Idiopathic pulmonary fibrosis: evaluation of progression and prognosis after the ATS/ERS/JRS/ALAT statement 2011

Objectives The prediction of usual interstitial pneumonia (UIP) progression and prognosis by the a application of HRCT criteria pattern recommended by ATS/ERS/JALAT guidelines 2011 Materials and methods Two radiologists after assessing the baseline HRCT have distributed 70 patients affected by fibrotic idiopathic interstitial pneumonia (IIP) in three groups (UIP type= group 1, possible-UIP=group 2, inconsistence UIP=group 3) on the basis of 2011 guidelines. The different abnormalities (honeycombing, reticulation, ground-glass, bronchiectasis) were visually scored at baseline and during the follow-up (total HRCT 179). Overall CT score and fibrotic score (honeycombing plus reticulation) were calculated. The progression of the abnormalities and the correlation with mortality rate were assessed (Kaplan-Mayer survival estimates). Results The inter-observed agreement was substantial or almost perfect (k=0.73-0.85). Forty-four patients were classified into group 1, 13 into group 2 and 13 into group 3. After a mean follow-up of 1386 days (DS 915), the mortality rate was significantly greater in the group 1 (18 died) versus group 2 and 3 (1 died each). In the group 1 patients whom showed at baseline a honeycombing rate greater than 25%, fibrotic score greater than 30, overall CT score greater than 45 and bronchiectasis in more than 4 lobes obtained the better prognostic value and significantly predicted mortality risk. A significant increment of fibrotic score and honeycombing rate was demonstrated in the group 1 and 3 but not in the group 2. Honeycombing progression was quantified in 3 points/year for UIP type. Conclusion In our study HRCT criteria for UIP pattern on the basis of 2011 guidelines showed high accuracy in the risk stratification of patients with idiopathic pulmonary fibrosis (IPF)

Characterization and development of semiconductor dosimeters in personal dosimetry and environmental monitoring

Il presente programma di ricerca di dottorato è focalizzato sui rivelatori di radiazioni ionizzanti a semiconduttore: analisi e caratterizzazione di dispositivi elettronici di uso commerciale al fine di poterli impiegare come dosimetri, sia personali che ambientali, in ambito industriale ed ospedaliero. Per quanto riguarda il settore industriale, nel presente lavoro sarà considerato in particolare il monitoraggio continuo di rifiuti in modo da individuare l’eventuale presenza di attività sopra soglia prima dell’arrivo al portale. Nel campo ospedaliero, saranno considerate le esposizioni dei pazienti e del personale sanitario in sale operatorie, diagnostiche o di radioterapia. Oggetto del presente studio è la caratterizzazione della risposta di alcuni dispositivi elettronici a seguito di esposizione a raggi-X ed a raggi-γ. Tali misure sperimentali sono accompagnate da simulazioni con metodi numerici di tipo Monte Carlo. Sono inoltre stati studiati rivelatori a semiconduttore più sensibili, quali i fotomoltiplicatori al silicio (SiPM) per utilizzo in campi a basse dosi

Clinical trials: ruolo dell'imaging nella valutazione della risposta farmacologica

A fronte di numerosi trattamenti di ridotta efficacia o alta tossicità si rende necessario procedere ad una continua ricerca di nuovi farmaci in campo oncologico e non. Tale ricerca si articola in 4 fasi cliniche che hanno come obiettivo la valutazione della sicurezza ed efficacia del farmaco in oggetto. In tale contesto le tecniche di imaging svolgono un ruolo fondamentale nella valutazione oggettiva della risposta tramite il ricorso a criteri RECIST (Response Evaluation Criteria In Solid Tumors) Secondo le nuove linee guida RECIST i criteri di classificazione della risposta terapeutica durante il trattamento con nuovi farmaci in sperimentazione sono i seguenti: -Risposta Completa (RC): scomparsa di tutte le lesioni, target e non target, e normalizzazione dei livelli sierici dei markers tumorali, confermate a distanza di almeno quattro settimane; -Risposta Parziale (RP): diminuzione ≥30% della somma dei diametri maggiori delle lesioni target rispetto al valore iniziale e/o persistenza di almeno una lesione non target e/o persistenza di elevati livelli sierici dei markers tumorali, confermate a distanza di almeno quattro settimane; -Progressione di Malattia (PM): aumento ≥20% della somma dei diametri maggiori delle lesioni target rispetto al minimo valore osservato e/o progressione inequivocabile delle preesistenti lesioni non target e/o comparsa di una o più nuove lesioni; -Malattia Stabile (MS): condizione in cui la somma dei diametri maggiori delle lesioni target mostra una variazione inferiore a quella della RP e della PM, in assenza di lesioni di nuova insorgenza. Obiettivo di questa tesi è valutare il ruolo delle tecniche di imaging negli studi clinici oncologici e non tramite il censimento di tutti i clinical trials attuati presso la Divisione di Radiologia Diagnostica dell’Università di Pisa negli ultimi 3 anni. Tale censimento ha permesso di quantificare le ore uomo radiologiche che si ricavano dal n esami * (durata acquisizione + durata refertazione e misurazione delle lesioni + preparazione media es. CD o copie di pellicole + compilazione forms) e che nella nostra casistica corrisponde a 160 ore. Tale valore ci aiuta a quantizzare quanto il lavoro radiologico sia importante nella sperimentazione clinica dei nuovi farmaci, sia che lo studio arruoli i pazienti sia che si concluda senza aver reclutato soggetti nel nostro centro. Viene infine riportato un esempio di studio clinico, il CRAD001C2325 il cui obiettivo è valutare se Everolimus 10mg/die aggiunto al trattamento con Octreotide Depot prolunghi la sopravvivenza libera da malattia rispetto al trattamento con Octreotide da solo in pazienti con tumore carcinoide avanzato. In tale studio vengono mostrate le immagini del tumore eseguite con scansioni TC e misurate secondo i criteri di valutazione della risposta tumorale

The A2B adenosine receptor modulates the epithelial- mesenchymal transition through the balance of cAMP/PKA and MAPK/ERK pathway activation in human epithelial lung cells

The epithelial-mesenchymal transition (EMT) is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2Badenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1), which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin) and the mesenchymal one (Vimentin, N-cadherin), respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to affect different intracellular pathways could represent a mechanism at the basis of EMT maintenance/inhibition based on the extracellular microenvironment. Despite further investigations are needed, herein for the first time the A2BAR has been related to the EMT process, and therefore to the different EMT-related pathologies

RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells

A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC >2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC >2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predominant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells's growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC

Lung Ultrasound B-Lines in the Evaluation of the Extent of Interstitial Lung Disease in Systemic Sclerosis

Background: Chest computed tomography (CT) is the gold standard for the evaluation of systemic sclerosis-related interstitial lung disease (SSc-ILD). Lung ultrasound (LUS) is a radiation-free tool that identifies the B-lines as a main feature of ILD. We aimed to investigate the role of LUS in the evaluation of the extent of SSc-ILD. Methods: Adult SSc patients underwent pulmonary function tests (PFTs), LUS and CT. The CT images were qualitatively, semi-quantitatively (the Wells score on five levels and the categorical Goh et al. staging) and quantitatively (histogram-based densitometry) analysed for ILD. LUS quantified B-lines in 21 intercostal spaces on both the anterior and posterior chest wall. Results: Out of the 77 SSc patients eligible for the study, 35 presented with ILD on CT (21 limited, 14 extensive). Total B-lines significantly differentiated ILD vs. no ILD (median 24 vs. 8, p < 0.001). Posterior and total B-lines significantly differentiated limited from absent ILD, while anterior B-lines distinguished extensive from limited ILD. Total B-lines correlated with the Wells score (r = 0.446, p < 0.001) and MLA (r = -0.571, p < 0.001); similar results were confirmed when anterior and posterior B-lines were analysed separately. Conclusions: LUS is a useful tool to identify SSc-ILD and to correlate with different evaluations of ILD extent and severity

Association between CYP2E1 polymorphisms and risk of differentiated thyroid carcinoma

Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard's reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N = 350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95 % confidence interval (CI) 1.03-1.48) and 1.56 (95 % CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process

The use of chest magnetic resonance imaging in interstitial lung disease: a systematic review

Thin-slices multi-detector computed tomography (MDCT) plays a key role in the differential diagnosis of interstitial lung disease (ILD). However, thin-slices MDCT has a limited ability to detect active inflammation, which is an important target of newly developed ILD drug therapy. Magnetic resonance imaging (MRI), thanks to its multi-parameter capability, provides better tissue characterisation than thin-slices MDCT.Our aim was to summarise the current status of MRI applications in ILD and to propose an ILD-MRI protocol. A systematic literature search was conducted for relevant studies on chest MRI in patients with ILD.We retrieved 1246 papers of which 55 original papers were selected for the review. We identified 24 studies comparing image quality of thin-slices MDCT and MRI using several MRI sequences. These studies described new MRI sequences to assess ILD parenchymal abnormalities, such as honeycombing, reticulation and ground-glass opacity. Thin-slices MDCT remains superior to MRI for morphological imaging. However, recent studies with ultra-short echo-time MRI showed image quality comparable to thin-slices MDCT. Several studies demonstrated the added value of chest MRI by using functional imaging, especially to detect and quantify inflammatory changes.We concluded that chest MRI could play a role in ILD patients to differentiate inflammatory and fibrotic changes and to assess efficacy of new ILD drugs

Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk

A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10 â '47). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability

Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist

Objectives: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). Methods: The writing committee selected the HRCT criteria\ue2\u80\u94the Delphi items\ue2\u80\u94for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as \ue2\u80\u9cessential\ue2\u80\u9d, \ue2\u80\u9coptional\ue2\u80\u9d, or \ue2\u80\u9cnot relevant\ue2\u80\u9d. The items rated \ue2\u80\u9cessential\ue2\u80\u9d by < 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. Results: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated \ue2\u80\u9cessential\ue2\u80\u9d by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated \ue2\u80\u9cessential\ue2\u80\u9d by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. Conclusions: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists