bluuebunny/crossref_metadata_2025_split huggingface dataset:
The sarculator stratified prognosis of patients with high-risk soft tissue sarcomas (STS) of extremities and trunk wall treated with perioperative chemotherapy in a randomised controlled trial (RCT).
Authors: Pasquali Sandro , Colombo Chiara , Bottelli Stefano , Verderio Paolo , Martin Broto Javier , Lopez-Pousa Antonio , Ferrari Stefano , Poveda Andres , De Paoli Antonino , Quagliuolo Vittorio , Cruz Josefina , Comandone Alessandro , Grignani Giovanni , De Sanctis Rita , Palassini Elena , Llombart-Bosch Antonio , Dei Tos Angelo Paolo , Casali Paolo Giovanni , Picci Piero , Gronchi Alessandro 
Published: September 2018

11016 Background: Patients with extremity and trunk wall STS with high malignancy grade and size larger than 5cm are considered at high risk of death, but in fact this risk varies broadly depending on histologic subtype and size. The Sarculator, a nomogram for STS, can improve prognostic assessment of these patients. This tool was evaluated for stratifying risk of distant metastasis (DM) and overall survival (OS) in a RCT investigating perioperative chemotherapy. Methods: High-risk STS patients were randomly assigned to receive either three cycles of preoperative chemotherapy with epirubicin (120 mg/m2) and ifosfamide (9 g/m2) or the same three preoperative cycles followed by two further postoperative cycles. The Sarculator was used to stratify patient risk according to predicted 10-year cumulative incidence of DM and OS rates. Results: The Sarculator identified three different prognostic groups of patients at low (N = 101), intermediate (N = 102), and high (N = 107) risk. Cumulative incidence of DM was 0.26 (SE: 0.04), 0.31 (SE: 0.05), and 0.48 (SE: 0.05) for low, intermediate, and high risk patients, respectively. Similarly, OS rates were 0.78 (95%CI 0.68-0.85), 0.63 (95%CI 0.53-0.72), and 0.42 (95%CI 0.32-0.52), respectively. Patients in the low risk group were at significantly lower risk of death compared to those in the intermediate (HR 0.51, 95%CI 0.34-0.78, P = 0.002) and high (HR 0.28, 95%CI 0.17-0.46, P < 0.001) risk groups. Subgroup analysis performed by jointly considering these three groups and the two study arms did not identify statistically significant survival differences between the treatment arms within each risk category. Conclusions: Patients with high-risk STS included in this RCT were not a homogeneous population. The Sarculator identified different risk groups for DM and OS even in patients included in a RCT investigating perioperative treatments. This tool should be considered for redefining high-risk STS and stratifying patient risk in future RCT investigating perioperative chemotherapy. Clinical trial information: 2004-003979-36.
Factors impacting contemporary management of high-grade extremity sarcoma: An analysis of 12,020 patients.
Authors: Ramey Stephen , Asher David , Zhao Wei , Kodiyan Joyson , Chinea Felix , Patel Vivek , Wang Lily , Wilky Breelyn A. , Subhawong Ty , Trent Jonathan C. , Yechieli Raphael 
Published: September 2018

11017 Background: Previous studies noted racial/ethnic disparities in high-grade extremity soft tissue sarcoma (ESS) treatment and overall survival (OS). Retrospective series have noted worse OS for Amputation (Amp) vs limb salvage surgery (LSS) and for LSS alone vs LSS plus radiation (RT). Given superior functional outcomes, LSS is now favored over Amp when possible. This study examines racial/ethnic disparities in receipt of Amp vs LSS and impact on OS using modern data from a national registry. Methods: The National Cancer Database was used to identify patients (pts) with stage II-III, high-grade ESS diagnosed between 2004-2014 and treated definitively with 1) Amp alone, 2) LSS alone, 3) Preoperative RT [pre RT] + LSS or 4) LSS + Post-operative RT [post RT]. Multivariate analyses (MVA) utilized logistic regressions for patterns of local treatment and Cox proportional hazards regression for OS. The Kaplan-Meier method was used to estimate 5-year OS. Results: Among 12,020 pts, receipt of LSS vs Amp did not differ significantly by race, ethnicity, age, insurance status, income, or educational attainment on MVA. The rate of Amp was higher in academic centers (OR 2.42; p = .006) or integrated network programs (OR 2.30; p = .014) vs community programs and rural vs. Metro settings (OR 1.88; p = .035). Actuarial 5-year OS by treatment was Amp 43%, LSS 59%, pre RT + LSS 61%, and LSS + post RT 66% (p < .001). On MVA, OS was worse with Amp vs. LSS alone (HR 1.37; p < .001) while pre RT + LSS (HR 0.70; p < .001) and LSS + post RT (HR 0.72; p < .001) had improved OS vs LSS alone. Treatment at a comprehensive community, academic, or integrated network programs vs community program; private insurance vs none; Hispanic vs. non-Hispanic (HR 0.85, p = .048); and higher educational attainment were associated with improved OS. More comorbidities, other primary cancers, older age, and no transitions in care were associated with worse OS. Conclusions: The only racial/ethnic disparity identified when evaluating rates of Amp and OS for ESS was a small OS benefit for Hispanic pts. OS was inferior with Amp and best with LSS with either pre RT or post RT. OS was improved at non-community programs, potentially indicating a need for referral to experienced centers.
Analysis of osteosarcoma subtypes by clinical genomic testing to identify clinically actionable alterations.
Authors: Livingston John Andrew , Posey Kristi , Subbiah Vivek , Daw Najat C. , Somaiah Neeta , Ravi Vinod , Patel Shreyaskumar , Benjamin Robert S. , Wang Wei-Lien , Lazar Alexander , Broaddus Russell , Meric-Bernstam Funda , Shaw Kenna Rael , Roszik Jason , Conley Anthony Paul 
Published: September 2018

11019 Background: Genomic testing is being utilized with increasing frequency to identify matched therapies for patients (pts) with advanced disease; however, the utility of such testing has not been defined in osteosarcoma (OS). We report our experience with 36 pts with recurrent/metastatic OS who underwent testing on a genomic testing protocol, including actionable alterations across multiple histologic subtypes of OS. Methods: Standardized hotspot mutation analysis was performed in 36 pts with recurrent/metastatic OS, using either a 46-, 50-gene, or 128-gene CLIA certified multiplex platform. 12 pts had a 200-gene analysis on a companion research protocol. We used the Catalogue Of Somatic Mutations In Cancer (COSMIC) database to identify alterations that are in mutation hotspots in OS or in other cancers. Clinical outcomes were retrospectively collected. Histologic subtype classifications were made by an experienced sarcoma pathologist based upon the pre-treatment and resection specimens. Cases with only metastatic samples available were classified as “other high-grade osteosarcoma.” Additional clinical correlations are ongoing. Results: A total of 36 pediatric and adult pts were analyzed. All osteosarcomas were high grade; the most common osteosarcoma histologic subtypes were chondroblastic, osteoblastic, and other. Samples analyzed were from primary tumor in 15/36 (42%), with the remaining from metastatic specimens (58%). Mutations were identified in 26 pts (72%). The most common mutations were in TP53. An activating PIK3CA E545K mutation was found in chondroblastic OS. Other notable hotspot mutations include a GNAS R201 mutation in osteoblastic osteosarcoma and a KRASG12V mutation in a fibroblastic osteosarcoma. Conclusions: Clinical gene panel sequencing can identify a limited number of potentially actionable mutations in patients with osteosarcoma. Given the heterogeneity of osteosarcoma at the molecular level, clinical genomic testing may be warranted to identify patients for participation on matched clinical trials.
Clone evolution and genomic alteration analysis of osteosarcoma and matched lung metastasis.
Authors: Wang Di , Wang Jie , Niu Xiaohui , Huang Zhen , Wang Zhijie , Zhang Qing , Duan Jianchun , Bai Hua , Hao Lin 
Published: September 2018

11032 Background: Lung metastasis (LM), as the most common metastatic site, is the main reason resulting in treatment failure and death of osteosarcoma (OS). But there was no report about the clone evolution and genomic alteration in the process of LM of OS. Methods: Multiregion whole-genome sequencing and whole-exome sequencing were performed on ten patients with primary OS and matched lung metastatic tumors. A set of high confident somatic nucleotide variants (SNV), small insertion and deletion (indel) and copy number variation (CNV) in each sample were identified, then the n-dimensional Bayesian Dirichlet process was applied to define the constituent mutation clusters as clone or subclone. Neoantigen prediction and HLA typing were performed using NetMHC3.0 and POLYSOLVER algorithm, respectively. Results: There were diversified metastatic progression during lung metastasis of OS including linear evolution (7/10) and parallel evolution (3/10), and metastasis-to-metastasis spread was also found in a patient with multiple metastasis; Mutation accumulative effect during the metastasis of OS was evident, LM had much higher mutation load (fold change = 4.1, P-value < 0.01) and neoantigen burden (fold change = 4.5, P-value < 0.001) than the primary tumor; DNA mismatch repair (MMR) genes relevant deleterious mutation events were found in germline in 8/10 metastatic OS cases and MMR genes mutation were much more in LM than primary cancer; The genome instability of LM was prevalently much more significant than primary tumor, with higher copy number variation frequency (fold change = 7.01, P-value < 0.01). Conclusions: The evolution of OS during LM was very complex with diversified metastatic progression. For the LM of OS, the novel therapy should be considering the much higher mutation load, especially those causing tumor neoantigens, higher genomic instability which were associated with tumor immune therapy. Furthermore, the findings of germline MMR genes mutation in primary OS which had occurred LM and more MMR genes mutation in LM of OS indicated potential clinical benefit on immune checkpoint inhibitor therapy and other small molecular drugs for MMR genes.
A DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas.
Authors: Wu Shengyang , Cooper Benjamin Thomas , Bu Fang , Bowman Christopher , Killian Keith , Serrano Jonathan , Wang Shiyang , Jackson Twana , Gorovets Daniel , Gorlick Richard Greg , Ladanyi Marc , Thomas Kristen , Snuderl Matija , Karajannis Matthias A. 
Published: September 2018

11034 Background: Bone sarcomas present a unique diagnostic challenge because of the considerable morphologic overlap between different entities. The choice of optimal treatment, however, is dependent upon accurate diagnosis. Genome-wide DNA methylation profiling has emerged as a new approach to aid in the diagnosis of brain tumors, with diagnostic accuracy exceeding standard histopathology. In this work we developed and validated a methylation based classifier to differentiate between osteosarcoma, Ewing’s sarcoma, and synovial sarcoma. Methods: DNA methylation status of 482,421 CpG sites in 15 osteosarcoma, 10 Ewing’s sarcoma, and 11 synovial sarcoma samples were measured using the Illumina HumanMethylation450 array. From this training set of 36 samples we developed a random forest classifier using the 400 most differentially methylated CpG sites (FDR q value < 0.001). This classifier was then validated on 10 synovial sarcoma samples from TCGA, 86 osteosarcoma samples from TARGET-OS, and 15 Ewing’s sarcoma from a recently published series (Huertas-Martinez et al., Cancer Letters 2016). Results: Methylation profiling revealed three distinct molecular clusters, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were correctly classified as synovial sarcoma (10/10, sensitivity and specificity 100%). All but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and all but one sample from the Ewing’s sarcoma series was classified as Ewing’s sarcoma (14/15, sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample was classified as Ewing’s sarcoma, and was later determined to be a misdiagnosed Ewing’s sarcoma based on RNA-Seq demonstrating high EWRS1 and ETV1 expression. An additional clinical sample that was misdiagnosed as a synovial sarcoma by initial histolopathology, was accurately recognized as osteosarcoma by the methylation classifier. Conclusions: Osteosarcoma, Ewing’s sarcoma and synovial sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide an accurate diagnosis when histological and standard techniques are inconclusive.
The role of neoadjuvant imatinib therapy of patients with primary locally advanced GIST.
Authors: Arkhiri Peter , Poddubnaya Irina , Nered Sergey N. , Peregorodiev Ivan N. , Nikulin Maxim P. , Stilidi Ivan S. 
Published: September 2018

11037 Background: percutaneous biopsy of gastrointestinal tumors is contraindicated, that is why prospective randomized trials of efficiency of preoperative imatinib therapy weren't conducted. According to the results of theRTOG S-0132/ACRIN 6665, CST1571-BDE43 and other studies, neoadjuvant imatinib therapy increase tumor resectability and improve progression-free and disease-specific survival. The optimal timing of surgical intervention is likely during the maximal response on treatment (6 to 12 months as a rule). Methods: We have analyzed the treatment results of 86 patients with locally advanced GIST which were treated since January 1st 2002 till 20 January 2016 at N.N. Blokhin Russian Cancer Centre. The primary tumor was located in the stomach - 32 pts (37,2%), duodenum and small bowel - 37 (43,1%), other (colon, rectum and extraorgan) – 17 pts ( 19,7%). The median follow-up time was 4.9 years. There are 4 groups in the trail: group 1 - 29 patients received only surgical treatment, group 2 - 12 pts– surgical resection with adjuvant imatinib therapy for 1 year; group 3 - 25 pts – adjuvant imatinib therapy for 3 years and group 4 - 17 pts– surgical resection with neoadjuvant and adjuvant imatinib therapy (1 - 3 years). The remained 3 patients received surgical resection with adjuvant imatinib therapy for 5 years. Results: Survival analyses showed a significant improvement of RFS and OS in patients who received combined treatment with neoadjuvant and adjuvant imatinib therapy. The five-year RFS in first group of patients was 10,8%, in 2 group - 16,7%, in 3 group - 68,4%, and 4 group - 79,8% (p = 0.0001). The 5-year overall survival in these groups was 42,6%, 66,7%, 76,1% and 91.6% ( p = 0,0072) respectively. In the patients with 5-years adjuvant therapy, diseases progression was not noted. During neoadjuvant therapy disease progression has been registered in two patients. The median time of preoperative imatinib therapy was 11 month (from 3 to 24 month). Neoadjuvant imatinib therapy increased the rate of R0 (14 pts – 82,4%) and organ-sparing (12 pts – 70,6%) resections. Conclusions: The optimal approach in patients with locally advanced GIST is combined surgical treatment with neoadjuvant and adjuvant (at least for 3 years) imatinib therapy.
Rechallenge in advanced GIST progressing to imatinib, sunitinib and regorafenib: An Italian survey.
Authors: Vincenzi Bruno , Nannini Margherita , Grignani Giovanni , Fumagalli Elena , Gasperoni Silvia , D'Ambrosio Lorenzo , Badalamenti Giuseppe , Dei Tos Angelo Paolo , Incorvaia Lorena , Casali Paolo G , Santini Daniele , Tonini Giuseppe , Stellato Marco , Catania Giovanna , Spalato Ceruso Mariella , Pantaleo Maria A. 
Published: September 2018

11038 Background: We retrospectively collected data from metastatic Italian GIST patients treated with imatinib or sunitinib reintroduction after progression to conventional three or four lines of therapy. Methods: 82 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected in the present analysis from 6 cancer centres. All patients received all three standard kinase inhibitors. Imatinib dose increase as active second line or 800 mg upfront in exon 9 mutant GIST were allowed. Specific mutations were recorded if available (deletion versus others) and correlated with survival and response according to RECIST 1.1 or CHOI criteria. Results: Seventy-four of 82 patients received Imatinib 400 mg as rechallenge, while 8 patients were treated with sunitinib at personalised dose and schedule according to the physician’s choice. Mutational status was available in all patients and in 68 patients details about type of mutation were achievable. The median follow-up was 13 months (range 1-42 months). The median time to progression (TTP) in patients receiving a rechallenge therapy was 5.4 months (95% CI 1.9-13.5) and Overall Survival (OS) was 10.6 months (95% CI 2.8-26.9). Apparently, in this setting a correlation between mutational status and response rate, TTP or OS was not found. On the contrary, considering only exon 11 mutated patients and comparing patients with deletion vs non deleted ones a significant difference was identified both in terms of TTP and OS (respectively, P = 0.04 and P = 0.02). Conclusions: Our retrospective data confirm that the rechallenge of imatinib or sunitinib is a reasonable option in advanced GIST patients after failure of previous treatments. As expected, imatinib is the most frequently prescribed option in the Italian real-life setting, demonstrating a TTP and OS longer than those observed in previous studies. Also the prognostic value of the specific type of exon 11 KIT mutations has been confirmed in our series.
Prognosis of desmoid tumors (DT): A prospective nationwide survey of 771 patients (pts).
Authors: Ryckewaert Thomas , Le Cesne Axel , Bonvalot Sylvie , Blay Jean-Yves , Giraud Antoine , Bompas Emmanuelle , Rios Maria , Salas S Bastien , Isambert Nicolas , Boudou-Rouquette Pascaline , Honoré Charles , Italiano Antoine , Ray-Coquard Isabelle Laure , Piperno-Neumann Sophie , Gouin Francois , Bertucci Francois , Ducimetiere Francoise , Coindre Jean-Michel , Penel Nicolas 
Published: September 2018

11047 Background: Prognostic factors and optimal management of DT are not yet established. Methods: We analyzed the outcome of 771 consecutive DT pts treated between 01/2010 and 12/2016 in France. We have calculated event-free survival (EFS) defined as local relapse after surgery, progressive disease during non surgical approach or change in treatment strategy (e.g. from wait and see to systemic treatment or local treatment). Results: The sex ratio M/F was 219/552, the median age was 39 (2-90), and the median size 57 mm (4-700). 596 DT are found CTNNB1-mutated (71%). The 1st treatment was wait and see (369, 48%), surgery (343, 44%), systemic treatment (25, 3%), or radiotherapy (3, 0%). The median follow-up was 32 mo. 230 events occurred (including 1 death). The median EFS was 27 mo. After initial wait and see, pts required systemic treatment in 61 cases (15%), radiotherapy (4; 1%), cryotherapy (3; 1%), surgery (2; 0%) and radiofrequency (1, 0%). After initial surgery, DT pts required wait and see for relapse in 88 cases (25%), systemic treatment in 17 cases (5%), radiotherapy (6; 2%), cryotherapy (2; 0%) and surgery (1, 0%). Univariate analysis identified 3 factors associated with EFS: favorable locations (median not reached (NR) vs. 21 mo; p = 0.0001), nature of sampling (core needle biopsy: 31 mo; resection 26 mo and open biopsy 15 mo, p = 0.046) and superficial DT (NR vs. 28 mo, p = 0.00001). Favorable locations included: abdominal wall (236 pts), intra-abdominal (78 pts), breast (27 pts) and digestive viscera (42 pts). Chest wall (209 pts), head and neck (28 pts), lower limb (90 pts), upper limb (25 pts) and pelvis (18 pts) were all associated with poor EFS. Multivariate analysis identified only 1 prognostic factor for EFS: favorable location HR = 0.52 [0.39-0.69]. Compared to surgery, wait and see as 1st treatment was associated with better EFS in unfavorable DT locations (HR = 0.74 [0.74-0.56]; p = 0.001) but not associated with EFS in favorable locations (HR = 0.89 [0.69-1.13]; p = 0.420). Conclusions: Since primary location of DT is the major determinant of DT outcome, stratified approach according to location has to be prospectively assessed. Correlative biology analyses are warranted to better understand these findings.
Effects of temozolomide and bevacizumab in relapsed patients with heavily pretreated uterine leiomyosarcoma.
Authors: Matsuura Hiroko , Ikeda Sayaka , Kudoh Kazuya , Sasaki Naoki , Takano Masashi , Goto Tomoko , Kikuchi Ryoko , Kita Tsunekazu , Sakamoto Masaru , Aoki Daisuke , Susumu Nobuyuki , Kouta Hiroko , Kikuchi Yoshihiro 
Published: September 2018

11056 Background: Uterine leiomyosarcomas (ULMs) tend to recur regardless of their stage, and there is no satisfactory report for relapsed ULMs. Temozolomide (T) is derivatives of dacarbazin and these agents have been used for treatment of ULMs. ULMs has a plenty of vessels compared to uterine myoma so that bevacizumab (B) was used in ULMs. In the present study, we evaluated the effect of TB in heavily pretreated relapsed ULMs. Methods: From 2009 to 2016, total 19 patients (pts) with heavily pretreated ULMs were enrolled. Patients were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse effect (AE) was assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seventeen of 19 pts were subjected to response evaluation. Median age of pts was 56.3 years (range: 31-69). Three pts (18%) had complete response (CR), 2 (12%) had partial response, and 7 (41%) had stable disease (SD). The response rate (RR: CR+PR) and clinical benefit rate (CBR: CR+PR+SD) were 29% and 71%. The median progression-free survival was 14.2 months (range: 0-89). Median administration cycle was 9.5 (range: 2-48). AE with grade 3 and more over were observed in 6 pts. There was one dead case from perforation, but toxicity was almost manageable. Conclusions: We experienced 3 cases of CR, and two of them had CR for more than two years. Intriguingly, TB could be substantially effective even in relapsed patients with heavily pretreated ULMs. These results warrant further prospective and randomized studies.