bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic landscape of soft-tissue sarcomas: Moving toward personalized medicine.
Authors: Italiano Antoine , Khalifa Emmanuel , Laizet Yec'han , Toulmonde Maud , Cousin Sophie , Lucchesi Carlo 
Published: September 2018

11002 Background: Patients with advanced soft-tissue sarcomas have a very poor outcome with a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving their outcomes. Methods: We have analyzed the mutational and copy number profiles of patients with sarcoma sequenced through the AACR Project GENIE Consortium in order to identify the proportion of cases bearing actionable mutation. Results: 587 patients (pts) were included in the study (295 males). 331 pts (56%) had complex genomics sarcomas, 144 (25%) translocation-related sarcomas and 112 (19%) others sarcomas (inactivating mutation, simple amplicon). The five most frequent histology were: Leiomyosarcoma (n = 112; 19.1%); Undifferentiated Pleomorphic Sarcomas (n = 74, 12.6%), dedifferentiated liposarcoma (n = 55, 9.4 %), angiosarcoma (n = 43, 7.3%), synovial sarcoma (n = 38, 6.5%). 430 pts (73%) had at least one mutation. The ten most frequently mutated genes were: TP53 (34.7%); ATRX (9.1%), RB1 (8.4%), KMT2D (5.8%), NF1 (5.3%), ATM (5.1%), PI3KCA (4.9%), ERBB4 (4.2%), PTEN (4%), and ARID1A (3.7%). 504 patients (85.9%) presented at least one copy number alteration. The 5 five most frequently amplified genes were: MDM2 (20%), CDK4 (16.7%), GLI1, MAP2KA, and TERT (3.2% for each gene), and the most frequently deleted were RB1 (12.7%), CDKN2A (10.3%), CDKN2B (9.7%), TP53(9.5%), PTEN (8.5). 92.5% of pts had at least one targetable mutation, copy number alteration and/or fusion gene ( Leiomyosarcoma n = 100/17%, UPS n = 74/12%, dedifferentiated diposarcoma n = 54/9%, angiosarcoma n = 41/7%, synovial Sarcoma n = 36/6%), with incidences reported that will be reported in details at the meeting. Conclusions: This is the first large report of genomic landscape including mutation and copy number profiling through NGS of soft-tissue sarcomas. Our results indicate a significant proportion of actionable mutations and represent a rationale for the MULTISARC study: the first study implementing Exome Seq and RNA Seq for clinical decision making in patients with advanced STS. The design of this study supported by the French government and launched in 09/2017 will be presented at the meeting.
Multi-institutional European single-arm phase II trial of pazopanib in advanced malignant/dedifferentiated solitary fibrous tumors (SFT): A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) sarcoma groups study.
Authors: Martin Broto Javier , Stacchiotti Silvia , Lopez-Pousa Antonio , Redondo Andres , Bernabeu Daniel , Casali Paolo Giovanni , Italiano Antoine , Grignani Giovanni , Dumont Sarah , Garcia del Muro Xavier , Gutierrez Antonio , Martinez Trufero Javier , Palmerini Emanuela , Hindi Nadia , de Alava Enrique , Collini Paola , Ranchère-Vince Dominique , Blay Jean-Yves , Cruz Josefina 
Published: September 2018

11003 Background: SFT is a rare soft tissue tumor. In advanced SFT chemotherapy has only limited activity. With the rationale of a rich vascular network & VEGF (tumor cells and endothelium) and VEGFR1/2 (endothelial cells) expression in SFT, we designed an international, single-arm phase II trial to test pazopanib (P) in advanced SFT. Clinical and preclinical evidence suggesting that antiangiogenics was less effective in more aggressive compared with less aggressive SFT (Stacchiotti et al), led us to conduct the trial on two different cohorts: typical and malignant (M)/dedifferentiated (DD) SFT. Here we present the outcome of the latter cohort. Methods: Most relevant inclusion criteria were: unresectable or metastatic, M/DD SFT confirmed by central pathologic review with evidence of STAT6 (IHC and /or FISH or RT-PCR), ≥ 18 years, ECOG 0-2, progressive and measurable disease. Main endpoint was response rate (RR) according Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously until progression or toxicity. Results: From June 2014 to November 2016, 34 patients (pts) were enrolled with a median age of 61 y (23-87). Median tumor size and mitosis at diagnosis were 77 mm and 8x10 HPF. Most relevant grade 3-4 toxicity were neutropenia (9%) and hypertension (12%). At the time of the present analysis, 31 pts are evaluable for response. RR according to Choi and RECIST were: PR 16 (52%), SD 7 (22%), PD 8 (26%) and PR 1 (3%), SD 19 (61%), PD 11 (35%) respectively. With a median follow-up of 15 months, the median PFS was 5.53 months (4.24-6.82), while 72% survived at 18 months. Size > 5 cm, mitosis > 8 and DD subtype showed significantly worse PFS. The 18-month OS was 90% for those with SD and PR and 25% for PD according to Choi (p < 0.001), while 94% for SD and PR and 45% for PD according RECIST (p = 0.002). In multivariate analysis, only Choi was an independent prognostic factor for OS with PD showing a HR of 11.9 (2.3-63.1), p = 0.003 for the risk of death. Conclusions: Pazopanib showed activity in malignant SFT. Choi criteria exhibited a more accurate assessment of response than RECIST. Clinical trial information: NCT02066285.
Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomised phase II trial (C2130/A12118).
Authors: Judson Ian Robert , Morden James P , Leahy Michael Gordon , Bhadri Vivek , Campbell-Hewson Quentin , Cubedo Ricardo , Dangoor Adam , Hennig Ivo M. , Joubert Warren Lance , Kernaghan Sarah , Lopez-Pousa Antonio , Seddon Beatrice M. , Snowdon Claire , Tatersall Martin , Toms Christy , Martinez-Trufero Javier , Bliss Judith ,   On Behalf of the CASPS Trial Management Group and Investigators
Published: September 2018

11004 Background: ASPS is a rare disease (0.5-1% of soft tissue sarcomas) mainly affecting young people. It is unresponsive to conventional chemotherapy. Cediranib (C), an inhibitor of vascular endothelial growth factor receptors and other receptor tyrosine kinases, has shown significant activity in ASPS in single arm phase II trials. CASPS (NCT01337401) was designed to permit discrimination between the impact of cediranib and the often intrinsically indolent nature of the disease. Methods: CASPS compared C (30mg od) with placebo (P) in a 2:1 double blind randomisation in patients (pts) age ≥16 years with metastatic ASPS progressive in the previous 6 months. Pts were unblinded at week 24, or at progression if sooner, when those on P started C. The primary endpoint of percentage change in the sum of target marker lesions (TMLsum) between baseline and week 24 (or progression if sooner) was compared between groups by Mann-Whitney test. Secondary endpoints were progression-free survival (PFS), week 24 response rate and best response (RECIST v1.1), safety/tolerability and overall survival (OS). One-sided p-values and two-sided 90% confidence intervals are reported. Results: 48 pts were recruited between 07/2011 and 07/2016 from 12 centres (UK, Australia & Spain). 52% of pts were female, median age was 31. Most common grade ≥3 adverse events on C were hypertension (23%), diarrhoea (14%) and fatigue (9%). In the evaluable population (N = 44) median change in TMLsum on C was minus 8.3% (IQR minus 26.2% to +5.9%); versus P: +13.4% (IQR minus 0.6% to +21.3%), p = 0.0013. Best response by week 24 was partial response for 6/28 (21%) C pts compared with 0/16 on P (p = 0.053) and stable disease for an additional 19/28 (68%) on C and 12/16 (75%) on P. The PFS HR (C versus P) was 0.54 (90% CI 0.30-0.97, p = 0.041), median PFS: 10.8 mths on C versus 3.7 mths on P, OS at 12 mths was C: 96%; P: 64.3%. Conclusions: CASPS, the largest randomised trial to date in this disease, confirms the activity of C in ASPS, showing a significant reduction in tumour burden and improvement in PFS. Tumour tissue and serial blood samples will subsequently be investigated to identify potential predictive and prognostic biomarkers. Clinical trial information: NCT01337401.
Failure rate of standard rescue with leucovorin for high-dose methotrexate (HDMTX) in osteosarcoma.
Authors: Eriksson Mikael , Rychlowska-Pruszynska Magdalena , Csóka Mónika , Hall Kirsten Sundby , Karlén Jonas , Kvistgaard Louise , Lisjö Pia , Ganlöv Karin 
Published: September 2018

11028 Background: HDMTX followed by leucovorin rescue is well established as part of MAP chemotherapy for osteosarcoma. However, leucovorin rescue is not always effective as rescue, resulting in delays to subsequent courses of chemotherapy. Methods: This retrospective observational study involved patients ≥2 years of age with osteosarcoma treated with MAP during 2009 - 2014. Data was extracted from medical records from five clinics in Poland, Hungary, Norway and Sweden. The study objective was to determine to what extent patients treated with MAP encountered treatment delays due to MTX-related toxicity or delayed MTX elimination. Results: All patients fulfilling the inclusion criteria were included. Of 116 patients (ages 5-39 with a mean of 14 years; 59% males), 97% completed their first MAP cycle while only 48% completed six treatment cycles. The analysis of the primary endpoint included 114 evaluable patients. At least one treatment delay due to MTX toxicity or delayed MTX elimination was reported for 89 patients (78%) and only six patients (5%) completed the entire MAP treatment according to plan. Delay in subsequent treatment was observed following 183 of 369 evaluated MAP cycles (50%). About three quarters of the delays were found to be due to MTX-related toxicity while only a small number were related to delayed MTX elimination. The treatment related issues most commonly registered were increased liver enzymes, hematological disturbances, increased bilirubin and mucositis. Conclusions: We found at least one treatment delay due to MTX toxicity or delayed MTX elimination in 78% of all MAP-treated patients and that 50% of the administered MAP cycles resulted in a delay in subsequent treatment, mostly due to MTX toxicity. Only six patients (5%) completed the entire MAP treatment according to plan. The retrospective methodology with broad inclusion criteria implies that the results can be extrapolated to the entire target population. Thus, there appears to be an unmet need for a more effective HDMTX rescue that could reduce MTX toxicity and be expected to enable more patients to maintain planned MAP treatment intensity and duration, thereby improving the overall efficacy of the MAP regimen.
Long-term survival (over 10 years) of inoperable/metastatic GISTs: A retrospective series of 141 patients (pts) of the french sarcoma group (FSG).
Authors: Duffaud Florence , Auclin Edouard , Italiano Antoine , Mancini Julien , Bertucci Francois , Penel Nicolas , Pracht Marc , Vogin Guillaume , Collard Olivier , Bompas Emmanuelle , Landi Bruno , Valentin Thibaud , Chaigneau Loic , Toulmonde Maud , Adenis Antoine , Ray-Coquard Isabelle Laure , Rios Maria , Salas S Bastien , Le Cesne Axel , Blay Jean-Yves ,   French Sarcoma Group
Published: September 2018

11041 Background: A subset of metastatic GIST exhibit very long-term survival after imatinib (IM) introduction. The aim of this study was to analyse the clinico-biological characteristics of GIST pts alive > 10 years (yrs) after diagnosis (dx) of metastases (mets) and identify possible factors associated with long-term survival. Methods: Pts were identified from 2 sarcoma databases; NetSarc and ConticaGIST. Clinical data prospectively registered in the databases were supplemented with retrospective review of medical records. Results: We identified 141 pts (75 men, 66 women) with median age 54 (17-84) yrs and median ECOG 0 (0-2). Primary tumors (T) were all CD117+, and mainly gastric or intestinal (64 & 45 pts), with median size 10 (2-40) cm, CD34+ (82 pts), mitoses/50 HPF ≤ 5 (n = 36), or > 5 (n = 81). Genotype was documented in 82 (58%) pts with 73 (89%) KIT mutations (in exons 11,9 and 12 of 69, 3, and 1 pts respectively) and 9 WT KIT. 129 (91%) T were resected, 124 upfront, 5 post IM, with R0/R1/R2 resections in 61, 11, and 10 pts. Mets were mainly hepatic or peritoneal (78 & 51 respectively). 1st line TKI was given to 139 pts: 130 received IM; 88 (63%) within a clinical trial (CT), 41 (29%) had mets resection. Second, 3d and 4th line TKI were given to 81, 51 and 37 pts respectively, comprising 27, 7 and 10 from CT. Median number of TKIs was 2 (0-7), but 60 (44%) pts received only 1st line with no GIST progression within or after 10 yrs. 2 pts never received TKI but had mets resection. After median FU of 14.3 yrs (10-34.5), 104 remain alive, 37 died. Mean and Median OS from initial dx are 24 yrs (CI95% 21.6-27) and 20,8 yrs. Median PFS on TKIs are 127, 29, 21 and 22 mos on 1st, 2d, 3d and 4th line of TKI. In univariate analysis no factor is significantly associated with OS, but T size (≤ 10 vs > 10 cm) and oligometastatic disease (≤5 vs > 5 mets) are borderline significant (p = 0.056 and 0.07), and good PS (ECOG ≤ 1) at 2dline TKI initiation is associated with better PFS (p = 0.03). Conclusions: This large series of long-term ( > 10 yrs) survivors of metastatic GIST shows a high proportion of mets resection and a longer duration of PFS for TKI at any line. In this selected population, no prognostic factor is associated with long OS.
Post-cross-over activity of regorafenib (RE) in soft tissue sarcoma: Analysis from the REGOSARC trial.
Authors: Kotecki Nuria , Brodowicz Thomas , Le Cesne Axel , Le Deley Marie-Cecile , Wallet Jennifer , Italiano Antoine , Blay Jean-Yves , Bertucci Francois , Chevreau Christine , Piperno-Neumann Sophie , Bompas Emmanuelle , Salas S Bastien , Perrin Christophe , Delcambre Corinne , Lieg-Atzwanger Bernadette , Toulmonde Maud , Ray-Coquard Isabelle Laure , Thery Julien , Mir Olivier , Penel Nicolas 
Published: September 2018

11052 Background: Based on the placebo (PBO) controlled phase 2 trial (Mir, Lancet Oncol 2016), RE has shown to be an active drug in patients (pts) with leiomyosarcoma (LMS), synovial sarcoma (SS) and other non-adipocytic sarcoma (OTH), but not in liposarcoma. Pts initially allocated to PBO were allowed to cross-over to RE after progression. We here report the activity of RE after cross-over. Methods: From July 2013 to Dec 2014, 138 pts were enrolled in the non-adipocytic sarcoma cohorts (LMS, SS & OTH). After update in Dec 2016, median follow-up was 32 mo (vs 17 mo in the initial publication). Benefit of RE vs PBO in terms of progression-free survival (PFS) and overall survival (OS) from randomization was estimated by hazard ratio (HR) in Cox models. In the PBO arm, intra-patient benefit of RE after cross-over was evaluated by the growth modulation index (GMI), where PFS1=PFS with PBO before cross-over, and PFS2=PFS with RE after cross-over. The impact of timing of RE allocation (delayed after cross-over, vs early at study entry) was evaluated by comparing PFS after cross-over in PBO arm to PFS after randomization in RE arm. Results: As detailed in the table, major PFS benefit of RE vs PBO allocated by randomization was confirmed with long follow-up (HR=0.50 [95%CI 0.35-0.71] p<.0001). However, this translates into a smaller and non-significant OS benefit (HR=0.78 [0.54-1.12] p=.18). This finding may partially be explained by the fact that 55 of the 68 pts who progressed in the PBO arm (81%) could receive RE after progression and benefit from RE: 56% of them had a GMI greater than 1.3. Delayed start of RE was associated with a non-significantly shorter PFS compared to earlier treatment (HR=1.21, [0.84-1.73] p=.30). Conclusions: Efficacy of RE vs PBO is confirmed with longer follow-up in non-adipocytic sarcoma. PFS of pts receiving RE after cross-over is not significantly shorter than that of pts initially randomized to receive RE. Clinical trial information: NCT01900743. [Table: see text]
SYNFRIZZ: A first-in-human (FIH) study of a radiolabeled monoclonal antibody (Mab) targeting frizzled homolog 10 (FZD10) in patients (pts) with advanced synovial sarcomas (SyS).
Authors: Cassier Philippe Alexandre , Giraudet Anne Laure , Iwao-Fukukawa Chicaco , Garin Gwenaelle , Badel Jean-Noel , Kryza David , Chabaud Sylvie , Cropet Claire , Sarrut David , Gilles-Afchain Laurence , Halty Adrien , Italiano Antoine , Penel Nicolas , Mori Masaharu , Tsunoda Takuya , Katagiri Toyomasa , Nakamura Yusuke , Baconnier Simon J , Pérol David , Blay Jean-Yves 
Published: September 2018

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.
Outcome of 212 malignant phyllod tumor patients: A retrospective study from the French Sarcoma Group (GSF-GETO).
Authors: Neron Mathias , Sajous Christophe , Piperno Neumann Sophie , Chakiba Camille , Ducoulombier Agnes , Owen Clémentine , Salas S Bastien , Bertucci Francois , Saada-Bouzid Esma , Valentin Thibaud , Bay Jacques-Olivier , Bompas Emmanuelle , Isambert Nicolas , Maran-Gonzalez Aurélie , Llacer Carmen , Carrère Sebastien , Cupissol Didier , Thezenas Simon , Blay Jean-Yves , Firmin Nelly ,   French Sarcoma Group (GSF-GETO)
Published: September 2018

11055 Background: The optimal management of malignant phyllod tumors (MPT) is poorly documented. Objective:To study the characteristics and outcome of MPT patients (pts). Methods: Retrospective study from the nation-wide French sarcoma network (NetSarc) from 2000 to 2016. Inclusion criteria was central pathological review of MPT. End-points were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Results: 212 pts, from 13 centers, were included. Median age was 52.8 years (range: 16.8 - 90.5). All localized MPT pts (96.7%) underwent surgery with 41.4% of mastectomy. The median size was 5.8 cm (range: 1.5 - 30). R1/R2 resection was achieved in 40.1% pts (26.9% 1-2 mm margin, 12.2% 3-7 mm, 20.3% ≥8 mm), with 44.8% of second surgery (SS) for a final mastectomy rate of 72.6%. Presurgical biopsy was performed in 86.3% and associated with R0 resection ( p=0.044) and better LRFS ( p=0.012). Median follow-up was 4.1 years (range 0-14.8) and revealed 34 (16.6%), 48 (22.9%), 44 (20.8%) events for LRFS, MFS and OS, respectively. The 2-year OS rate was 89%. Prognostic factors found in multivariate analysis are presented in Table 1. Wider margins (≥8mm) were not associated with better outcomes. Adjuvant radiotherapy and chemotherapy were performed in 43.6% and 13.3% respectively and associated with longer LRFS, not significant in multivariate analysis. Conclusions: Mastectomy is associated with better local control, but not with MFS and OS. Age, tumor necrosis and metastatic disease are associated with poor prognosis in MPT pts. Our study suggests that margins of 3 mm are necessary and sufficient for the surgical management of MPT and emphasizes the importance of SS to obtain clear margins. [Table: see text]
International single-arm phase II trial of pazopanib in advanced extraskeletal myxoid chondrosarcoma: A Collaborative Spanish (GEIS), Italian (ISG) and French (FSG) Sarcoma Groups study.
Authors: Stacchiotti Silvia , Ferrari Stefano , Redondo Andres , Palmerini Emanuela , Hindi Nadia , Vaz M. Angeles , Frezza Anna Maria , Gutierrez Antonio , Lopez-Pousa Antonio , Grignani Giovanni , Italiano Antoine , Dumont Sarah , Blay Jean-Yves , Penel Nicolas , Bernabeu Daniel , de Alava Enrique , Ranchère-Vince Dominique , Collini Paola , Cruz Josefina , Martin Broto Javier 
Published: September 2018

11062 Background: Extraskeletal myxoid chondrosarcoma (EMC) is an exceedingly rare sarcoma, marked by a specific translocation involving the gene NR4A3 that can be rearranged with different partners. Preliminary retrospective data suggest that sunitinib is active, but no formal prospective studies are available. We report on a multicentric European prospective, investigator-driven, Phase 2 study on pazopanib (P) in NR4A3+ advanced EMC patients (pts), carried out by the Spanish, Italian and French Sarcoma groups. Methods: From June 2014 to November 2016, 24 advanced EMC pts entered this study (median age: 64 yrs - disease extent: metastatic 77%, locally advanced 23% - prior medical treatment: 18 (86%) naive; 2 (9%) 1 line, 1 (5%) > 1 line). Path diagnosis and NR4A3 rearrangement (FISH and/or real-time PCR analysis) were centrally confirmed. Pts received P 800 mg/day (relative dose intensity = 0,82%, 658 mg/day), until progression or toxicity. The primary study end-point was response rate as per RECIST 1.1. Secondary end-points were overall survival, progression-free survival (PFS), clinical benefit rate (CBR) (RECIST CR+PR+SD≥6mos). An exploratory evaluation of the correlation between the rearrangement subtype and the outcome is ongoing. Results: 20/24 pts were evaluable for response (1 early death; 3 too early). One patient (5%) had a partial response, 17 (75%) stable disease, 2 (10%) progression as their best RECIST responses. At the time of this analysis, 12 pts were still under treatment, while 12 interrupted P (10 progression, 1 toxicity, 1 other). At a 13-month median follow-up, the median PFS was 13 months (range 1.6-25.1), with 29% pts progression-free at 18 months and a 65% CBR. Median OS was not reached. Conclusions: This Phase 2 study is formally negative since the target of at least 3/21 RECIST responses was not reached. However, looking at PFS, P was associated with a prolonged disease stabilization in a significant proportion of pts. This suggests to further explore the use of P in EMC. Clinical trial information: NCT02066285.