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6. Identification of biomarkers of metastatic disease in uveal melanoma using proteomic analyses

Author

Angi, Martina

Subjects
616.99, RB Pathology, RE Ophthalmology
Abstract

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Despite successful ocular treatment, about 50% of patients succumb to metastatic dissemination, which occurs haematogenously and mainly affects the liver. On the basis of clinical, histopathological and genetic features of the primary tumour it is possible to predict if the individual patient is at high risk (HR) or low risk (LR) of developing metastases. However, the mechanisms responsible for the development of metastatic disease in UM are still largely unknown; therefore no adjuvant treatment is currently offered to HR patients to prevent development of fatal disease. As the time to discovery of clinically detectable metastases can range from months to decades, a secreted biomarker(s) that could be routinely tested in blood is much needed. The scope of the work presented in this thesis was to use proteomics as a tool to identify potential novel, UM-specific biomarkers. Moreover, the proteomic data acquired would complement genomic and transcriptomic information already generated by the Liverpool Ocular Oncology Research Group, with the ultimate aim of increasing our understanding of UM development and dissemination. The aim of Chapter 2’s project was to compare the proteome of UM tissue samples at HR versus LR of developing metastatic disease using isobaric tags for relative and absolute quantitation (iTRAQ) labelling and mass spectrometry (MS). The quantification of proteins in our samples, proteomic analysis and further validation by immunohistochemistry has led to the identification of two novel prognostic and potentially therapeutic target, S100A6 and the tumour suppressor PDCD4. In Chapter 3 we focused on proteins released in the conditioned medium (secretome) of short-term cultures of HR and LR UM cells, as well as normal melanocytes. Using a label-free quantitative proteomic approach, almost 2000 proteins were identified and quantified, with more than 30% of these identified as secreted and/or previously described in exosomes. Using these data, an 18-protein signature able to discriminate between HR and LR UM was identified. Further validation will be necessary in secretome samples and in the peripheral blood of UM patients, but this has the potential of being translated into a clinically useful assay to detect early development of metastatic disease. As reported in Chapter 4, we also conducted a pilot clinical study on circulating tumour cells (CTC) in UM, using the CellSearch® platform with the novel melanoma kit to enumerate CTC in the peripheral blood of UM patients at LR, HR or with overt metastatic disease. CTC were detected in metastatic and HR tumours and were not present in LR UM, however, the number of CTC detected varied widely, calling into question the clinical value of using this platform in UM patients. The research detailed in Chapter 5 had a direct clinical value, as it addressed the procedures undertaken during the acquisition and processing of prognostic biopsies from UM tumours treated conservatively. The modifications introduced led to a significant improvement of the success rate of such prognostic biopsies for risk stratification, which is essential for clinical management, follow-up and research purposes. In conclusion, the work conducted throughout this PhD has provided further insight into the molecular characteristics that can differentiate between HR and LR UM, identifying novel potential biomarkers that will need validation in the clinical setting.

Published
2015
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11. Characterizing Different Multidisciplinary Team Models Implemented Within One Comprehensive Cancer Center

Author

Alfieri,Sara, Brunelli,Cinzia, Borreani,Claudia, Capri,Giuseppe, Angi,Martina, Bianchi,Giulia V, Lo Dico,Silvia, Spada,Pierangelo, Fusetti,Viviana, Zecca,Ernesto, Caraceni,Augusto, Alfieri,Sara, Brunelli,Cinzia, Borreani,Claudia, Capri,Giuseppe, Angi,Martina, Bianchi,Giulia V, Lo Dico,Silvia, Spada,Pierangelo, Fusetti,Viviana, Zecca,Ernesto, and Caraceni,Augusto

Abstract

Sara Alfieri,1,* Cinzia Brunelli,2,* Claudia Borreani,1 Giuseppe Capri,3 Martina Angi,4 Giulia V Bianchi,3 Silvia Lo Dico,2 Pierangelo Spada,5 Viviana Fusetti,2,6 Ernesto Zecca,2 Augusto Caraceni2,7 1Clinical Psychology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3Medical Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 4General Oncology Surgery 4, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 5Nursing, Technicians and Rehabilitation Management Service (SITRA), Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 6Biomedicine and Prevention Department, University of Rome “Tor Vergata”, Rome, Italy; 7Department of Clinical and Community Sciences, Università degli Studi, Milan, Italy*These authors contributed equally to this workCorrespondence: Cinzia Brunelli, Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy, Tel +39 0223903179, Email cinzia.brunelli@istitutotumori.mi.itBackground: The multidisciplinary approach is considered “best practice” in oncology. Multidisciplinary Teamwork (MDTW) can be broadly classified into Multidisciplinary Team Meetings (MDTM) and Multidisciplinary Cancer Clinics (MDCC; involving also patients), yet both models are heterogeneously implemented.Purpose: This study aims at describing the different MDTW implemented models in a Comprehensive Cancer Center.Methods: All clinical unit directors of the hospital were contacted to identify any MDTW activities the personnel of the unit were involved in. Structured interviews were carried out to collect MDTWs information, ie, type (MDTM vs MDCC), team composition, aims, disease phase, use of Patient Reported Outcome Measures (PROMs). Descriptive analyses and Social Network Analysis (SNA) wer

Published
2023

16. Tips to optimize digital education in ophthalmology: Results from ESASO survey

Author

Ferrara, Mariantonia, primary, Romano, Vito, additional, Iovino, Claudio, additional, Kadhim, Mustafa R, additional, van Dijk, Elon HC, additional, Boon, Camiel JF, additional, Grassi, Piergiacomo, additional, Demirel, Sibel, additional, Cartes, Cristian, additional, Romano, Mario R, additional, Agarwal, Aniruddha, additional, Aiello, Francesco, additional, Amed, Aseef, additional, Amoroso, Francesca, additional, Angi, Martina, additional, Au, Adrian, additional, Bali, Ernesto, additional, Chandra, Aman, additional, Cennamo, Gilda, additional, Cennamo, Michela, additional, Coassin, Marco, additional, Di Zazzo, Antonio, additional, Coco, Giulia, additional, D'Alterio, Francesco Maria, additional, Del Turco, Claudia, additional, La Spina, Carlo, additional, Dell'Omo, Roberto, additional, Napolitano, Pasquale, additional, Fiore, Tito, additional, Govetto, Andrea, additional, Malachkova, Nataliia, additional, Mastropasqua, Rodolfo, additional, Matarazzo, Francesco, additional, McGowan, Gerard, additional, Reibaldi, Michele, additional, Rejdak, Robert, additional, Reyes-Delfino, Catherine Dianne, additional, Rocha-de-Lossada, Carlos, additional, Romano, Davide, additional, Romano, Francesca, additional, Rombetto, Luca, additional, Rossi, Tommaso, additional, Scorcia, Vincenzo, additional, Steel, David, additional, Toro, Mario, additional, Valldeperas, Xavier, additional, Vallejo-Garcia, Jose L, additional, Vavvas, Demetrios, additional, Vaiano, Agostino S, additional, and Zur, Dinah, additional

Published
2022
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18. Tips to optimize digital education in ophthalmology: Results from ESASO survey.

Author

Ferrara, Mariantonia, Romano, Vito, Iovino, Claudio, Kadhim, Mustafa R, van Dijk, Elon HC, Boon, Camiel JF, Grassi, Piergiacomo, Demirel, Sibel, Cartes, Cristian, Romano, Mario R, Agarwal, Aniruddha, Aiello, Francesco, Amed, Aseef, Amoroso, Francesca, Angi, Martina, Au, Adrian, Bali, Ernesto, Chandra, Aman, Cennamo, Gilda, and Cennamo, Michela

Published
2023
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19. Multimodal Imaging Approach in a Patient with Vogt-Koyanagi-Harada-like Syndrome Due to Dabrafenib and Trametinib Use for Cutaneous Melanoma.

Author

Bellanca, Riccardo Francesco, Pinna, Antonio, Catania, Giovanna, Belcastro, Elena, Angi, Martina, and D'Amico Ricci, Giuseppe

Subjects
EYE inflammation, SYNDROMES, MELANOMA, VISION disorders, IRIDOCYCLITIS, CANCER chemotherapy
Abstract

To describe a case of ocular inflammation associated with dabrafenib and trametinib chemotherapy for cutaneous melanoma by using a multimodal image approach. We report on a 51-year-old woman with Vogt-Koyanagi-Harada-like syndrome, which occurred while she was undergoing treatment with dabrafenib and trametinib for cutaneous melanoma. The patient complained of sudden, bilateral vision loss of 2 days' duration. Anatomical and functional improvement was observed after administration of systemic steroids and cessation of chemotherapy. Later on, 6 weeks after restarting dabrafenib, she had an episode of granulomatous anterior uveitis, which was successfully managed with topical mydriatics and steroids. Strict follow-up with multimodal imaging was performed until recovery. This report emphasizes the importance of strict ophthalmological follow-up with multimodal imaging in patients receiving dabrafenib and trametinib, and the need for a multidisciplinary approach in the management of ocular inflammation during chemotherapy. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Liquid Biopsy and Radiological Response Predict Outcomes Following Discontinuation of Targeted Therapy in Patients with BRAF Mutated Melanoma

Author

Di Guardo, Lorenza, primary, Randon, Giovanni, additional, Corti, Francesca, additional, Vallacchi, Viviana, additional, Raimondi, Alessandra, additional, Fucà, Giovanni, additional, Bini, Marta, additional, Maurichi, Andrea, additional, Patuzzo, Roberto, additional, Gallino, Gianfrancesco, additional, Mattavelli, Ilaria, additional, Ruggeri, Roberta, additional, Angi, Martina, additional, Cossa, Mara, additional, Valeri, Barbara, additional, Cimminiello, Carolina, additional, Santinami, Mario, additional, Rivoltini, Licia, additional, Braud, Filippo, additional, Rodolfo, Monica, additional, and Vecchio, Michele Del, additional

Published
2021
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23. Survival in Patients With Sentinel Node–Positive Melanoma With Extranodal Extension

Author

Maurichi, Andrea, primary, Barretta, Francesco, additional, Patuzzo, Roberto, additional, Miceli, Rosalba, additional, Gallino, Gianfranco, additional, Mattavelli, Ilaria, additional, Barbieri, Consuelo, additional, Leva, Andrea, additional, Angi, Martina, additional, Lanza, Francesco Baldo, additional, Spadola, Giuseppe, additional, Cossa, Mara, additional, Nesa, Francesco, additional, Cortinovis, Umberto, additional, Sala, Laura, additional, Di Guardo, Lorenza, additional, Cimminiello, Carolina, additional, Del Vecchio, Michele, additional, Valeri, Barbara, additional, and Santinami, Mario, additional

Published
2021
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31. Facing COVID-19 in Ophthalmology Department

Author

Romano, Mario R., primary, Montericcio, Alessio, additional, Montalbano, Clara, additional, Raimondi, Raffaele, additional, Allegrini, Davide, additional, Ricciardelli, Gabriella, additional, Angi, Martina, additional, Pagano, Luca, additional, and Romano, Vito, additional

Published
2020
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34. Clinical Features and Diagnosis of Anterior Segment Inflammation Related to Cytomegalovirus in Immunocompetent African, Asian, and Caucasian Patients

Author

Leleu, Igor, primary, Jhanji, Vishal, additional, Touhami, Sara, additional, Westcott, Mark, additional, Angi, Martina, additional, Titah, Cherif, additional, Rousseau, Antoine, additional, Hamard, Pascale, additional, Brasnu, Emmanuelle, additional, Manicom, Thomas, additional, Blumen-Ohana, Esther, additional, Rozenberg, Flore, additional, Vauloup-Fellous, Christelle, additional, Deback, Claire, additional, Labetoulle, Marc, additional, Sahel, Jose-Alain, additional, Bodaghi, Bahram, additional, Merabet, Lilia, additional, Kobal, Alfred, additional, Brignole-Baudouin, Françoise, additional, and Errera, Marie-Hélène, additional

Published
2019
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35. Comparative Cytogenetic Abnormalities in Paired Choroidal Melanoma Samples Obtained Before and After Proton Beam Irradiation by Transscleral Fine-Needle Aspiration Biopsy and Endoresection

Author

Matet, Alexandre, primary, Aït Raïs, Khadija, additional, Malaise, Denis, additional, Angi, Martina, additional, Dendale, Rémi, additional, Tick, Sarah, additional, Lumbroso-Le Rouic, Livia, additional, Lévy-Gabriel, Christine, additional, Rodrigues, Manuel, additional, Pierron, Gaëlle, additional, and Cassoux, Nathalie, additional

Published
2019
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37. Clinical Features and Diagnosis of Anterior Segment Inflammation Related to in Immunocompetent African, Asian, and Caucasian Patients.

Author

Leleu, Igor, Jhanji, Vishal, Touhami, Sara, Westcott, Mark, Angi, Martina, Titah, Cherif, Rousseau, Antoine, Hamard, Pascale, Brasnu, Emmanuelle, Manicom, Thomas, Blumen-Ohana, Esther, Rozenberg, Flore, Vauloup-Fellous, Christelle, Deback, Claire, Labetoulle, Marc, Sahel, Jose-Alain, Bodaghi, Bahram, Merabet, Lilia, Kobal, Alfred, and Brignole-Baudouin, Françoise

Subjects
IRIDOCYCLITIS, DIAGNOSIS, CAUCASIAN race, ETHNIC groups, CYTOMEGALOVIRUSES
Abstract

Objective: To report the clinical features and treatment outcomes in immunocompetent patients with anterior segment inflammation (ASI) related to human cytomegalovirus (HCMV) depending on their ethnic origin.Material and Methods: Multicenter retrospective study of 38 patients with at least one test, either HCMV-positive PCR or GWc.Results: Features of Posner-Schlossman syndrome were observed in 50% of the eyes, Fuchs heterochromic iridocyclitis in 13% of the eyes, chronic nonspecific anterior uveitis in 21% of the eyes, and corneal endotheliitis in 18% of the eyes. PCR and GWc were positive for HCMV in 50% and 96.2% of the eyes, respectively. Glaucoma was diagnosed in 50% of eyes. Treatment was oral valganciclovir in about half of the patients. Other treatments were intravenous ganciclovir and/or ganciclovir topical ointment and/or intravitreal ganciclovir.Conclusions: No obvious association of specific clinical features with individual ethnicity could be identified. We found a high rate of glaucoma in all ethnic groups. There was a delay in diagnosis and specific treatment of HCMV in most patients. [ABSTRACT FROM AUTHOR]

Published
2021
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39. Identification of biomarkers of metastatic disease in uveal melanoma using proteomic analyses

Author

Angi, Martina

Subjects
RE, RB
Abstract

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Despite successful ocular treatment, about 50% of patients succumb to metastatic dissemination, which occurs haematogenously and mainly affects the liver. On the basis of clinical, histopathological and genetic features of the primary tumour it is possible to predict if the individual patient is at high risk (HR) or low risk (LR) of developing metastases. However, the mechanisms responsible for the development of metastatic disease in UM are still largely unknown; therefore no adjuvant treatment is currently offered to HR patients to prevent development of fatal disease. As the time to discovery of clinically detectable metastases can range from months to decades, a secreted biomarker(s) that could be routinely tested in blood is much needed. The scope of the work presented in this thesis was to use proteomics as a tool to identify potential novel, UM-specific biomarkers. Moreover, the proteomic data acquired would complement genomic and transcriptomic information already generated by the Liverpool Ocular Oncology Research Group, with the ultimate aim of increasing our understanding of UM development and dissemination. The aim of Chapter 2’s project was to compare the proteome of UM tissue samples at HR versus LR of developing metastatic disease using isobaric tags for relative and absolute quantitation (iTRAQ) labelling and mass spectrometry (MS). The quantification of proteins in our samples, proteomic analysis and further validation by immunohistochemistry has led to the identification of two novel prognostic and potentially therapeutic target, S100A6 and the tumour suppressor PDCD4. In Chapter 3 we focused on proteins released in the conditioned medium (secretome) of short-term cultures of HR and LR UM cells, as well as normal melanocytes. Using a label-free quantitative proteomic approach, almost 2000 proteins were identified and quantified, with more than 30% of these identified as secreted and/or previously described in exosomes. Using these data, an 18-protein signature able to discriminate between HR and LR UM was identified. Further validation will be necessary in secretome samples and in the peripheral blood of UM patients, but this has the potential of being translated into a clinically useful assay to detect early development of metastatic disease. As reported in Chapter 4, we also conducted a pilot clinical study on circulating tumour cells (CTC) in UM, using the CellSearch® platform with the novel melanoma kit to enumerate CTC in the peripheral blood of UM patients at LR, HR or with overt metastatic disease. CTC were detected in metastatic and HR tumours and were not present in LR UM, however, the number of CTC detected varied widely, calling into question the clinical value of using this platform in UM patients. The research detailed in Chapter 5 had a direct clinical value, as it addressed the procedures undertaken during the acquisition and processing of prognostic biopsies from UM tumours treated conservatively. The modifications introduced led to a significant improvement of the success rate of such prognostic biopsies for risk stratification, which is essential for clinical management, follow-up and research purposes. In conclusion, the work conducted throughout this PhD has provided further insight into the molecular characteristics that can differentiate between HR and LR UM, identifying novel potential biomarkers that will need validation in the clinical setting.

Published
2016
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42. Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis

Author

Arcidiacono, Barbara, Semeraro,Francesco, Nascimbeni,Giuseppe, Angi,Martina, Parolini,Barbara, and Costagliola,Ciro

Subjects
Drug Design, Development and Therapy
Abstract

Francesco Semeraro,1 Barbara Arcidiacono,2 Giuseppe Nascimbeni,1 Martina Angi,1 Barbara Parolini,2 Ciro Costagliola31Eye Clinic, Department of Neurological Sciences and Vision, University of Brescia, Brescia, Italy; 2Department of Ophthalmology, S. Anna Hospital, Brescia, Italy; 3Eye Clinic, Department of Health Sciences, University of Molise, Campobasso, ItalyAbstract: Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds.Keywords: adalimumab, etanercept, infliximab

Published
2014

43. Inflammation and Macular Oedema after Pars Plana Vitrectomy

Author

Romano, Vito, Angi, Martina, Scotti, Fabrizio, del Grosso, Renata, Romano, Davide, Semeraro, Francesco, Vinciguerra, Paolo, Costagliola, Ciro, and Romano, Mario R.

Subjects
genetic structures, Article Subject, sense organs, eye diseases
Abstract

Cystoid macular oedema (CMO) is a major cause of reduced vision following intraocular surgery. Although the aetiology of CMO is not completely clarified, intraocular inflammation is known to play a major role in its development. The macula may develop cytotoxic oedema when the primary lesion and fluid accumulation occur in the parenchymatous cells (intracellular oedema) or vasogenic oedema when the primary defect occurs in the blood-retinal barrier and leads to extracellular fluid accumulation (extracellular oedema). We report on the mechanisms of CMO formation after pars plana vitrectomy and associated surgical procedures and discuss possible therapeutic approaches.

Published
2013
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44. Vitreous Analysis in the Management of Uveitis

Author

Damato, Erika M., Angi, Martina, Romano, Mario R., Semeraro, Francesco, and Costagliola, Ciro

Subjects
genetic structures, Article Subject, eye diseases
Abstract

A correct diagnosis of uveitis is often challenging, given the wide range of possible underlying conditions and the lack of typical phenotypes. Management decisions may be difficult in view of the risk of visual loss with either inappropriate or delayed therapy. Analysis of the vitreous may therefore be used to provide the clinician with valuable information. In this paper, we describe the main clinical situations in which vitreous sampling is indicated and provide some guidance to clinicians for tailoring their requests. These situations include suspected intraocular infection and suspected intraocular malignancy. We describe the principal tests carried out on vitreous samples, including cultures, polymerase chain reaction-based testing, and cytokine analysis. Limitations of the tests used are likely to become less as more advanced testing methods are introduced. The importance of selecting the appropriate investigations to support a clinical suspicion is emphasised, as is the interpretation of test results within a clinical context.

Published
2012
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45. Proteomic Analyses of the Vitreous Humour

Author

Angi, Martina, Kalirai, Helen, Coupland, Sarah E., Damato, Bertil E., Semeraro, Francesco, and Romano, Mario R.

Subjects
Article Subject, sense organs, eye diseases
Abstract

The human vitreous humour (VH) is a transparent, highly hydrated gel, which occupies the posterior segment of the eye between the lens and the retina. Physiological and pathological conditions of the retina are reflected in the protein composition of the VH, which can be sampled as part of routine surgical procedures. Historically, many studies have investigated levels of individual proteins in VH from healthy and diseased eyes. In the last decade, proteomics analyses have been performed to characterise the proteome of the human VH and explore networks of functionally related proteins, providing insight into the aetiology of diabetic retinopathy and proliferative vitreoretinopathy. Recent proteomic studies on the VH from animal models of autoimmune uveitis have identified new signalling pathways associated to autoimmune triggers and intravitreal inflammation. This paper aims to guide biological scientists through the different proteomic techniques that have been used to analyse the VH and present future perspectives for the study of intravitreal inflammation using proteomic analyses.

Published
2012
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49. Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis

Author

Semeraro,Francesco, Arcidiacono,Barbara, Nascimbeni,Giuseppe, Angi,Martina, Parolini,Barbara, Costagliola,Ciro, Semeraro,Francesco, Arcidiacono,Barbara, Nascimbeni,Giuseppe, Angi,Martina, Parolini,Barbara, and Costagliola,Ciro

Abstract

Francesco Semeraro,1 Barbara Arcidiacono,2 Giuseppe Nascimbeni,1 Martina Angi,1 Barbara Parolini,2 Ciro Costagliola31Eye Clinic, Department of Neurological Sciences and Vision, University of Brescia, Brescia, Italy; 2Department of Ophthalmology, S. Anna Hospital, Brescia, Italy; 3Eye Clinic, Department of Health Sciences, University of Molise, Campobasso, ItalyAbstract: Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds.Keywords: adalimumab, etanercept, infliximab

Published
2014

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