bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of a chordoma xenograft and in vivo testing of compounds identified by high-throughput screening.
Authors: Trucco Matteo Maria , Wilky Breelyn A. , Awad Ola , Shah Preeti , Gul Naheed , Xia Menghang , Huang Ruili , Loeb David Mark 
Published: March 2020

10025 Background: Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. Therapy primarily consists of surgical resection and radiation. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents for chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Methods: Primary tumor from a classic sacral chordoma was obtained, immediately processed into a single cell suspension and injected in to the parasacral area of a NOD/SCID/IL-2R gamma-null mouse, and tumor grew after 3 months. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds. Two established chordoma cell lines, U-CH1 and UCH2B, were treated and cell viability measured by CellTiter-Glo assay. Cells were incubated for 48 hours with drug concentrations ranging from 0.5nM to 46uM. The screen yielded several compounds that showed activity and two were tested in the xenograft. Results: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth. Conclusions: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth.
Pharmacokinetic analyses of vorinostat in patients with metastatic soft tissue sarcoma.
Authors: Schmitt Thomas , Andres Bianca , Liu Lu , Leisen Margarete , Ho Anthony D , Burhenne Juergen , Mikus Gerd , Egerer Gerlinde 
Published: March 2020

10041^ Background: New treatment options for patients with metastatic soft tissue sarcoma (STS) are urgently needed. Preclinical studies suggest activity of vorinostat (V), a histone desacetylase (HDAC) inhibitor, in STS. Methods: We initiated a multicenter, open-label, non-randomized phase II trial (SAHA-I, NCT00918489) to investigate efficacy and safety of V in patients with metastatic STS failing 1°-line anthracycline-based CTX. Patients were treated with V 400 mg po QD for 28 days followed by a therapy-free period of 7 days. Blood samples for pharmacokinetic (PK) analyses were collected on day 7 of treatment cycle 1. Samples were acquired before and 30, 60, 90, 120, 240, 360, and 480 minutes after oral administration of V. Plasma- and intracellular concentration of V in peripheral blood mononuclear cells (PBMCs) was determined by mass spectrometry. Statistical differences were assessed by Wilcoxon matched-pairs signed rank test. This trial is ongoing. Results: Data on PK was available for n=8 subjects (male=4, female=4, median age=62 years). In plasma samples, mean Cmax (maximum concentration), tmax (time to reach max. concentration), AUC (area under the plasma-concentration time curve), t1/2 (elimination half-life) and Cl/F (apparent total clearance) were 350 ng/mL, 101 min, 71.1 min*µg/mL, 103 min and 5903 mL/min. The corresponding parameters in PBMCs were 558 ng/mL, 97.5 min, 208.4 min*µg/mL, 286 min and 2475 mL/min, respectively.The AUC plasma/PBMC ratio was 2.93, indicating accumulation of V in PBMCs. Differences in AUC (p=.008) and t1/2 (p=.01) reached statistical significance. Conclusions: Interestingly, significantly higher concentrations of V were achieved in PBMCs andelimination half-life was prolonged compared to plasma. These results suggest potent intracellular activity of V.
Differential gene expression in liposarcoma: Insight into pathways for dedifferentiation?
Authors: Han Dale , Bloom Gregory C , Bui Marilyn M , Enkemann Steven , Yamauchi Hideko , Han Gang , Conley Anthony Paul , Zager Jonathan S. , Cheong David , Reed Damon R. , Lavey Robert S , Sondak Vernon K. , Letson Douglas D , Gonzalez Ricardo Jorge 
Published: March 2020

10048 Background: Liposarcoma (LPS) dedifferentiation signifies conversion to a clinically aggressive phenotype, but the biologic processes required for this change have not been determined. We describe differential gene expression patterns between well-differentiated (WD) and dedifferentiated (DD) tumors to determine pathways involved in LPS dedifferentiation. Methods: From 1999 to 2006, 121 fatty tumors were resected at a single institution. Twenty tumors, consisting of atypical lipomatous tumors (ALT), WD LPS or DD LPS, were randomly selected and clinicopathologic characteristics were retrospectively reviewed. Gene expression profiling was performed on extracted RNA using the Affymetrix GeneChip platform. Differentially expressed genes were obtained and gene network analysis was done using GeneGO by MetaCore. Results: Median age was 59 years and 70% of cases were male. WD tumors, consisting of 3 ALT and 6 WD LPS, were compared with 11 DD LPS. After a median follow-up of 64 months, 7 patients had died of whom 6 had DD LPS. DD histology was associated with lower overall survival (p<0.05). Significance Analysis of Microarrays for WD tumors vs. DD LPS using a 0% false discovery rate showed differential expression of 188 genes. Network analysis of genes from WD tumors vs. DD LPS showed significant (p<0.001) differential regulation of glucose-activated transcription factor ChREBP (carbohydrate response element binding protein), a key element involved in lipogenesis, gluconeogenesis and glycolysis. There was also significant differential regulation of insulin signaling, PI3K-dependent and PKA signal transduction pathways and of amino acid, fatty acid and glucose metabolism pathways (p<0.05). These pathways, based on Gene Ontology cellular processes, mapped to gene networks primarily involved in lipid metabolism (p<0.05). Conclusions: Differential expression of genes involved in lipid metabolism networks is seen in DD LPS and changes in lipid metabolism may be associated with dedifferentiation. These differential gene expression patterns may help identify fatty tumors potentially at risk for progressing to a malignant or DD state and provide prognostic factors and therapeutic targets for patients with LPS.
Phase II study of neoadjuvant high-dose ifosfamide with concurrent radiotherapy followed by surgical resection in high-risk soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Garcia del Muro Xavier , Lopez-Pousa Antonio , Flor Maria Jose , Redondo Andrés , Jurado Josefina Cruz , Andres Raquel , Casado Antonio , Fra Joaquin , Lopez-Martin Jose A. , Maurel Juan , Valverde Claudia María , Gallego Oscar , Narvaez Jose Antonio , Bague Silvia , Sanjuan Xavier , Vinyals Juan M 
Published: March 2020

10052 Background: High-dose ifosfamide (HDI) has shown promising activity as single agent in first-line chemotherapy for advanced soft tissue sarcoma (STS). The purpose of this study was to assess the activity and toxicity of a preoperative doxorubicin-free regimen of HDI given concurrently with radiotherapy (RT) and followed by surgery in patients (pts) with localized high-risk STS. Methods: Pts with localized > 5 cm grade 2-3 and deep STS of the extremities and trunk wall, ≤65 years, no prior chemotherapy and ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and concomitant external beam RT to a total dose of 50 Gy, followed by surgical resection. Postoperatively, pts with pathological response received 2 cycles of HDI and those with positive surgical margins 16 Gy of RT. The primary study endpoint was pathologic response (≥ 95% pathologic necrosis). A Simon 2-stage design (response rate P0=15%, P1=35%, α=0.10, β=0.10) required at least 2 responses in the first 17 pts to expand to a second cohort, and 7/32 responses to be considered of positive. Results: From March 08 to December 10, 34 pts were included. Two pts were ineligible. Median age was 54 (18-65). Tumor location was extremity (28 pts) and trunk wall (4). Preoperative planned treatment was completed in 87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 were R0 resections, of which 2 were amputations, and 4 were R1 resections. Pathologic response was ≥ 95% necrosis in 9 pts (28%) and 50%-94% necrosis in 12 pts. After a median follow-up of 21 months, estimated 2-year rates for disease-free survival and overall survival were 58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. Conclusions: Preoperative treatment with HDI given concurrently with RT in pts with high-risk STS is feasible and safe, yielding promising pathologic response rates.
The Italian Rare Cancer Network.
Authors: Sanfilippo Roberta , Tricomi Marco , Grosso Federica , Baldi Giacomo , De Troia Beatrice , Fumagalli Elena , Palassini Elena , Stacchiotti Silvia , Bertulli Rossella , Fiore Marco , Dei Tos Angelo Paolo , Casali Paolo Giovanni 
Published: March 2020

10053 Background: Rare cancers (RC) are a challenge in terms of quality of care, access to health resources and clinical research. The Italian Rare Cancer Network (RTR: “Rete Tumori Rari”) is a clinical collaborative effort to improve quality of care in adult rare solid cancers in Italy. RTR enables institutions to share clinical cases and to rationalize access to distant reference centers minimizing patient migration. It indirectly promotes collaborative clinical research by encouraging accrual into clinical trials and supporting observational studies. Methods: RTR includes 150 oncology institutions across Italy. Clinical cases are shared asynchronously over a secure Web resource. Data, images and transactions are stored in an online clinical record. Patients are shared: 1. "logically”, when they are dealt with following common clinical practice guidelines; 2. "virtually”, when they are discussed over the network between two or more centers; 3: "physically", when they are referred to an excellence center for a specific treatment modality. Pathology review is arranged through transferal of paraffin-embedded specimens and upload of consultations. While it was chosen not to implement telepathology facilities, a teleradiology resource is now available. Results: From 2003 to 2011, more than 5,000 rare cancers cases (mostly sarcomas) have been uploaded. More than 1,300 teleconsultations have been delivered, while more than 1,000 patients moved across the network during their experience of disease. 700 cases were reviewed pathologically: amongst 365 cases originally diagnosed as soft tissues sarcomas up to 2010, treatment-relevant discordances were recorded in more than one third. An observational prospective study on gastrointestinal stromal tumors was done, enrolling 800 patients. An original paper documenting the activity of a drug in a highly specific sarcoma subgroup was published. Conclusions: Clinical asynchronous online collaboration on RC is feasible through a Web-based secure environment and proved the most practical way of clinical distant sharing. Pathologic review was a crucial network service, with a special added value in RC. Retrospective and prospective observational studies, and unplanned observations in very rare cases, were an interesting by-product.
Advanced soft-tissue sarcoma in patients over age 75: Patterns of care and survival.
Authors: Garbay Decoopman Delphine , Keohan Mary Louise , Cioffi Angela , Maki Robert G. , Bui Nguyen Binh , Italiano Antoine 
Published: March 2020

10057 Background: There are no data regarding the management and the outcome of elderly patients (pts) diagnosed with advanced soft-tissue sarcoma (STS). Methods: The charts of pts aged ≥ 75 years and diagnosed with metastatic and/or unresectable STS between 1990 and 2011 at Memorial Sloan Kettering (New York) and Institut Bergonié (Bordeaux, France) were reviewed. Results: 189pts were included.Median age was 79 years (range 75-93).160 pts (84.5%) had metastatic disease. The most frequent histological subtype was leiomyosarcoma (n=57, 30%). The median age-adjusted Charlson comorbidity score was 10 (range 5-17). 120 pts (63.5%) received systemic therapy whereas 69 pts (36.5%) were managed with best supportive care (BSC) only. Pts who received BSC only were more likely ≥ 80 years old (58% versus 38%, p=0.01) and with performance status (PS) ≥ 2 (35% versus 14%, p=0.01). Single agent and combination therapy were delivered in 87 (72.5%) and 33 (27.5%) cases respectively. 67 pts (56%) received a 1st-line anthracycline-containing regimen. The median progression-free survival of pts treated with systemic therapy was 4 months (95% CI: 2.5-5.5). 21 pts (17.5%) had to stop 1st line treatment because of toxicity. On multivariate analysis, age ≥ 80 years, PS ≥ 2, and single-agent therapy were significantly associated with poor PFS. 51 pts received one or more further lines of therapies. At the time of analysis, 170 pts (90%) had died. 96% of deaths were related to the disease. The median OS for the entire cohort of pts was 9.6 months (95% CI: 7.3-12). The 1-year and 2-year OS rates were 43% (95% CI: 36–50), and 22% (95% CI: 16–28), respectively. The median OS of pts managed with systemic therapy and BSC were 12.5 months (95% CI: 8.4-16.6) and 5.1 months (95% CI: 3.7-6.5), respectively (p=0.02). However, on multivariate analysis, PS ≥ 2 and age-adjusted Charlson score ≥ 10 were the sole independent factors significantly associated with OS. Conclusions: A high proportion of elderly pts with advanced STS were considered unfit for chemotherapy. The OS of STS pts ≥ 75 years who were managed with systemic therapy seems similar to that of younger pts. Further efforts are needed to better define the optimal care for fit and unfit elderly pts with advanced STS.
Drug treatment (tx) patterns and survival among patients (pts) with metastatic or recurrent soft tissue sarcoma (m/rSTS) refractory to at least one prior therapy.
Authors: Wagner Michael , Amodu Leo , Duh Mei Sheng , Korves Caroline , Solleza Franco , Mykletun Andrew , Manson Stephanie , Diaz Jose , Neery Maureen P. , Demetri George D. 
Published: March 2020

10061 Background: Limited clinical data on real-world practice patterns are available for care of pts with m/rSTS. This study evaluated drug tx patterns and outcomes in m/rSTS pts following failure of prior chemotherapy based on data from a U.S. referral academic cancer center. Methods: Data from medical records consented for research use were retrospectively reviewed at Dana-Farber Cancer Institute for pts with m/rSTS who were ≥18 years, commenced 2nd-line systemic therapy between 1/1/2000 and 2/4/2011, had confirmed disease progression on or after 1st-line therapy and had ≥3 months of observation. Pts were excluded if they had been diagnosed with gastrointestinal stromal tumor, bone sarcoma or dermatofibrosarcoma protuberans, or had ever been treated with pazopanib. Histologic subtype, tx type and duration, tx modifications (e.g., discontinuation) and reasons for modifications were examined. Overall survival, time to progression and clinician-assessed tumor response were collected. Results: Study pts had leiomyosarcoma (n=50), synovial cell sarcoma (n=7), liposarcoma (n=5) and other histologic subtypes (n=39). These 101 pts received an average 4 lines of tx (maximum=10 lines). Wide variations were noted in each line of tx (Table) with no consistent nor dominant regimens. Median 2nd-line tx duration was 4.1 months (95%CI 2.9-5.0). Among 98 pts who discontinued 2nd-line tx, 72 (73%) did so due to progressive disease, 10 due to “completion” of planned tx, and 6 to adverse events. Median progression-free survival from initiation of 2nd-line tx varied across regimens from 2.0 to 6.5 months (overall median 5.5 months). Conclusions: The wide variation in ≥2nd-line tx confirms there is no single “standard” of care for m/rSTS. The majority of pts discontinued 2nd-line tx due to progressive disease and often received additional lines of tx, indicating frequent physician and pt switching of tx. [Table: see text]
Rechallenge with trabectedin in patients with locally advanced or metastatic soft tissue sarcoma following drug holiday: The experience of the French Sarcoma Group (FSG).
Authors: Saada Esma , Rahal Chahineze , Ray Coquard Isabelle , Italiano Antoine , Chevreau Christine , Isambert Nicolas , Bui Binh , Cassar Alexia , Desmoulins Isabelle , Le Cesne Axel , Blay Jean-Yves , Thyss Antoine 
Published: March 2020

10062 Background: Trabectedin (T) is a marine-derived alkaloid used to treat advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins failure. Since then, the FSG evaluated the clinical benefit in re-administrating T after an initial hold, either medically indicated or upon patient’s request. Methods: Following an online request, clinical and histopathological data were collected from six centers of the FSG who declared to have rechallenged patients. Baseline data were collected and analyze will be used. Results: From 1999 to 2011, 49 pts with T drug holiday have been identified (26 male/ 23 female), with a median age of 50 y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 (39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities incidence decreased with the number of TS (occurred in 36%, 29%, 14% and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 (31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 (14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y [0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2nd, 3rd and 4th T reintroduction respectively. Objective response after TS2 were seen in 4 cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative toxicities over time with T, its rechallenging in responding patients to T (no progression under T) have to be considered in advanced STS.
Whole-body PET/MR in soft tissue sarcoma (STS) patients.
Authors: Richter Stephan , Platzek Ivan , Beuthien-Baumann Bettina , van den Hoff Joerg , Laniado Michael , Kotzerke Joerg , Kroschinsky Frank , Ehninger Gerhard , Schuler Markus Kajo 
Published: March 2020

10068 Background: PET/MR (positron emission tomography/magnetic resonance imaging) is a new whole-body hybrid imaging technique that combines metabolic and cross-sectional diagnostic imaging. To date the only available clinical data are drawn from feasibility studies in small series of head and neck cancers and intracranial tumors. Imaging by combined PET and computed tomography (PET/CT) has been investigated in STS for biopsy guidance, response assessment and grading. Methods: This exploratory analysis evaluated the outcomes of PET/MRI in 21 patients with STS in different treatment settings: (a) neoadjuvant setting, (b) metabolic-driven local therapy in metastatic sarcoma, and (c) palliative treatment. For examination we used an Ingenuity PET/MR system (Philips Healthcare). It combines a 3-Tesla MRI and a PET scanner with time-of-flight technology. Results: PET/MR shows a high contrast imaging without significant artifacts or distortions. (a) Four patients with high-risk sarcoma (3 rhabdo, 1 pleomorphic) completed the planned neoadjuvant therapy. Change in tumor size did not correlat with pathologic response, whereas surgical outcome was well predicted by metabolic changes. Due to this finding the preplanned course of chemotherapy for one patient was changed. (b) To prolong disease stabilization of 3 patients with a remnant metabolic activity in a single spot they underwent a surgical resection of a single metastatic lesion or had a local radiotherapeutic approach. (c) In 3 patients with stable disease after first-line treatment with combination of anthracyline and ifosfamide persisting metabolic activity indicated a switch to another alternative 2nd line regime. Trabectedin as 2nd line therapy decreased metabolic activity that finally resulted in a tumor regression. Conclusions: To our knowledge this is the first report on patients with STS examined with whole-body-PET/MR. PET/MR is feasible in STS and may provide valuable information in treatment, monitoring and prognosis of patients with STS. This technique may help to choose accurate and on-time treatment option without unnecessary time delay. Further prospective studies to evaluate PET/MR in STS are warranted.
Atypical vascular neoplasms and risk of development of angiosarcoma.
Authors: Ravi Vinod , Gupta Rohan , Demicco Elizabeth G , Araujo Dejka M. , Ludwig Joseph A. , Benjamin Robert S. , Wang Wei-Lien , Patel Shreyaskumar 
Published: March 2020

10071 Background: Atypical vascular neoplasms are rare cutaneous lesions that develop following radiation therapy to the breast that have evidence of atypia but do not meet all criteria for a diagnosis of angiosarcoma. They typically have a benign course and are managed by surgical resection. Histopathological changes consistent with atypical vascular neoplasm are commonly found adjacent to angiosarcoma and have lead some investigators to believe that these may be precursor lesions to development of angiosarcoma. Methods: We performed a retrospective review of all patients with a diagnosis of atypical vascular neoplasm from 2002 to 2012. Patient with a prior/concurrent history of angiosarcoma were excluded from the analysis. Primary objective of the study was to determine the percentage of patients with atypical vascular neoplasms that progressed to angiosarcoma on long-term follow-up. Results: 37 patients were identified in the tumor registry at MD Anderson cancer center with a diagnosis of atypical vascular neoplasm between 2002 and 2012 with a median follow-up of 24 months. The median age of the study population was 53. Females represented 89% of the study population. Atypical vascular neoplasms occurred most frequently in the breast/chest (70%) and 68% of patients had a prior history of breast cancer. 54% of patients had prior radiation therapy. The median time to development of atypical vascular neoplasms from radiation therapy was 52 months. Among patients who underwent surgical resection with negative margins, there were no recurrences. We failed to observe any progression to angiosarcoma in the study population. Conclusions: Patients with atypical vascular neoplasms may not progress to angiosarcoma and are best managed with surgical resection.