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Gronchi A.,Sarcoma Service | Casali P.G.,Adult Mesenchymal Tumor Medical Oncology Unit
Current Treatment Options in Oncology | Year: 2013

Opinion statement: Adult-type soft tissue sarcomas (STS) are curable in roughly one half of cases. Surgery is the treatment mainstay in patients with localized STS and should be performed in centers that have specific expertise with the disease. Radiation therapy complements surgery in several cases, improving the local control. The value of adjuvant chemotherapy is still debated. There is some evidence, however, backing the notion that adjuvant chemotherapy may add to the systemic control of the disease, and thereby overall survival, in the subgroup of patients with high-risk STS. These patients are those with a high-grade, large, and deep tumor. Unfortunately, benefit is apparent when merging all data generated by several trials performed throughout decades, but it was not confirmed by the largest trials, including one that was recently reported. A confounding factor for large clinical trials is that STS are a family of 50-plus different histological subtypes. It is difficult to perform studies that focus on each of them separately, and subgroup analyses suffer from many limitations. Indeed, some histological types are more sensitive to standard chemotherapy and other are less. Furthermore, some histologies are specifically sensitive to some agents that may be completely inactive in others. A prospective, randomized trial is underway to compare standard neoadjuvant chemotherapy in high-risk STS versus a neoadjuvant regimen that is tailored to different histologies. Some rare histological subtypes (alveolar soft part sarcoma, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, solitary fibrous tumor) have shown promising sensitivity to molecular target agents in the metastatic setting, but the value of these therapies in the adjuvant one has not been studied yet. It is probable that in the future the biological background of the different soft tissue sarcoma subtypes will guide the selection of therapies as well as the setting to deliver them. © 2013 Springer Science+Business Media New York. Source

Dagrada G.P.,Laboratory of Experimental Molecular Pathology | Spagnuolo R.D.,Laboratory of Experimental Molecular Pathology | Mauro V.,Laboratory of Experimental Molecular Pathology | Gronchi A.,Fondazione Istituto Nazionale Dei Tumori | And 4 more authors.
Modern Pathology | Year: 2015

Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor. © 2015 USCAP, Inc All rights reserved. Source

De Cecco L.D.,Functional Genomics and Bioinformatics | Negri T.,Laboratory of Experimental Molecular Pathology | Brich S.,Laboratory of Experimental Molecular Pathology | Mauro V.,Laboratory of Experimental Molecular Pathology | And 10 more authors.
Oncotarget | Year: 2014

Aim: to investigate the events involved in the progression of myxoid liposarcoma (MLS). Gene expression profiling and immunohistochemical/biochemical analyses were applied to specimens representative of the opposite ends of the MLS spectrum: pure myxoid (ML) and pure round cell (RC) liposarcomas. The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component. In this model, a switch in the vascular landscape from a normal to a pro-angiogenic signature and the silencing of DLK1-DIO3 region mark the progression from ML to RC in concert with the acquisition by the latter of the overexpression of YY1/C-MYC/HDAC2, together with over-expression of genes involved in cell proliferation and stemness: MKNK2, MSX1 and TRIM71. Taken together, these findings strongly suggest that to progress from ML to RC liposarcoma the cells have to overcome the epigenetic silencing restriction point in order to reset their new stem-like differentiation signature. Our findings provide a first attempt at identifying the missing links between ML and RC liposarcomas, that may also have broader applications in other clinico-pathological settings characterised by a spectrum of progression. Source

Sanfilippo R.,Adult Mesenchymal Tumor Medical Oncology Unit | Dei Tos A.P.,Treviso General Hospital | Casali P.G.,Adult Mesenchymal Tumor Medical Oncology Unit
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: Myxoid/round cell liposarcoma (MRCL) represents about 10% of all soft-tissue sarcomas. Therapeutic options for this subgroup of tumours are limited, essentially doxorubicin-based regimens and trabectedin. Recently, the mammalian target of rapamycin (mTOR) pathway has been identified as a therapeutic target in several sarcomas. MRCLs should be included among these, as various molecular aberrations of the mTOR pathway have been recently reported. RECENT FINDINGS: PI3KCA mutations were identified in 10-20% of MRCLs. Other molecular aberrations include loss of PTEN, Akt activation and overexpression of IGF1R. Recently, two minor responses to mTOR inhibitors were reported. SUMMARY: The relatively high frequency of mTOR signalling pathway alterations in MRCL provides a preclinical rationale for considering mTOR inhibition as a potential novel therapeutic strategy warranting further investigation. Copyright © Lippincott Williams & Wilkins. Source

Popescu R.A.,Hirslanden Medical Center | Schafer R.,European Society for Medical Oncology | Califano R.,The Christie NHS Foundation Trust | Califano R.,University of Manchester | And 18 more authors.
Annals of Oncology | Year: 2014

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.© The Author 2013.Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

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