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Gandini S.,Italian National Cancer Institute | Massi D.,University of Florence | Mandala M.,Unit of Medical Oncology
Critical Reviews in Oncology/Hematology | Year: 2016

Background: Despite the success of immunotherapy directed at inhibiting of programmed death-1 (PD-1)/PD-ligand (L)1 signaling, it is not established whether PD-L1 expression correlates with the clinical response and outcome in different tumors. The present meta-analysis investigates whether the PD-L1 status, detected by immunohistochemistry, is associated with clinical response and mortality in patients treated with anti-PD-1/PD-L1 therapy. Methods: A systematic literature search and quantitative analysis were planned, conducted and reported following CONSORT and QUORUM checklists, up to December 2015, to identify clinical trials with information on cancer outcome by PD-L1 immunohistochemical expression in tumor tissues. We used random effects models to estimate Summary Objective Response Rates (SORRs) and Summary Odd Ratio (SOR) for the comparison of PD-L1 positive and negative patients. Results: We summarized 20 trials carried out in metastatic melanoma (MM), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) patients receiving anti-PD-1/PD-L1 antibodies (4230 MM, 1417 NSCLC and 312 RCC patients). Positive PD-L1 MM patients showed a significant decrease (53%) in the risk of mortality vs. negative cases with no heterogeneity. Furthermore, SORRs were 45% and 27% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference in term of responses: 2.14 (95% CI: 1.65, 2.77), with low between-study heterogeneity (I2 = 35%). Furthermore, results from randomized clinical trials on MM showed that PD-L1 expression is significantly associated with greater clinical response rates to anti-PD1 treatments (SOR 1.89; 95%CI: 1.35, 2.64) but not to other treatments (SOR 0.96; 95%CI: 0.5, 1.87).In non-squamous NSCLC SORRs were 29% and 11% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference between responses: 3.78 (1.54, 9.24), with no between-study heterogeneity. Squamous NSCLC and RCC did not show any significant difference in response according to the PD-L1 status. Conclusion: PD-L1 expression is significantly associated with mortality and clinical response to anti-PD-1/PD-L1 antibodies in MM patients and with clinical response in patients with non-squamous NSCLC. © 2016 Elsevier Ireland Ltd. Source


Massi D.,University of Florence | De Giorgi V.,University of Florence | Mandala M.,Unit of Medical Oncology
Pathology | Year: 2016

In recent years, advances in molecular genetic characterisation have revealed that atypical Spitz tumours (ASTs) are basically heterogeneous diseases, although the clinical relevance of these findings is yet to be determined. Evidence of molecularly-defined diverse groups of lesions continues to accumulate; however, conflicting, confusing, and overlapping terminology has fostered ambiguity and lack of clarity in the field in general. The lack of fundamental diagnostic (morphological) unambiguous classification framework results in a number of challenges in the interpretation of the molecular genetic data. In this review, we discuss the main difficulties for pathologists and clinicians in the complex management of ASTs, with particular emphasis on the different genetic and biological features of recently-described entities, and offer our view of what could be medically reasonable to guide a rational approach in light of current data. © 2015 The Royal College of Pathologists of Australasia. Published by Elsevier Ltd. All rights reserved. Source


Bregni M.,Unit of Medical Oncology
Journal of Medicine and the Person | Year: 2010

Quality of life (QoL) in medicine and in oncology is an accepted parameter for the evaluation of the benefit of treatments. Scientific methods exist to assess QoL measures in clinical trials. However, many components of the person that are properly humane and determine the patient's attitude towards the disease are not measured by current criteria. Based on clinical experience, the author considers that a shift in knowledge and in doctors' attitudes is required to also include non-measurable parameters in the doctor-patient relationship. © Springer-Verlag 2010. Source


Mandala M.,Unit of Medical Oncology | Voit C.,Charite - Medical University of Berlin
Critical Reviews in Oncology/Hematology | Year: 2013

Melanoma is an aggressive form of skin cancer that causes the greatest number of skin cancer-related deaths worldwide. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The discovery of activating BRAF mutations in ~50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. This review summarizes the critical role of BRAF in melanoma pathophysiology, the clinical and pathological determinants of BRAF mutation status and finally addresses the current state of the art of BRAF inhibitors. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. © 2013 Elsevier Ireland Ltd. Source


Mandala M.,Unit of Medical Oncology | Merelli B.,Unit of Medical Oncology | Massi D.,University of Florence
Critical Reviews in Oncology/Hematology | Year: 2014

RAS belongs to the guanosine 5'-triphosphate (GTP)-binding proteins' family, and oncogenic mutations in codons 12, 13, or 61 of RAS family occur in approximately one third of all human cancers with N-RAS mutations found in about 15-20% of melanomas. The importance of RAS signaling as a potential target in cancer is emphasized not only by the prevalence of RAS mutations, but also by the high number of RAS activators and effectors identified in mammalian cells that places the RAS proteins at the crossroads of several, important signaling networks. Ras proteins are crucial crossroads of signaling pathways that link the activation of cell surface receptors with a wide variety of cellular processes leading to the control of proliferation, apoptosis and differentiation. Furthermore, oncogenic ras proteins interfere with metabolism of tumor cells, microenvironment's remodeling, evasion of the immune response, and finally contributes to the metastatic process. After 40 years of basic, translational and clinical research, much is now known about the molecular mechanisms by which these monomeric guanosine triphosphatase-binding proteins promote cellular malignancy, and it is clear that they regulate signaling pathways involved in the control of cell proliferation, survival, and invasiveness. In this review we summarize the biological role of RAS in cancer by focusing our attention on the biological rational and strategies to target RAS in melanoma. © 2014 Elsevier Ireland Ltd. Source

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