A proof-of-concept of cross-luminescent metascintillators: testing results on a BGO:BaF2metapixel.

Objective: Time-of-flight positron emission tomography (PET) is the next frontier in improving the effective sensitivity. To achieve superior timing for time-of-flight PET, combined with high detection efficiency and cost-effectiveness, we have studied the applicability of BaF2 in metascintillators driven by the timing of cross-luminescence photon production.Approach: Based on previous simulation studies of energy sharing and analytic multi-exponential scintillation pulse, as well as sensitivity characteristics, we have experimentally tested a pixel of 3 × 3 × 15 mm3 based on 300µm BGO and 300µm BaF2 layers. To harness the deep ultraviolet cross-luminescent light component, which carries improved timing, we use the FBK VUV SiPM. Metascintillator energy sharing is addressed through a double integration approach.Main results: We reach an energy resolution of 22%, comparable to an 18% resolution of simple BGO pixels using the same readout, through the optimized use of the integrals of the metascintillator pulse in energy sharing calculation. We measure the energy sharing extent of each pulse with a resolution of 25% and demonstrate that experimental and simulation results agree well. Based on the energy sharing, a timewalk correction is applied, exhibiting significant improvements for both the coincidence time resolution (CTR) and the shape of the timing histogram. We reach 242 ps CTR for the entire photopeak, while for a subset of 13% of the most shared events, the CTR value improves to 108 ps, comparable to the 3 × 3 × 5 mm3 LYSO:Ce:Ca reference crystal.Significance: While we are considering different ways to improve further these results, this proof-of-concept demonstrates the applicability of cross-luminescence for metascintillator designs through the application of VUV compatible SiPM coupling, and easily implementable digital algorithms. This is the first test of BaF2-based metascintillators of sufficient stoppng power to be included in a PET scanner, demonstrating the industrial applicability of such cross-luminescent metascintillators.

A novel semi-robotized device for high-precision 18F-FDG-guided breast cancer biopsy / Un nuevo dispositivo semirrobotizado para biopsia de alta precisión guiada por la captación de 18F-FDG en el cáncer de mama

Purpose. To assess the 3D geometric sampling accuracy of a new PET-guided system for breast cancer biopsy (BCB) from areas within the tumour with high 18F-FDG uptake. Materials and methods. In the context of the European Union project MammoCare, a prototype semi-robotic stereotactic prototype BCB-device was incorporated into a dedicated high resolution PET-detector for breast imaging. The system consists of 2 stacked rings, each containing 12 plane detectors, forming a dodecagon with a 186mm aperture for 3D reconstruction (1mm3 voxel). A vacuum-assisted biopsy needle attached to a robot-controlled arm was used. To test the accuracy of needle placement, the needle tip was labelled with 18F-FDG and positioned at 78 target coordinates distributed over a 35mm×24mm×28mm volume within the PET-detector field-of-view. At each position images were acquired from which the needle positioning accuracy was calculated. Additionally, phantom-based biopsy proofs, as well as MammoCare images of 5 breast cancer patients, were evaluated for the 3D automated locating of 18F-FDG uptake areas within the tumour. Results. Needle positioning tests revealed an average accuracy of 0.5mm (range 0-1mm), 0.6mm (range 0-2mm), and 0.4mm (range 0-2mm) for the x/y/z-axes, respectively. Furthermore, the MammoCare system was able to visualize and locate small (<10mm) regions with high 18F-FDG uptake within the tumour suitable for PET-guided biopsy after being located by the 3D automated application. Conclusions. Accuracy testing demonstrated high-precision of this semi-automatic 3D PET-guided system for breast cancer core needle biopsy. Its clinical feasibility evaluation in breast cancer patients scheduled for neo-adjuvant chemotherapy will follow (AU)

Objetivo. Evaluar la precisión de un nuevo sistema de biopsia de mama (BM) guiado por PET que permite tomar muestras en áreas tumorales de alta captación de 18F-FDG en 3D con alta precisión geométrica. Materiales y métodos. El proyecto MammoCare financiado por la Unión Europea desarrolló un dispositivo de BM estereotáctica incorporado en un PET dedicado de alta resolución provisto de 2 anillos apilados con 12 detectores planos cada uno formando un dodecágono con una apertura de 186mm para la adquisición de PET en posición prona y reconstrucción 3D con vóxeles de 1mm3. El sistema utiliza agujas de biopsia asistida por vacío colocadas en un dispositivo robotizado. Su exactitud se estableció marcando con 18F-FDG la punta de la aguja en un objetivo de 35×24×28mm colocado dentro del campo visual del anillo PET. Se utilizaron 78 coordenadas realizando una adquisición por posición. Adicionalmente, se evaluó la localización 3D automatizada de las áreas de captación de 18F-FDG utilizando las imágenes de 5 pacientes con cáncer de mama. Resultados. Se estableció una precisión media de 0,5mm (rango 0-1mm); 0,6mm (rango 0-2mm) y 0,4mm (rango 0-2mm) respectivamente para los ejes x/y/z, en la colocación de la aguja. La aplicación 3D automatizada localizó múltiples regiones (<10mm) intratumorales con alta captación de 18F-FDG adecuadas para BM guiada por PET. Conclusión. El sistema de BM guiada por PET con localización semirrobotizada alcanzó alta precisión lo que permitirá evaluar su viabilidad clínica en pacientes con cáncer de mama programados para quimioterapia neoadyuvante (AU)

A novel semi-robotized device for high-precision 18F-FDG-guided breast cancer biopsy.

PURPOSE: To assess the 3D geometric sampling accuracy of a new PET-guided system for breast cancer biopsy (BCB) from areas within the tumour with high 18F-FDG uptake. MATERIALS AND METHODS: In the context of the European Union project MammoCare, a prototype semi-robotic stereotactic prototype BCB-device was incorporated into a dedicated high resolution PET-detector for breast imaging. The system consists of 2 stacked rings, each containing 12 plane detectors, forming a dodecagon with a 186mm aperture for 3D reconstruction (1mm3 voxel). A vacuum-assisted biopsy needle attached to a robot-controlled arm was used. To test the accuracy of needle placement, the needle tip was labelled with 18F-FDG and positioned at 78 target coordinates distributed over a 35mm×24mm×28mm volume within the PET-detector field-of-view. At each position images were acquired from which the needle positioning accuracy was calculated. Additionally, phantom-based biopsy proofs, as well as MammoCare images of 5 breast cancer patients, were evaluated for the 3D automated locating of 18F-FDG uptake areas within the tumour. RESULTS: Needle positioning tests revealed an average accuracy of 0.5mm (range 0-1mm), 0.6mm (range 0-2mm), and 0.4mm (range 0-2mm) for the x/y/z-axes, respectively. Furthermore, the MammoCare system was able to visualize and locate small (<10mm) regions with high 18F-FDG uptake within the tumour suitable for PET-guided biopsy after being located by the 3D automated application. CONCLUSIONS: Accuracy testing demonstrated high-precision of this semi-automatic 3D PET-guided system for breast cancer core needle biopsy. Its clinical feasibility evaluation in breast cancer patients scheduled for neo-adjuvant chemotherapy will follow.

ALBIRA: a small animal PET∕SPECT∕CT imaging system.

PURPOSE: The authors have developed a trimodal PET∕SPECT∕CT scanner for small animal imaging. The gamma ray subsystems are based on monolithic crystals coupled to multianode photomultiplier tubes (MA-PMTs), while computed tomography (CT) comprises a commercially available microfocus x-ray tube and a CsI scintillator 2D pixelated flat panel x-ray detector. In this study the authors will report on the design and performance evaluation of the multimodal system. METHODS: X-ray transmission measurements are performed based on cone-beam geometry. Individual projections were acquired by rotating the x-ray tube and the 2D flat panel detector, thus making possible a transaxial field of view (FOV) of roughly 80 mm in diameter and an axial FOV of 65 mm for the CT system. The single photon emission computed tomography (SPECT) component has a dual head detector geometry mounted on a rotating gantry. The distance between the SPECT module detectors can be varied in order to optimize specific user requirements, including variable FOV. The positron emission tomography (PET) system is made up of eight compact modules forming an octagon with an axial FOV of 40 mm and a transaxial FOV of 80 mm in diameter. The main CT image quality parameters (spatial resolution and uniformity) have been determined. In the case of the SPECT, the tomographic spatial resolution and system sensitivity have been evaluated with a (99m)Tc solution using single-pinhole and multi-pinhole collimators. PET and SPECT images were reconstructed using three-dimensional (3D) maximum likelihood and ordered subset expectation maximization (MLEM and OSEM) algorithms developed by the authors, whereas the CT images were obtained using a 3D based FBP algorithm. RESULTS: CT spatial resolution was 85 µm while a uniformity of 2.7% was obtained for a water filled phantom at 45 kV. The SPECT spatial resolution was better than 0.8 mm measured with a Derenzo-like phantom for a FOV of 20 mm using a 1-mm pinhole aperture collimator. The full width at half-maximum PET radial spatial resolution at the center of the field of view was 1.55 mm. The SPECT system sensitivity for a FOV of 20 mm and 15% energy window was 700 cps∕MBq (7.8 × 10(-2)%) using a multi-pinhole equipped with five apertures 1 mm in diameter, whereas the PET absolute sensitivity was 2% for a 350-650 keV energy window and a 5 ns timing window. Several animal images are also presented. CONCLUSIONS: The new small animal PET∕SPECT∕CT proposed here exhibits high performance, producing high-quality images suitable for studies with small animals. Monolithic design for PET and SPECT scintillator crystals reduces cost and complexity without significant performance degradation.

Expectation maximization (EM) algorithms using polar symmetries for computed tomography (CT) image reconstruction.

We suggest a symmetric-polar pixellation scheme which makes possible a reduction of the computational cost for expectation maximization (EM) iterative algorithms. The proposed symmetric-polar pixellation allows us to deal with 3D images as a whole problem without dividing the 3D problem into 2D slices approach. Performance evaluation of each approach in terms of stability and image quality is presented. Exhaustive comparisons between all approaches were conducted in a 2D based image reconstruction model. From these 2D approaches, that showing the best performances were finally implemented and evaluated in a 3D based image reconstruction model. Comparison to 3D images reconstructed with FBP is also presented. Although the algorithm is presented in the context of computed tomography (CT) image reconstruction, it can be applied to any other tomographic technique as well, due to the fact that the only requirement is a scanning geometry involving measurements of an object under different projection angles. Real data have been acquired with a small animal (CT) scanner to verify the proposed mathematical description of the CT system.

Design and evaluation of the MAMMI dedicated breast PET.

PURPOSE: A breast dedicated positron emission tomography (PET) scanner has been developed based on monolithic LYSO crystals coupled to position sensitive photomultiplier tubes (PSPMTs). In this study, we describe the design of the PET system and report on its performance evaluation. METHODS: MAMMI is a breast PET scanner based on monolithic LYSO crystals. It consists of 12 compact modules with a transaxial field of view (FOV) of 170 mm in diameter and 40 mm axial FOV that translates to cover up to 170 mm. The patient lies down in a prone position that facilitates maximum breast elongation. Quantitative performance analysis of the calculated method for the attenuation correction specifically developed for MAMMI, and based on PET image segmentation, has also been conducted in this evaluation. In order to fully determine the MAMMI prototype's performance, we have adapted the measurements suggested for National Electrical Manufacturers Association (NEMA) NU 2-2007 and NU 4-2008 protocol tests, as they are defined for whole-body and small animal PET scanners, respectively. RESULTS: Spatial resolutions of 1.6, 1.8, and 1.9 mm were measured in the axial, radial, and tangential directions, respectively. A scatter fraction of 20.8% was obtained and the maximum NEC was determined to be 25 kcps at 44 MBq. The average sensitivity of the system was observed to be 1% for an energy window of (250 keV-750 keV) and a maximum absolute sensitivity of 1.8% was measured at the FOV center. CONCLUSIONS: The overall performance of the MAMMI reported on this evaluation quantifies its ability to produce high quality PET images. Spatial resolution values below 3 mm were measured in most of the FOV. Only the radial component of spatial resolution exceeds the 3 mm at radial positions larger than 60 mm. This study emphasizes the need for standardized testing methodologies for dedicated breast PET systems similar to NEMA standards for whole-body and small animal PET scanners.

Small animal PET scanner based on monolithic LYSO crystals: performance evaluation.

PURPOSE: The authors have developed a small animal Positron emission tomography (PET) scanner based on monolithic LYSO crystals coupled to multi-anode photomultiplier tubes (MA-PMTs). In this study, the authors report on the design, calibration procedure, and performance evaluation of a PET system that the authors have developed using this innovative nonpixelated detector design. METHODS: The scanner is made up of eight compact modules forming an octagon with an axial field of view (FOV) of 40 mm and a transaxial FOV of 80 mm diameter. In order to fully determine its performance, a recently issued National Electrical Manufacturers Association (NEMA) NU-4 protocol, specifically developed for small animal PET scanners, has been followed. By measuring the width of light distribution collected in the MA-PMT the authors are able to determine depth of interaction (DOI), thus making the proper identification of lines of response (LORs) with large incidence angles possible. PET performances are compared with those obtained with currently commercially available small animal PET scanners. RESULTS: At axial center when the point-like source is located at 5 mm from the radial center, the spatial resolution measured was 1.65, 1.80, and 1.86 mm full width at half maximum (FWHM) for radial, tangential, and axial image profiles, respectively. A system scatter fraction of 7.5% (mouse-like phantom) and 13% (rat-like phantom) was obtained, while the maximum noise equivalent count rate (NECR) was 16.9 kcps at 12.7 MBq (0.37 MBq/ml) for mouse-like phantom and 12.8 kcps at 12.4 MBq (0.042 MBq/ml) for rat-like phantom The peak absolute sensitivity in the center of the FOV is 2% for a 30% peak energy window. Several animal images are also presented. CONCLUSIONS: The overall performance of our small animal PET is comparable to that obtained with much more complex crystal pixelated PET systems. Moreover, the new proposed PET produces high-quality images suitable for studies with small animals.

Hepatitis C virus infection associated with human hepatocellular carcinoma: lack of correlation with p53 abnormalities in Caucasian patients.

BACKGROUND: Several lines of evidence indicate that there is a close association between hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC). However, the role of the virus itself in the development of the disease is not yet well understood. METHODS: In liver samples from 15 anti-HCV positive Caucasian patients with HCC, the authors searched for the presence and genomic characteristics of the infecting virus, and also analyzed the p53 gene by single strand conformation polymorphism and sequencing of abnormal bands. RESULTS: In all cases but one, HCV RNA was detected in nonneoplastic liver tissue, whereas in neoplastic tissue, viral sequences were detected in 6 of 6 samples containing moderately differentiated HCC (Edmondson grades I-II) and in 2 of 9 containing poorly differentiated HCC (Edmondson grade III) (P=0.007). Seventy-three percent of the cases were infected by genotype 1 and 20% by genotype 2, whereas the liver cells of 1 patient with a previous history of hepatitis B infection were HCV RNA negative. p53 mutations, observed in 2 patients, consisted of a G-to-A transition at codon 176 of exon 5 in 1 patient and a G-to-T transversion at codon 287 of exon 8 in the other. CONCLUSIONS: The results of this study indicate that HCV may contribute to liver tumor development during the early stages of carcinogenesis, whereas p53 gene mutations were detected only in 2 of 15 patients in this cohort.

Serum and liver HCV RNA levels in patients with chronic hepatitis C: correlation with clinical and histological features.

BACKGROUND: Liver disease in chronic hepatitis C virus (HCV) infection ranges from minimal lesions to liver cirrhosis, eventually evolving to hepatocellular carcinoma. Whether and how HCV determines the different clinical and histological manifestations of the disease is not fully understood. AIMS: To verify whether the amount of virus in individual patients could be related to the severity of liver injury. PATIENTS AND METHODS: Levels of HCV RNA were measured in serum in 96 consecutive patients with chronic hepatitis type C using a signal amplification assay. The relation between viraemic values and the corresponding viral load in the liver was assessed in a subgroup of 21 patients in whom HCV RNA was measured in serum samples and liver specimens obtained at the same time. RESULTS: A positive correlation was observed between the amount of viral nucleic acid in the two compartments, indicating that levels of viraemia reflect the amount of virus present in the liver. Viral load did not correlate with aminotransferase activities nor with histological diagnosis, and serum and liver levels of HCV RNA were not significantly different in patients infected by the various HCV genotypes. CONCLUSIONS: Measurement of HCV replication in serum is a mirror of viral replication in the liver. The extent of replicative activity of HCV does not seem to play a role in the modulation of the associated hepatic disease.

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.

BACKGROUND/AIMS: Chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up. PATIENTS: One hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis. RESULTS: Thirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen. CONCLUSIONS: Even considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.

Long-term persistence of hepatitis B virus DNA in the serum of children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion.

To evaluate the prevalence and duration of viremia in relation to the features of liver disease, we investigated hepatitis B virus (HBV) DNA by the polymerase chain reaction in the serum of 39 children with chronic hepatitis B, after hepatitis B e antigen to antibody seroconversion. During a mean observation period of 8.2 +/- 3.8 years after seroconversion, all patients were asymptomatic; 36 had persistently normal alanine aminotransferase levels, and three had occasional mild alterations. Liver histology, checked in 21 patients, showed persistent hepatitis in nine, fibrosis in 10, and cirrhosis in two cases. HBV DNA was always undetectable by dot blot hybridization. Five children eventually cleared hepatitis B surface antigen, including one with cirrhosis who developed liver cancer at 19 years. HBV DNA was detected by polymerase chain reaction in 87% of children within 5 years of follow-up, in 58% of cases 6-10 years after seroconversion (p < 0.001), and in 50% of patients investigated later. Long-term viremia was found in two patients (40%) who cleared HBsAg, including the one who developed liver cancer. The chances of clearing viremia during follow-up were higher in children with acute hepatitis at the onset of illness (86%) than in those with asymptomatic onset (37%; p < 0.05). Our results show that low levels of HBV viremia, probably reflecting low levels of virus replication, persist for several years in children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion and remission of liver disease, even after the clearance of hepatitis B surface antigen. Persistent replication could support mild biochemical alterations and inflammatory liver lesions. It could allow late reactivation of liver disease and may play a role in the development of carcinoma.

Recombinant interferon-alfa therapy in children with chronic hepatitis C.

The efficacy of recombinant interferon-alfa therapy in children with chronic hepatitis C has been evaluated in a randomized, controlled pilot study including 27 patients, aged 2 to 14 years, without underlying systemic diseases. On entry, all patients had abnormal alanine transaminase (ALT) levels, 22 were hepatitis C virus (HCV) RNA positive, 19 had mild chronic active hepatitis, and 8 had chronic persistent hepatitis on liver biopsy. Fourteen children received 5 MU/m2 of recombinant interferon-alfa2b thrice weekly for 4 months. If at this time ALT had been reduced to at least 50% the baseline level, treatment was continued up to 12 months. The other 13 children remained untreated. The whole follow-up period lasted 24 months. Interferon was stopped at 4 months in 4 children because of an ALT increase (2 cases), unchanged ALT and febrile convulsions (1 case), and slight ALT decrease (1 case). This latter patient, however, had normal ALT at 6 months and throughout further follow-up, and cleared HCV RNA, thus behaving as a sustained responder. All 10 children treated for 12 months had normal levels of ALT, and 9 were HCV RNA negative at the end of treatment. Of the 9 children who could be followed to 24 months, 4 relapsed soon after therapy withdrawal and 5 maintained a sustained biochemical and virologic response. Overall, 6 (43%) of 14 treated children had a sustained ALT normalization associated with HCV RNA clearance as compared with only 1 (7.5%) untreated child who had a sustained ALT normalization but did not clear HCV RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of antibodies to hepatitis C virus and hepatitis C virus replication in children with chronic non-A, non-B hepatitis.

Antibodies to hepatitis C virus (HCV), investigated by second- and third-generation assays, were detected in 74% of 43 children with chronic non-A, non-B hepatitis. The polymerase chain reaction identified HCV ribonucleic acid in 26 (93%) of 28 seropositive and in 1 of 10 seronegative cases. Intermittent HCV ribonucleic acid positivity, suggesting low and fluctuating viremia, was frequent in younger patients.

Interferon for chronic hepatitis C in patients cured of malignancy.

Six patients with chronic hepatitis C who were cured of malignancy were treated with recombinant interferon-alpha at the dose of 4 MU/m2 for 12 months; the post-treatment follow up period was 12 months. Therapy was stopped within 6 months in three patients because of persistently abnormal alanine aminotransferase levels. In the remaining three patients, a complete normalization of alanine aminotransferase levels was obtained during treatment but it was not maintained after the end of interferon therapy. In addition, no patient cleared hepatitis C virus ribonucleic acid in serum. These results suggest that recombinant interferon is not effective in patients with chronic hepatitis C who were cured of a previous malignancy.

Hepatitis C in childhood: epidemiological and clinical aspects.

Hepatitis C virus (HCV) is responsible for most cases of chronic non-A, non-B hepatitis in multi-transfused children, but has been also implicated in at least one third of cases without history of parenteral exposure. We have recently evaluated the natural history of chronic hepatitis C in 37 children without underlying systemic diseases. None of the patients had a history of acute hepatitis and only 22 were symptomatic at presentation. Liver histology was consistent with active liver disease of mild to moderate activity in 42% of cases (one child had cirrhosis) and with persistent or lobular hepatitis in the remaining cases. During a mean follow-up period of 3.4 +/- 3.2 years symptoms were rarely observed and none of the patients developed liver failure, but 97% maintained abnormal alanine-aminotransferase levels. These results suggest that chronic hepatitis C in children, at least in its early stage, is a mild disease infrequently associated with severe liver lesions; however the persistence of liver damage over the years raises questions about the long-term outcome of the illness and about the rationale of antiviral therapy.