Malignant peritoneal mesothelioma in a woman with bilateral ovarian serous borderline tumour: Potential interactions between the two diseases

We report a case of a 59-year-old woman with peritoneal malignant mesothelioma and no previous exposure to asbestos with a diagnosis of bilateral ovarian serous borderline tumour with peritoneal implants one year before. We discuss the histopathological and immunohistochemical findings to explain possible and potential interactions between the two diseases. To our knowledge, the association of both serous borderline ovarian tumour and malignant peritoneal mesothelioma has never been described before in the same woman and in such a tight temporal connection. This finding raises numerous issues about the origin of the two tumours and further biomolecular studies are needed to fully understand the carcinogenetic process. From a clinical point of view, this case report can be useful to gynaecologists because it leads to recommend a careful examination of the peritoneal cavity during a surgical resection of borderline serous tumour. Moreover, it may suggest performing a close follow-up associated with a careful surveillance of the patient, especially in the case of micropapillary pattern, to oncologists. A complete clinical approach could help to detect sooner possible relapses or other metachronous malignancies

Loss of expression of μ-protocadherin and protocadherin-24 in sporadic and hereditary nonpolyposis colorectal cancers

Colorectal cancer (CRC) is a neoplastic disease in which normal mucosa undergoes a process of malignant transformation due to the progressive accumulation of molecular alterations affecting proto-oncogenes and oncosuppressor genes. Some of these modifications exert their carcinogenic potential by promoting a constitutive activation of the β-catenin signaling proliferation pathway, and when present, loss of cadherin expression also significantly contributes to the same effect. Using a combined approach of molecular and immunohistochemical analysis, we have previously demonstrated that most sporadic CRCs exhibit a down-regulated expression of a cadherin, named μ-protocadherin, that is generally observed in association with a higher proliferation rate and a worse prognosis. The aim of this report was to perform a comparative immunohistochemical assessment of μ-protocadherin and a similar cadherin, named protocadherin-24, in sporadic CRC and hereditary nonpolyposis colorectal cancer. The data obtained put in evidence that double-negative CRCs, lacking both the analyzed protocadherins, are more represented among sporadic tumors, whereas double-positive CRCs, maintaining their expression, exhibit an opposite trend. As expected, loss of protocadherin expression was accompanied by nuclear localization of β-catenin and increased positivity of the Ki-67 proliferation marker. This finding is consistent with the different clinical evolution of the 2 considered CRC sets according to which patients with hereditary nonpolyposis colorectal cancer experience a better prognosis as compared with those affected by a sporadic CRC

Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death‑1 ligand 1 (PD‑L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD‑L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor‑infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD‑L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD‑L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD‑L1 assessment guidelines to apply in the field of immunotherapy

Progettazione concettuale di un dispositivo meccatronico per la rimozione delle CTC (cellule tumorali circolanti)

L'attività di ricerca si è concentrata sullo sviluppo e sulla progettazione concettuale di un sistema innovativo in grado di rimuovere le CTC (Cellule Tumorali Circolanti) dal flusso sanguigno. L'attività ha fatto parte del progetto CLEAR, the CTC targeted Liquid surgEry AppaRatus, volto a creare un dispositivo medico in grado di rimuovere le CTC dal sangue periferico di un paziente oncologico. L'obiettivo della tesi è stato quello di condurre un’ analisi preliminare dei fenomeni fisici alla base della progettazione concettuale del dispositivo, con la conseguente realizzazione di un possibile prototipo, applicabile in campo diagnostico e clinico. Da un lato, questa ricerca è stata caratterizzata da uno studio delle proprietà biofisiche ed elettrofisiologiche delle CTC in funzione della loro relazione con un campo elettrico, che funge da principio operativo di base del dispositivo. Dall'altro lato, il lavoro si è concentrato sulla validazione di una metodologia di calcolo innovativa basata sull'uso dell'analisi fluidodinamica computazionale (CFD). La metodologia è stata applicata allo studio del moto e dell’interazione fluida delle particelle sospese nel sangue in presenza di sorgenti elettriche. Inizialmente l'attività di ricerca è stata interessata da un'approfondita analisi bibliografica, focalizzata sul campo dell’ elettrofisiologia; in particolare, è stato identificato un parallelismo tra un condensatore e una cellula biologica, in virtù delle sue caratteristiche di membrana elettrica. La cellula può quindi essere considerata come un condensatore elettrico e il modello di condensatore equivalente può essere utilizzato per rappresentare diversi tipi di cellule normalmente presenti nel sangue, così come vari tipi di CTC. Questo approccio ha permesso che le caratteristiche biologiche delle cellule fossero trasformate in “informazioni digitali”. Modellando le CTC e le cellule del sangue attraverso il parallelismo elettrofisiologico, è stata calcolata teoricamente la carica elettrica superficiale di ogni cellula. Tale parametro ha permesso di discriminare le cellule tumorali da quelle normalmente presenti nel flusso sanguigno, e di studiare la loro interazione con un campo elettrico. È stata poi condotta una campagna sperimentale per la qualificazione della carica elettrica delle cellule tumorali in collaborazione con l'IRCCS-IRST di Meldola, con l'Università di Bologna, l'Università di Modena e Reggio Emilia, e infine con l'Università di Twente. In questo contesto, sono state analizzate tramite la tecnica del Patch Clamp cellule del cancro al seno (MCF-7) e cellule del cancro alla prostata (LNCaP). In parallelo, l'attività di ricerca ha incluso l'analisi numerica CFD del comportamento delle CTC nel flusso sanguigno, per capire come le cellule tumorali circolino all'interno del sangue in funzione della loro carica elettrica. In seguito, è stata condotta un’analisi CFD di un dispositivo concettuale per l'intrappolamento delle CTC, in grado di prevedere il comportamento di tali cellule quando interagiscono con un campo elettrico. L'analisi ha evidenziato l'influenza del fattore di forma del condotto e l'intensità del campo elettrico sulle caratteristiche di movimento delle CTC nel sangue. I risultati ottenuti con l'analisi numerica e le attività sperimentali hanno permesso di progettare una versione preliminare del dispositivo meccatronico e di costruire un primo prototipo del sistema CLEAR, utilizzabile nel prossimo futuro. In conclusione, è stato possibile condurre la progettazione concettuale e la definizione di un primo prototipo del sistema di filtraggio per le CTC, valutando l'efficienza del dispositivo e supportando il possibile risultato clinico che questo approccio innovativo potrebbe portare.The research activity focused on the development of the conceptual design of an innovative system able to remove the CTCs (Circulating Tumor Cells) from the human blood flow. The activity was part of the CLEAR project, the CTC targeted Liquid surgEry AppaRatus, aimed at creating a medical device capable of removing CTCs from the peripheral blood of a cancer patient. The objective of this thesis was the preliminary analysis of the physical phenomena underlying the functioning of the concept and the conception of a possible prototype of such a device that can be applied in the diagnostic and clinical field. On the one hand, this research was characterized by a study of the biophysical and electrophysiological properties of CTCs as a function of their relationship with an electric field, which serves as the basic operating principle of the device. On the other hand, this work focused on the validation of an innovative calculation methodology based on the use of fluid dynamics computational analysis (CFD). This methodology was applied to the study of the motion and fluid interaction of particles suspended within the blood in the presence of electrical sources. The research activity included a bibliographic analysis focused on the electrophysiology studies; therefore, a parallelism was identified between a capacitor and a biological cell, by virtue of its electrical membrane characteristics. Then, the cell can be considered as an electric capacitor and the equivalent capacitor model system can be used to represent different types of cells normally present in the blood as well as various types of CTCs. This approach allowed the biological characteristics of the cells to be transformed into digital twin information useful for engineering applications. By modelling CTCs and blood cells through this electro-physiological parallelism, the surface electric charge of each cell was theoretically calculated. This parameter allowed the circulating cancer cells to be discriminated and this characteristic was used to study their interaction with an electric field. Subsequently, an experimental campaign for the qualification of the electric charge of cancer cells was carried out together with the IRCCS-IRST of Meldola and in collaboration with the University of Bologna, the University of Modena and Reggio Emilia, and finally with the University of Twente. In this context, both breast (MCF-7) and prostate (LNCaP) cancer cells were analyzed using the Patch Clamp technique. The analysis of the obtained results was used to validate the theoretical approach. In parallel, the research activity included the numerical analysis of the CTCs behavior in the blood flow through CFD analysis, to understand how cancer cells circulate within the blood flow, as a function of their electrical charge. Then, a CFD design of a conceptual device for CTCs entrapment was developed, capable of predicting the behavior of CTCs when interacting with an electric field. The analysis highlighted the influence of the duct shape factor, as well as the intensity of the electric field on the motion characteristics of CTCs within the blood flow. These results provided the guidelines for the design of the active filtration system in liquid surgery apparatus for extra corporeal flow conditions. The results achieved with both the numerical analysis and the experimental activities made it possible to design a preliminary version of the mechatronic device and build a first prototype of the CLEAR system, that can be used in the future. In conclusion, it was possible to analyze the conceptual design and define a first prototype of the filtering system for CTCs and to evaluate the efficiency of the device and to support the possible clinical outcome that this innovative approach could bring

Malignant peritoneal mesothelioma in a woman with bilateral ovarian serous borderline tumour: Potential interactions between the two diseases

We report a case of a 59-year-old woman with peritoneal malignant mesothelioma and no previous exposure to asbestos with a diagnosis of bilateral ovarian serous borderline tumour with peritoneal implants one year before. We discuss the histopathological and immunohistochemical findings to explain possible and potential interactions between the two diseases. To our knowledge, the association of both serous borderline ovarian tumour and malignant peritoneal mesothelioma has never been described before in the same woman and in such a tight temporal connection. This finding raises numerous issues about the origin of the two tumours and further biomolecular studies are needed to fully understand the carcinogenetic process. From a clinical point of view, this case report can be useful to gynaecologists because it leads to recommend a careful examination of the peritoneal cavity during a surgical resection of borderline serous tumour. Moreover, it may suggest performing a close follow-up associated with a careful surveillance of the patient, especially in the case of micropapillary pattern, to oncologists. A complete clinical approach could help to detect sooner possible relapses or other metachronous malignancies