeutic efficacy of new drugs. This article reviews the contribution of PET and MRI in the research field on Huntingtons disease, focusing in particular on some most relevant achievements that have helped recognize the molecular changes, the clinical symptoms and evolution of the disease. J. Cell. Physiol. 232: 1988–1993, 2017.

Radiopharmaceuticals for the Diagnosis and Therapy of Neuroendocrine Differentiated Prostate Cancer

Neuroendocrine differentiation of prostate cancer (PCa) is a relatively frequent event, generally understudied, that carries important prognostic information. It is the most frequently observed during the advanced stages of disease, when PCa has lost its sensitivity to androgen deprivation therapy or to chemotherapy, moderate to diffuse bone metastatic spread dominates the imaging scenario and it is responsible for painful clinical symptomatology. However, evidences indicate that neuroendocrine differentiation is a progressive phenomenon that starts at the very early part of the pathogenesis of cancer transformation contributing to it. Neuroendocrine tumor phenotypes have reduced capability to secrete the prostate specific antigen (PSA) and therefore PSA does not represent a reliable marker to follow-up neuroendocrine differentiation. Tumor progression may be monitored by measuring plasma concentration of neuroendocrine tumor markers, primarily chromogranin A and neuron-specific enolase. Several nuclear medicine tracers are available for studying different biochemical properties of tumor cells with neuroendocrine differentiation. Single photon computed emission tomography (SPECT) with [111In-diethylenetriaminepentaacetic acid] ([111In-DTPA0])- octreotide (Octreoscan) has been extensively used in the past. However, the development of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which in comparison to DTPA allows higher affinity bindings for beta-emitting radionuclides and for somatostatin (SST) analogues, and the increased availability of the Germanium-68/Gallium-68 (68Ge/68Ga)-generator, which enables positron emission tomography/computed tomography (PET/CT) imaging, have allowed the synthesis of several PET tracers for different SST receptors. The receptor of the bombesin/ gastrin releasing peptide (GRP), which is overexpressed in PCa with neuroendocrine differentiation, also represents an innovative research field with diagnostic and therapeutic applications through, respectively, positron and beta emitters. At the moment, however, we observe some discrepancy between the high number of preclinical studies and the small number of clinical studies, most likely related to competing and, at the moment, more effective radiopharmaceuticals for imaging and for radiometabolic therapy, such PET/CT with radiolabeled choline and prostate-specific membrane antigene (PSMA)-ligands, the latter being labeled either with 68Ga for imaging or with Lutetium-177 for therapy. Radium-223 dichloride has also been recently successfully introduced for palliative therapy of bone metastases in PCa. For these reasons, while the development of radiopharmaceuticals for diagnosis and therapy (theranostics concept) of neuroendocrine differentiated PCa is scientifically stimulating, the ultimate clinical impact remains presently difficult to predict. Similar effectiveness in comparison to other forms of diagnostic and radiometabolic radiopharmaceuticals that have already gained convincing acceptance among referring clinicians needs to be demonstrated.

PET/CT WITH 68Ga-PSMA IN PROSTATE CANCER: RADIOPHARMACEUTICAL BACKGROUND AND CLINICAL IMPLICATIONS

BACKGROUND AND OBJECTIVE In the last twenty years, positron emission tomography / computed tomography (PET/CT) with radiolabeled choline, represented the most powerful imaging modality for prostate cancer (PCa). However, the low positive detection rate of the technique for PSA < 1 ng/ml prompted the development of other tracers for imaging PCa. METHODS We performed a critical review of 68Ga-PSMA, a receptor ligand tracer, which has been identified as the most promising radiopharmaceutical for imaging PCa. RESULTS The most promising feature of this radiopharmaceutical is the high positive detection rate for prostate specific antigen (PSA) levels < 1 ng/ml or less (i.e., PSA < 0.5 ng/ml). 68Ga-PSMA detection rate is also sensitive to PSA kinetics, expressed either as PSA doubling time or PSA velocity. There are initial results indicating that 68Ga-PSMA may significantly affect the clinical management of PCa patients, even though the additional advantages in comparison to radiolabeled choline need to be further supported in future perspective studies. Other clinical implications, such as whether 68Ga-PSMA PET/CT predicts PCa-specific survival, have not yet been investigated. Numerous clinical studies have been published, some of them with histopathological verification so that despite the recent introduction in the clinical field reliable estimation of sensitivity and specificity of 68Ga-PSMA PET/CT have been obtained through meta-analyses. Most clinical studies with PET/CT with 68Ga-PSMA are retrospective, single-institutional studies and in many cases include heterogeneous patient cohorts. Thus, multidisciplinary, well-throughout prospective trials are needed to better define the clinical implications of 68Ga- PSMA PET/CT in PCa patients. The increasing availability of positron emission tomography / magnetic resonance (PET/MR) hybrid devices promotes the use of this radiopharmaceutical especially at initial staging when identification of tumor localization and of extra-prostatic disease represent clinically relevant questions. PSMA cold ligands can also be labeled with beta emitters with good chemical stability so that 68Ga-PSMA PET/CT can be used to guide radiometabolic therapy of advanced metastatic PCa patients through 177Lu-labeled PSMA ligands. CONCLUSION PSMA labeled ligands appear very promising for diagnosis and treatment of PCa.

An unusual case of metastatic extramammary Paget's disease of the vulva identified by 18F-FDG PET/CT.

Fig. 1. Whole-body maximum intensity projection (MIP) F-FDG PET image (A), performed for restaging in a patient who underwent surgical excision of a vulvar extramammary Paget’s disease three years before, showed multiple areas of increased radiopharmaceutical uptake in the abdomen and pelvis. Fused PET/CT images in axial projection (B–G) showed increased F-FDG uptake corresponding to a vaginal mass (green arrow), multiple abdominal and pelvic lymph nodes (yellow arrows) and two liver lesions (red arrows). Histology on lymph nodal and liver lesions showed the presence of a metastatic extramammary Paget’s disease.