Publications by authors named "Paolo Giovanni Casali"

43 Publications

Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin.

Cancers (Basel) 2021 Mar 22;13(6). Epub 2021 Mar 22.

Adult Mesenchymal Tumour Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Background: We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin.

Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS).

Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22-0.94; adjusted = 0.035).

Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.
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http://dx.doi.org/10.3390/cancers13061453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005098PMC
March 2021

Selinexor versus doxorubicin in dedifferentiated liposarcoma PDXs: evidence of greater activity and apoptotic response dependent on p53 nuclear accumulation and survivin down-regulation.

J Exp Clin Cancer Res 2021 Mar 1;40(1):83. Epub 2021 Mar 1.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133, Milan, Italy.

Background: Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines.

Methods: Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic (N = 2) and rhabdomyoblastic (N = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.

Results: Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46-80 % vs. 37-60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin.

Conclusions: Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.
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http://dx.doi.org/10.1186/s13046-021-01886-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923610PMC
March 2021

Unplanned Excision of Extremity and Trunk Wall Soft Tissue Sarcoma: To Re-resect or Not to Re-resect?

Ann Surg Oncol 2021 Jan 28. Epub 2021 Jan 28.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: The need for systematic reexcision in patients who underwent unplanned excision (UE) for extremity and superficial trunk soft tissue sarcoma (ESTSTS) has been questioned. We investigated the outcome of patients who underwent reexcision for ESTSTS compared with primarily resected at our institution and the prognostic impact of microscopic residual disease (MR) in the reexcision specimen.

Methods: Primary ESTSTS patients surgically treated at our institution between 1997 and 2017 were divided in three groups: primarily resected (A), reexcised after macroscopically complete UE (B), and incomplete UE (C). Weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR), and distant metastasis (CCI-DM) were calculated and compared. In group B, multivariable models were performed to assess factors associated with the outcomes.

Results: A total of 1962 patients were identified: 1076, 697 and 189 in groups A, B, and C, respectively. Overall median follow-up was 85 months. Seven-year weighted-OS was 73.8%, 84.1%, and 80.7% (p < 0.001) for groups A, B, and C respectively. Seven-year CCI-LR and DM were 5.0% and 25.3%, 12.1% and 15.8%, and 13.6% and 29.4% (both p < 0.001) for groups A, B, and C, respectively. At multivariable analysis, the presence MR was associated with LR (p < 0.001) but not with OS nor CCI-DM.

Conclusions: UE and the presence of MR at pathology in reexcision specimen are associated to a higher risk of LR but not to a higher risk of DM or lower OS. After macroscopic complete UE, postponing reexcision until a LR occurs may be considered on an individualized basis.
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http://dx.doi.org/10.1245/s10434-020-09564-6DOI Listing
January 2021

Evaluating the effectiveness of clinical ethics committees: a systematic review.

Med Health Care Philos 2021 Mar 21;24(1):135-151. Epub 2020 Nov 21.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Clinical Ethics Committees (CECs), as distinct from Research Ethics Committees, were originally established with the aim of supporting healthcare professionals in managing controversial clinical ethical issues. However, it is still unclear whether they manage to accomplish this task and what is their impact on clinical practice. This systematic review aims to collect available assessments of CECs' performance as reported in literature, in order to evaluate CECs' effectiveness. We retrieved all literature published up to November 2019 in six databases (PubMed, Ovid MEDLINE, Scopus, Philosopher's Index, Embase and Web of Science), following PRISMA guidelines. We included only articles specifically addressing CECs and providing any form of CECs performance assessment. Twenty-nine articles were included. Ethics consultation was the most evaluated of CECs' functions. We did not find standardized tools for measuring CECs' efficacy, but 33% of studies considered "user satisfaction" as an indicator, with 94% of them reporting an average positive perception of CECs' impact. Changes in patient treatment and a decrease of moral distress in health personnel were reported as additional outcomes of ethics consultation. The highly diverse ways by which CECs carry out their activities make CECs' evaluation difficult. The adoption of shared criteria would be desirable to provide a reliable answer to the question about their effectiveness. Nonetheless, in general both users and providers consider CECs as helpful, relevant to their work, able to improve the quality of care. Their main function is ethics consultation, while less attention seems to be devoted to bioethics education and policy formation.
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http://dx.doi.org/10.1007/s11019-020-09986-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910230PMC
March 2021

In Reply.

Oncologist 2020 12 1;25(12):e2018. Epub 2020 Oct 1.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

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http://dx.doi.org/10.1002/ONCO.13518DOI Listing
December 2020

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

Oncologist 2020 11 12;25(11):e1777-e1784. Epub 2020 Jul 12.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers.

Materials And Methods: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method.

Results: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine.

Conclusion: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules.

Implications For Practice: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.
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http://dx.doi.org/10.1634/theoncologist.2020-0352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648357PMC
November 2020

A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in high-grade uterine sarcoma after stabilization or response to doxorubicin ± ifosfamide following surgery or in metastatic first line treatment (EORTC62113).

Int J Gynecol Cancer 2020 10 15;30(10):1633-1637. Epub 2020 Jun 15.

Medical Oncology, NHS Greater Glasgow and Clyde, Glasgow, Glasgow, UK.

Background: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas.

Primary Objective: To assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy.

Study Hypothesis: Maintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placebo TRIAL DESIGN: This is a randomized double blinded phase II trial.

Major Inclusion/exclusion Criteria: The study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosarcoma, and high-grade adenosarcoma, FIGO (Federation International gynecologue Obstétricien) stage II/III to IV in stable disease or who achieved complete or partial response with doxorubicin ± ifosfamide, who are assigned 1:1 to 60 mg daily cabozantinib (experimental arm) or placebo (control arm), as maintenance therapy. Exclusion criteria include low-grade sarcoma.

Primary Endpoint: Progression-free survival at 4 months.

Sample Size: The study plans to enroll 90 patients to allow the randomization of 54 patients to detect an improvement in 4-month progression-free survival from 50% to 80% with 15% significance level and 85% power. Estimated dates for accrual completion: recruitment for the trial started in February 2015, and has currently enrolled 83 patients, of whom 35 patients have been randomized. The end of recruitment is anticipated for December 2020.

Trial Registration Number: ClinicalTrials.gov, number NCT01979393.
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http://dx.doi.org/10.1136/ijgc-2020-001519DOI Listing
October 2020

Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups.

J Clin Oncol 2020 07 18;38(19):2178-2186. Epub 2020 May 18.

Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall.

Patients And Methods: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176).

Results: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank = .323) and 0.76 and 0.66 (log-rank = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed.

Conclusion: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
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http://dx.doi.org/10.1200/JCO.19.03289DOI Listing
July 2020

Correction: Establishment and characterisation of a new patient-derived model of myxoid liposarcoma with acquired resistance to trabectedin.

Br J Cancer 2020 Mar;122(7):1120

Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41416-020-0746-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109093PMC
March 2020

Combination of PPARγ Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas.

Clin Cancer Res 2019 12 3;25(24):7565-7575. Epub 2019 Sep 3.

Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Purpose: This study was aimed at investigating whether the PPARγ agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin.

Experimental Design: The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting.

Results: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation.

Conclusions: The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0976DOI Listing
December 2019

Establishment and characterisation of a new patient-derived model of myxoid liposarcoma with acquired resistance to trabectedin.

Br J Cancer 2019 09 14;121(6):464-473. Epub 2019 Aug 14.

Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.

Background: Myxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients.

Methods: Through repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin.

Results: At basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance.

Conclusions: This is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.
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http://dx.doi.org/10.1038/s41416-019-0550-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738121PMC
September 2019

Pazopanib for treatment of advanced extraskeletal myxoid chondrosarcoma: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2019 09 19;20(9):1252-1262. Epub 2019 Jul 19.

Department of Medical Oncology, University Hospital Virgen del Rocio, Seville, Spain; Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain.

Background: Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma.

Methods: In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285.

Findings: Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]).

Interpretation: Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients.

Funding: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(19)30319-5DOI Listing
September 2019

Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft.

Cancers (Basel) 2019 Jul 19;11(7). Epub 2019 Jul 19.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin-ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin-ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.
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http://dx.doi.org/10.3390/cancers11071015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678245PMC
July 2019

Gain of FGF4 is a frequent event in KIT/PDGFRA/SDH/RAS-P WT GIST.

Genes Chromosomes Cancer 2019 09 16;58(9):636-642. Epub 2019 Apr 16.

Department of Specialized, Experimental and Diagnostic Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GIST) lacking mutations in KIT/PDGFRA or RAS pathways and retaining an intact SDH complex are usually referred to as KIT/PDGFRA/SDH/RAS-P WT GIST or more simply quadruple WT GIST (~5% of all GIST). Despite efforts made, no recurrent genetic event in quadruple WT GIST has been identified so far. To further investigate this disease, we performed high throughput copy number analysis on quadruple WT GIST specimens identifying a recurrent focal gain in band 11q13.3 (involving FGF3/FGF4) in 6/8 cases. This event was not found in the other molecular GIST subgroups. FGF3/FGF4 duplication was associated with high expression of FGF4, both at mRNA and protein level, a growth factor normally not expressed in adult tissues or in KIT/PDGFRA-mutated GIST. FGFR1 was found to be the predominant FGF receptor expressed and phosphorylation of AKT was detected, suggesting that a FGF4-FGFR1 autocrine loop could stimulate downstream signaling in quadruple WT GIST. Together with the recent reports of quadruple WT cases carrying FGFR1 activating alterations, these findings strengthen the hypothesis of a potential involvement of FGFR pathway deregulation in quadruple WT GIST, which may represent a rationale for novel therapeutic approaches.
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http://dx.doi.org/10.1002/gcc.22753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619263PMC
September 2019

Treatment Outcomes and Sensitivity to Hormone Therapy of Aggressive Angiomyxoma: A Multicenter, International, Retrospective Study.

Oncologist 2019 07 5;24(7):e536-e541. Epub 2018 Dec 5.

Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

Background: Aggressive angiomyxoma (AA) is a rare, locally aggressive tumor usually arising from pelvis or perineum, with a high local-recurrence rate after complete surgery. Anecdotal responses to hormone therapy have been reported. In the present study we aimed at studying surgical treatment outcomes and sensitivity to hormone therapy of AA.

Materials And Methods: We conducted a multicenter, international retrospective effort including patients with AA treated at three European referral centers (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and the Italian Rare Cancer Network; Centre Léon Bérard, Lyon, France; and Hospital Universitario Virgen del Rocio, Seville, Spain).

Results: A total of 36 patients were included. Median follow-up was 51.3 months. Thirty-three patients (92%) underwent complete (R0 + R1) surgery, with a local relapse rate of 50% and a median relapse-free survival of 39 months (95% confidence interval [CI], 27-68.1). Thirteen patients received a first-line systemic treatment with hormone therapy for locally advanced disease, with an overall response rate of 62% and a median progression-free survival of 24.6 months (95% CI, 11.0-39.7). In two patients, adding an aromatase inhibitor (AI) on progression to first-line GnRH agonist (GnRHa) resulted in a new tumor response.

Conclusion: Our findings confirm that in AA, surgical local control may be challenging, with a significant rate of local relapse despite complete surgery. Hormone therapy is an active treatment option, with a potential of disease control and of being combined with surgery. The addition of an AI to first-line GnRHa could be an effective second-line systemic therapy in premenopausal female patients with AA.

Implications For Practice: In this retrospective effort including 36 patients with aggressive angiomyxoma, local relapse rate after complete surgery was 50%, with a median relapse-free survival of 39 months, confirming that local control is challenging. Overall response rate to first-line hormone therapy was 62%, with a median progression-free survival of 24.6 months. Thus, hormone therapy has a potential of disease control and of being combined with surgery.
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http://dx.doi.org/10.1634/theoncologist.2018-0338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656447PMC
July 2019

Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME).

Cancer Treat Rev 2018 Dec 5;71:76-87. Epub 2018 Oct 5.

Department of Medical Oncology, Humanitas Clinical and Research Hospital, Rozzano (Milan), Italy.

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system.
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http://dx.doi.org/10.1016/j.ctrv.2018.10.001DOI Listing
December 2018

Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib.

Ther Adv Med Oncol 2018 29;10:1758835918794623. Epub 2018 Aug 29.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna.

Background: Rechallenge with imatinib is an option in advanced gastrointestinal stromal tumor (GIST) patients following progression with standard tyrosine-kinase inhibitors (TKIs), imatinib, sunitinib and regorafenib. We retrospectively collected data from metastatic Italian GIST patients treated with imatinib resumption after progression to conventional TKIs.

Methods: A total of 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected from six referral Italian institutions. Mutational analysis was recorded and correlated with survival and response according to RECIST 1.1 or CHOI criteria.

Results: Overall, 71 patients treated with imatinib 400 mg as rechallenge were included. Mutational status was available in all patients. The median follow up was 13 months. In patients who received a rechallenge therapy, the median time to progression (TTP) was 5.4 months [95% confidence interval (CI) 1.9-13.5] and overall survival (OS) was 10.6 months (95% CI 2.8-26.9). A correlation between mutational status, response rate, TTP and OS was not found but comparing deleted nondeleted exon 11 patients, a significant difference was identified in terms of TTP and OS ( = 0.04 and  = 0.02, respectively).

Conclusions: Our retrospective data confirm that imatinib rechallenge is a reasonable option in advanced GIST. The prognostic value of the specific mutations was confirmed in our series.
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http://dx.doi.org/10.1177/1758835918794623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116078PMC
August 2018

Identification of an Actionable Mutation of KIT in a Case of Extraskeletal Myxoid Chondrosarcoma.

Int J Mol Sci 2018 Jun 23;19(7). Epub 2018 Jun 23.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.

Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of . The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 mutation was detected only in one out of 20 EMC cases analyzed, indicating that alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified.
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http://dx.doi.org/10.3390/ijms19071855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073125PMC
June 2018

Identification of SRF-E2F1 fusion transcript in EWSR-negative myoepithelioma of the soft tissue.

Oncotarget 2017 Sep 17;8(36):60036-60045. Epub 2017 May 17.

"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.

Myoepithelial neoplasms (MN) are rare and not well-circumstanced entities displaying a heterogeneous spectrum of genetic abnormalities, including EWSR1, FUS and PLAG1 rearrangements. However, in the remaining MN no other fusion gene has been described and knowledge concerning secondary acquired molecular alterations is still poor. Therefore, we screened 5 cases of MN of the soft tissue by RNA sequencing with the aim of identifying novel fusion transcripts. A novel SRF-E2F1 fusion was detected in two cases: one was negative for other fusions while the other showed also the presence of FUS-KLF17. The fusion was validated through independent techniques and, in both cases, SRF-E2F1 was detected only in a subclone of the tumoral mass. SRF-E2F1 maintained the coding frame, thus leading to the translation of a chimeric protein containing the DNA-binding domain of SRF and the trans-activation domain of E2F1. Moreover, ectopical expression of SRF-E2F1 demonstrated that the chimeric transcript is functionally active and could affect tumor growth. Occurrence in two cases and biological relevance of the two genes involved suggest that the SRF-E2F1 fusion might become a helpful diagnostic tool. Further biologic studies are needed to better assess its role in MN biology.
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http://dx.doi.org/10.18632/oncotarget.17958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601120PMC
September 2017

Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial.

Lancet Oncol 2017 06 9;18(6):812-822. Epub 2017 May 9.

Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Background: Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy.

Methods: For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m on day 1 intravenously over 180 min plus dacarbazine 500 mg/m on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry.

Findings: Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis.

Interpretation: In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma.

Funding: European Union grant (Eurosarc FP7 278472).
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http://dx.doi.org/10.1016/S1470-2045(17)30334-0DOI Listing
June 2017

Long-term Efficacy of Methotrexate Plus Vinblastine/Vinorelbine in a Large Series of Patients Affected by Desmoid-Type Fibromatosis.

Cancer J 2017 Mar/Apr;23(2):86-91

From the Departments of *Medical Oncology, †Statistics, and ‡Surgery, IRCCS Fondazione Istituto Nazionale Tumori; §Department of Medical Oncology, Humanitas Cancer Center, IRCCS; and Departments of ∥Radiology and ¶Pathology, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy.

Purpose: Today, surgery and radiation therapy have a limited role in desmoid-type fibromatosis. Different systemic treatments were shown to be effective. Herein, we report on our institutional experience with low-dose methotrexate (MTX) + vinca alkaloids in this disease over the last 25 years.

Methods: We retrospectively reviewed data from all adult patients with sporadic desmoid-type fibromatosis treated with MTX and vinca alkaloids at our institution between 1989 and 2014.

Results: We identified 75 patients treated with MTX + vinblastine (40%), MTX + vinorelbine (57%), and vinorelbine alone (3%). All patients had progressive disease before chemotherapy; 72%, 10%, and 48% of patients had received previous surgery, radiation therapy, and/or systemic treatments, respectively. Chemotherapy was administered for a median duration of 14 months and a median number of 37.5 cycles. Eight patients interrupted chemotherapy because of toxicity. According to RECIST (Response Evaluation Criteria in Solid Tumors) complete response, partial response, stable disease, and progressive disease were observed in 1%, 47%, 51%, and 1% of patients, respectively. Symptomatic relief was obtained in 80% of symptomatic cases. The median progression-free survival (PFS) was 75 months; it was 136 months in responding patients. Upon progression, after chemotherapy withdrawal, MTX plus vinblastine/vinorelbine was offered to 11 patients with partial response, stable disease, and progressive disease in 4, 6, and 1 cases, resulting in a median PFS of 53 months.

Conclusions: In this series, chemotherapy with MTX and vinca alkaloids is confirmed to be active and effective, with a remarkable PFS, higher in responding patients, and limited toxicity. Even progression can be successfully rechallenged.
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http://dx.doi.org/10.1097/PPO.0000000000000254DOI Listing
May 2017

HSPA8 as a novel fusion partner of NR4A3 in extraskeletal myxoid chondrosarcoma.

Genes Chromosomes Cancer 2017 07 4;56(7):582-586. Epub 2017 May 4.

Adult Mesenchymal Tumour and Rare Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori Milan, Italy.

Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG, and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumor cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology.
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http://dx.doi.org/10.1002/gcc.22462DOI Listing
July 2017

How a Clinical Trial Unit can improve independent clinical research in rare tumors: the Italian Sarcoma Group experience.

Clin Sarcoma Res 2017 28;7. Epub 2017 Feb 28.

Laboratory of Experimental Oncology, Orthopedic Rizzoli Institute, Bologna, Italy.

Background: The Italian Sarcoma Group (ISG) is a nonprofit group of professionals established in 1997 aimed to improve the quality of care and promote the independent research in sarcomas. The increased regulatory requirements, the chance to increase the number of trials with other cooperative groups and an interest from pharmaceutical companies in supporting independent research, generated the need of an internal service for research management.

Methods And Results: In 2010, ISG implemented in its organization a Clinical Trial Unit (CTU). The CTU was appointed to fully manage Clinical Trial Operations, to guarantee regulation compliance and provide a central support to the investigators, fostering a collaboration both at national and international level. In 2016 ISG promoted 25 studies in about 120 centers, with a fivefold increase in the last 5 years: 68% were interventional and 32% observational. Nine of the 17 interventional studies (52%) were supported by pharmaceutical companies, while 4 (24%) were funded by European Commission within specific projects on sarcomas and 4 (24%) were supported by the ISG itself.

Conclusion: The contribution of ISG researchers to the international community was striking from the earliest years of the ISG creation. The challenges of the regulatory clinical research scenario, which imposes solid and hard-fast methodology with deep knowledge and expertise, highlighted the need to identify qualified and dedicated experts able to run and follow the multifaceted aspects of trials. Our analysis demonstrated how this model has led to a growth in competitiveness of the group. The collaboration between clinicians and CTU made possible to support the research with high scientific and ethical standards and to increase the number of trials, sites and overall enrolled patients. The reduced time for approvals, the continuous support to sites, the increased speed in data collection and analysis make the ISG research attractive for pharmaceutical industries, despite the problems that have characterized the independent research in the last years. The ability to fully manage and oversight Clinical Operations and the high quality of delivered services, have led the ISG to be recognized as a reliable partner and coordinator within the international sarcoma networks.
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http://dx.doi.org/10.1186/s13569-017-0068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329913PMC
February 2017

Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: A retrospective MITO group study.

Gynecol Oncol 2017 Jan 4;144(1):90-95. Epub 2016 Nov 4.

Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Gynecologic Oncology, Milan, Italy. Electronic address:

Objective: To investigate the impact of morcellation on survival outcomes of patients affected by undiagnosed uterine sarcoma.

Methods: This is a retrospective study performed in 8 referral centers of MITO group. Data of women undergoing morcellation for apparent benign uterine myomas who were ultimately diagnosed with stage I uterine sarcoma on final pathology were compared with data of women who did not undergo morcellation. Uterine sarcoma included: leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), low-grade endometrial stromal sarcomas (LG-ESS) and undifferentiated uterine sarcomas (UUS). Two-year survival outcomes were evaluated using Kaplan-Meir and Cox models.

Results: Overall 125 patients were identified: 31(24.8%), 21(16.8%) and 73(58.4%) patients had power morcellation during laparoscopy, non power morcellation during open surgery and non morcellation during open procedures, respectively. Considering patients affected by LMS, morcellation did not correlated with disease-free survival. However, patients undergoing either morcellation or power morcellation experienced a 3-fold increase risk of death in comparison to patients who had not morcellation (p=0.02). A trend towards an increase of recurrence was observed for patients undergoing morcellation for STUMP (HR 7.7, p=0.09); while no differences in survival outcomes were observed for patients with LG-ESS and UUS.

Conclusions: Our data suggest that morcellation increase the risk of death in patients affected by undiagnosed LMS. Further prospective studies are warranted in order to assess the risk to benefit ratio of power morcellator utilization in patients with apparent benign uterine myomas.
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http://dx.doi.org/10.1016/j.ygyno.2016.11.002DOI Listing
January 2017

Adjuvant Imatinib for GI Stromal Tumors: When and For How Long?

J Clin Oncol 2016 Jan 7;34(3):215-8. Epub 2015 Dec 7.

Istituto Nazionale Tumori, Milan, Italy.

A 45-year-old woman presented with syncope. She was severely anemic, with a hemoglobin level of 6 g/dL, and was found to have lower GI bleeding. A diagnostic colonoscopy was negative. A subsequent computed tomography scan of the abdomen and pelvis was performed, revealing a 3.2 × 3 × 2.9-cm contrast-enhancing right lower-quadrant mass arising from the wall of the ileum. There was no evidence of metastatic disease. The patient underwent laparotomy, and a 3.5-cm mass was resected with negative margins. Pathology revealed a GI stromal tumor with mixed spindle and epithelioid features involving the mucosa and submucosa (Fig 1A). The tumor cells were positive for CD117 (c-kit) (Fig 1B) and DOG-1(Fig 1C). There were eight to 10 mitoses per 50 high-power fields (Fig 1D). Molecular studies showed a 42-base pair deletion in exon 11 of the KIT gene that would delete all or part of codons 558 to 572 (V559_D572del) and would change the 558-encoding amino acid from Lys to Asn (K558N).
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http://dx.doi.org/10.1200/JCO.2015.64.0102DOI Listing
January 2016

Understanding Deviations from Clinical Practice Guidelines in Adult Soft Tissue Sarcoma.

Stud Health Technol Inform 2015 ;216:280-4

IBM Research, Haifa, Israel.

In recent years we have witnessed the increasing adoption of clinical practice guidelines (CPGs) as decision support tools that guide medical treatment. As CPGs gain popularity, it has become evident that physicians frequently deviate from CPG recommendations, both erroneously and due to sound medical rationale. In this study we developed a methodology to computationally identify these deviation cases and understand their movitation. This was achieved using an integrated approach consisting of natural language processing, data modeling, and comparison methods to characterize deviations from CPG recommendations for 1431 adult soft tissue sarcoma patients. The results show that 48.9% of patient treatment programs deviate from CPG recommendations, with the largest deviation type being overtreatment, followed by differences in drug treatments. Interestingly, we identified over a dozen potential reasons for these deviations, with those directly related to the patients' cancer status being most abundant. These findings can be used to modify CPGs, increase adherence to CPG recommendations, reduce treatment cost, and potentially impact sarcoma care. Our approach can be applied to additional diseases that are subject to high deviation levels from CPGs.
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December 2016

High-dose continuous-infusion ifosfamide in advanced well-differentiated/dedifferentiated liposarcoma.

Clin Sarcoma Res 2014 22;4(1):16. Epub 2014 Nov 22.

Adult Mesenchymal Tumor Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milano, Italy.

Background: Liposarcomas represent the most common histological type of soft-tissue sarcomas (STS). Its main subgroups, WD/DD, is known to be poorly sensitive to chemotherapy, with few active agents, i.e., anthracyclines +/- ifosfamide and trabectedin. High-dose ifosfamide (HDIFX >12 g/m2) is active in STS pts pretreated with standard-dose IFX, though with greater toxicity. A prolonged continuous-infusion (ci) through a portable external pump may be an alternative way to administer HDIFX.

Methods: From March 2002 to August 2013, 28 pts (median age =60, range =37-73 yrs) with advanced disease (6 WD and 22 WD/DD) were given ciHDIFX, at the dose of 14 g/m2 as a 14-day continuous infusion every 4 weeks. Twenty-four pts (86%) were previously treated with chemotherapy (19 with anthracyclines and ifosfamide; 4 with anthracycline monotherapy; 1 with trabectedin).

Results: Seven PR (all in DDLPS), 2 minor response (MR) and 11 SD were observed. Of interest, 6 of 9 patients with PR or MR had had SD with the previous therapy with anthracycline plus ifosfamide. The median progression-free survival was 7 months. Most common side effects were mild myelosuppression (anemia G2-3 in 3 pts; G2-3 neutropenia in 3 pts and G4 in 1; G3 thrombocytopenia in 1 pt); nausea (G3 in 3 pts) and fatigue (G3 in 6 pts). One pts had transient G3 confusion.

Conclusions: These data suggest that ciHDIFX is active in WD/DDLPS, even in patients already treated with a combination of anthracyclines plus ifosfamide. In this series, ciHDIFX regimen was better tolerated than HDIFX in published studies.
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http://dx.doi.org/10.1186/2045-3329-4-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307996PMC
January 2015

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

Lancet Oncol 2015 Jan 11;16(1):98-107. Epub 2014 Dec 11.

Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.

Background: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment.

Methods: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374.

Findings: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths.

Interpretation: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater.

Funding: Italian Sarcoma Group.
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http://dx.doi.org/10.1016/S1470-2045(14)71136-2DOI Listing
January 2015

Tenosynovial giant cell tumour/pigmented villonodular synovitis: outcome of 294 patients before the era of kinase inhibitors.

Eur J Cancer 2015 Jan 24;51(2):210-7. Epub 2014 Nov 24.

Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Tenosynovial giant cell tumour/pigmented villonodular synovitis (TGCT/PVNS) is a benign neoplasm of synovium and tendon sheath. We conducted a retrospective pooled analysis in three major referral centers.

Methods: Patients treated between 1998 and 2008 were examined. Only patients presenting with primary disease or first relapse were included. 5-year local failure free survival (5-year-LFFS) was analysed.

Results: 294 patients were included: 254 with new diagnosis and 40 in 1st local recurrence (171 F/123 M; median age: 36 years; tumour size ⩽2 cm in 27% of patients, >2 to ⩽5 cm in 41%, and >5 cm in 32%). A diffuse pattern was reported in 69%, localised in 31%. No metastases were documented. Local failure (LF) was reported in 28% of patients: 36% in diffuse pattern, 14% in localised (p = 0.002); median time to LF: 16 months. With a median follow-up of 4.4 years, 5-year-LFFS was 66%, with multiple (up to five) local recurrences in 40% of relapsed patients. Size <2 cm, macroscopically complete resection, female gender and new diagnosis were associated with a better local control. After multivariate analysis, a previous relapse was independently associated with local failure.

Conclusions: This study underlines the propensity of TGCT/PVNS to multiple local recurrences. In absence of clinical factors, biological studies are needed to identify prognostic factors of local failure. After a first local recurrence, surgery does not seem to have a curative potential. In these high risk patients, studies addressing the role of target therapies are needed.
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http://dx.doi.org/10.1016/j.ejca.2014.11.001DOI Listing
January 2015