Increased Sensitivity of Computed Tomography Scan for Neoplastic Tissues Using the Extracellular Vesicle Formulation of the Contrast Agent Iohexol.

Computed tomography (CT) is a diagnostic medical imaging modality commonly used to detect disease and injury. Contrast agents containing iodine, such as iohexol, are frequently used in CT examinations to more clearly differentiate anatomic structures and to detect and characterize abnormalities, including tumors. However, these contrast agents do not have a specific tropism for cancer cells, so the ability to detect tumors is severely limited by the degree of vascularization of the tumor itself. Identifying delivery systems allowing enrichment of contrast agents at the tumor site would increase the sensitivity of detection of tumors and metastases, potentially in organs that are normally inaccessible to contrast agents, such as the CNS. Recent work from our laboratory has identified cancer patient-derived extracellular vesicles (PDEVs) as effective delivery vehicles for targeting diagnostic drugs to patients' tumors. Based on this premise, we explored the possibility of introducing iohexol into PDEVs for targeted delivery to neoplastic tissue. Here, we provide preclinical proof-of-principle for the tumor-targeting ability of iohexol-loaded PDEVs, which resulted in an impressive accumulation of the contrast agent selectively into the neoplastic tissue, significantly improving the ability of the contrast agent to delineate tumor boundaries.

Neurosyphilis Mimicking Behavioral Variant of Frontotemporal Dementia in a 59-Year-Old Man.

We present the case of a man exhibiting a clinical phenotype of behavioral variant of frontotemporal dementia (bvFTD). The man had developed psychiatric disturbances with verbal aggressiveness over a few months, followed by cognitive and frontal behavioral disorders, fulfilling the clinical criteria for bvFTD. Atrophy and hypometabolism in frontotemporal regions were consistent with the diagnosis. However, serum-screening exams for syphilis infection were positive, and CSF analysis, despite a negative Venereal Disease Research Laboratory Test, suggested the diagnosis of neurosyphilis. After specific antibiotic therapy, the man's behavioral abnormalities and cognitive deficits notably improved, confirming neurosyphilis as the cause of the clinical phenotype. The cognitive deficits completely recovered 1 year post therapy and remained stable for 2 years. After ∼2½ years from the first treatment, the man's behavioral disorders mildly worsened, at which time we re-evaluated him. His cognition was stable, and a positive Venereal Disease Research Laboratory Test confirmed the diagnosis of neurosyphilis. With this case, we demonstrated that in some instances, neurosyphilis can mimic frontotemporal dementia. As a cause of treatable dementia, it should be considered in the differential diagnosis of bvFTD, particularly when psychiatric symptoms and a rapid cognitive decline are noted, even in the presence of brain atrophy and/or hypometabolism.

Psychiatric Disorders in Alzheimer Disease With the Presenilin-1 L226F Mutation.

The presenilin-1 (PSEN1) L226F mutation has been linked to very early onset of prominent behavioral and psychiatric disturbances followed by cognitive decline within a few years. We report a novel case of early-onset Alzheimer disease that was originally diagnosed as psychotic depression in a patient with this gene mutation. We also compare our patient's clinical data to those of other cases of this mutation that have been described in the literature. Because atypical behavioral and psychiatric disturbances in young (<40 years) individuals can herald Alzheimer disease, a tight collaboration between psychiatrists and neurologists is crucial for an early diagnosis.

Identifying the epileptogenic zone by four non-invasive imaging techniques versus stereo-EEG in MRI-negative pre-surgery epilepsy patients.

OBJECTIVE: We evaluated four imaging techniques, i.e. Electroencephalography (EEG)-functional Magnetic Resonance Imaging (MRI) (EEG-fMRI), High-resolution EEG (HR-EEG), Magnetoencephalography (MEG) and 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET), for the identification of the epileptogenic zone (EZ) in 41 patients with negative MRI, candidate to neurosurgery. METHODS: For each technique, results were compared to the Stereo-EEG. Diagnostic measures were calculated with respect to the post-surgical outcome, either for all the patients (39/41, two patients excluded) and for the subgroup of patients with the EZ involving more than one lobe (20/41). RESULTS: When considered individually, each functional technique showed accuracy values ranging 54,6%-63,2%, having PET, MEG and HR-EEG higher sensitivity, and EEG-fMRI higher specificity. In patients with multilobar epileptogenic zone, functional techniques achieved the best accuracies (up to 80%) when three techniques, including EEG-fMRI, were considered together. CONCLUSIONS: The study highlights the accuracy of a combination of functional imaging techniques in the identification of EZ in MRI negative focal epilepsy. The best diagnostic yield was obtained if the combination of PET, MEG (or HR-EEG as alternative), EEG-fMRI were considered together. SIGNIFICANCE: The functional imaging techniques may improve the presurgical workup of MRI negative focal epilepsy, if epileptogenic zone involves more than one lobe.

The ideal marker for measuring GFR: what are we looking for?

INTRODUCTION: The most accurate way of assessing kidney function is the measurement of the glomerular filtration rate (GFR). Since, we do not have good formulae to estimate GFR in elderly, in this study we  evaluate the accuracy of the most commonly used formulas for the estimation of GFR in comparison with direct measurement in elderly. MATERIALS AND METHODS: 85 patients (51 males and 34 females), with an average age of 76.2 ± 4.4 years, 42% already diagnosed with chronic kidney disease (CKD) were investigated. Two plasma samples were collected between  60-90 and 165-195 minutes after injection of 99mTc-DTPA, and the GFR was calculated applying Charles D. Russell's two-sample method. RESULTS: When comparing the GFR values obtained from the various formulae by creatinine levels with the GFR values obtained by measuring 99mTc-DTPA residue, the following concordance values emerged: (1) MDRD: 57.5 ± 9.59 %; (2) Cockroft-Gault: 48.33 ± 24.93; (3) CKD-EPI: 49.40 ± 26.30; (4) BIS1: 58 ± 6.79. CONCLUSION: Our data shows a greater concordance between the GFR values calculated with the Russell's method and the estimated values of GFR when the latter are calculated using the MDRD or BIS1 formulae.

Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis.

We report the case of a 42-year-old woman who presented with vertigo and migraine and rapidly developed cognitive decline and seizures. Both serum and cerebro-spinal fluid samples showed high titer of anti-glutamic acid decarboxylase (anti-GAD65) antibodies (998,881 IU/ml and 54,687 IU/ml respectively). Limbic encephalitis was diagnosed and high dose steroids treatment started. During one-year follow-up, without further immunomodulatory therapy, the patient became seizure free, and cognitive functions returned to normal. Serum anti-GAD65 antibodies titer decreased significantly but remained elevated (192,680 IU/ml). We discuss the prognostic and pathogenic value of high titer anti-GAD65 antibodies and its variations in a case of autoimmune limbic encephalitis.

Impact of low-dose SPECT imaging on normal databases and myocardial perfusion scores.

PURPOSE: We have recently demonstrated that iterative reconstruction algorithms with resolution recovery require the adoption of specific normal databases (NDBs) for perfusion SPECT quantification. This work was aimed at investigating the impact of patient low-dose imaging on NDBs and percent summed rest (SR%) and stress (SS%) scores. METHODS: Assuming that count statistics of shorter acquisition time may simulate that of lower patient dose, three simultaneous scans were acquired (BrightView, Philips) with different acquisition-time/projection: 30, 15 and 8 s (from 100% to 25% of the reference). Fifty-two normal patients with low likelihood of coronary artery disease were enrolled and three homemade NDBs were then generated and compared (Astonish™ algorithm with default parameters): 100%-HM-NDBs, 50%-HM-NDBs and 25%-HM-NDBs. SR% and SS% were subsequently calculated for another group of 38 patients (normal/abnormal = 5/33). SR% and SS% values of 100%-HM-NDBs were compared with those obtained with the NDBs available on the workstation. Moreover, the impact of the study count statistics on perfusion scores was evaluated using the count-specific NDBs. RESULTS: Significantly higher standard-deviation values were found for 25%-HM-NDBs compared to the other HM-NDBs (p < 0.02). Significantly higher SS% were also found for the 100%-HM-NDBs compared to the workstation NDBs (95%CI: 0.15-2.11%). Moreover, a post-hoc test showed significantly lower SR% and SS% for 25%-count statistics compared to 100%-HM-NDBs (p < 0.03). CONCLUSIONS: NDBs and perfusion scores depend significantly on study count-statistics. A 50% reduction in patient dose is ultimately the limit for Astonish™ (with the default parameters) in order to prevent a significant variation in myocardial perfusion quantification.

Impact of non-specific normal databases on perfusion quantification of low-dose myocardial SPECT studies.

AIM: To evaluate the impact of non-specific normal databases on the percent summed rest score (SR%) and stress score (SS%) from simulated low-dose SPECT studies by shortening the acquisition time/projection. METHODS: Forty normal-weight and 40 overweight/obese patients underwent myocardial studies with a conventional gamma-camera (BrightView, Philips) using three different acquisition times/projection: 30, 15, and 8 s (100%-counts, 50%-counts, and 25%-counts scan, respectively) and reconstructed using the iterative algorithm with resolution recovery (IRR) AstonishTM (Philips). Three sets of normal databases were used: (1) full-counts IRR; (2) half-counts IRR; and (3) full-counts traditional reconstruction algorithm database (TRAD). The impact of these databases and the acquired count statistics on the SR% and SS% was assessed by ANOVA analysis and Tukey test (P < 0.05). RESULTS: Significantly higher SR% and SS% values (> 40%) were found for the full-counts TRAD databases respect to the IRR databases. For overweight/obese patients, significantly higher SS% values for 25%-counts scans (+19%) are confirmed compared to those of 50%-counts scan, independently of using the half-counts or the full-counts IRR databases. CONCLUSIONS: AstonishTM requires the adoption of the own specific normal databases in order to prevent very high overestimation of both stress and rest perfusion scores. Conversely, the count statistics of the normal databases seems not to influence the quantification scores.

68Ga-PSMA-PET: added value and future applications in comparison to the current use of choline-PET and mpMRI in the workup of prostate cancer.

Positron emission tomography (PET) has been commonly and successfully used, in combination with computed tomography (CT) and more recently magnetic resonance (MRI), in the workup of intermediate or high-risk prostate cancer (PCa). Nowadays, new specific receptor targeted PET tracers in prostate cancer imaging have been introduced; one of the most used is 68Ga-PSMA, that evaluates the expression of prostate-specific membrane antigen (PSMA). This tracer has been rapidly taken into account for its better sensitivity and specificity compared to lipid metabolism tracers, such as 11C/18F labelled fluorocholine. Besides, in the era of theranostics, this tracer is having a useful application not only for imaging but also for therapeutic purposes. The aim of this review article is, in the first part, to give an overview of the main indications and future development of 68Ga-PSMA imaging, using PET/CT or PET/MRI, according to the clinical course of the disease and in view of the current use of multiparametric MRI (mpMRI) and choline PET in the management of PCa. In the second part, a brief overview of the promising 18F-labelled PSMA tracers and the current use of PSMA radionuclide therapy will be provided.

Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation.

Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS. However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2, that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features.

Quality control on radiochemical purity in Technetium-99m radiopharmaceuticals labelling: three years of experience on 2280 procedures.

OBJECTIVE: the purpose of this study was to offer an example of evaluations of the ISO9001 certified internal quality assurance (QA) system of 99mTc-radiopharmaceutical preparations and quality control in vivo use, using industrial kits and generators in order to identify possible sources of errors in the procedures labeling and quality control procedures. METHODS: The study was performed at a single institution over a period of three years (July 1st, 2011 - July 1st, 2014), and included a total of 2280 radiopharmaceutical preparations prepared by four different technologists. All the radiopharmaceutical preparations and quality controls were performed according to each SPC provided by the manufacturer. The radiopharmaceutical preparations were the following (trade names are reported in brackets): 99mTc-albumin colloid [Nanocoll] (n=349), 99mTc-oxidronate [Technescan®hdp] (n=701), 99mTc-exametazime [Ceretec] (n=169), 99mTc-sestamibi [Cardiolite] (n=92), 99mTc-albumin aggregated [Technescan®lyomaa] (n=140), 99mTc-tetrofosmin [Myoview]) (n=567), 99mTc-diethylene triamine pentacetic acid [Technescan®dtpa] (n=254), and 99mTc-dimercapto succinic acid [Renocis®] (n=8). Data were analyzed to determine the number and type of radiopharmaceutical labelling failure and to derive the sources of these failures to define corrective actions and optimize the quality assurance program. RESULTS: A total of 2280 procedures were performed and recorded. Following the quality control procedure six out of the 2280 preparations (0.26%) were non-conforming for clinical use with the RCP limits indicated in the SPC. Five of these were due to gross technical errors in measurements and manual procedures and were immediately repeated, returning within the limits of acceptability. The sixth failure was due to short incubation time, though compliant with the manufacturer's instructions. CONCLUSIONS: We concluded that the quality of the final product depends on a controlled production system based on the implementation of specific standard operating procedures (ISO9001, SOP) for each radiopharmaceutical production, according to strict adherence to the SPC of each radiopharmaceutical. Based on these conclusions, in our opinion every quality control suggesting a possible error in the synthesis procedure recommended in the SPC should be immediately reported to the manufacturer, for a revision of the SPC, as well as to the regulatory agencies for an alert. This strategy may in fact allow the continuous improvement of the labelling procedures and therefore the optimization of the quality control procedures frequency to ensure both patients safety and a more rational management of resources for economic sustainability.

Comparative analysis of iterative reconstruction algorithms with resolution recovery and time of flight modeling for 18F-FDG cardiac PET: A multi-center phantom study.

BACKGROUND: The purpose of this study was to evaluate the image quality in cardiac 18F-FDG PET using the time of flight (TOF) and/or point spread function (PSF) modeling in the iterative reconstruction (IR). METHODS: Three scanners and an anthropomorphic cardiac phantom with an insert simulating a transmural defect (TD) were used. Two sets of scans (with/without TD) were acquired, and four reconstruction schemes were considered: (1) IR; (2) IR + PSF, (3) IR + TOF, and (4) IR + TOF + PSF. LV wall thickness (FWHM), contrast between LV wall and inner chamber (C IC), and TD contrast in LV wall (C TD) were evaluated. RESULTS: Tests of the reconstruction protocols showed a decrease in FWHM from IR (13 mm) to IR + PSF (11 mm); an increase in the C IC from IR (65%) to IR + PSF (71%) and from IR + TOF (72%) to IR + TOF + PSF (77%); and an increase in the C TD from IR + PSF (72%) to IR + TOF (75%) and to IR + TOF + PSF (77%). Tests of the scanner/software combinations showed a decrease in FWHM from Gemini_TF (13 mm) to Biograph_mCT (12 mm) and to Discovery_690 (11 mm); an increase in the C IC from Gemini_TF (65%) to Biograph_mCT (73%) and to Discovery_690 (75%); and an increase in the C TD from Gemini_TF/Biograph_mCT (72%) to Discovery_690 (77%). CONCLUSION: The introduction of TOF and PSF increases image quality in cardiac 18F-FDG PET. The scanner/software combinations exhibit different performances, which should be taken into consideration when making cross comparisons.

Comparative analysis of cadmium-zincum-telluride cameras dedicated to myocardial perfusion SPECT: A phantom study.

BACKGROUND: This investigation used image data generated by an anthropomorphic phantom with a cardiac insert for a comparison between two solid state cameras: D-SPECT and D530c. METHODS: For each camera, two sets (with and without a simulated transmural defect (TD)) of scans were acquired starting from the in vivo standard count statistics in the left ventricle (LV). Other two acquisitions corresponding to 150% and 50% of the reference count statistics were acquired. Five performance indices related to spatial resolution, contrast, and contrast-to-noise ratio (CNR) were analyzed. RESULTS: D-SPECT showed a lower LV wall thickness and an inferior sharpness than D530c. No significant differences were found in terms of contrast between LV wall and the inner cavity, TD contrast or CNR. No significant differences were observed in CNR when moving from the reference level of count statistics down to 50% or up to 150% of the counts acquired on the LV. CONCLUSIONS: Our results show that D-SPECT and D530c have different performances. The lack of differences in the image performance indices along the range of count statistics explored, indicates that there is the possibility for a further reduction in the injected activity and/or the acquisition time, for both systems.

Variability of [18F]FDG administered activities among patients undergoing PET examinations: an international multicenter survey.

Given the large number of [(18)F]fluorodeoxyglucose (FDG) PET examinations performed annually throughout the world, reduction of the administered activity without compromise of the clinical information being sought is encouraged. Guidelines issued by the SNMMI and European Association of Nuclear Medicine (EANM) differ greatly on the choice of the activity that should be administered to patients: the EANM suggests a personalised activity based on the patient's body weight, whereas the SNMMI recommends the administration of fixed activities. The authors analysed a database of 24 716 [(18)F]FDG administrations performed worldwide in 15 PET centres to assess the degree of heterogeneity, in relation to available technology, operational protocols and reference guidelines. Median activities based on the patients' body weight were 43 % lower than fixed-activity administrations (p < 0.001). When TOF scanners are available, the median activity is lowered, but when comparing centres with the same technology or those that use the same operational protocols, weight-based activities are still significantly lower than fixed activities.

Correlation between 123I-FP-CIT brain SPECT and parkinsonism in dementia with Lewy bodies: caveat for clinical use.

INTRODUCTION: Although parkinsonism is considered a core feature of dementia with Lewy bodies (DLB), it is occasionally mild or even absent. I-FP-CIT SPECT has been accepted as a diagnostic support tool in this context, given that low striatal uptake is associated with neuronal loss. The aim of this retrospective study was to look for correlations between I-FP-CIT uptake in the striatum and clinical extrapyramidal signs (EPSs) in patients with a diagnosis of probable DLB to clarify the extent to which the supporting role of I-FP-CIT is related to motor impairment. METHODS: Semiquantitative I-FP-CIT uptake was analyzed and correlated with Unified Parkinson Disease Rating Scale Part III scores in a sample of 22 patients with a diagnosis of probable DLB and a wide range of EPSs. RESULTS: A significant negative linear correlation between I-FP-CIT uptake and Unified Parkinson Disease Rating Scale Part III score was found both in the caudate and the putamen (r = -0.69 and -0.72, respectively, P < 0.001). Striatal uptake in patients with no or questionable EPS was comparable to that recorded in normal age-matched subjects (99% [22%] in the putamen) but significantly reduced in those with mild and severe EPS (43% [35%] and 30% [17%], respectively, P < 0.0001, but P = nonsignificant between mild and severe EPS). CONCLUSIONS: SPECT may be redundant when there are no doubts about the parkinsonism (ie, when it is absent or unequivocally present), but it may be helpful in identifying presynaptic nigrostriatal degeneration in patients with mild EPSs.