Yttrium-90 radioembolization treatment for unresectable hepatocellular carcinoma: a single-centre prognostic factors analysis.

The aim of this study was to evaluate the efficacy and the safety of Y90 radioembolization (Y90-RE) in patients with unresectable hepatocellular carcinoma (HCC) analysing our results and correlating them with independent prognostic factors for overall survival (OS) and for complications. Forty-three patients with advanced inoperable HCC including those with multiple bilobar lesions or portal vein thrombosis (PVT) treated with Y90-RE were reviewed. Treatment efficacy and safety were evaluated. Survival was calculated by the Kaplan-Meier method. Univariate analyses were performed for identifying potential prognostic factors. Radiologic response was evaluated with the modified Response Evaluation Criteria in Solid Tumours (mRECIST) criteria. Clinical toxicities were prospectively recorded. Median overall progression-free survival and OS were 27.7 and 16.8 months, respectively. Longer median OS was revealed in those without PVT (p = 0.0241) and those whose pre-treatment haemoglobin values was higher (p = 0.0471). According with mRECIST criteria, we observed a disease control rate of 69.2 and 61.9% at 3- and 6-month follow-up, respectively. Complications developed in 28 patients (65.1%), among which grade 2-3 events were reported in 17 patients. We noted that activity administered dose presented a correlation with intra-procedural toxicity (p = 0.039259) while common hepatic artery use as release site was associated with a most frequent presentation of remote adverse events. Y90-RE is an alternative treatment with a promising outcome for poor-risk advanced inoperable HCC. PVT and pre-treatment haemoglobin values can be predictors of efficacy. Activity administered dose and arterial release site can be predictors of safety.

Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model.

PURPOSE: Hypoxia-inducible factor 1α (HIF-1α) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1α modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model. METHODS: U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1α activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging. RESULTS: This cell model can be used to monitor HIF-1α activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1α activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1α activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action. CONCLUSION: The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1α activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures.

Validation of an engineered cell model for in vitro and in vivo HIF-1α evaluation by different imaging modalities.

PURPOSE: The aim of this study was to characterize a cell-based model for the molecular study of hypoxia-inducible factor (HIF)-1α activity, in the context of hypoxia, by means of different imaging techniques. PROCEDURES: Engineered U251-HRE glioma cells were used to analyze the molecular mechanisms underlying HIF-1α activity in vitro in relation to luciferase expression. The same cells were orthotopically implanted in mice to evaluate tumor progression and hypoxia induction by bioluminescence imaging, fluorescence imaging, positron emission tomography (PET), and magnetic resonance imaging (MRI). RESULTS: In vitro analyses highlighted the relationship between HIF-1α and luciferase activity in hypoxic conditions and after pharmacological treatments in U251-HRE cells. Through in vivo studies, it was possible to assess hypoxia establishment in relation to tumor growth by optical imaging, PET and MRI. CONCLUSIONS: The findings of this study indicate that the U251-HRE orthotopic murine model can be used to reliably evaluate processes modulating HIF-1α activity, using both molecular and preclinical non-invasive imaging techniques.

Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals.

Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered limits their use in the clinical practice. This overview summarizes the state of art of NETs imaging, focusing the attention mainly on gamma-emitting tracers.

The dynamics of estrogen receptor activity.

In the latest few years, the merging of imaging and animal engineering technologies has led to the generation of innovative tools that provide the opportunity to look into the dynamics of specific molecular events in living animals during their entire life under a completely renewed perspective. These tools will have a profound impact not only on basic research, but also on drug discovery and development allowing to depict the activity of any therapeutic agents in all their designed targets as well as in the organs where they may cause undesired effects. Along this research line, our laboratory has recently described the first animal model reporting the state of activity of estrogen receptors (ERs) in real time: the ERE-luc reporter mouse. The application of optical imaging to the ERE-luc has allowed an unprecedented in depth view of estrogen signaling in all of its target tissues. For example, the analysis of the state of activity of ERs in the physiological setting of the estrous cycle has provided compelling evidence that hormone-independent mechanisms are responsible for activating ERs in non-reproductive organs. This discovery may pave the way to a rational basis for the development of novel, more selective and effective treatments for menopause.

Molecular imaging: a new way to study molecular processes in vivo.

Non-invasive imaging of reporter gene expression using different imaging modalities is increasing its role for the in vivo assessment of molecular processes. Multimodality imaging protocols overcome limitations to a single imaging modality and provide a thorough view of specific processes, often allowing a quantitative measurement and direct visualization of the process in a specific target organ or tissue. The use of the right reporter gene for the development of animal models and the characterization of its expression in different conditions and tissues is fundamental for basic, translational and future pharmacological applications of a given model. This paper summarizes the major steps in the development and evaluation of a specific animal model for in vivo molecular imaging studies and describes the first example of an animal model designed for the in vivo assessment of a specific receptor activity and its possible evolution towards multimodality imaging analysis.

Assessing cell trafficking by noninvasive imaging techniques: applications in experimental tumor immunology.

Tracer methods are increasingly being exploited to examine the trafficking patterns of cells transferred into recipient models of diseases, to optimize immune cell therapies, and to assess cancer gene therapy and vaccines in various cancer models. In animal cancer models, noninvasive monitoring by imaging tumor response could significantly facilitate the development of immune cell therapies against cancer. Currently, ex vivo lymphocyte labeling is primarily done by direct labeling. Major advances in cell labeling procedures have led to the use of reporter constructs to assess gene expression in vivo. With this novel technique, the reporter gene marks the cell with a specific protein that distinguishes the cell and its cellular progeny from other cells after migration, homing and mitosis. Several in vivo imaging procedures, including positron emission tomography, single photon emission tomography and magnetic resonance imaging, have been rescaled for studies in small animals. Other methods initially used for in vitro bioluminescence and fluorescence studies have also been refined for in vivo studies. When combined, these methods allow to assess cell trafficking in a noninvasive fashion, beyond lymphocyte response to inflammation, including metastatic diffusion and stem cell transplantation.

Comparative evaluation of two methods to assay thyroglobulin serum concentrations in patients with differentiated thyroid carcinomas.

AIM: This study was aimed at the comparative assessment of the analytical and clinical performances of 2 tests for thyroglobulin (Tg) assays: the Dynotest Tg-Plus immunoradiometric assay (IRMA), a new method that might be of interest for its claimed superior sensitivity compared to other methods, and the HTGK-2 IRMA, one of the test currently used in clinical routine. METHODS: The study was performed in serum samples from 157 patients with differentiated thyroid carcinoma (DTC). The clinical sensitivity of the test was evaluated in patients with and without thyroid stimulating hormone (TSH) suppression. RESULTS: The lowest detectable Tg concentration values and the within-assay coefficient of variation (CV) were 0.4 and 0.8 microg/L and 5% and 3% for the Dynotest Tg-Plus assay and the HTGK-2 assay, respectively; the between-assay CV was 6% for both assays. The clinical results of the Dynotest Tg-Plus and those of the HTGK-2 kit were similar in both DTC patient populations, either under or off the TSH suppressive treatment. In spite of the manufacturer's statement that the calibrators of both assays had been standardized against the same common reference (standard CRM 457 of the Community Bureau of References), the Dynotest Tg-Plus test underrated by a factor of 0.5 the Tg values measured by means of HTGK-2 IRMA. CONCLUSION: The sensitivity of the Dynotest Tg-Plus IRMA appears to be similar to that of the HTGK-2 assay.

Position of nuclear medicine techniques in the diagnostic work-up of brain tumors.

Although any patient with a suspected brain tumor, either primary or metastatic, should be studied with anatomic imaging modalities such as angiography, computerized tomagraphy (CT) or magnetic resonance imaging (MRI), nuclear medicine techniques are available to further characterize some biological features of brain lesions and help in diagnosis and therapy planning. Bloob-brain-barrier disruption can be easily assessed with single-photon emission tomography (SPET), whereas focal metabolic changes can be better demonstrated by positron emission tomography (PET) as specific radiopharmaceuticals are available to detect changes in glucose utilization and aminoacid uptake with this technique. Expression of specific tumoral antigens is the basis of imaging with radioimmunoscintigraphy, a promising technique that can be applied to brain tumor therapy. The major clinical applications of nuclear medicine in the study of brain tumors -- evaluation of the extension of a tumoral mass, differential diagnosis and evaluation of therapy and prognosis -- are discussed.

The use of standardized uptake values for assessing FDG uptake with PET in oncology: a clinical perspective.

Among clinicians who use positron emission tomography (PET), the standardized uptake value (SUV) is a popular semi-quantitative value that can be easily assessed whenever a PET study is performed under physiological and pathological conditions. It provides an index of regional tracer uptake normalized to the administered dose of tracer. The simplicity of SUV assessment contrasts with the complexity of full quantitative procedures requiring blood sampling and possibly dynamic scanning, which limits patient throughput and significantly increases the workload of a PET centre. Two main clinical conditions/variables affect the significance and usefulness of the SUV: the type and stage of the disease being assessed. Diagnosis, prognosis and therapy monitoring represent the possible uses of SUV. In the above clinical conditions an SUV may provide information about the single lesion in which it is assessed, but the utility of such information depends largely on its integration with all the available clinical and instrumental data.

Economic analyses on the use of positron emission tomography for the work-up of solitary pulmonary nodules and for staging patients with non-small-cell-lung-cancer in Italy.

AIM: Increasing ageing of the population and tumor incidence, along with worldwide rationing of the resources for public health systems, spur the use of economic analyses for the choice of strategies and technologies in the assessment and management of cancer patients. Incidence and clinical managing of tumors vary in different countries even if positron emission tomography (PET) with 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) is becoming a routine clinical method for diagnosis, staging, treatment monitoring and follow-up in a variety of tumors. Available data indicate that PET can be considered a superior alternative or complementary tool to other well-established methods. However, in spite of the above and of the rapidly increasing number of PET centers in Europe, USA and Japan, only a few studies have dealt with some of the economic aspects raised by the clinical use of PET because of differences in values of reimbursements and health costs. The main aim of this study is to propose and discuss an economic model of analysis for PET applications in the field of detection and management of pulmonary tumors. METHODS: In this study 2 assessments were performed by decision tree analysis on the economic impact of the availability of PET on decision-making processes for 2 conditions: solitary pulmonary nodules assessment and non-small-cell lung cancer (NSCLC) staging. In order to define a methodology consistent with the system of reimbursement and the prevalent clinical views of the Italian National Health Service, data on costs, death probability, and life expectancy were gathered from the literature and from the Italian system of reimbursement (ROD-DRGs). RESULTS: The results of the cost minimization analysis demonstrate that the use of PET in the diagnostic path for the workup of patients with SPN reduces the overall diagnostic costs, by approximately 50 Euro per patient, by reducing inappropriate invasive diagnostic investigation and their complications. The results of the cost effectiveness analysis demonstrate that the use of PET in the diagnostic path for the staging of patients with NSCLC reduces the overall diagnostic costs by approximately 108 Euro for added year, by reducing inappropriate surgical interventions and their complications. CONCLUSION: Both analyses are based on standard methods used in the literature, so our conclusions can be compared with results and assessments of similar studies in different countries and health care systems. Also in the Italian case, the use of an economic assessment provides relevant information on the efficacy and effectiveness of PET.

Accuracy and clinical correlates of two different methods for chromogranin A assay in neuroendocrine tumors.

Measurement of chromogranin A (CgA) plays a major role in the management of neuroendocrine tumors (NET); however, reliable assaying of CgA is made difficult by the rapid hydrolysis following its release into the bloodstream. This study was aimed at the assessment of two assays for CgA in NET patients. CgA was measured in 93 patients by means of an enzyme-linked immunosorbent assay (ELISA) and an immunoradiometric assay (IRMA). The specificity and sensitivity of CgA were evaluated in relation to tumor histology. The clinical accuracy of the two assays was evaluated by receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated different immunoreactivity for CgA of the antibodies used in the two kits (r = 0.61). The two assays had different accuracy also in classifying patients according to their clinical condition (91% vs 64% specificity and 79% vs 79% sensitivity for the ELISA and IRMA assay, respectively) and tumor histology (81% vs 85% sensitivity for the ELISA and IRMA assays, respectively, in carcinoids; 92% vs 67% sensitivity for the ELISA and IRMA assays, respectively, in pancreatic islet cell tumors). The different clinical accuracy of the two assays was confirmed by the ROC analysis (AUC = 0.90 vs AUC = 0.87 for the ELISA and IRMA assays, respectively). In conclusion, because of the poor standardization of the commercially available measurement tools the clinical accuracy of CgA measurement depends on the assay used. This makes it difficult to compare CgA values measured with different kits and affects the clinical accuracy of the different assays for CgA.

Anatomical and biochemical investigation of primary brain tumours.

Cancerous transformation entails major biochemical changes including modifications of the energy metabolism of the cell, e.g. utilisation of glucose and other substrates, protein synthesis, and expression of receptors and antigens. Tumour growth also leads to heterogeneity in blood flow owing to focal necrosis, angiogenesis and metabolic demands, as well as disruption of transport mechanisms of substrates across cell membranes and other physiological boundaries such as the blood-brain barrier. All these biochemical, histological and anatomical changes can be assessed with emission tomography, X-ray computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Whereas anatomical imaging is aimed at the diagnosis of brain tumours, biochemical imaging is better suited for tissue characterisation. The identification of a tumoural mass and the assessment of its size and vascularisation are best achieved with X-ray CT and MRI, while biochemical imaging can provide additional information that is crucial for tumour classification, differential diagnosis and follow-up. As the assessment of variables such as water content, appearance of cystic lesions and location of the tumour are largely irrelevant for tissue characterisation, a number of probes have been employed for the assessment of the biochemical features of tumours. Since biochemical changes may be related to the growth rate of cancer cells, they can be thought of as markers of tumour cell proliferation. Biochemical imaging with radionuclides of processes that occur at a cellular level provides information that complements findings obtained by anatomical imaging aimed at depicting structural, vascular and histological changes. This review focusses on the clinical application of anatomical brain imaging and biochemical assessment with positron emission tomography, single-photon emission tomography and MRS in the diagnosis of primary brain tumours, as well as in follow-up.

Indium-111 labelled white blood cell scintigraphy in cranial and spinal septic lesions.

Cranial and spinal infections are severe events that require timely diagnosis and treatment. Physical and neurological examination, laboratory tests and radiological imaging may be insufficient for assessing cranial and spinal septic lesions. This study aimed to evaluate the accuracy of indium-111 white blood cell (WBC) scan in assessing the presence of leucocytes in intracranial and spinal lesions, and in the diagnosis, management and follow-up of primary, post-traumatic and post-surgical infections. One hundred and twenty-four subjects were included in the study (48 with post-traumatic or post-surgical lesions, 73 with primary cerebral lesions, and 3 with spinal lesions). All patients underwent a diagnostic work-up including planar scans with 111In-labelled WBCs, at 4 and 24 h post tracer injection. All subjects underwent surgical treatment. Patients who did not recover from the infection as suggested by clinical evolution underwent further treatment (up to three times) and further WBC scans (up to four times). WBC scintigraphy correctly identified all the areas of leucocyte accumulation, as confirmed after surgery. WBC scintigraphy also correctly excluded the presence of leucocytes in all other lesions, as demonstrated at surgery. The results of this study confirm the accuracy of WBC scan for the assessment of patients with cranial and spinal lesions, in whom the demonstration of leucocyte accumulation can ease the diagnosis of infection, and indicate that the method is also accurate for the follow-up and management of neurosurgical patients.

FDG/PET and spiral CT image fusion for medistinal lymph node assessment of non-small cell lung cancer patients.

BACKGROUND: To assess the potential usefulness of 18F-FDG/PET and spiral-CT images concurrent assessment and coregistration in staging mediastinal lymph node involvement in patients with non small cell lung cancer. METHODS: 28 patients waiting to undergo surgical treatment underwent spiral-CT and PET examinations on the same day. The results of the two studies were interpreted separately, together (CT&PET) and following their fusion in a single image (CT+PET). Results of spiral-CT, PET, CT&PET and CT+PET were assessed with respect to the histological diagnosis. RESULTS: A correct assessment of mediastinal lymph nodes was achieved by spiral-CT in 21 of the 28 patients, in 22 of the 28 patients by PET, in 24 patients by CT&PET and in 25 patients by CT+PET. CONCLUSIONS: CT+PET is more accurate than spiral-CT and PET alone in staging mediastinal lymph node involvement in lung cancer patients, with possible implications for their prognosis and therapy.

Comparison of dual-head coincidence PET versus ring PET in tumor patients.

UNLABELLED: This study compared the multiring detector (Ring-PET) and the dual-head coincidence imaging system (DH-PET) for staging/ restaging neoplastic patients before or after surgery or radiochemotherapy. METHODS: Seventy patients with suspected tumor recurrence or metastatic dissemination received an intravenous dose of 18F-fluorodeoxyglucose (FDG) under overnight fasting and were studied in sequence with a dedicated positron emission tomograph with Ring-PET and a DH-PET. Ring-PET studies were performed 45-75 min postinjection and were followed by a DH-PET scan approximately 3 h postinjection. Number and location of the hypermetabolic lesions detected on DH-PET and Ring-PET reconstructed images were blindly assessed by three independent observers. RESULTS: DH-PET identified all 14 head lesions detected by Ring-PET, 53 of 63 thoracic lesions and 36 of 45 abdominal lesions. Of the 19 lesions not identified by DH-PET, 6 were smaller than 10 mm, 8 were between 10 and 15 mm and 1 was 18 mm; dimensions of 4 bone lesions were not available. A concordant restaging, based on location and number of lesions detected, was found in all 14 patients with head tumors, in 28 of 30 patients with thoracic tumors and in 24 of 26 patients with abdominal tumors. CONCLUSION: We found a good agreement between Ring-PET and DH-PET assessment of oncologic patients in detecting hypermetabolic lesions > or = 10-15 mm.

Assessment of CABG-related risk in patients with CAD and LVD. Contribution of PET with [18F]FDG to the assessment of myocardial viability.

BACKGROUND: Previous studies have demonstrated that hibernating myocardium can be assessed by [18F]fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). This study evaluated the use of [18F]FDG-PET for CABG related risk assessment in patients with coronary artery disease (CAD) and left ventricle dysfunction (LVD). METHODS: We retrospectively evaluated 241 to patients candidate CABG presenting with signs and symptoms of congestive heart failure (CHF) prevailing over ischemic signs. Of the 241 patients, 153 had undergone [18F]FDG-PET as well as conventional assessment: 110 out of 153 (group A) were operated because of PET evidence of hibernation. Of the 241 patients, 88 had not undergone [18F]FDG-PET: 86 out of 88 (group B) were operated on. The outcome of surgical patients was evaluated by considering all major perioperative complications including the use of mechanical and pharmacological support and in-hospital mortality. After hospital discharge, each patient was examined at 1, 4 and every 6 months thereafter. RESULTS: Perioperative use of mechanical supports and inotropic drugs, was significantly lower for the PET selected group (A) than for the non PET selected group (B). Mortality within 30 days of surgery was 0.9% in group A and 19.8% in group B. The only predictors of perioperative outcome were the presence of hibernating tissue and the ejection fraction. CONCLUSIONS: [18F]FDG-PET prior to CABG can be crucial for the assessment of perioperative risk in patients with CAD.

Positron emission tomography for the assessment of myocardial viability: a synopsis of methods and indications.

An improvement of regional and global left ventricle dysfunction can be achieved in patients with coronary artery disease either by coronary revascularization with percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. Several techniques have been developed to identify dysfunctional but viable myocardium. In the last decade, positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) has been used for the detection of hibernating myocardium. It can accurately predict the recovery of abnormal wall motion in hibernating segments prior to surgery. In particular, assessment of viability with 18F-FDG is indicated in high-risk surgical candidates being considered for revascularization or transplantation. Moreover, patient selection criteria and economic consideration are also relevant for cost-effective use of the technique.