Prediction Nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for Prostate Cancer

Objective The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure. Materials and methods Seven hundred three (n = 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced stage PCa before second-line systemic therapies: group 4). First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram’s derived cut-off. Decision curve analysis (DCA) was implemented to quantify nomogram’s clinical benefit. Results 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p < 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cut-off value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%. Conclusions This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cut-off in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.

Effects of environmental complexity on neurogenesis in the hippocampal dentate gyrus

Introduction. Postnatal neurogenesis in the hippocampal dentate gyrus, can be modulated by numerous determinants, such as hormones, transmitters and stress. Among the factors positively interfering with neurogenesis, the complexity of the environment appears to play a particularly striking role. Adult mice reared in an enriched environment produce more neurons and exhibit better performance in hippocampus-specific learning tasks. While the effects of complex environments on hippocampal neurogenesis are well documented, there is a lack of information on the effects of living under socio-sensory deprivation conditions. Due to the immaturity of rats and mice at birth, studies dealing with the effects of environmental enrichment on hippocampal neurogenesis were carried out in adult animals, i.e. during a period of relatively low rate of neurogenesis. The impact of environment is likely to be more dramatic during the first postnatal weeks, because at this time granule cell production is remarkably higher than at later phases of development. The aim of the present research was to clarify whether and to what extent isolated or enriched rearing conditions affect hippocampal neurogenesis during the early postnatal period, a time window characterized by a high rate of precursor proliferation and to elucidate the mechanisms underlying these effects. The experimental model chosen for this research was the guinea pig, a precocious rodent, which, at 4-5 days of age can be independent from maternal care. Experimental design. Animals were assigned to a standard (control), an isolated, or an enriched environment a few days after birth (P5-P6). On P14-P17 animals received one daily bromodeoxyuridine (BrdU) injection, to label dividing cells, and were sacrificed either on P18, to evaluate cell proliferation or on P45, to evaluate cell survival and differentiation. Methods. Brain sections were processed for BrdU immunhistochemistry, to quantify the new born and surviving cells. The phenotype of the surviving cells was examined by means of confocal microscopy and immunofluorescent double-labeling for BrdU and either a marker of neurons (NeuN) or a marker of astrocytes (GFAP). Apoptotic cell death was examined with the TUNEL method. Serial sections were processed for immunohistochemistry for i) vimentin, a marker of radial glial cells, ii) BDNF (brain-derived neurotrofic factor), a neurotrophin involved in neuron proliferation/survival, iii) PSA-NCAM (the polysialylated form of the neural cell adhesion molecule), a molecule associated with neuronal migration. Total granule cell number in the dentate gyrus was evaluated by stereological methods, in Nissl-stained sections. Results. Effects of isolation. In P18 isolated animals we found a reduced cell proliferation (-35%) compared to controls and a lower expression of BDNF. Though in absolute terms P45 isolated animals had less surviving cells than controls, they showed no differences in survival rate and phenotype percent distribution compared to controls. Evaluation of the absolute number of surviving cells of each phenotype showed that isolated animals had a reduced number of cells with neuronal phenotype than controls. Looking at the location of the new neurons, we found that while in control animals 76% of them had migrated to the granule cell layer, in isolated animals only 55% of the new neurons had reached this layer. Examination of radial glia cells of P18 and P45 animals by vimentin immunohistochemistry showed that in isolated animals radial glia cells were reduced in density and had less and shorter processes. Granule cell count revealed that isolated animals had less granule cells than controls (-32% at P18 and -42% at P45). Effects of enrichment. In P18 enriched animals there was an increase in cell proliferation (+26%) compared to controls and a higher expression of BDNF. Though in both groups there was a decline in the number of BrdU-positive cells by P45, enriched animals had more surviving cells (+63) and a higher survival rate than controls. No differences were found between control and enriched animals in phenotype percent distribution. Evaluation of the absolute number of cells of each phenotype showed that enriched animals had a larger number of cells of each phenotype than controls. Looking at the location of cells of each phenotype we found that enriched animals had more new neurons in the granule cell layer and more astrocytes and cells with undetermined phenotype in the hilus. Enriched animals had a higher expression of PSA-NCAM in the granule cell layer and hilus Vimentin immunohistochemistry showed that in enriched animals radial glia cells were more numerous and had more processes.. Granule cell count revealed that enriched animals had more granule cells than controls (+37% at P18 and +31% at P45). Discussion. Results show that isolation rearing reduces hippocampal cell proliferation but does not affect cell survival, while enriched rearing increases both cell proliferation and cell survival. Changes in the expression of BDNF are likely to contribute to he effects of environment on precursor cell proliferation. The reduction and increase in final number of granule neurons in isolated and enriched animals, respectively, are attributable to the effects of environment on cell proliferation and survival and not to changes in the differentiation program. As radial glia cells play a pivotal role in neuron guidance to the granule cell layer, the reduced number of radial glia cells in isolated animals and the increased number in enriched animals suggests that the size of radial glia population may change dynamically, in order to match changes in neuron production. The high PSA-NCAM expression in enriched animals may concur to favor the survival of the new neurons by facilitating their migration to the granule cell layer. Conclusions. By using a precocious rodent we could demonstrate that isolated/enriched rearing conditions, at a time window during which intense granule cell proliferation takes place, lead to a notable decrease/increase of total granule cell number. The time-course and magnitude of postnatal granule cell production in guinea pigs are more similar to the human and non-human primate condition than in rats and mice. Translation of current data to humans would imply that exposure of children to environments poor/rich of stimuli may have a notably large impact on dentate neurogenesis and, very likely, on hippocampus dependent memory functions.

Enabling Techniques and Algorithms for Integrated Communication and Navigation Satellite Systems

This thesis presents the outcomes of my Ph.D. course in telecommunications engineering. The focus of my research has been on Global Navigation Satellite Systems (GNSS) and in particular on the design of aiding schemes operating both at position and physical level and the evaluation of their feasibility and advantages. Assistance techniques at the position level are considered to enhance receiver availability in challenging scenarios where satellite visibility is limited. Novel positioning techniques relying on peer-to-peer interaction and exchange of information are thus introduced. More specifically two different techniques are proposed: the Pseudorange Sharing Algorithm (PSA), based on the exchange of GNSS data, that allows to obtain coarse positioning where the user has scarce satellite visibility, and the Hybrid approach, which also permits to improve the accuracy of the positioning solution. At the physical level, aiding schemes are investigated to improve the receiver’s ability to synchronize with satellite signals. An innovative code acquisition strategy for dual-band receivers, the Cross-Band Aiding (CBA) technique, is introduced to speed-up initial synchronization by exploiting the exchange of time references between the two bands. In addition vector configurations for code tracking are analyzed and their feedback generation process thoroughly investigated.

Small Molecules as Modulators of Different Targets Involved in Tumor Progression

Tumor is a lesion that may be formed by an abnormal growth of neoplastic cells. Many factors increase the risk of cancer and different targets are involved in tumor progression. Within this thesis, we have addressed two different biological targets, independently connected with tumor formation, e.g. Hsp90 and androgen receptor. The ATP-dependent chaperone Hsp90 is responsible for the conformational maturation and the renaturation of proteins. “Client” proteins are associated with the cancer hallmarks, as cell proliferation and tumor progression. Consequently, Hsp90 has evolved into promising anticancer target. Over the past decade, radicicol has been identified as potential anticancer agent targeting Hsp90, but it is not active in vivo. With that aim of obtaining radicicol-related derivatives, we developed the design and synthesis of new chalcones analogs. Chalcones, which are abundant in edible plants, own a diverse array of pharmacological activities and are considered a versatile scaffold for drug design. Antiproliferative assays and western blot analysis on the new compounds showed that some of those display an interesting cytotoxic effect and the ability to modulate Hsp90 client proteins expression. Androgen Receptor (AR) hypersensitivity plays crucial role in prostate cancer, which progression is stimulated by androgens. The therapy consists in a combination of surgical or chemical castration, along with antiandrogens treatment. Casodex® (bicalutamide), is the most widespread antiandrogen used in clinic. However, hormonal therapy is time-limited since many patients develop resistance. Commercially available antiandrogens show a common scaffold, e.g. two substituted aromatic rings linked by a linear or a cyclic spacer. With the aim of obtaining novel pure AR antagonists, we developed a new synthetic methodology, which allowed us to introduce, as linker between two suitably chosen aromatic rings, a triazole moiety. Preliminary data suggest that the herein reported new molecules generally decrease PSA expression, thus confirming their potential AR antagonistic activity.

Valutazione della psoriasi ungueale come fattore di rischio per lo sviluppo di artropatia psoriasica - studio pilota

Scopo della tesi è verificare se i pazienti affetti da psoriasi puramente ungueale sviluppano psoriasi artropatica e se esistono parametri clinici che possano permettere di predire lo sviluppo del danno articolare. Viene inoltre valutato l'impatto che la psoriasi ungueale, associata alla psoriasi artropatica, determina sulla qualità di vita dei nostri pazienti. L'artrite psoriasica è spesso associata a psoriasi ungueale, che è più frequente nei pazienti con artrite psoriasica rispetto ai pazienti con psoriasi cutanea. Vi è una stretta relazione funzionale tra l'unghia e l'articolazione interfalangea distale, i tendini e i legamenti: lo sviluppo di entesite della falange distale è infatti associato ad una infiammazione dell'apparato ungueale. Riportiamo i dati preliminari emersi dal nostro studio pilota, che conferma come siano necessari e doverosi ulteriori studi su popolazioni più ampie per determinare la relazione che sussiste fra psoriasi ungueale e psoriasi artropatica

Analisi dell’influenza dei moti rigidi di una trattrice agricola sulle vibrazioni a corpo intero trasmesse all’operatore

L’esposizione degli operatori in campo agricolo alle vibrazioni trasmesse al corpo intero, produce effetti dannosi alla salute nel breve e nel lungo termine. Le vibrazioni che si generano sulle trattrici agricole hanno una elevata intensità e una bassa frequenza. Le componenti orizzontali, amplificate dalla posizione elevata della postazione di guida dall’asse di rollio, presentano maggiori criticità per quanto riguarda i sistemi di smorzamento rispetto alle componenti verticali. Queste caratteristiche rendono difficoltosa la progettazione dei sistemi dedicati alla riduzione del livello vibrazionale per questa categoria di macchine agricole. Nonostante l’installazione di diversi sistemi di smorzamento, il livello di vibrazioni a cui è sottoposto l’operatore può superare, in diverse condizioni di impiego, i livelli massimi imposti dalla legge per la salvaguardia della salute. L’obiettivo di questo lavoro è quello di valutare l’influenza dei moti rigidi di una trattrice (beccheggio, rollio e saltellamento) dotata di sospensione assale anteriore, sospensione cabina e sospensione sedile, sul livello vibrazionale trasmesso all’operatore.E’ stata pertanto strumenta una trattrice con accelerometri e inclinometri installati su telaio, cabina e sedile e utilizzata in diverse condizioni di lavoro in campo e di trasporto su strada. Dall’analisi delle prove effettuate emerge che durante il trasporto su strada è predominante l’accelerazione longitudinale, a causa dell’elevata influenza del beccheggio. La sospensione riduce notevolmente il moto rigido di beccheggio mentre l’effetto della sospensione della cabina è quello di incrementare, in ogni condizione di lavoro, il livello di accelerazione trasmesso dal telaio della macchina.

Efficacia e complicanze durante la curva di apprendimento della Thulep: risultati a breve e medio termine delle prime 48 procedure

MATERIALI E METODI: Tra il 2012 e il 2013, abbiamo analizzato in uno studio prospettico i dati di 48 pazienti sottoposti a ThuLEP con approccio autodidatta. I pazienti sono stati rivalutati a 3, 6, 12 e 24 mesi con la valutazione del PSA, il residuo post-minzionale (RPM), l'uroflussometria (Qmax), l'ecografia transrettale e questionari validati (IPSS: international prostate symptom score e QoL: quality of life) RISULTATI: Il volume medio della prostata è di 63 ± 5,3 ml. Il tempo operatorio medio è stato di 127,58 ± 28.50 minuti. Il peso medio del tessuto asportato è stato di 30,40 ± 13,90 gr. A 6 mesi dopo l'intervento l'RPM medio è diminuito da 165,13 ± 80,15 ml a 7,78 ± 29.19 ml, mentre il Qmax medio è aumentato da 5.75 ± 1.67ml / s a 18.1 ± 5.27 ml / s. I valori medi dei IPSS e QoL hanno dimostrato un progressivo miglioramento: da 19.15 (IQR: 2-31) e 4 (IQR: 1-6) nel preoperatorio a 6.04 (IQR: 1-20) e 1.13 (IQR: 1-4), rispettivamente. Durante la curva di apprendimento si è assistito ad un progressivo aumento del peso del tessuto enucleato e ad una progressiva riduzione del tempo di ospedalizzazione e di cateterismo. Tra le principali complicanze ricordiamo un tasso di incontinenza transitoria del 12,5% a 3 mesi e del 2.1% a 12 mesi. CONCLUSIONI: ThuLEP rappresenta una tecnica chirurgica efficace, sicura e riproducibile indipendentemente dalle dimensioni della prostata. I nostri dati suggeriscono che la ThuLEP offre un miglioramento significativo dei parametri funzionali comparabili con le tecniche tradizionali, nonostante una lunga curva di apprendimento.

Influence of plant structure, cultural pratices and environmental conditions on the development of the bacterial canker of kiwifruits

Italy has a preeminent rank in kiwifruit industry, being the first exporter and the second largest producer after China. However, in the last years kiwifruit yields and the total cultivated area considerably decreased, due to the pandemic spread of the bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa). Several climatic conditions and cultural practices affect the development of the bacterial canker. This research work focused on the impact of agricultural practices and microclimate conditions on the incidence and epidemiology of Psa in the orchard. Therefore, the effect of fertilization, irrigation, use of bio-regulators, rootstock, training system and pruning were examined. The effect of different tunnel systems was analyzed as well, to study the plant-pathogen interaction. Considering the importance of insects as vectors in other pathosystems, the role of Metcalfa pruinosa in the spread of the bacterial canker was investigated in controlled conditions. In addition, quality and storage properties of fruits from infected plants were assessed. The study of all these aspects of the agronomic practices is useful to define a strategy to limit the bacterial diffusion in the orchard. Overall, excess nitrogen fertilization, water stress, stagnant water supplies, pruning before summer and the high number of Metcalfa pruinosa increased the Psa incidence. In contrast, tunnel covers may be useful for the control of the disease, with special attention to the kind of material.

Studi epidemiologici su Pseudomonas syringae pv.actinidiae agente causale del cancro batterico in actinidia

Il cancro batterico dell’actinidia causato da Pseudomonas syringae pv.actinidiae (Psa) suscita grande interesse a livello globale a partire dal 2008. La malattia è comparsa in Giappone e in due anni ha avuto una diffusione epidemica in tutte le aree di coltivazione mondiale di actinidia. Gravi perdite economiche hanno attirato l’attenzione internazionale su questa problematica e grandi sforzi sono stati rivolti allo studio di questo patosistema ancora poco conosciuto. E’ emerso infatti che il patogeno può rimanere in fase latente per lunghi periodi senza causare sintomi caratteristici nelle piante infette, e che dalla comparsa dei sintomi la pianta muore nell’arco di un paio d’anni. Il monitoraggio ed il controllo della situazione è perciò di fondamentale importanza ed è ancora più importante prevenire la comparsa di nuovi focolai di infezione. A questo proposito sarebbe opportuno l’impiego di materiale vegetale di propagazione non infetto, ma in molti casi questo diventa difficile, dal momento che il materiale impiegato è generalmente quello asintomatico, non analizzato precedentemente per la presenza del patogeno. Negli ultimi anni sono state perciò messe a punto molte tecniche molecolari per l’identificazione di Psa direttamente da materiale vegetale. L’obiettivo di questo lavoro è stato quello di studiare l’epidemiologia di Psa in piante adulte infette e di verificare l’efficacia di metodi di diagnosi precoce per prevenire la malattia. A tale scopo il lavoro sperimentale è stato suddiviso in diverse fasi: i) studio della localizzazione, traslocazione e sopravvivenza di Psa nelle piante, a seguito di inoculazione in piante adulte di actinidia di ceppi marcati Psa::gfp; ii) studio della capacità di Psa di essere mantenuto in germogli di actinidia attraverso sette generazioni di micropropagazione dopo l’inoculazione delle piante madri con lo stesso ceppo marcato Psa::gfp; iii) studio ed applicazioni di un nuovo metodo di diagnosi precoce di Psa basato sull’analisi molecolare del “pianto”.

Ultra-hypofractionated stereotactic radiotherapy for prostate cancer in 5 fractions: current evidences and our clinical experience

AIMS: The present is a retrospective evaluation of acute genito-urinary (GU) and gastro-intestinal (GI) toxicity, in addition to biochemical recurrence rate in 57 prostate cancer patients treated at our Institution with ultra-hypofractionated RT (UHRT) schedule. METHODS: From January 2021 to December 2022 we have treated 57 patients with prostate cancer, using an UHRT scheme of 5-fractions every other day for a total dose delivered of 36.25 Gy, according to the PACE-B trial treatment schedule. Good urinary function, assessed by International Prostate Symptom Score (IPSS), were required. The simulation CT scans were acquired in supine position and fused with MRI for CTVs definition for every patient. Each treatment was performed by Accuray's TomoTherapy with daily IGRT. The evaluation of the set-up was very restrictive before daily treatment delivery. RESULTS: According to RTOG toxicity scale, the acute GU toxicity at 3 months from RT, GU toxicity was G0 for 30 patients (52.6%), G1 for 26 (45.6%) and G2 for one only (1.75%); rectal toxicity was G0 for 56 patients (98.25%) and G1 for one only (1.75%). The median follow-up (FU) was 9 months (2-24 months). In the following FU months, we observed progressively lower urinary and rectal toxicity, except for one patient who showed G2 GU toxicity at 12 months. All but one patient had a progressive PSA value decrease. CONCLUSIONS: In our experience, UHRT appears to be safe and well tolerated even without the use of rectal spacer devices. A longer FU is necessary to evaluate late toxicity and disease control rate.

A prospective study on the early evaluation of response to androgen receptor-targeted agents with 11C-Choline, 68Ga-PSMA and 18F-FACBC PET in metastatic castration-resistant prostate cancer: a single center experience.

Background: The early identification of responsive and resistant patients to androgen-receptor targeting agents (ARTA) in metastatic castration resistant-prostate cancer (CRPC) is not completely possible with PSA assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, PET assessment might be a promising tool. Materials and methods: We performed a monocentric prospective study in patients with metastatic CRPC under treatment with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, 18F-FACBC or 68Ga-PSMA PET, one scan before therapy onset and one two months later. The primary aim was to investigate the performance of three different novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; with regards to this aim, the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical PFS (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809). Results: With regards to the primary endpoint, at univariate analysis a statistically significant correlation was found between MTV_VARIATION% (p=0.018) and TLA_VARIATION% (p=0.025) with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA PET MTV_TOT_PET1 (p=0.001), TLA_TOT_PET1 (p=0.025), MTV_VARIATION% (p=0.031). For OS, statistically significant correlations were found for: MAJ_SUV_MAX_PET1 with 11C-Choline PET (p=0.007); MTV_TOT_PET1 (p=0.004), MAJ_SUV_MAX_PET1 (p=0.029), SUVMAX_VARIATION% (p=0.04), MTV_VARIATION% (p=0.015), TLA_VARIATION% (p=0.03) with 68Ga-PSMA PET,; MTV_TOT_PET1 (p=0.011), TLA_TOT_PET1 (p=0.009), MAJ_SUV_MAX_PET1 (p=0.027), MTV_VARIATION% (p=0.048) with 18F-FACBC. Conclusions: Our prospective study highlighted that several 68Ga-PSMA and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS and a correlation with biochemical response, that could help to assess response to ARTA.