L'uso degli acceleratori in medicina nucleare

In questo lavoro di tesi si indaga come gli acceleratori di particelle si siano rivelati di fondamentale utilità nel settore medico-sanitario, risolvendo problematiche fisiche ed economiche legate alla produzione di radioisotopi. Per riuscire ad effettuare procedure terapeutiche e diagnostiche di qualità senza ricondursi a tecniche invasive, sta diventando sempre più importante disporre di ciclotroni nelle vicinanze delle strutture ospedaliere. Di fronte alla carenza di radionuclidi e alla necessità di produrre nuovi radiofarmaci, il mondo si sta muovendo per affiancare ai pochi reattori nucleari rimasti operativi, progetti nati dalla collaborazione di diversi centri di ricerca. In particolare in Italia è in corso un progetto, il TECHN-OPS, portato avanti da diverse sezioni INFN (compreso quella di Bologna), che si pone l’obiettivo di supplire al bisogno di 99m-Tc sfruttando una rete limitata di ciclotroni (che utilizzano bersagli di molibdeno arricchito) e lo sviluppo di metodi di riciclo di 100-Mo e di ottimizzazione delle varie fasi di produzione.

Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia

OBJECTIVE:To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis. METHODS:Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2). RESULTS:Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [(adj)OR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; (adj)OR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels ((adj)OR 0.549, 95% CI 0.341-0.883 in model 1; (adj)OR 0.560, 95% CI 0.353-0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C-reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 ((adj)OR 1.390, 95% CI 1.040-1.860). CONCLUSION:Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke.

Added value of coronary artery calcium score as an adjunct to gated SPECT for the evaluation of coronary artery disease in an intermediate-risk population

The coronary artery calcium (CAC) score is a readily and widely available tool for the noninvasive diagnosis of atherosclerotic coronary artery disease (CAD). The aim of this study was to investigate the added value of the CAC score as an adjunct to gated SPECT for the assessment of CAD in an intermediate-risk population. METHODS: Seventy-seven prospectively recruited patients with intermediate risk (as determined by the Framingham Heart Study 10-y CAD risk score) and referred for coronary angiography because of suspected CAD underwent stress (99m)Tc-tetrofosmin SPECT myocardial perfusion imaging (MPI) and CT CAC scoring within 2 wk before coronary angiography. The sensitivity and specificity of SPECT alone and of the combination of the 2 methods (SPECT plus CAC score) in demonstrating significant CAD (>/=50% stenosis on coronary angiography) were compared. RESULTS: Forty-two (55%) of the 77 patients had CAD on coronary angiography, and 35 (45%) had abnormal SPECT results. The CAC score was significantly higher in subjects with perfusion abnormalities than in those who had normal SPECT results (889 +/- 836 [mean +/- SD] vs. 286 +/- 335; P < 0.0001). Similarly, with rising CAC scores, a larger percentage of patients had CAD. Receiver-operating-characteristic analysis showed that a CAC score of greater than or equal to 709 was the optimal cutoff for detecting CAD missed by SPECT. SPECT alone had a sensitivity and a specificity for the detection of significant CAD of 76% and 91%, respectively. Combining SPECT with the CAC score (at a cutoff of 709) improved the sensitivity of SPECT (from 76% to 86%) for the detection of CAD, in association with a nonsignificant decrease in specificity (from 91% to 86%). CONCLUSION: The CAC score may offer incremental diagnostic information over SPECT data for identifying patients with significant CAD and negative MPI results.

Synthesis of NO-donor bisphosphonates and their in-vitro action on bone resorption

A new class of bisphosphonates containing nitrooxy NO-donor functions has been developed. The products proved to display affinity for hydroxyapatite. Injection of (99m)Tc-labeled derivatives 11 and 18 into male rats showed a preferential accumulation of the compounds in bone as compared to blood and muscles. The products were found to inhibit the differentiation of pre-osteoclasts to functional osteoclasts induced by receptor activator of NF-kappaB ligand (RANKL), through a prevalent NO-dependent mechanism.

Critical point and scale setting in SU(3) plasma: An update

We explore a method developed in statistical physics which has been argued to have exponentially small finite-volume effects, in order to determine the critical temperature Tc of pure SU(3) gauge theory close to the continuum limit. The method allows us to estimate the critical coupling βc of the Wilson action for temporal extents up to Nτ∼20 with ≲0.1% uncertainties. Making use of the scale setting parameters r0 and t0−−√ in the same range of β-values, these results lead to the independent continuum extrapolations Tcr0=0.7457(45) and Tct0−−√=0.2489(14), with the latter originating from a more convincing fit. Inserting a conversion of r0 from literature (unfortunately with much larger errors) yields Tc/ΛMS¯¯¯¯¯=1.24(10).

Bone marrow-derived stem/progenitor cells play an important role in the growth of Ewing's sarcoma tumors

Both angiogenesis and vasculogenesis contribute to the formation and expansion of tumor neovasculature. We demonstrated that bone marrow (BM)-derived cells migrated to TC71 Ewing's tumors and differentiated into endothelial cells lining perfused, functional tumor neovessels. In addition, a substantial fraction of recruited, BM-derived cells resided in the vessel vicinity but did not demonstrate endothelial differentiation. Rather, these perivascular cells expressed desmin and PDGFR-β, implying pericyte-like/vascular smooth muscle cell differentiation. No defined, consensus set of markers exists for endothelial progenitor cells (EPCs) and the specific subsets of BM cells that participate in vessel formation are poorly understood. We used a functional in vivo assay to investigate the roles performed by specific human- and murine-derived stem/progenitor subpopulations within Ewing's sarcoma tumors. CD34 +45+, CD34+38-, VEGFR2 + and Sca1+Gr1+ cells were demonstrated to establish residence within the expanding tumor vascular network and differentiate into endothelial cells and pericytes. By constrast, CD34-45 + and Sca1-Gr1+ cells predominantly localized to sites outside the Ewing's tumor vasculature, and differentiated into macrophages. Cytokines, such as VEGF, influence the recruitment of BM cells and their incorporation into the tumor vasculature. VEGF165-inhibited TC/siVEGF7-1 Ewing's tumors showed delayed in vivo tumor growth, decreased vessel density, and reduced infiltration of BM progenitor cells. We tested whether another chemoattractant, Stromal Cell-Derived Factor-1 (SDF-1), could augment the growth of these VEGF165-inhibited TC/siVEGF 7-1 tumors by enhancing the recruitment of BM cells and stimulating neovasculature expansion. SDF-1 promoted progenitor cell chemotaxis and retainment of BM-derived pericyte precursors in close association with functional, perfused tumor blood vessels. Treatment of TC/siVEGF7-1 tumors with adenovirus-SDF-1α resulted in augmented tumor size, enhanced pericyte coverage of tumor neovessels, remodeling of vascular endothelium into larger, functional structures, and upregulation of PDGF-BB, with no effect on VEGF165. Taken together, these findings suggest that the recruitment of BM stem/progenitor cells plays an important role in the growth of Ewing's tumors. ^

Microspheres for liver radiomicrospheres therapy and planning

Liver cancer accounts for nearly 10% of all cancers in the US. Intrahepatic Arterial Radiomicrosphere Therapy (RMT), also known as Selective Internal Radiation Treatment (SIRT), is one of the evolving treatment modalities. Successful patient clinical outcomes require suitable treatment planning followed by delivery of the microspheres for therapy. The production and in vitro evaluation of various polymers (PGCD, CHS and CHSg) microspheres for a RMT and RMT planning are described. Microparticles with a 30±10 µm size distribution were prepared by emulsion method. The in vitro half-life of the particles was determined in PBS buffer and porcine plasma and their potential application (treatment or treatment planning) established. Further, the fast degrading microspheres (≤ 48 hours in vitro half-life) were labeled with 68Ga and/or 99mTc as they are suitable for the imaging component of treatment planning, which is the primary emphasis of this dissertation. Labeling kinetics demonstrated that 68Ga-PGCD, 68Ga-CHSg and 68Ga-NOTA-CHSg can be labeled with more than 95% yield in 15 minutes; 99mTc-PGCD and 99mTc-CHSg can also be labeled with high yield within 15-30 minutes. In vitro stability after four hours was more than 90% in saline and PBS buffer for all of them. Experiments in reconstituted hemoglobin lysate were also performed. Two successful imaging (RMT planning) agents were found: 99mTc-CHSg and 68Ga-NOTA-CHSg. For the 99mTc-PGCD a successful perfusion image was obtained after 10 minutes, however the in vivo degradation was very fast (half-life), releasing the 99mTc from the lungs. Slow degrading CHS microparticles (> 21 days half-life) were modified with p-SCN-b-DOTA and labeled with 90 Y for production of 90Y-DOTA-CHS. Radiochemical purity was evaluated in vitro and in vivo showing more than 90% stability after 72 and 24 hours respectively. All agents were compared to their respective gold standards (99mTc-MAA for 68Ga-NOTA-CHSg and 99m Tc-CHSg; 90Y-SirTEX for 90Y-DOTA-CHS) showing superior in vivo stability. RMT and RMT planning agents (Therapy, PET and SPECT imaging) were designed and successfully evaluated in vitro and in vivo.

Infección de transmisión vertical por Toxoplasma gondii: seguimiento de los hijos de mujeres con primoinfección en una institución de asistencia médica colectiva; 2010-2015

La toxoplasmosis congénita (TC) afecta 1 a 2 niños cada 1.000 nacimientos al año. La mayoría de los recién nacidos infectados son asintomáticos pero la ausencia de tratamiento puede determinar secuelas oftalmológicas y neurológicas. Objetivo: describir el seguimiento de los hijos de mujeres con primoinfección por Toxoplasma gondii durante el embarazo derivados a una Policlínica de Infectología de la Médica Uruguaya entre diciembre de 2010 y mayo de 2015. Material y método: se incluyeron los hijos de mujeres con primoinfección por T.gondii durante el embarazo entre el 1 de diciembre de 2010 y el 31 de mayo de 2015. Se confirmó primoinfección mediante determinación inmunoenzimática de IgG e IgM específicas, complementada por IgM por inmunofluorescencia indirecta o test de avidez de IgG según el caso. El diagnóstico de infección congénita se realizó por la presencia de IgM o títulos de IgG estables o en aumento en los primeros 9 meses de seguimiento del niño. Resultados: se diagnosticó primoinfección en 34 mujeres. La mayoría controló adecuadamente el embarazo y ninguna presentó infección por VIH, sífilis o Chagas. Se confirmó TC en 3 niños nacidos a término, con peso adecuado, hijos de mujeres con primoinfección adquirida en el tercer trimestre y tratadas con espiramicina. Uno presentó coriorretinitis, los otros fueron asintomáticos. En todos la IgM fue negativa, el diagnóstico se confirmó con curva de IgG. Todos recibieron piremetamina, sulfadiazina y ácido folínico sin efectos adversos. A la fecha continúan en tratamiento y seguimiento dos de los tres niños. Discusión y conclusión: la captación temprana de la mujer embarazada, la indicación oportuna de medidas de prevención constituyen pilares fundamentales para reducir la TC. El tratamiento oportuno y adecuado puede prevenir las secuelas.

Estimating glomerular filtration rate in kidney transplantation: Still searching for the best marker

Kidney transplantation is the treatment of choice for end-stage renal disease. The evaluation of graft function is mandatory in the management of renal transplant recipients. Glomerular filtration rate (GFR), is generally considered the best index of graft function and also a predictor of graft and patient survival. However GFR measurement using inulin clearance, the gold standard for its measurement and exogenous markers such as radiolabeled isotopes ((51)Cr EDTA, (99m)Tc DTPA or (125)I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol), is laborious as well as expensive, being rarely used in clinical practice. Therefore, endogenous markers, such as serum creatinine or cystatin C, are used to estimate kidney function, and equations using these markers adjusted to other variables, mainly demographic, are an attempt to improve accuracy in estimation of GFR (eGFR). Nevertheless, there is some concern about the inability of the available eGFR equations to accurately identify changes in GFR, in kidney transplant recipients. This article will review and discuss the performance and limitations of these endogenous markers and their equations as estimators of GFR in the kidney transplant recipients, and their ability in predicting significant clinical outcomes.

Tc-99m-sestamibi scintigraphy used to evaluate tumor response to neoadjuvant chemotherapy in locally advanced breast cancer: A quantitative analysis

To evaluate the tumor response to neoadjuvant chemotherapy, Tc-99m-sestamibi breast scintigraphy was proposed as a quantitative method Fifty-five patients with ductal carcinoma were studied They underwent breast scintigraphy before and after neoadjuvant chemotherapy, along with clinical assessment and surgical specimen analysis The regions of interest on the lesion and contralateral breast were identified, and the pixel counts were used to evaluate lesion uptake in relation to background radiation The ratio of these counts before to after neoadjuvant chemotherapy was assessed The decrease in uptake rate due to chemotherapy characterized the scintigraphy tumor response The Kruskal-Wallis test was used to compare the mean scintigraphic tumor response and histological type Dunn's multiple comparison test was used to detect differences between histological types The Mann-Whitney test was used to compare means between quantitative and qualitative variables scintigraphic tumor response vs clinical response and uptake before chemotherapy vs scintigraphic tumor response The Spearman's test was used to correlate the quantitative variables of clinical reduction in tumor size and scintigraphic tumor response All of the variables compared presented significant differences The change in Tc-99m-sestamibi uptake noted on breast scintigraphy, before to after neoadjuvant chemotherapy, may be used as an effective method for evaluating the response to neoadjuvant chemotherapy, since this quantification reflects the biological behavior of the tumor towards the chemotherapy regimen Furthermore, additional analysis on the uptake rate before chemotherapy may accurately predict treatment response

Accuracy of Tc-99m-sestamibi scintimammography for breast cancer diagnosis

Scintimammography using Tc-99m-sestamibi is a noninvasive and painless diagnostic imaging method that is used to detect breast cancer when mammography is inconclusive Because of the advantages of labeling v '7,ith Tc-99m-sestamibi and its high efficiency in detecting carcinomas, it is the most widespread agent for this purpose Its accumulation in the tumor has multifactorial causes and does not depend on the presence of architectural distortion or local or diffuse density variation in the breast The objective of tfiis study was to evaluate the accuracy of scintimammography 1 for detecting breast cancer One hundred and fifty-seven patients presenting 158 palpable and non-palpable breast nodules were evaluated Three patients were male and 154 were female, aged between 14 and 81 years All patients underwent scintimammography, and the nodule was subjected i to cytological or histological study, i e, the gold standard for diagnosing cancer One hundred and eleven malignant and 47 benign nodules were detected, with predominance of ductal carcinomas (n=94) and fibroadenoma/fibrocysiic condition (n=11/n=11), respectively The mean size was 3 11 cm (7-10 cm) among the malignant nodules and 2 07 cm among the benign nodules (0 5-10 cm) The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 89, 89, 95, 78 and 89%, respectively Analysis on the histological types showed that the technique was more effective on tumors that were more aggressive, such as ductal carcinoma In this study, Tc-99m-sestamibi scintim immography was shown to be an important tool for diagnosing breast cancer when mammography was inconclusive

Evaluation of mammographic density and Tc-99m-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy

Objective: To evaluate changes in mammographic density and Tc-99m-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy (HRT).Methods: Seventy-five postmenopausal women were prospectively studied and allocated into three groups: 50 women were randomized to either Group 1 (G1, n = 25), which received 2 mg of 17 beta-oestradiol continuously combined with 1 mg of norethisterone acetate (E-2/NETA, Kliogest (R), Medley) or Group 2 (G2), which received 2.5 mg/day of tibolone (Livial (R), Organon). The remaining 25 women, who were asymptomatic and had no desire to undergo HRT, constituted the control group (G3). Each patient was submitted to both mammography and scintimammography at baseline and after six months. Mammographic density was evaluated by using the BI-RADS classification system. The classification system of Barros et al. was used in the interpretation of scintimammography. For statistical analysis, the Chi-square test, ANOVA and Pearson's correlation were used.Results: At six months, increased mammographic density was observed in 48% of G1, 12% of G2 and 16% of G3 patients (p < 0.001). The increase in sestamibi uptake was 56% in G1, 28% in G2 and 24% in G3 (p < 0.001). Increases in both density and uptake were significantly higher in the group on E-2/NETA than among tibolone users and the controls.Conclusion: In postmenopausal women, HRT with E-2/NETA was associated with increased mammographic density and increased Tc-99m-sestamibi scintimammographic uptakes, suggesting greater mithochondrial activity in the cells of the mammary duct. This was not observed in users of 2.5 mg of tibolone, demonstrating that the effects on the breast were reduced. The same was observed in the control group. (c) 2005 Elsevier B.V.. All rights reserved.

Sentinel node detection in cervical cancer with Tc-99m-phytate

Objectives. The aim of this study was to investigate the feasibility of sentinel lymph node (SLN) identification using radioisotopic lymphatic mapping with technetium-99 m-labeled phytate in patients undergoing radical hysterectomy with pelvic lymphadenectomy for treatment of early cervical cancer.Methods. Between July 2001 and February 2003, 56 patients with cervical cancer 1160 stage I (it 53) or stage 11 (it 3) underwent sentinel lymph node detection with preoperative lymphoscintigraphy (Te-99m-labeled phytate injected into the uterine cervix, at 3, 6, 9, and 12 o'clock, at a dose of 55-74 MBq in a volume of 0.8 ml) and intratoperative lymphatic mapping with a handheld gamma probe, Radical hysterectomy was aborted in three cases because parametrial invasion was found intraoperatively and we performed only sentinel node resection. The remaining 53 patients underwent radical hysterectomy with complete pelvic lymphadenectomy, Sentinel nodes were detected using a handheld gamma-probe and removed for pathological assessment during the abdominal radical hysterectomy and pelvic lymphadenectomy.Results. One or more sentinel nodes were detected in 52 out of 56 eligible patients (92.8%). A total of 120 SLNs were detected by lymphoscintigraphy (mean 2.27 nodes per patient) and intraoperatively by gamma probe, Forty-four percent of SLNs were found in the external iliac area, 39% in the obturator region, 8.3% in interiliae region, and 6.7),) in the common iliac area. Unilateral sentinel nodes were found in thirty-one patients (59%). The remaining 21 patients (4100 had bilateral sentinel nodes, Microscopic nodal metastases were confirmed in 17 (32%) cases. In 10 of these patients, only SLNs had metastases. The 98 sentinel node.,, that were negative on hematoxylin and eosin were submitted to cytokeratin immunohistochemical analysis. Five (5.1%) micrometastases were identified with this technique. The sensitivity of the sentinel node was 82.3% (CI 95% - 56.6-96.2) and the negative predictive value was 92.1% (CI 95% 78.6 98.3) the accuracy of sentinel node in predicting the lymph node status was 94.2%,Conclusion. Preoperative lymphoscintigraphy and intraoperative lymphatic mapping with Tc-99-labeled phytate are effective in identifying sentinel nodes in patients undergoing radical hysterectomy and to select women in whom lymph node dissection call be avoided. (c) 2005 Elsevier B.V. All rights reserved.

Studio di fattibilità della produzione diretta di tc-99m mediante ciclotrone

Le caratteristiche del 99mTc e la possibilità per gli ospedali di produrlo in loco quotidianamente grazie ai generatori, hanno reso questo radioisotopo il più utilizzato della fisica medica: è richiesto in circa l’80% delle procedure di medicina nucleare con circa 7 milioni di somministrazioni all’anno in Europa e 8 milioni negli USA. Inoltre il campo di applicabilità del 99mTc è molto vasto: viene infatti utilizzato per scintigrafie ossee, epatiche, renali, celebrali, tiroidee e per il controllo della funzionalità epatica. A causa del notevole incremento dell’insorgenza di patologie oncologiche e dell’aumento della popolazione, la richiesta di 99mTc è sempre cresciuta negli anni ed è ancora destinata a crescere nei prossimi; l’unico fattore attenuante è lo sviluppo di altre tecniche di diagnostica funzionale come la PET ( Positron Emission Tomography ). Nonostante la creazione del 99mTc da generatori di 99Mo sia ancora oggi il metodo di produzione più efficiente, si sta ponendo recentemente la necessità di ricercare nuove tecniche di produzione dell’isotopo per soddisfare le grandi quantità richieste dal mercato globale. Questo accade perché malgrado l’utilizzo del 99mTc sia in forte crescita, la produzione di 99Mo è destinata a diminuire in quanto necessita di reattori nucleari: gli ingenti costi delle moderne centrali e le elevate quantità di scorie prodotte, stanno guidando la politica mondiale verso una denuclearizzazione che renderà in pochi anni impossibile soddisfare la richiesta di 99Mo della medicina nucleare. Questo lavoro di tesi si colloca in questo contesto, cioè nella ricerca di un metodo alternativo per la produzione di 99mTc: l’irraggiamento con protoni di un target di 100Mo arricchito, in un ciclotrone ad uso medicale. L’obbiettivo che si vuole raggiungere è fornire una stima attendibile su tale produzione, valutare la qualità dell’isotopo e mettere in luce eventuali problematiche riscontrabili.

Novel 1122 thallium cuprates showing high Tc superconductivity: TlCa1-xY,Ba2Cu2Oy,T,1-xPbxCaSr2Cu2Oy and TlCa0.5Ln0.5Sr2Cu2Oy

Substitution of Ca by Y in TlCaBa2Cu2Oy does not favour superconductivity, but substitution of Tl by Pb or of Ca by Ln (Ln = Y or rare earth) in TlCaSr2Cu2Oy results in high Tc superconductivity (Tc π 60-90 K). TlCa1-xLnxSr2Cu2Oy is a new series of high Tc superconductors, but the x = 0.0 composition does not exhibit bulk superconductivity.