57 research outputs found
A Journey through the Multifaceted Landscape of Prostate Cancer: from Bench to Bedside Studies
No full textIntroduzione
Il tumore alla prostata è una delle cause oncologiche più frequenti di decesso nell'uomo nel mondo. La prognosi è tuttavia strettamente collegata dallo stadio di malattia.
L'immunoterapia ha fallito in questo tumore, che è considerato un tumore freddo in quanto caratterizzato da un elevato numero di linfociti T regolatori e cellule mieloidi soppressive che promuovono un ambiente immunosoppressivo. La fase metastatica sensibile a castrazione è caratterizzata da un estremo range di andamenti clinici e una volta in progressione verso la resistenza a castrazione, è caratterizzata da una prognosi infausta.
Scopo del lavoro e Metodi
La presente tesi consta di 3 lavori.
Il primo è uno studio traslazionale incentrato sulla rappresentazione della risposta immunitaria sistemica nel tumore alla prostata in stadio precoce, in pazienti candidati a prostatectomia. L'obiettivo è indagare le popolazioni di cellule immunitarie coinvolte e analizzare se esistono differenze nelle diverse classi di rischio. Pertanto, sono stati raccolti campioni di sangue e di tumore di pazienti sottoposti a chirurgia curativa e analizzati rispettivamente con FACS e in patologia.
La seconda parte è il disegno di uno studio clinico in pazienti con tumore prostatico metastatico ormono-sensibile, che prevede un approccio innovativo caratterizzato dal trattamento con terapia di deprivazione androgenica, darolutamide +/- un agente senolitico (S64315). L’obiettivo è studiare se la riduzione della senescenza, mediante questa strategia, possa ritardare l'insorgenza della fase di resistenza a castrazione e quindi migliorare la prognosi.
Il terzo è un lavoro clinico retrospettivo, monocentrico, volto a studiare l’outcome della presenza di mutazioni dei geni oncosoppressori TP53, PTEN e RB1, identificate mediante sequenziamento (NGS) in pazienti affetti da tumore prostatico avanzato ormono-sensibile.
Risultati
Nei 79 pazienti arruolati nello studio traslazionale. Tra questi abbiamo osservato livelli relativamente elevati di cellule CD11b+CD33+ circolanti e questa tendenza era significativamente più rappresentato nei pazienti con tumore ad alto rischio (p=0,018). Questo potrebbe suggerire come anche in tumori indolenti e in fase precoce, le cellule mieloidi immature siano implicate. Contrariamente, l'analisi dell'infiltrato peri-tumorale nei campioni tumorali non ha mostrato alcuna variazione tra le diverse classi di rischio.
Abbiamo arruolato 158 pazienti nello studio clinico retrospettivo. I pazienti che non presentavano alcuna alterazione dei tre geni soppressori tumorali presentavano una sopravvivenza libera da progressione (HR 0,58, p=0,012) e una sopravvivenza globale (HR 0,48, p=0,025) significativamente più lunghe. Inoltre, integrando lo stato mutazionale dei tre geni target con i noti fattori prognostici clinici (criteri CHAARTED), si è ottenuta una maggiore discriminazione prognostica e predittiva in questo stadio, creando tre classi che presentano una prognosi significativamente differente.
Conclusioni
I risultati evidenziano la complessità di questo tumore, e mostrano la presenza di una risposta immunitaria sistemica già nella malattia localizzata. Abbiamo inoltre rinforzato l'impatto prognostico sfavorevole delle alterazioni a carico geni oncosoppressori nella malattia avanzata ormono-sensibile. Ulteriori studi sono necessari per validare l’impatto di questi risultati.Background
Prostate cancer (PCa) is one of the main causes of death from cancer in men worldwide, however, the prognosis is mainly influenced by the stage. Immunotherapy has failed in PCa, which is considered a cold tumor as it is characterized by a high amount of regulatory T lymphocytes (T-reg) and myeloid-derived suppressor cells (MDSCs) that turn off the anti-tumor immune response and sustain tumor progression. Metastatic hormone-sensitive prostate cancer (mHSPC) presents a wide range of clinical outcomes, and once progressing to the castration-resistant (CR) phase, it is characterized by a poor prognosis.
Aim of the work and methods
This thesis consists of 3 works.
The first is a translational study focused on depicting the systemic immune response in localized PCa, in patients candidates for radical prostatectomy. The aim is to investigate the immune cell populations involved in this stage and analyze whether there are differences among different risk classes of tumors. Therefore, blood and tumor samples from patients undergoing curative surgery were collected and analyzed with flow cytometry assay and in pathology, respectively.
The second part is the design of a clinical trial for mHSPC patients, involving an innovative approach characterized by treatment with a senolytic agent (S64315) in addition to standard of care therapy, to study whether the reduction of tumoral senescent cells can delay the onset of the CR phase and thus improve prognosis.
The third is a retrospective, single-center clinical study investigating the impact of tumor suppressor gene (TSG) alterations, specifically in TP53, PTEN, and RB1, identified through next-generation sequencing (NGS), on progression-free survival (PFS) and overall survival (OS) in patients with mHSPC.
Results
We enrolled 79 patients in the translational study. We observed a relatively high amount of circulating CD11b+CD33+ cells in PCa patients. Furthermore, patients with high-risk diseases exhibited an even greater expansion of CD11b+CD33+ cells and a broader increase in the immature myeloid compartment, suggesting that systemic immunosuppression may escalate in parallel with tumor aggressiveness. Differently, the analysis of the peri-tumoral infiltrate in the tumoral specimens did not show any variation among the different risk classes.
We enrolled 158 patients in the retrospective clinical trial. Patients who did not present any alteration of the three TSG presented a significantly longer PFS (HR 0.58, p=0.012) and OS (HR 0.48, p=0.025). Moreover, integrating the AVPC-TSG status with the known clinical prognostic factors CHAARTED criteria, the results were an enhanced prognostic and predictive discrimination in mHSPC, creating three classes that present significantly different PFS.
Conclusions
The results highlight the complexity of this disease, where the presence of a systemic immune response is revealed since the early stages. The unfavourable prognostic impact of TSG alteration in mHSPC has been clarified. Further analyses are needed to reinforce the impact of these evaluations
Feasibility of multiple immunoexpression assay for immune tumor micrornvironment (I-TME) on matched metastatic and primary renal cell carcinoma (RCC) for patient prognostication and predictiveness to immunotherapy (preliminary analyses of the Meet URO 18 study).
No full textBackground: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to >400 spots (mean 240; >400 in 7 samples) and intratumoral T/CD4 cells from 4 to >400 spots (mean 168; >400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to >400 spots (mean 175, >400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (<20% variability of single immuno-test) whereas the remaining 9 patients showed significant differences as percentage of immuno-tissue expression in at least one of the 5 immuno-indicators (T/CD8-CD4, C15, CD68, CD56, phmTOR). The remaining 8 samples of patients without matched analyses were used to test the feasibility of multiple analyses; among all antibodies exclusion of the CD20 and FOXP-3 final evaluation was needed, due to technical standardization. According to the 5 immuno-indicators, double-triple positive or penta-positive TME indicators may be identified and graded. Conclusions: Providing multiple immunoexpression platforms on a single specimen may be used as routine workflow. Profiling I-TME, especially CD56, CD15 on TCs and CD68 cells and phmTOR, deserves investigation with extensive control groups. A validation cohort will be tested at tissue level and in correlation with peripheral blood markers
Prognostic model for advanced breast carcinoma with luminal subtype and impact of hormonal maintenance: Implications for post-progression and conditional survival
No full textThe aim of this analysis was to develop and validate a prognostic model for advanced breast cancer (ABC) with luminal subtype based on the combination of clinical, pathological and therapeutic predictors to provide a practical tool to evaluate patients' prognosis
Bank liquidation in the European Union: clarification needed. Bruegel Policy Contribution Issue n˚01 | January 2018
No full textCritical functions and public interest. What role do they play in Member States’ decision to grant liquidation aid? The author of this paper looks at how resolution and liquidation differ substantially when it comes to the scope of legislation applicable to the use of public funds and how the diversity in national insolvency regimes is a source of uncertainty about the outcome of liquidation procedures
Bank liquidation in the European Union: Clarification needed
No full textUnder the current European Union frameworks for dealing with banking problems, resolution of banks is seen as an exception to be activated only if liquidation under national insolvency proceedings would not be warranted. This is most notably the case when the bank provides critical functions to the economy, or when its liquidation might threaten financial stability. The two options - resolution and liquidation - differ substantially when it comes to the scope of legislation that is applicable to the use of public funds. The EU Bank Recovery and Resolution Directive (2014/59/EU) covers resolution, while liquidation is regulated by national insolvency laws. The liquidations of Veneto Banca and Banca Popolare di Vicenza in Italy highlight how this two-tier framework raises important questions in the context of EU banking union. The first question is whether the definitions of critical functions and public interest - key elements in the context of liquidation - should be clarified. A second question is whether the current legal and regulatory situation within banking union ensures that similar banks can expect predictable equal treatment in case of failure. The author argues that there should be more clarity over the role that the concepts of critical functions and public interest play in Member States' decision to grant liquidation aid, as the current framework might give rise to situations in which the views of national authorities seem to contradict the Single Resolution Board's assessment. While the purpose of this Policy Contribution is not to provide a comprehensive overview of different national insolvency regimes, the author argues that the current diversity is a source of uncertainty about the outcome of liquidation procedures, for all participants. For banking union to function effectively, the framework should be changed to provide the same level of certainty in liquidation as there is expected to be in resolution
L'Emigrazione cinese e gli immigrati dallo Zhejiang meridionale a Sassari
No full textThis work aims to analyze, firstly, the Chinese migrations from a more complex view with the purpose of finding the causes of these movements; secondly, it focalizes on the common factors that guide the behavior of overseas Chinese in the different countries; thirdly, it studies the peculiarities of southern Zhejiang, as the main source of Chinese immigrants in Sassari. The author tries to identify, from a national perspective to a local perspective, the factors that influence the integration of Chinese immigrants originating from southern Zhejiang in the local society. Finally, the linguistic-cultural mediation is proposed as a practical tool that, at the collective level, will improve the mutual recognition and at the individual level, will facilitate the access of Chinese users to public services to improve their adaptability
Strengthening the Evidence-Based Approach to Guiding Effective Influenza Vaccination Policies
No full textThe availability of several effective and safe vaccines enables health systems to counteract annual influenza epidemics. However, the criteria of appropriateness and sustainability require that each citizen should receive the right vaccine. The value of each vaccine can be assessed within well-known frameworks, such as the Health Technology Assessment (HTA), a step that is fundamental to the process of allocating resources to vaccination strategies. The paper describes how HTA has been incorporated as an evidence-based tool to support the definition of Italian vaccination strategies, reports the results of the HTA report on the most recently available influenza vaccine in Italy (cell-based quadrivalent vaccine (QIVc)-Flucelvax® Tetra) and elaborates on current and future recommendations in the field of influenza vaccination. Recommendations issued by the Italian Ministry of Health foster the appropriate use of influenza vaccines from 2018-2019 onwards. Evidence of the value of newly available vaccines will hopefully support future decisions and promote the appropriate use of these vaccines on the basis of the characteristics of the target population. However, the success of influenza vaccination will also depend on citizens' empowerment and engagement in the decision-making process
Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage ‘pure’ and ‘mixed’ lobular breast cancer
No full textDisease-Free Survival (DFS) [Panel A and C] and Overall Survival (OS) [Panel B and D], according to dichotomized Ki67 [Cut-off 6 %: Panel A-B; Cut-off 21 % Panel C-D] for patients with invasive lobular carcinoma (ILC); p-value: log-rank analysis. (TIFF 5811 kb
Alle origini della cooperazione europea fra organizzazioni di studi latinoamericani
No full textL’espansione degli studi sull’America Latina in Europa, avutasi soprattutto negli ultimi decenni e nel campo delle scienze sociali, fornisce all’Autore l'occasione per riproporre la questione del modo in cui l’Università decide «politicamente» e opera «socialmente» superando il puro ambito di organizzazione della singola ricerca e di comunicazione del suoi risultati. L’Autore tenta di aprire un dibattito tendente a individuare «motori» europei di coordinamento e informazione, secondo uno schema pluridimensionale «a continuum», capace pure di elaborare proprie specializzazioni professionali funzionali, in un rapporto biunivoco con l’America Latina e sottolineando la funzione delle associazioni e delle organizzazioni più che il ruolo dei singoli ricercatori e studiosi.La expansión de los estudios sobre América Latina en Europa ha alcanzado especial relieve en los últimos decenios y en al área de las ciencias sociales. El análisis de tal expansión conduce al Autor a replantearse el modo en que la universidad decide «políticamante» y opera «socialmente» superando el ámbito de la organización de cada investigación y al de la comunicación de sus resultados. El Autor trata de abrir una discusión que tiende a individualizar «motores» europeos de coordinación e información, según un esquema pluridimensional «a continuum», capaz de elaborar incluso sus propias especializaciones profesionales funcionales, en una relación biunívoca con América Latina y haciendo hincapié en la función de las asociaciones y organizaciones en lugar de la función de los investigadores y estudiosos individuales.The increasing number of European studies on Latin America, particularly in the last few decades and in the field of social science, is the starting point for the Author to discuss the issue of how the University comes to take "political" decisions and to operate socially well over the mere organization of research work and the communica-tion of its results. The Author tries to start a debate in order to single out some European "propelling centres" of coordination and information in a multidimensional "continuum-type" scheme, also capable to elaborate professional functional specialization of its own in biunivocal relation with Latin America and emphasizing the function of associations and organizations rather than the role of individual researchers and scholars
L'Emigrazione cinese e gli immigrati dallo Zhejiang meridionale a Sassari
No full textThis work aims to analyze, firstly, the Chinese migrations from a more complex view with the purpose of finding the causes of these movements; secondly, it focalizes on the common factors that guide the behavior of overseas Chinese in the different countries; thirdly, it studies the peculiarities of southern Zhejiang, as the main source of Chinese immigrants in Sassari. The author tries to identify, from a national perspective to a local perspective, the factors that influence the integration of Chinese immigrants originating from southern Zhejiang in the local society. Finally, the linguistic-cultural mediation is proposed as a practical tool that, at the collective level, will improve the mutual recognition and at the individual level, will facilitate the access of Chinese users to public services to improve their adaptability
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