Innovatività e sostenibilità della ricerca e dello sviluppo dei farmaci per il trattamento delle malattie rare: un'analisi comparata.

La tesi esamina i profili giuridici inerenti alla ricerca e allo sviluppo dei farmaci orfani, con particolare enfasi sulla determinazione del prezzo. Analizza il sistema giuridico degli Stati Uniti, con particolare riferimento all’Orphan Drug Act, confrontandolo con il regolamento europeo (CE) n. 141/2000. Successivamente, vengono esaminati i meccanismi di definizione del prezzo negli Stati Uniti e in Italia, evidenziando le dinamiche di mercato e i criteri di valutazione costo-efficacia, mettendo a confronto gli effetti prodotti dalle normative federali e europee sui sistemi sanitari dei due Paesi.The thesis examines the legal profiles associated with the research and development of orphan medicinal products, with a focus on pricing. It analyses the US legal system with particular reference to the Orphan Drug Act and compares it with the European Regulation (EC) No 141/2000. It then examines the pricing mechanisms in the United States and Italy, highlighting the market dynamics and the criteria for evaluating cost-effectiveness and comparing the impact of federal and European regulations on the healthcare systems of the two countries

The multiple facets of ovarian high grade serous carcinoma: A review on morphological, immunohistochemical and molecular features

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive subtype of epithelial ovarian cancer and a leading cause of mortality among gynecologic malignancies. This review aims to comprehensively analyze the morphological, immunohistochemical, and molecular features of HGSOC, highlighting its pathogenesis and identifying biomarkers with diagnostic, prognostic, and therapeutic significance. Special emphasis is placed on the role of tumor microenvironment (TME) and genomic instability in shaping the tumor's behavior and therapeutic vulnerabilities. Key advancements, such as the identification of TP53 and BRCA mutations, the classification of homologous recombination repair (HRR) deficiencies, and the clinical implications of biomarkers like folate receptor alpha (FRα) and PD-L1 are discussed. These findings reveal actionable insights into targeted therapies, including immune checkpoint inhibitors and PARP inhibitors, which hold promise for improving outcomes in HGSOC. This synthesis of knowledge aims to bridge gaps in understanding HGSOC's multifaceted biology, enhance clinical decision-making, and foster the development of precision therapies

Age-Related Variations in Clinical, Histological, and Genetic Characteristics in Multiple and Familial Melanomas: A Study of 333 Patients

Background/Objectives: Melanoma is an aggressive cutaneous malignancy with a rising incidence. While most cases are sporadic, 5–10% are hereditary, especially in patients with multiple or familial melanomas. The aim of this study is to explore the epidemiological, clinical, histological, and genetic features of this class of patients to identify risk factors for better management and surveillance. Methods: Between 2021 and 2024, patients with multiple melanomas or a familial history of melanoma were recruited. Collected data included demographic, clinic-pathologic features, and genetic analyses. Results: Patients >60 years had a higher prevalence of multiple melanomas (>50%, p = 0.0002), while familial melanoma was more common in those <40 years (54.3%). UV exposure increased with age, while sunscreen use decreased (p = 0.0004). Younger patients showed the highest nevi counts (mean: 139.6) and density (p < 0.0001). Dermatologists more frequently detected subsequent melanomas in older patients (>60 years) (p = 0.001). Genetic testing and melanoma subtypes showed no significant age-related differences. Conclusions: melanoma can develop at any age, and early detection through regular screening is crucial. Older patients (>60 years) have a higher prevalence of multiple melanomas, influenced by UV exposure and genetics. Indeed, in our cohort, a history of sun exposure, sunburns, and tanning bed use emerged as key risk factors, particularly among older individuals. Genetic testing showed a 4.3% rate of pathogenic/likely pathogenic variants, mainly in CDKN2A. Family history and nevus burden are significant risk factors, highlighting the need for targeted surveillance in high-risk populations

Immunophenotype of uterine tumor resembling ovarian sex cord tumor (UTROSCT): Case series and meta-analysis of the literature

Objectives: This study aimed to define the frequency of positivity of several immunohistochemical markers in uterine tumor resembling ovarian sex cord tumor (UTROSCT). Methods: All consecutive UTROSCT cases were retrieved from consultation files of one of the authors. Histological and immunohistochemical slides were reviewed. In addition, three electronic databases were searched from their inception to January 2024 for all studies assessing the immunophenotype of UTROSCT. Exclusion criteria were: sample size < 10 patients, overlapping patient data, reviews. Endometrial stromal tumors with sex cord-like areas (formerly called "type I UTROSCT") were excluded. Immunohistochemical markers assessed in >= 10 cases in at least 3 different series were included. For each marker, pooled positivity rate was calculated by using a random effect model; mean labeling index was calculated for Ki67. Results: Thirty UTROSCT cases were retrieved Six studies were included, and 30 new cases were obtained, with a total of 181 UTROSCTs. Fourteen immunohistochemical markers were assessed. Pooled positivity rates were (in descending order): CD56 = 97 %, progesterone receptor = 91 %, estrogen receptor = 85.5 %, WT1 = 84 %, widespectrum cytokeratins = 78.7 %, CD99 = 77 %, desmin = 74.5 %, calretinin = 70.6 %, smooth muscle actin = 56.4 %, inhibin = 44.5 %, CD10 = 41 %, caldesmon = 21.9 %, Melan-A/MART-1 = 10.4 %. Mean Ki67 labeling index was 8.7 %. Conclusions: Immunophenotypically, UTROSCT is less consistent than ovarian sex cord tumors and overlaps with other mesenchymal and epithelial tumors; an integrated clinico-pathological and immunohistochemical evaluation appears necessary for a correct diagnosis

Exploring Torque Teno Virus-Host Immune Interactions

Background: Torque Teno Virus (TTV) is a ubiquitous component of human virome, not associated with any disease. TTV ability to establish persistent replication without overt clinical symptoms suggests a complex interaction with the host immune system. Aims & Objectives: As its load increases when the immune system is compromised, such as in kidney transplant (KT) recipients, TTV load monitoring has been proposed as a method to assess immunosuppression. Simultaneously to investigate the interaction between TTV and host immune responses in the context of cytokine production may help to understand complex interaction with the host immune system. Methodology: In this prospective study, TTV load was measured in plasma and urine samples from 42 KT recipients, immediately before KT and in the first 150 days after it. Furthermore, respiratory samples were also collected from 97 patients with respiratory changes caused by viruses to see the trend of TTV viral load and compare it with the cytokine expression also to see the trend across different age demographics. Results: Data obtained suggest that TTV could be a relevant marker for evaluating immune status and could be used as a guide to predict the onset of infectious complications in the follow-up of KT recipients. Nevertheless, the study on cytokine profiling showed a significant positive correlation between TTV and the expression levels of key cytokines such as IFNL1 (p = 0.0416) and IFNL2 (p = 0.0007). Conclusions: Since we observed no differences considering distance from transplantation, while we found a changing trend in days before viral infections, we suggest to consider changes over time in the same subjects, irrespective of time distance from transplantation. Other the other hand the nature of interaction between TTV and cytokines expression is at the moment unknown, this upregulation could contribute to the body defence against other pathogens by priming the immune system.Background: Torque Teno Virus (TTV) is a ubiquitous component of human virome, not associated with any disease. TTV ability to establish persistent replication without overt clinical symptoms suggests a complex interaction with the host immune system. Aims & Objectives: As its load increases when the immune system is compromised, such as in kidney transplant (KT) recipients, TTV load monitoring has been proposed as a method to assess immunosuppression. Simultaneously to investigate the interaction between TTV and host immune responses in the context of cytokine production may help to understand complex interaction with the host immune system. Methodology: In this prospective study, TTV load was measured in plasma and urine samples from 42 KT recipients, immediately before KT and in the first 150 days after it. Furthermore, respiratory samples were also collected from 97 patients with respiratory changes caused by viruses to see the trend of TTV viral load and compare it with the cytokine expression also to see the trend across different age demographics. Results: Data obtained suggest that TTV could be a relevant marker for evaluating immune status and could be used as a guide to predict the onset of infectious complications in the follow-up of KT recipients. Nevertheless, the study on cytokine profiling showed a significant positive correlation between TTV and the expression levels of key cytokines such as IFNL1 (p = 0.0416) and IFNL2 (p = 0.0007). Conclusions: Since we observed no differences considering distance from transplantation, while we found a changing trend in days before viral infections, we suggest to consider changes over time in the same subjects, irrespective of time distance from transplantation. Other the other hand the nature of interaction between TTV and cytokines expression is at the moment unknown, this upregulation could contribute to the body defence against other pathogens by priming the immune system