bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of mutant-free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor (GIST) harboring activating mutations of C-Kit or PDGFRA.
Authors: von Bubnoff Nikolas , Kerle Irina , Specht Katja , Bruegel Melanie , Wickenhauser Claudia , Jost Philipp , Niederwieser Dietger , Peschel Christian , Duyster Justus , Lange Thoralf , Maier Jacqueline 
Published: March 2020

10508 Background: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients. Methods: We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA. Results: We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies. Conclusions: Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clinical trial information: NCT01462994.
Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.
Authors: Dickson Mark Andrew , Tap William D. , Keohan Mary Louise , D'Angelo Sandra P. , Gounder Mrinal M. , Chi Ping , Antonescu Cristina R. , Landa Jonathan , Qin Li-Xuan , Rathbone Dustin D. , Ustoyev Yelena , Crago Aimee Marie , Singer Samuel , Schwartz Gary K. , Condy Mercedes M. 
Published: March 2020

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.
Potentially actionable kinase fusions in inflammatory myofibroblastic tumors.
Authors: Lovly Christine Marie , Lipson Doron , Otto Geoff , Brennan Tina , Sankar Sabita , Stephens Philip J. , Miller Vincent A. , Coffin Cheryl M. 
Published: March 2020

10513 Background: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that harbors anaplastic lymphoma kinase (ALK) gene rearrangements in approximately 50% of cases. ALK inhibitors have been validated as an effective therapeutic approach in this subset of IMTs. The goal of this study was to characterize a series of IMTs using both immunohistochemistry (IHC) and next generation sequencing (NGS). Methods: 30 formalin-fixed, paraffin-embedded IMT specimens from 28 patients were evaluated by IHC for ALK expression using standard techniques. DNA was extracted and sequenced using a targeted capture-based NGS assay for 3769 exons of 236 cancer-related genes and 47 introns of 19 commonly rearranged genes, including 8 tyrosine kinases in a CLIA laboratory (Foundation Medicine). Selected specimens were also evaluated for ALK fusions by fluorescence in-situ hybridization (FISH). Results: 20 samples were ALK positive and 10 samples were ALK negative by IHC. Targeted NGS was successfully performed in 16/20 ALK positive and 10/10 ALK negative cases. Among the 16 ALK positive cases analyzed by NGS, 12 harbored ALK fusions with various 5’ gene fusion partners, including LMNA, TPM3, TPM4, SEC31A, TFG, RANBP2, and CLTC. The remaining 4 were also negative by FISH suggesting a different mechanism of ALK overexpression. Among the 10 ALK negative cases, 2 harbored ALK fusions (EML4-ALK, TPM3-ALK). In the other 8 ALK negative samples, 2 contained distinct ROS1 fusions (YWHAE-ROS1, TFG-ROS1) and 1 contained a PDGFRβ fusion (NAB2-PDGFRβ), none of which have been described in IMT samples to date. Overall, kinase gene fusions were identified in 18/26 (69%) evaluable samples. Conclusions: This study represents the most comprehensive NGS analysis of IMTs. 12/12(100%) ALK IHC and FISH positive cases contained ALK fusions, while 5/8 (63%) of distinct ALK IHC negative cases harbored kinase fusions, involving ALK, ROS1, or PDGFRβ. Since these fusions are all targetable with existing kinase inhibitors (i.e. crizotinib, dasatinib), this study suggests that IMTs should be routinely profiled for kinase fusions and not just by ALK IHC. Efforts are ongoing to identify “driver mutations” in the fusion-negative specimens.
Results of the randomized phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as first-line therapy in patients (pts) with translocation-related sarcoma (TRS).
Authors: Hendifar Andrew Eugene , Chawla Sant P. , Leahy Michael Gordon , Italiano Antoine , Patel Shreyaskumar , Santoro Armando , Staddon Arthur P. , Penel Nicolas , Piperno-Neumann Sophie , Demetri George D. , Hayward Larry , White Jeff , Gouw Launce G. , De Miguel Bernardo , Lardelli Pilar , Soto Arturo , Nieto Antonio , Blay Jean-Yves 
Published: March 2020

10517 Background: T is the first of a new class of anticancer agents with a transcription-targeted mechanism of action. In vitro,T interferes with the aberrant transcription factors binding to DNA promoters in TRS. Methods: Pts with advanced TRS of the subtypes: myxoid liposarcoma (ML), alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma, myxoid chondrosarcoma and synovial sarcoma, stratified by performance status (0 vs 1-2) and subtype (ML vs other TRS) were randomized (1:1 ratio) to T (1.5 mg/m2 in 24h iv infusion q3wk) or doxorubicin, either single agent 75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide (6-9 g/m2 q3wk) as 1st line treatment. Primary endpoint: efficacy of T vs DXCT by comparing progression-free survival (PFS). Secondary: PFS at 6 months (PFS6), response rate (RR), PFS/RR by subtype (ML vs other TRS); overall survival (OS), safety. Results: 121 pts enrolled from 22 centers, 88 were confirmed by central pathology review and evaluable for the primary efficacy endpoint by independent review assessment (IR), and all 121 pts randomized were evaluable by investigators’ assessment (IA). The main limitation of the study analyses in both arms was high censoring rate (70% IR; 61% IA) mostly due to surgery (~30%) or chemotherapy/ radiotherapy (~30%). PFS results are shown in the Table. PFS6 was not different between arms (IR: 66.4% vs 80.8% p=0.18/IA: 60.7% vs 62.4% p=0.88). Current median OS:not reached (NR) for T (24.1-NR) and 21.7 mo. for DXCT (21.2-NR).Safety: Most frequent AEs in both arms were nausea (70% vs 65%), vomiting (44% vs 26%) and fatigue (64% vs 63%). ALT increase G4 occurred in 10% pts treated with T and neutropenia G4 in 25% of pts in the T arm vs 52% in the DXCT arm. Conclusions: Although with a high censoring rate, this prospective study suggests thatPFS/OS with trabectedin are not significantly different from DXCT in first-line treatment. Clinical trial information: NCT00796120. [Table: see text]
A model for multi-institutional, multidisciplinary sarcoma videoconferencing.
Authors: Attia Steven , Maki Robert G. , Trent Jonathan C. , Okuno Scott H. , Indelicato Daniel J. , Webber Nicolas P , Curtis Kelly Kevelin , Kozak Kevin Robert 
Published: March 2020

10521 Background: Sarcomas are rare cancers, with > 50 subtypes, and require multi-disciplinary care. Their management benefits from multi-institutional input due to the paucity of concentrated experience with each subtype. However, sarcoma tumor boards, wherein a patient-specific, consensus treatment approach is determined, are predominantly conducted in isolation at individual centers. Methods: Since March 2010, we have conducted a weekly multi-institutional, multi-disciplinary sarcoma tumor board to combine knowledge and experience in the management of our most challenging patients. The Mayo Clinic bridge links sites by interactive videofeed. Each site may contribute cases. De-identified history, radiology and pathology are reviewed. A didactic series reviews a rotation of seminal papers, newly published research, or our own data. An “Expert Guest" series allows outside experts to connect to one conference. A yearly participant survey assesses quality. Conference is free to sites and is CME accredited. Results: Currently, 8 sarcoma programs connect Mondays from 8-9am ET. Median attendance is 20 (range: 8-27). In 2012, 342 cases were reviewed over 43 conferences (median: 8 cases/conference; range: 4-12 cases/conference). The 2012 survey revealed 96% (25/26) agreed HIPAA rules are followed; 93% (25/27) agreed conference is educational; 93% (25/27) agreed recommendations are evidenced-based or reasonable; 100% (27/27) agreed participants are respectful; and 86% (18/21) agreed input from other sites has changed their management. Staff attendance (quantity) rated as meets/exceeds needs was 100% (25/25) for medical oncology; 96% (26/27) for pathology; 93% (25/27) for orthopedic oncology; 92% (23/25) for radiation oncology, surgical oncology and radiology; and 61% (17/23) for thoracic oncology. Conclusions: To our knowledge, this is the only weekly multi-institutional sarcoma tumor board in existence. It permits consistent oncology care across a wide geographic area, and is a model for providing consensus recommendations regardless of the remoteness of the patient and care team. Future plans for this group include prospective collection of outcomes data.
Phase II trial of ifosfamide in combination with sorafenib in patients with advanced soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Garcia del Muro Xavier , Maurel Joan , Martinez Trufero Javier , Lavernia Javier , Lopez-Pousa Antonio , De Las Penas Ramon , Cubedo Ricardo , Fra Joaquin , Casado Antonio , De Juan Ana , Jimenez Colomo Laura , Martin Broto Javier 
Published: March 2020

10523 Background: Recent studies suggest that VEGFR inhibition could play a role in the treatment of soft tissue sarcoma (STS). Prior studies by our group showed that the combination of ifosfamide with sorafenib resulted in preclinical additive activity and that was feasible and safe in the phase I trial. Methods: Patients (pts) with advanced STS, previously treated with doxorubicin, no prior ifosfamide, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this multicenter phase II study, receiving sorafenib 400 mg bid po continuously and ifosfamide 2 g/m2 iv for 3 days together with mesna 400 mg/m2 every 3 weeks. The primary endpoint was progression-free rate (PFR) at 3 months. A one-sample binomial design was used (PFR P0=40%, P1=60%, α=0.10, β=0.20), requiring at least 19 of 35 pts free of progression at 3 months to be considered positive. Results: From September 09 to March 12, 35 pts were enrolled at 11 centers. Median age was 55 (18-73). PS: 0-13, 1-18; 2-4 pts. Histologic types were: LMS 12, Lipo 6, SS 5, MPNST 2, other 10 pts. . The median number of cycles administered per patient was 4. PFR at 3 months was 67%, with 23 pts being free of progression at 3 months. Median progression-free survival was 4.8 months (95% CI, 1.9-6.3) and median overall survival was 16.2 months. PR was achieved in 17% pts. Most common grade 3-4 toxicities were asthenia (25%), hand-foot syndrome (11%) and neutropenia (20%) resulting in 3 episodes of neutropenic fever. Other common toxicities (G1-4) included emesis (34%), rash (22%), diarrhea (34%), hypertension (11%) and mucositis (9%). Conclusions: The combination of ifosfamide and sorafenib is active and has acceptable toxicity in pts with doxorubicin pretreated STS. The PFR at 3 months might exceed the expected with ifosfamide alone warranting further investigation. Clinical trial information: EudraCT: 2007-002176-34.
Neo/adjuvant doxorubicin (A) and ifosfamide (I) versus gemcitabine (G) and docetaxel (T) in patients (PTS) with localized, high risk soft tissue sarcoma (STS): A randomized phase II comparative effectiveness trial.
Authors: Davis Elizabeth J. , Chugh Rashmi , Zhao Lili , Biermann J. Sybil , Wong Sandra L. , Feng Mary Uan-Sian , Lucas David Robert , Featherstone D'Andra , Reinke Denise , Zalupski Mark M. , Schuetze Scott 
Published: March 2020

10524 Background: Approximately 50% of pts with localized, >5 cm, high grade STS develop metastatic disease. Although controversial, adjuvant chemotherapy has demonstrated improved disease-free (DFS) and overall survival (OS). AI can cause significant toxicities that often lead to hospitalization. GT is active in metastatic STS pts and as compared to AI has a favorable schedule and toxicity profile. Methods: In a single-institution phase II study, pts with localized, resectable, high grade STS >5 cm were randomized to receive AI or GT. Pts were stratified by neo- or adjuvant treatment and extremity or non-extremity tumor. Pts received A (75 mg/m2 over 48 hrs) and I (2.5 g/m2/d on D1-3) or G (900 mg/m2 over 90 min on D1,8) and T (100 mg/m2 on D8), both arms with GCSF, for 4 cycles unless progression. Radiation was given after chemotherapy. The primary endpoint of the trial was hospitalization rate during chemotherapy and was compared using a chi square test and multiple logistic regression adjusting for other variables. The trial was powered to detect a reduction in hospitalization rate from 35% to 10% using GT. Survival functions were estimated using Kaplan-Meier method. Results: 84 pts were enrolled from 11/04-8/12 with 80 pts evaluable. The median age is 56 yrs (19-76) and tumor size is 7.8 cm (3.2-25). 55 pts received neoadjuvant therapy and 48 had extremity STS. In the AI arm, 13/37 (35%) pts were hospitalized vs. 11/43 (26%) in the GT arm (p=0.25). The most frequent reason for hospitalization in AI arm was febrile neutropenia (7 events) and in GT arm was hypersensitivity reaction (4 events). The median DFS of pts treated with AI vs GT is 24 months vs not reached, respectively; median follow up is 30 (1-87) months. The 2-year DFS rate is 53% (SD 9%) in the AI arm vs. 71% (SD 7%) in the GT arm and remains marginally significant after adjusting for age, gender, neoadjuvant therapy, tumor site and size (p=0.054). OS rates are not significantly different between arms. Conclusions: Hospitalization rate was not significantly lower with GT compared to AI, although toxicity profile was different. DFS but not OS is marginally improved with GT. Clinical trial information: NCT00189137.
Wnt antagonists in osteosarcoma patients.
Authors: Bravo Dalibel , Shogren Kristen L. , Riester Scott M. , Wagner Eric R. , Herrick James L. , Okuno Scott H. , Yaszemski Michael J. , Maran Avudaiappan 
Published: March 2020

10531 Background: Osteosarcoma (OS) is a clinically challenging primary malignant bone tumor that has a high rateof local recurrence and metastasis. Disease free survival has been reported to be as low as 19% despite contemporary chemotherapy regimens and surgery. Wnt signaling is known to play a role in osteogenesis and cancer pathogenesis, therefore is a promising target for therapeutic intervention in OS. Secreted Frizzled Related Proteins (sFRPs), Dickkopf-1 (DKK1), and Sclerostin (SOST) are secreted Wnt inhibitor proteins that regulate Wnt signaling in bone. This study investigates the activity of sFRP3, DKK1, and SOST in serum from OS patients with the goal of developing therapeutic Wnt inhibitors and clinically useful biomarkers. Methods: Enzyme linked immunosorbent assayswere used to quantify sFRP3, DKK1 and SOST levels in human serum (n=40 pairs; 20 OS patients, 20 aged matched non-diseased controls). Patients were stratified into 2 age groups: >35 (n=26 pairs) and <30 (n=14 pairs) years of age. Clinical data from the medical records was correlated with experimental results. Using a Wilcoxon signed rank test, a p–value <0.05 was significant. Results: sFRP3 levels were significantly decreased in 55% (22/40) of diseased samples compared to 20% (8/40) of the non-diseased controls (p= 0.007). DKK1 levels were elevated in 40% (16/40) of OS samples compared to 30% (12/40) of the non-diseased controls (p= 0.08). SOST levels were increased in 42.5% (17/40) of diseased samples compared to 32.5% (13/40) of the non-diseased controls (p= 0.38). When stratified by age, the younger patients showed a statistically significant decrease in sFRP3 expression (p<0.001). Serum levels of sFRP3, DKK1, and SOST were not statistically significant between metastatic and non-metastatic OS. Conclusions: Serum sFRP3 levels were significantly decreased in OS patients, a difference that was even more pronounced in the pediatric strata. Since sFRP3 is differentially expressed in patient serum it has potential as a clinical biomarker for initial tumor diagnosis and early detection of recurrence. Decreased sFRP3 expression may be responsible for the up regulation of Wnt signaling in OS. Wnt inhibitors such as sFRP3 have potential as therapeutic agents in OS warranting further investigation.
MicroRNA profiling analysis in a series of high-risk intestinal GISTs.
Authors: Calabuig Silvia , Martin Broto Javier , Sanchez-Izquierdo Dolors , Obrador Antonia , Ortega Luis , Casado Herraez Antonio , Valverde Claudia María , de Torres Ines , Poveda Andres , Ugalde Aitziber , Sala Angeles , Ramos Rafael , Gonzalez de Sande Luis Miguel , Losa Ferran , Lainez Nuria , Luna Fra Pablo , Cruz Josefina , Cubedo Ricardo , Lopez-Guerrero Jose Antonio ,   Spanish Group for Research on Sarcomas (GEIS)
Published: March 2020

10532 Background: Resected localized GISTs exhibit a wide range of biological behavior from low to high risk of recurrence. Risk categories (low, intermediate and high) are built from mitotic count, size and location. However, the molecular mechanism related to GIST relapse has not yet been fully clarified. The purpose of this study is to characterize miRNA expression profile in high risk GIST patients for both, recurred and not recurred, and detect those differentially expressed in these two subsets. Methods: Twelve cases of high risk intestinal GIST, 6 with relapse and 6 without relapse, were selected for this analysis. Sections were obtained for RNA extraction using the miRNeasy FFPE kit (Qiagen) and miRNA was hybridized to the GeneChip miRNA 3.0 Array (Affymetrix) including more than 1800 human miRNA. Normalization and statistical analysis were performed with Partek Genomic Suite 6.6 software by means of ANOVA test. Fold-change (FC) and p-values were applied to generate miRNA differentially expressed lists. Results: A subset of 85 miRNA were significantly deregulated (p<0.05; FC=1.5) when comparing both groups. Among them, the highest p-values and associated FC were: mir-4776 (FC= 1,95, p= 0,011;), mir-1973 (FC= 1,59, p= 0,014) mir-4649 (FC 1,74, p= 0,028) and mir-3605 (GC= 1,58, p=0,045). All of these were up-regulated in recurred patients. Interestingly, the two samples that correspond to the biggest tumors with relapse showed a significantly different expression profile that separated them from the rest of the samples. We have identified 44 miRNAs that discriminate these two samples from the rest and show a very high statistical significance. The most significantly up regulated miRNAs were miR-100 (FC= 90,87, p<0.0001), miR-30a (FC= 156,086, p<0.0001) and down regulated miR-1184 (FC= -24,94, p<0.0001) and miR-4529 (FC= -16,61, p<0.0001). These miRNAs are involved in cell cycle and cell proliferation. Conclusions: This is the first wide characterization of miRNA profile in high risk GIST. The highest differences in expression are related to not previously described miRNAs in GIST tumors. All of them are involved in cell cycle and cell proliferation, thus expecting to regulate many GISTs associated genes, related to the relapse event.