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Van Der Graaf W.T.A.,Radboud University Nijmegen | Blay J.-Y.,Center Leon Berard | Chawla S.P.,Santa Monica Oncology Center | Kim D.-W.,Seoul National University | And 19 more authors.
The Lancet | Year: 2012

Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. Methods This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitornaive,metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. Findings 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Interpretation Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.


Stacchiotti S.,Adult Sarcoma Medical Oncology Unit | Negri T.,Experimental Molecular Pathology Unit | Libertini M.,Adult Sarcoma Medical Oncology Unit | Palassini E.,Adult Sarcoma Medical Oncology Unit | And 7 more authors.
Annals of Oncology | Year: 2012

Background: To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor (SFT) treated at a single institution. Patients and methods: From April 2008, 35 patients with progressive advanced SFT (male/female: 20/15; mean age: 58 years; meningeal/extrameningeal: 6/29; locally advanced/metastatic: 15/20; prior chemotherapy: 25) were treated, on an individual use basis, with continuous-dosing sunitinib 37.5 mg/day. Platelet-derived growth factor receptor beta (PDGFRB) and vascular endothelial growth factor receptor 2 (VEGFR2) status were assessed by immunohistochemistry and, in a subgroup of patients, by real time PCR. Results: Thirty-one patients were assessable for response by RECIST (one early death; three early interruptions). Best responses were 2 partial response (PR), 16 stable disease, 13 progressive disease. A <30% decrease in size was observed in three patients. Fourteen of 29 patients assessable by Choi criteria had a PR. Median progression-free survival by RECIST was 6 months (range 1-22). In two of six patients, resistance to sunitinib was overcome by increasing sunitinib to 50 mg/day. PDGFRB and/or VEGFR2 were positive in all cases and not predictive of response; a less aggressive morphology corresponded to an increased response rate (53% PR by Choi in the malignant SFT, 20% PR in the pleomorphic/dedifferentiated SFT). Conclusions: Sunitinib is active in SFT. Response can be long-lasting. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Joensuu H.,University of Helsinki | Vehtari A.,Aalto University | Riihimaki J.,Aalto University | Nishida T.,Osaka Police Hospital | And 14 more authors.
The Lancet Oncology | Year: 2012

Background: The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. Methods: Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. Findings: Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90). Interpretation: The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. Funding: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds. © 2012 Elsevier Ltd.


Stacchiotti S.,Fondazione Instituto Of Ricovero E Cura A Carattere Scientifico Instituto Nazionale Dei Tumori | Palassini E.,Fondazione Instituto Of Ricovero E Cura A Carattere Scientifico Instituto Nazionale Dei Tumori | Sanfilippo R.,Fondazione Instituto Of Ricovero E Cura A Carattere Scientifico Instituto Nazionale Dei Tumori | Vincenzi B.,Biomedical University of Rome | And 9 more authors.
Annals of Oncology | Year: 2012

Background: Angiosarcoma is a highly aggressive soft tissue sarcoma. Responses to anthracyclines plus/minus ifosfamide, and taxanes alone or in combination with gemcitabine are well documented. Very few data are available on gemcitabine as a single agent. Patients and methods: We retrospectively reviewed all cases of advanced progressive angiosarcoma treated with gemcitabine as a single agent (1000 mg/m. 2 i.v. every week for 3 weeks every 4 weeks), at Istituto Nazionale Tumori and within the Italian Rare Cancers Network from January 2008 to November 2010. Results: Twenty-five patients [mean age: 52 years; radiation therapy (RT)-related: 8] received gemcitabine. Best tumor response by RECIST was as follows: complete response = 2, partial response = 14, stable disease = 2, progressive disease = 7 cases, for an overall response rate (PR + CR) of 68%. Six of eight post-RT angiosarcomas responded to treatment. Median overall survival (OS) was 17 months. Median progression-free survival (PFS) was 7 months (range 1-40 months). One patient with a locally advanced thyroid angiosarcoma became resectable after 5 months of gemcitabine, with <10% residual viable tumor cells seen on surgical specimen. Overall, gemcitabine was well tolerated. Conclusions: Gemcitabine is active in both RT- and non-RT-related angiosarcoma, with dimensional and possibly long-lasting responses. A formal phase II study on gemcitabine as a single agent is warranted. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Angeli P.,University of Padua | Fasolato S.,University of Padua | Mazza E.,University of Padua | Okolicsanyi L.,General Hospital of Treviso | And 7 more authors.
Gut | Year: 2010

Objective: The aim of the study was to compare sequential versus combined diuretic therapy in patients with cirrhosis, moderate ascites and without renal failure. Design: One hundred patients were randomly assigned to the two diuretic treatments. The sequential treatment provided potassium canrenoate at the initial dose of 200 mg/day, then increased to 400 mg/day. Nonresponders were treated with 400 mg/day of potassium canrenoate and furosemide at an initial dose of 50 mg/ day, then increased to 150 mg/day. The combined treatment provided the initial dose of 200 mg/day of potassium canrenoate and 50 mg/day of furosemide, then increased to 400 mg/day and 150 mg/day, respectively. Results: Most patients who received sequential treatment responded to potassium canrenoate alone (19% to 200 mg/day and 52.63% to 400 mg/day, respectively). Most patients who received the combined treatment responded to the first two steps (40% to the first step and 50% to the second, ie, 400 mg/day of potassium canrenoate plus 100 mg/day of furosemide). Adverse effects (38% vs 20%, p<0.05), in particular, hyperkalaemia (18% vs 4%, p<0.05), were more frequent in patients who received sequential therapy. As a consequence, the per cent of patients who resolved ascites without changing the effective diuretic step was higher in those who received the combined treatment (56% vs 76%, p<0.05). Conclusions: The combined diuretic treatment is preferable to the sequential one in the treatment of moderate ascites in patients with cirrhosis and without renal failure. NCT00741663. This work is an open randomised clinical trial.


Dei Tos A.P.,General Hospital of Treviso
Histopathology | Year: 2014

Liposarcomas represent the most common histotype among soft tissue sarcomas. However, liposarcomas in fact constitute a heterogeneous group of distinctive lesions that pose several diagnostic difficulties. The current World Health Organization classification of soft tissue and bone tumours recognizes four major liposarcoma subtypes: (i) atypical lipomatous tumour/well-differentiated liposarcoma; (ii) de-differentiated liposarcoma; (iii) myxoid liposarcoma; and (iv) pleomorphic liposarcoma. These four main subgroups are characterized by distinctive morphologies, unique genetic findings as well as distinct clinical behaviour. Accurate classification requires the integration of morphological, immunohistochemical and (in selected situations) genetic findings, and is essential for providing patients with the best available treatments. This review will focus upon the main diagnostic pitfalls encountered in the routine diagnosis of liposarcoma, underlining the diagnostic value of combining morphology with cytogenetics and molecular genetics. © 2013 John Wiley & Sons Ltd.


Romeo S.,General Hospital of Treviso | Dei Tos A.P.,General Hospital of Treviso
Virchows Archiv | Year: 2010

The Ewing sarcoma breakpoint region 1 (EWSR1; also known as EWS) represents one of the most commonly involved genes in sarcoma translocations. In fact, it is involved in a broad variety of mesenchymal lesions which includes Ewing's sarcoma/peripheral neuro-ectodermal tumor, desmoplastic small round cell tumor, clear cell sarcoma, angiomatoid fibrous histiocytoma, extraskeletal myxoid chondrosarcoma, and a subset of myxoid liposarcoma. The fusion products between EWSR1 and partners usually results in fusion of the N-terminal transcription-activating domain of EWSR1 and the C-terminal DNA-binding domain of the fusion partner, eventually generating novel transcription factors. EWSR1 rearrangement can be visualized by the means of fluorescence in situ hybridization (FISH). As soft tissue sarcomas represent a diagnostically challenging group, FISH analysis is an extremely useful confirmatory diagnostic tool. However, as in most instances a split-apart approach is used, the results of molecular genetics must be evaluated in context with morphology. © Springer-Verlag 2010.


Gallucci M.,General Hospital of Treviso | Zanardo A.,General Hospital of Treviso | Bendini M.,General Hospital of Treviso | Di Paola F.,General Hospital of Treviso | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2014

Background: The role of folate and homocysteine in brain atrophy associated with Alzheimer's disease is not completely understood. Objective: The aim of this study was to investigate the relationships between serum folate and homocysteine levels and the degree of cortical-subcortical and hippocampal atrophy in a first relatively preliminary sample of the Treviso Dementia (TREDEM) study using a potent data mining method. Methods: Physiological data, biochemical parameters, clinical assessment data, brain atrophy severity assessed with CT scans, and neuropsycological and disability data were assessed in a group of 232 outpatients (93 men and 139 women, aged 40.2-100 years) enrolled in the TREDEM study carried out in Treviso (Italy). A semantic connectivity map obtained through the Auto-CM system, a fourth generation artificial neural network (ANN), was used to offer some insight regarding the complex biological connections between the studied variables and the degree of brain atrophy. Results: Close associations between low serum folate levels and severe cortical-subcortical atrophy along with severe hippocampal atrophy measured by the width of the temporal horns of lateral ventricles were found. We also showed an association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Conclusion: The role of folate, which is inversely associated with the severity of brain atrophy, was confirmed. Our results also confirm the association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Auto-CM ANN is able to highlight associations sometimes visible only in longitudinal studies through intelligent data mining of a cross-sectional study. © 2014 - IOS Press and the authors. All rights reserved.


Stacchiotti S.,Fondazione IRCCS Instituto Nazionale Tumori | Marrari A.,Fondazione IRCCS Instituto Nazionale Tumori | Dei Tos A.P.,General Hospital of Treviso | Casali P.G.,Fondazione IRCCS Instituto Nazionale Tumori
Hematology/Oncology Clinics of North America | Year: 2013

This article highlights the data currently available on the activity of targeted medical treatment in a subgroup of rare entities within soft tissue sarcomas, including inflammatory myofibroblastic tumor, alveolar soft part sarcoma, solitary fibrous tumor, malignant perivascular epithelioid cell tumor (PEComa), and clear cell sarcoma. © 2013 Elsevier Inc.


Cacciatore M.,General Hospital of Treviso | Dei Tos A.P.,General Hospital of Treviso
Pathology | Year: 2014

Epithelioid mesenchymal malignancies represent a major diagnostic challenge. Epithelioid morphology can be observed in a variety of soft tissue neoplasms, however there exist specific subtypes in which an epithelioid apperance constitutes the most distinctive morphological feature. Moving from epithelioid sarcoma of Enzinger (the prototype of sarcoma with epithelioid morphology), this review will focus on the most relevant entities: namely epithelioid haemangioendothelioma and angiosarcoma, pseudomyogenic haemangioendothelioma, epithelioid malignant peripheral nerve sheath tumour, epithelioid sclerosing fibrosarcoma, epithelioid pleomorphic liposarcoma, alveolar soft part sarcoma, and undifferentiated soft tissue sarcoma with epithelioid morphology. Differential diagnoses and major pitfalls will be discussed in detail. © 2013 Royal College of Pathologists of Australasia.

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