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Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recent preclinical data regarding biological signaling machinery as well as genetic and epigenetic mechanisms associated with molecular patterns of tumors have contribute to explain the pathogenesis and the differentiation of TGCTs and to understand the mechanisms responsible for the development of resistance to treatment. In this review, we discuss the main genetic and epigenetic events associated with TGCTs development in order to better define their role in the pathogenesis of these tumors and in cisplatin-acquired resistance.

// Daniela Vanacore 1, 2, * , Mariarosaria Boccellino 2, * , Sabrina Rossetti 1, 3 , Carla Cavaliere 1, 4 , Carmine D’Aniello 1, 5 , Rossella Di Franco 1, 6 , Francesco Jacopo Romano 1 , Micaela Montanari 1, 7 , Elvira La Mantia 1, 8 , Raffaele Piscitelli 1, 9 , Flavia Nocerino 1, 10 , Francesca Cappuccio 1, 11 , Giovanni Grimaldi 1, 12 , Alessandro Izzo 1, 12 , Luigi Castaldo 1, 12 , Maria Filomena Pepe 1, 8 , Maria Gabriella Malzone 1, 8 , Gelsomina Iovane 3 , Gianluca Ametrano 1, 6 , Paola Stiuso 2 , Lucio Quagliuolo 2 , Daniela Barberio 1, 11 , Sisto Perdona 12 , Paolo Muto 6 , Maurizio Montella 10 , Piera Maiolino 9 , Bianca Maria Veneziani 7 , Gerardo Botti 8, 13 , Michele Caraglia 2 and Gaetano Facchini 1, 3 1 Progetto ONCONET2.0, Linea progettuale 14 per l’implementazione della Prevenzione e Diagnosi Precoce del Tumore alla Prostata e Testicolo, Regione Campania, Italy 2 Department of Biochemistry, Biophysics and General Pathology, University of Campania “L. Vanvitelli” Naples, Naples, Italy 3 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 4 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy 5 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli, Italy 6 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 7 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy 8 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy 9 Pharmacy Unit, Istituto Nazionale Tumori, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy 10 Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 11 Psicology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 12 Division of Urology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 13 Scientific Directorate, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy * These authors have contributed equally to this work Correspondence to: Michele Caraglia, email: michele.caraglia@unina2.it , michele.caraglia@alice.it Keywords: microRNAs, prostate cancer, biomarkers, oncogenic miRNAs, tumor suppressor miRNAs Received: February 06, 2017 Accepted: March 25, 2017 Published: April 07, 2017 ABSTRACT Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs’ functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

// Vincenzo Quagliariello 1,2,3,16 , Sabrina Rossetti 1,2 , Carla Cavaliere 1,4 , Rossella Di Palo 1,5 , Elvira Lamantia 1,6 , Luigi Castaldo 1,7 , Flavia Nocerino 8 , Gianluca Ametrano 1,5 , Francesca Cappuccio 1,9 , Gabriella Malzone 1,6 , Micaela Montanari 1,10 , Daniela Vanacore 1 , Francesco Jacopo Romano 1 , Raffaele Piscitelli 1,11 , Gelsomina Iovane 2 , Maria Filomena Pepe 1,6 , Massimiliano Berretta 12,16 , Carmine D’Aniello 1,13 , Sisto Perdona 7 , Paolo Muto 5 , Gerardo Botti 6 , Gennaro Ciliberto 14,17 , Bianca Maria Veneziani 10 , Francesco De Falco 9 , Piera Maiolino 11 , Michele Caraglia 15 , Maurizio Montella 8 , Rosario Vincenzo Iaffaioli 3,16 and Gaetano Facchini 1,2,16 1 Progetto ONCONET2.0 - Linea progettuale 14 per l’implementazione della prevenzione e diagnosi precoce del tumore alla prostata e testicolo, Regione Campania, Italy 2 Division of Medical Oncology, Department of Uro-Gynaecological Oncology , Istituto Nazionale Tumori ‘Fondazione G. Pascale’ - IRCCS, Naples, Italy 3 Medical Oncology, Abdominal Department, National Cancer Institute G. Pascale Foundation, Napoli, Italy 4 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy 5 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 6 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy 7 Division of Urology, Department of Uro-Gynaecological Oncology , Istituto Nazionale Tumori ‘Fondazione G. Pascale’ - IRCCS, Naples, Italy 8 Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 9 Psicology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 10 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy 11 Pharmacy Unit, Istituto Nazionale Tumori, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy 12 Department of Medical Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy 13 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli, Italy 14 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 15 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy 16 Association for Multidisciplinary Studies in Oncology and Mediterranean Diet, Piazza Nicola Amore, Naples, Italy 17 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Regina Elena’ - IRCCS, Roma, Italy Correspondence to: Vincenzo Quagliariello, email: // Keywords : metabolic syndrome, endocrine disruptors, prostate, cancer, nutrition Received : October 28, 2016 Accepted : February 06, 2017 Published : March 30, 2017 Abstract This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world’s leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the worlds leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs).

In metastatic renal cell carcinoma, complete response to first-line antiangiogenic agents is rare and resistance to therapy often develops. Protocols for sequential treatment with angiogenesis and mTOR inhibitors are under evaluation to improve outcomes. In this observational, real-world study, patients received a first-line therapy with pazopanib until discontinuation for disease progression or toxicity, then a second-line with everolimus. Primary endpoints were overall survival (OS) for sequence, progression free survival (PFS) for each agent, and safety. Thirty-one patients were included in the analysis: 73.3% of patients underwent nephrectomy before treatment, 25.8% had at least three comorbidities. At the beginning of therapy, the median age was 68 years, with more than 60% of patients older than 65 years. The median OS for sequence was 26.5 months (95% CI 17.4-nc); median PFS was 10.6 months (95% CI 6.3-12.1) with pazopanib and 5.3 months (95% CI 3.8-6.7) with everolimus. The median persistence in pazopanib therapy was 8.1 months (Interquartile Range IQR 5.3-12.7), with 31% of patients who required dose reduction, while persistence in everolimus was 4.4 months (IQR 3.4-6.5). Sequence was well tolerated with a different profile of adverse events for each agent. These data confirmed that pazopanib was effective, even in reduced dosing, and well tolerated and suggested that everolimus may represent an opportunity to continue a therapy when patients cannot further tolerate angiogenesis inhibitors or develop a resistance.

// Micaela Montanari 1,2 , Sabrina Rossetti 1 , Carla Cavaliere 1,3 , Carmine D’Aniello 1,4 , Maria Gabriella Malzone 1,5 , Daniela Vanacore 1 , Rossella Di Franco 1,6 , Elvira La Mantia 1,5 , Gelsomina Iovane 1,7 , Raffaele Piscitelli 1 , Raffaele Muscariello 8 , Massimiliano Berretta 9 , Sisto Perdona 8 , Paolo Muto 6 , Gerardo Botti 5,10 , Attilio Antonio Montano Bianchi 11 , Bianca Maria Veneziani 2 and Gaetano Facchini 1,7 1 Progetto ONCONET2.0, Linea Progettuale 14 per L’implementazione della Prevenzione e Diagnosi Precoce del Tumore alla Prostata e Testicolo, Regione Campania, Italy 2 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy 3 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy 4 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Naples, Italy 5 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy 6 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy 7 Department of Uro-Gynaecological Oncology, Division of Medical Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 8 Department of Uro-Gynaecological Oncology, Division of Urology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 9 Department of Medical Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy 10 Scientific Directorate, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 11 Directorate-General for Management, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy Correspondence to: Micaela Montanari, email: // Keywords : prostate cancer; epithelial-mesenchymal transition; androgen receptor; TGF-β signaling; EGF/EGFR Received : November 10, 2016 Accepted : February 15, 2017 Published : February 25, 2017 Abstract Prostate cancer is a main urological disease associated with significant morbidity and mortality. Radical prostatectomy and radiotherapy are potentially curative for localized prostate cancer, while androgen deprivation therapy is the initial systemic therapy for metastatic prostate disease. However, despite temporary response, most patients relapse and evolve into castration resistant cancer. Epithelial-mesenchymal transition (EMT) is a complex gradual process that occurs during embryonic development and/or tumor progression. During this process, cells lose their epithelial characteristics and acquire mesenchymal features. Increasing evidences indicate that EMT promotes prostate cancer metastatic progression and it is closely correlated with increased stemness and drug resistance. In this review, we discuss the main molecular events that directly or indirectly govern the EMT program in prostate cancer, in order to better define the role and the mechanisms underlying this process in prostate cancer progression and therapeutic resistance.