Tumori primitivi multipli del polmone. Profilo clinico e biologico in pazienti affetti da neoplasie polmonari multiple. Analisi di elementi clinici e marcatori biologici come possibili fattori di differenziazione dei tumori polmonari multipli

Background: MPLC represents a diagnostic challenge. Topic of the discussion is how to distinguish these patients as a metastatic or a multifocal disease. While in case of the different histology there are less doubt on the opposite in case of same histology is mandatory to investigate on other clinical features to rule out this question. Matherials and Methods: A retrospective review identified all patients treated surgically for a presumed diagnosis of SPLC. Pre-operative staging was obtained with Total CT scan and fluoro-deoxy positron emission tomography and mediastinoscopy. Patients with nodes interest or extra-thoracic location were excluded from this study. Epidermal growth factor receptor (EGFR) expression with complete immunohistochemical analisis was evaluated. Survival was estimated using Kaplan-Meyer method, and clinical features were estimated using a long-rank test or Cox proportional hazards model for categorical and continuous variable, respectively. Results: According to American College Chest Physician, 18 patients underwent to surgical resection for a diagnosis of MPLC. Of these, 8 patients had 3 or more nodules while 10 patients had less than 3 nodules. Pathologic examination demonstrated that 13/18(70%) of patients with multiple histological types was Adenocarcinoma, 2/18(10%) Squamous carcinoma, 2/18(10%) large cell carcinoma and 1/18(5%) Adenosquamosu carcinoma. Expression of EGFR has been evaluated in all nodules: in 7 patients of 18 (38%) the percentage of expression of each nodule resulted different. Conclusions: MPLC represent a multifocal disease where interactions of clinical informations with biological studies reinforce the diagnosis. EGFR could contribute to differentiate the nodules. However, further researches are necessary to validate this hypothesis.

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.

Tumor burden as assessed by 18 F FDG PET scan as predictive biomarker for immune checkpoint blockers in advanced NSCLC - a multi centric study

Introduction Only a proportion of patients with advanced NSCLC benefit from Immune checkpoint blockers (ICBs). No biomarker is validated to choose between ICBs monotherapy or in combination with chemotherapy (Chemo-ICB) when PD-L1 expression is above 50%. The aim of the present study is to validate the biomarker validity of total Metabolic Tumor Volume (tMTV) as assessed by 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography ([18F]FDG-PET) Material and methods This is a multicentric retrospective study. Patients with advanced NSCLC treated with ICBs, chemotherapy plus ICBs and chemotherapy were enrolled in 12 institutions from 4 countries. Inclusion criteria was a positive PET scan performed within 42 days from treatment start. TMTV was analyzed at each center based on a 42% SUVmax threshold. High tMTV was defined ad tMTV>median Results 493 patients were included, 163 treated with ICBs alone, 236 with chemo-ICBs and 94 with CT. No correlation was found between PD-L1 expression and tMTV. Median PFS for patients with high tMTV (100.1 cm3) was 3.26 months (95% CI 1.94–6.38) vs 14.70 (95% CI 11.51–22.59) for those with low tMTV (p=0.0005). Similarly median OS for pts with high tMTV was 11.4 months (95% CI 8.42 – 19.1) vs 33.1 months for those with low tMTV (95% CI 22.59 – NA), p .00067. In chemo-ICBs treated patients no correlation was found for OS (p = 0.11) and a borderline correlation was found for PFS (p=0.059). Patients with high tMTV and PD-L1 ≥ 50% had a better PFS when treated with combination of chemotherapy and ICBs respect to ICBs alone, with 3.26 months (95% CI 1.94 – 5.79) for ICBs vs 11.94 (95% CI 5.75 – NA) for Chemo ICBs (p = 0.043). Conclusion tMTV is predictive of ICBs benefit, not to CT benefit. tMTV can help to select the best upfront strategy in patients with high tMTV.

Toxicological effects related to a novel heated tobacco product

The tobacco epidemic is a public health burden. Nicotine-Delivery-Systems(NDS) are devices designed to help people replace conventional cigarette(CC) and among these devices we find electronic cigarettes(e-cig), which are classified as Electronic-NDS(ENDS). E-cigs use different technologies to vaporize a liquid or to heat the tobacco avoiding the combustion phenomenon(IQOS). The US Food and Drug Administration(FDA) has labelled IQOS as modified risk tobacco products(MRTPs), indirectly encouraging the perception of safety in the consumers, but IQOS smoke, although to a lesser extent than conventional, still presents a great deal of harmful or potentially harmful compounds. My PhD thesis aims to study the toxic effects related to IQOS exposure. I sought to answer the question of whether the toxic compounds released by IQOS, albeit in reduced concentrations, could lead to genotoxicity and damage to the airways and liver in vivo. At the University of Nottingham, I have investigated in vitro the effects generated by the IQOS, e-cigs and CC exposure on PBMCs and human lung epithelial cell line. Finally, at University of Milano–Bicocca, I have developed a in vivo Positron Emission computed Tomography(PET) imaging procedure meant to be applied to the monitoring of ENDS toxicity, particularly in the brain. These results indicate that IQOS is not a low-risk product in vivo, for primary target organs but also for secondary organs, although we have observed a small impact in vitro. Labelling as MRTP may mislead consumers who interpret “a lower level of toxic compounds” as an indication of “harmlessness” when there is a health risk for users. In the last part, I set up a methodology for studying temporal fluctuations of regional brain metabolism and connectivity derived from mice of different ages allowing researchers to obtain normative values in investigations of the efficacy or toxicity of substances at the functional level of the CNS.

Combining molecular alterations and functional imaging in metastatic castration resistant prostate cancer treated with taxanes

The treatment of metastatic castration-resistant prostate cancer (mCRPC) is currently characterized by several drugs with different mechanisms of action, such as new generation hormonal agents (abiraterone, enzalutamide), chemotherapy (docetaxel, cabazitaxel), PARP inhibitors (olaparib) and radiometabolic therapies (radium-223, LuPSMA). There is an urgent need to identify biomarkers to guide personalized therapy in mCRPC. In recent years, the status of androgen receptor (AR) gene detected in liquid biopsy has been associated with outcomes in patients treated with abiraterone or enzalutamide. More recently, plasma tumor DNA (ptDNA) and its changes during treatment have been identified as early indicators of response to anticancer treatments. Recent works also suggested a potential role of tumor-related metabolic parameters of 18Fluoro-Choline Positron Emission Tomography (F18CH-PET)-computed tomography (CT) as a prognostic tool in mCRCP. Other clinical features, such as the presence of visceral metastases, have been correlated with outcome in mCRPC patients. Recent studies conducted by our research group have designed and validated a prognostic model based on the combination of molecular characteristics (ptDNA levels), metabolic features found in basal FCH PET scans (metabolic tumor volume values, MTV), clinical parameters (absence or presence of visceral metastases), and laboratory tests (serum lactate dehydrogenase levels, LDH). Within this PhD project, 30 patients affected by mCRPC, pre-treated with abiraterone or enzalutamide, candidate for taxane-based treatments (docetaxel or cabazitaxel), have been prospectively evaluated. The prognostic model previously described was applied to this population, to interrogate its prognostic power in a more advanced cohort of patients, resulting in a further external validation of the tool.

Multiwavelenght study of cluster mergers and consequences for the radio emission properties of galaxy clusters

In the present thesis a thourough multiwavelength analysis of a number of galaxy clusters known to be experiencing a merger event is presented. The bulk of the thesis consists in the analysis of deep radio observations of six merging clusters, which host extended radio emission on the cluster scale. A composite optical and X–ray analysis is performed in order to obtain a detailed and comprehensive picture of the cluster dynamics and possibly derive hints about the properties of the ongoing merger, such as the involved mass ratio, geometry and time scale. The combination of the high quality radio, optical and X–ray data allows us to investigate the implications of the ongoing merger for the cluster radio properties, focusing on the phenomenon of cluster scale diffuse radio sources, known as radio halos and relics. A total number of six merging clusters was selected for the present study: A3562, A697, A209, A521, RXCJ 1314.4–2515 and RXCJ 2003.5–2323. All of them were known, or suspected, to possess extended radio emission on the cluster scale, in the form of a radio halo and/or a relic. High sensitivity radio observations were carried out for all clusters using the Giant Metrewave Radio Telescope (GMRT) at low frequency (i.e. ≤ 610 MHz), in order to test the presence of a diffuse radio source and/or analyse in detail the properties of the hosted extended radio emission. For three clusters, the GMRT information was combined with higher frequency data from Very Large Array (VLA) observations. A re–analysis of the optical and X–ray data available in the public archives was carried out for all sources. Propriety deep XMM–Newton and Chandra observations were used to investigate the merger dynamics in A3562. Thanks to our multiwavelength analysis, we were able to confirm the existence of a radio halo and/or a relic in all clusters, and to connect their properties and origin to the reconstructed merging scenario for most of the investigated cases. • The existence of a small size and low power radio halo in A3562 was successfully explained in the theoretical framework of the particle re–acceleration model for the origin of radio halos, which invokes the re–acceleration of pre–existing relativistic electrons in the intracluster medium by merger–driven turbulence. • A giant radio halo was found in the massive galaxy cluster A209, which has likely undergone a past major merger and is currently experiencing a new merging process in a direction roughly orthogonal to the old merger axis. A giant radio halo was also detected in A697, whose optical and X–ray properties may be suggestive of a strong merger event along the line of sight. Given the cluster mass and the kind of merger, the existence of a giant radio halo in both clusters is expected in the framework of the re–acceleration scenario. • A radio relic was detected at the outskirts of A521, a highly dynamically disturbed cluster which is accreting a number of small mass concentrations. A possible explanation for its origin requires the presence of a merger–driven shock front at the location of the source. The spectral properties of the relic may support such interpretation and require a Mach number M < ∼ 3 for the shock. • The galaxy cluster RXCJ 1314.4–2515 is exceptional and unique in hosting two peripheral relic sources, extending on the Mpc scale, and a central small size radio halo. The existence of these sources requires the presence of an ongoing energetic merger. Our combined optical and X–ray investigation suggests that a strong merging process between two or more massive subclumps may be ongoing in this cluster. Thanks to forthcoming optical and X–ray observations, we will reconstruct in detail the merger dynamics and derive its energetics, to be related to the energy necessary for the particle re–acceleration in this cluster. • Finally, RXCJ 2003.5–2323 was found to possess a giant radio halo. This source is among the largest, most powerful and most distant (z=0.317) halos imaged so far. Unlike other radio halos, it shows a very peculiar morphology with bright clumps and filaments of emission, whose origin might be related to the relatively high redshift of the hosting cluster. Although very little optical and X–ray information is available about the cluster dynamical stage, the results of our optical analysis suggest the presence of two massive substructures which may be interacting with the cluster. Forthcoming observations in the optical and X–ray bands will allow us to confirm the expected high merging activity in this cluster. Throughout the present thesis a cosmology with H0 = 70 km s−1 Mpc−1, m=0.3 and =0.7 is assumed.