bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the TPO-receptor agonist Eltrombopag in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models.
Authors: Roth Michael , Nevil Grace , Gill Jonathan Benjamin , Zhang Wendong , Teicher Beverly A. , Erickson Stephen W , Gatto Gregory , Smith Malcolm A. , Kolb E. Anders , Gorlick Richard Greg 
Published: March 2020

e22502 Background: Eltrombopag (EP) is a small molecule, thrombopoietin receptor (TPO-R) agonist indicated for the treatment of patients with chronic immune thrombocytopenia and severe aplastic anemia. EP is a polyvalent cation chelator and inhibits leukemia cell proliferation via depletion of intracellular iron. Recent studies show EP inhibits the proliferation of osteosarcoma cells lines via depletion of polyvalent cations. The in vivo effects of EP were studied in osteosarcoma patient derived xenograft models by the Pediatric Preclinical Testing Consortium (PPTC). Methods: The in vivo anticancer effects of EP were assessed in a panel of six osteosarcoma PPTC PDX models with limited MPL mRNA expression (OS2, OS9, OS31, OS33, OS36, OS60). EP was administered at an oral dose of 5 mg/kg/day given for 5 days each week with planned treatment period of 4 weeks. High dose EP (50mg/kg/day) was also tested in 2 PDX models (OS2, OS9) on the same schedule. A control cohort that received vehicle was included for each PDX model. Tumor volumes were measured and responses defined utilizing the PPTC statistical analyses. Results: EP at 5 mg/kg failed to inhibit tumor growth or induce significant differences in event-free survival (EFS) in any of the 6 osteosarcoma PDX models. At the higher dose of 50 mg/kg a significant prolongation in time to event in the EP-treated group was observed, but the effect was small with the ratio of the median time to event for treated versus control animals (EFS T/C) being only 1.2 in the 2 OS PDX models tested. No objective responses were observed with EP at either dose, with all models demonstrating progressive disease. Conclusions: EP did not exhibit significant antitumor activity against the PPTC osteosarcoma PDX panel. However, EP also did not enhance tumor growth. EP’s lack of anti-tumor activity against the OS PDX models suggests leukemia and osteosarcoma cells likely have different dependencies on intracellular polyvalent cations. Given EPs effect on stimulating platelet production, and the demonstration that EP does not stimulate in vivo growth of osteosarcoma, EP may be considered in patients with osteosarcoma as a supportive care agent in supporting platelet recovery.
Combination treatment for giant cell tumors of the bone.
Authors: Barashev Artem A. , Kit Oleg I. , Vashchenko Larisa N. , Nepomnyashchaya Evgeniya M. , Karnaukhov Nikolay S. , Ulianova Elena P. , Sidorenko I. P. , Ausheva Tatiana V. , Dashkova Irina , Andreyko Elena A. , Mozulyaka V. V. 
Published: March 2020

e22504 Background: Positive effect of the monoclonal antibody denosumab in cancer treatment has been reported in recent years. Since surgical treatment is considered the main method of treatment for giant-cell tumors of the bone (GCTB), the purpose of our study was to improve treatment outcomes using denosumab. Methods: The study included 10 patients with verified GCTB (5 men, 5 women, mean age 36±3.14 years). Tumors were located in the upper third of the tibia (3 patients), the lower third of the tibia (3), iliac bone (1), heel bone - 1, the lower third of the femur - 1, the lower third of the humerus - 1.Patients received 2 cycles of neoadjuvant denosumab treatment (120 mg subcutaneously once every 4 weeks) with further tumor resection. The bone defect was reconstructed with bone grafting in marginal resections and endoprosthetics in segmental resections. The effect of neoadjuvant therapy was assessed morphologically by optical light microscopy; histological and histochemical methods were used. Results: Neoadjuvant treatment reduced pain syndrome and restored the support ability. X-ray and spiral X-ray CT showed sclerotic sites in the lytic foci. Consolidation of pathological fractures in the tumor area was registered, as well as fibrosis of the tumor focus. The tissue on the sections of removed material appeared dryish and whitish, it replaced the medullary canal. Microscopic examination of tumors revealed areas of extensive sclerosis foci, and a slight lymphohistiocytic infiltration in some cases. Osteoclasts and osteoblasts were absent in the histological preparations. Conclusions: Neoadjuvant denosumab in GCTB with the following surgery has a pronounced positive effect. This was confirmed by the morphological picture of the operative material demonstrating the development of extensive foci of loose and dense fibrous connective tissue with a small amount of lymphohistiocytic elements.
Metabolic profile and neoadjuvant chemotherapy sensitivity in high-grade bone sarcoma.
Authors: Boudou-Rouquette Pascaline , Gataa Ithar , Jouinot Anne , De Percin Sixtine , Bellesoeur Audrey , Alexandre Jerome , Dumaine Valérie , Babinet Antoine , Biau David , Audard Virginie , Larousserie Frederique , Anract Philippe , Tlemsani Camille , Goldwasser Francois 
Published: March 2020

e22506 Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Methods: We recruited 121 pts with new primary localized or metastatic BS, measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance was calculated, and patients with HOMA-IR > 2.6 were considered as insulin resistant (IR). We collected characteristics usually associated with insulin resistance (IR): age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 121 pts, 48 (40%) were IR: HOMA-IR > 2.6. Thirty IR patients (62%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI > 30 kg/m2)(23% vs 3%, p = 0.0013), but not with age (median 38.4 vs 43.3 years, p = 0.15). IR was more prevalent in Ewing sarcoma (12/21; 57%) and chondrosarcoma (7/13; 54%) followed by osteosarcoma (25/61; 41%) and other rare bone sarcomas (4/26; 15.3%)(p = 0.037). After preoperative chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (85.8 vs 69.3%, p = 0.012). Using multivariate linear regression models, IR was independently associated with pathologic tumor necrosis (p = 0.042) but not with obesity (p = 0.55). Conclusions: Our results suggest that tumor-induced metabolic profile may help to discriminate best candidates for preoperative chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results.
Antitumor activity of pazopanib (P) and trametinib (T) in preclinical models of osteosarcoma (OS).
Authors: Chiabotto Giulia , Centomo Maria Laura , Merlini Alessandra , D'Ambrosio Lorenzo , Sangiolo Dario , Miglio Umberto , Todorovic Maja , Napione Lucia , Berrino Enrico , Capozzi Federica , Venesio Tiziana , Maldi Elena , Sapino Anna , Aglietta Massimo , Grignani Giovanni , Pignochino Ymera 
Published: March 2020

e22509 Background: Receptor tyrosine kinases (RTKs) and their signal transducers are suitable targets for the treatment of advanced OS. We evaluated the antitumor activity of the RTK inhibitor P and the MEK inhibitor T and deeply investigated molecular mechanisms behind their activity and potential escape. Methods: Flow cytometry and western blot analyses were carried out in 7 OS cell lines to study the expression of RTK P targets and the activation of their pathways, respectively. Cell viability and colony growth were evaluated after 72h and 7-day treatment respectively, with scalar doses of both single agents and their constant combination. Cell cycle distribution and apoptosis were evaluated by flow cytometry after 72h. In vivo antitumor activity was studied in NOD/SCID mice bearing MNNG-HOS xenografts after 3 weeks of treatment. Cell migration was studied by scratch assays. The involvement of MAPK-PI3K pathway key transducers was explored by Vantage 3D RNA Panel and Nanostring technology, validated by western blot and confirmed by silencing experiments. Results: P targets are expressed on OS cell lines and their pathways are activated. P+T have synergistic antitumor activity (combination index < 1) in OS cell lines by inducing apoptosis (6/7) and inhibiting both ERK1/2(7/7) and AKT (7/7). Furthermore, in vivo antitumor activity was shown in OS bearing mice (tumor volume: P+T/untreated = 0.036, p = 0.002). P+T significantly down-modulated RTK EphaA2 (mean log2 fold change RNA P+T/untreated = -2.02±0.50) and induced Janus kinase MEK6 (mean log2 fold change RNA P+T/untreated = 2.9±0.51). EphA2 silencing reduced cellular proliferation and migration of OS cells. Impeding MEK6-up-regulation in P+T treated cells significantly increased the antitumor effect (51.5±14.3%) of the studied drugs. Conclusions: P+T exert antitumor activity in OS preclinical models through ERK and AKT inhibition and EphA2 downmodulation. MEK6-upregulation after P+T is likely implied in escape mechanism.
Relationship among ETV1 genetic polymorphisms, PFS, and microRNA in gastrointestinal stromal tumors.
Authors: Qiu Haibo , Zhuang Wei , Zhou Xiaojun , Wang Xueding , Zhou Zhiwei , Huang Min 
Published: March 2020

e22513 Background: In order to evaluate the pharmacokinetic and pharmacogenomic determinants for prognosis of gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the germline mutation and its mechanisms. Methods: A total of 75 GIST patients treated with Imatinib were enrolled. 35 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ ETV1/ FLT1/ MAPK1 et. al were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. COX regression analyses were performed to evaluate the key factors of PFS. The luciferase reporter system of rs3735343 wild type and mutation were established. The GIST-T1 cell line was used to evaluate the biology effect of rs3735343. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Several factors influence the PFS, including KIT somatic mutation, tumor size and germline mutation ABCC4 rs4148551, ETV1 rs3735343, FLT1 rs3751397, KIT rs3822214. And COX regression showed that rs3735343 and tumor size are associated with PFS (P = 0.009 and 0.032, Risk Ratio = 8.995 and 4.173). And we found that rs3735343 mutation type can regulate ETV1 3’UTR and protein expression level through miR-4311 in vitro. Conclusions: The primary determinants of PFS in this somatic and germline mutation model suggested new biomarkers and different mechanisms involved in prognosis. This is the first report showed that ETV1 genetic polymorphisms may influence the prognosis through miRNA-4311. Targeting ETV1, miRNA-4311 or their relative pathway might be a new therapy strategy.
Comparative DNA cytometry of primary and recurrent soft tissue sarcomas.
Authors: Dashkova Irina , Vashchenko Larisa N. , Kit Oleg Ivanovich , Novikova Inna A. , Komarova Ekaterina , Ausheva Tatiana V. , Andreyko Elena A. , Komarova Elizaveta , Kechedzhieva Emma 
Published: March 2020

e22516 Background: Soft tissue sarcomas (STS) are aggressive tumors with a high degree of recurrence. Radical resection within healthy tissues allows to reduce the recurrence percentage to 25-30% without subsequent therapy. The literary analysis has shown that the study of various biological properties of primary and recurrentsoft tissue tumorsis being conducted. However, currently there is a lack of information to understand the reasons for STS recurrence. The goal of investigation was to reveal the distinctive features of the DNA content and cell distribution in the phases of the cell cycle of recurrent STS. Methods: DNA cytometry in the tumor tissue of 30 primary soft tissue sarcomas and 30 STS recurrences was carried out using the method of flow cytofluorometry. The tumor ploidy and cell distribution in the cell cycle phases were analyzed. Results: A number of differences in the DNA cytometric parameters of primary and recurrent STS have been revealed, they include: an increase in the proportion of aneuploid tumors in case of recurrence, the number of tumors with DNA index within the mitotic cycle, an increase in the proportion of cells in G2+M- phase of diploid and aneuploid tumors and a decrease in S- phase of aneuploid ones. It has been shown that with a G2 differentiation degree, the proportion of cells in G2+M, S- and proliferation index of recurrent STS is significantly lower than the primary parameters. An increase in the proportion of cells in G2+M- phase and a decrease in the rate of proliferation of recurrent STS, depending on the stage, are shown only in case of stage III. Conclusions: The revealed features of DNA content and cell cycle of tumor cells of soft tissue sarcomas will allow to approach to understanding of biological bases of recurrence of this malignant disease.
Survival outcomes following cytoreductive nephrectomy (CN) in patients with metastatic renal cell sarcomas (MRCS).
Authors: Malla Midhun , Johnston Sarah E , Zhao Yan D , Pareek Vipul 
Published: March 2020

e22519 Background: RCS are rare soft tissue sarcomas and account for 0.8-2.7% of malignant kidney tumors. Level 1 evidence guiding optimal patient management is lacking due to the rarity of this disease. Utilizing the NCDB, we analyzed prognostic factors, the current treatment patterns and outcomes in patients with RCS in the United States. Methods: The NCDB was queried from 2004- 2015 for patients diagnosed with MRCS. Baseline patient characteristics were summarized using descriptive statistics. Impact of baseline demographic, Clinicopathologic variables and treatment on overall survival (OS) was evaluated using univariate (UV) and multivariable (MV) cox proportional hazards analysis. Results: 454 patients diagnosed with MRCS between 2004- 2015 were included in this analysis. Median age at diagnosis was 63. Males (62%) had higher incidence of RCS compared with females. 86% (n = 389) were Caucasian, while only 9.5% (n = 43) were African American. Right and left kidneys were equally affected. Spindle cell sarcoma was the most common histology (n = 276). 37.5% (n = 170) underwent CN. 49% of patients received chemotherapy (n = 216) and 24% received radiation therapy (n = 109). Overall, 48% (n = 82) of patients who underwent nephrectomy had chemotherapy. Median OS was 4.5 months (3.8-5.2 mos.). On UV analysis age ≥ 55 years (HR: 1.92, p < 0.001), no systemic treatment (HR: 1.91, P < 0.01), and no CN (HR: 2.1, p < .001) had worse OS. On MV analysis, patients who did not undergo CN had significantly worsened OS compared to CN (7.56 vs 3.35 mos., HR-1.91, CI: 1.52- 2.41 p < 0.001). Patients who received chemotherapy after CN had a better OS (13.3 vs 3.7 mos., p < 0.001). Conclusions: MRCS is an aggressive malignancy with a median OS of less than 5 months. Age at diagnosis, CN and systemic therapy had a statistically significant impact on OS. Given the rarity of the tumor and inadequacy of guidelines, these results can be considered in making management decisions. We understand the limitations of a registry-based study and hence, prospective multi-national clinical trials are essential to further guide us on management of this rare tumor. [Table: see text]
Cardio-toxicity among patients with sarcoma: A Cardio-Oncology Registry.
Authors: Shamai Sivan , Merimsky Ofer , laufer-Perl Michal 
Published: March 2020

e22530 Background: Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracycline (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutic related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (EF) reduction of > 10%, to a value below 53%. Our objective was to estimate the prevalence of CTRCD among patients with sarcoma, to evaluate echocardiography parameters associated with its development and whether CTRCD is associated with mortality. Methods: Data were collected as part of the International Cardio-Oncology Registry (ICOR), enrolling all patients who were evaluated in the cardio-oncology clinic at our institution. All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. "Preserved EF" group. Results: Among 43 consecutive patients, 6 (14%) developed CTRCD. Elevated left ventricular end systolic diameter (p = 0.007) and a trend of reduced Global Longitudinal Strain (p = 0.092) were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the "Preserved EF" group. In a multivariate analysis, adjusted to age and EF, CTRCD remained a significant predictor for mortality (p = 0.039). Conclusions: CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors, and is associated with mortality. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.
Chinese largest cohort data from NCT03120846: Efficacy and safety of VEGFR2 inhibitor apatinib for metastatic soft tissue sarcomas.
Authors: Yang Jilong , Liao Zhichao , Liu Xinyue 
Published: March 2020

e22532 Background: There is no standard treatment for stage IV soft tissue tumor (STS) after the failure of Adriamycin-based chemotherapy. This opening, single-arm, multi-center phase II study (NCT03120846) assessed the efficacy and safety of Apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV soft tissue tumor after the failure of chemotherapy. Methods: Between September 2015 and February 2018, we recruited 42 patients with stage IV STS who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Secondary endpoint was overall survival (OS). Treatment-related adverse effects (AEs) were evaluated. Results: Patients (19 men, 23 women; 14-83 years, average age: 47.67years) received 500 mg apatinib on Days 1–28 of 4-week cycles (median 5.7 cycles; range: 0–23 cycles). Median follow-up was 9 months (range: 1–28 months). We assessed 42 patients for AEs and 38 for efficacy. At 12 weeks, PFR was 70% and the ORR was 26.32% (10/38) and DCR was 86.84% (33/38). For the overall responses, the ORR was 23.68% (9/38) and DCR was 57.89% (22/38). The median PFS was 7.87 months and median OS was 17.55 months. The top AEs included hypertension ( n= 18, 42.86%), hand-foot-skin reaction ( n= 15, 35.71%), Apositia (13, 30.95%), and proteinuria ( n= 11, 26.19%). No patients had grade-4 AEs. 11 (26.19%) had grade-3 AEs. 2 patients (4.76%) quit because the AE. Notably, the 26 patients (61.90%) who suffered hypertension, hand-foot-skin reaction or proteinuria had significantly longer OS than those without these AEs (20.94 vs. 8.93 months; Log Rank (Mantel-Cox) = 12.94, P= 0.0003). Conclusions: Apatinib is effective and well tolerated in patients with advanced soft tissue sarcomas. The adverse events hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in STS patients. Clinical trial information: NCT03120846.
10-year follow-up results of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-grade soft tissue sarcomas (STS) in the extremities: Japan Clinical Oncology Group study JCOG0304.
Authors: Tanaka Kazuhiro , Mizusawa Junki , Naka Norifumi , Kawai Akira , Katagiri Hirohisa , Hiruma Toru , Matsumoto Yoshihiro , Tsuchiya Hiroyuki , Nakayama Robert , Hatano Hiroshi , Emori Makoto , Hosaka Masami , Yoshida Yukihiro , Okamoto Takeshi , Abe Satoshi , Asanuma Kunihiro , Yokoyama Ryohei , Fukuda Haruhiko , Ozaki Toshifumi , Iwamoto Yukihide 
Published: March 2020

e22533 Background: STS are rare malignant tumors and relatively resistant against chemotherapy. We have previously reported 3-year follow-up on the efficacy results of perioperative chemotherapy with DXR and IFM for STS in the extremities (JCOG0304) in ASCO 2011 (abstract ID:#10078). In the present report, we analyzed 10-year follow-up results of JCOG0304. Methods: Patients with operable, FNCLCC grade 2/3 STS (T2bN0M0, AJCC 6th edition) in the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy consisted of DXR 60 mg/m2plus IFM 10 g/m2in 3-week interval. Primary endpoint was progression-free survival (PFS). Prognostic factors were evaluated by log-rank test. Results: A total of 72 patients were enrolled between March 2004 and September 2008, and 70 patients were eligible. Median follow-up period was 10.0 years for all eligible cases. The local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. Ten-year progression-free survival (PFS) was 65.7% (95% CI, 53.4%-75.5%) with no PFS event within last 5-year of follow-up. Ten-year overall survival (OS) was 78.1% (95% CI, 66.3%-86.2%). Subgroup analysis demonstrated no significant difference in PFS and OS regarding age, sex, histological grade, and histology. Secondary malignancy occurred in 6 patients. Conclusions: Only a few long-term results of clinical trials of perioperative chemotherapy for STS have been reported. Our results demonstrated that the 10-year outcome of JCOG0304 for the patients with operable, high-grade STS in the extremities was stable and remained favorable. Clinical trial information: C000000096.