bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged survival and disease control in the academic phase II trial of regorafenib in GIST: Response based on genotype.
Authors: George Suzanne , Feng Yang , von Mehren Margaret , Choy Edwin , Corless Christopher L. , Hornick Jason L. , Butrynski James E. , Wagner Andrew J. , Solomon Sarah , Morgan Jeffrey A. , Heinrich Michael C. , Demetri George D. 
Published: March 2020

10511 Background: Regorafenib (REGO) is a broad spectrum tyrosine kinase inhibitor with activity against KIT, PDGFR, VEGFR, and FGFR. Phase II and III trials demonstrated significant activity in patients (pts) with advanced GIST following failure of at least imatinib and sunitinib. Pts have continued on the Phase II trial, and we now report longer-term follow-up as related to primary and secondary tumor genotype (KIT, PDGFRA) and SDH expression. Methods: This multicenter Phase II study of RE in GIST enrolled 33 pts with metastatic GIST. REGO was started at a dose of 160mg per day, d1-21 of each 28d cycle. Anatomic restaging was performed every 2 cycles. Clinical benefit rate (CBR) was defined as CR, PR or prolonged SD (>16 wks) per RECIST 1.1. KIT genotype was determined for tumors with adequate tissue available. SDHB staining was performed on a subset of patients whose tumors lacked activating mutations in KIT or PDGFRA. Response, progression free survival (PFS), and overall survival (OS) were determined for the entire cohort and for subsets based on KIT genotype and SDHB immunohistochemical status. Results: Median followup as of 20Jan2013 was 20 mos. Four pts remain on REGO without progression. CBR for the entire cohort was 81%, with 9% PR (n=3). Median PFS for the entire cohort was 13 mos (95%CI 9-18). Median OS was 27 mos (95%CI 16-NR). Tumor primary KIT mutations and associated median PFS are as follows: exon 11(n=19), 13 mos (95%CI 10-21); exon 9(n=3), 6 mos (95%CI 2-NR) (log-rank p-value=0.93). 6 pts had SDH-deficient GIST, 2 of whom experienced PR. Median PFS of pts with SDH-deficient GIST was 12 mos (95%CI 7-NR). Secondary KITmutations in a GIST lesion were identified prior to enrollment in 9 pts : exon 17 (n=7); one each in exon 13 and exon 18. Median PFS for pts with a documented exon 17 mutation was 18 mos (95%CI 6-NR). Conclusions: REGO is an active agent in advanced GIST. Prolonged disease control and OS is demonstrated in heavily pre-treated pts with KIT exon 11-mutant GIST; although with small sample size, there is no statistical significance in outcomes between genotypes. Objective responses were seen in 2 of 6 of pts with SDHB-deficient GIST. Other biomarkers of response and benefit are under active investigation. Clinical trial information: NCT01068769.
Reversing the oncogenic roles of misdirected chromatin remodeling: Mechanistic insights into the SS18-SSX fusion protein in synovial sarcoma.
Authors: Kadoch Cigall , Crabtree Gerald R. 
Published: March 2020

10515 Background: Synovial sarcoma (SS) accounts for ~10% of soft-tissue malignancies and is generally resistant to chemotherapy-based approaches, underscoring the need for a mechanistic understanding of its pathogenesis and the development of disease-specific biologic agents. The hallmark molecular feature is a precise and uniform translocation, t(X;18), which results in the fusion of exactly 78 amino acids of SSX to the SS18 C-terminus. Because the SS18-SSX genetic lesion is observed in 100% of cases, it is likely the driving oncogenic event in these tumors; however, the molecular basis for its role in oncogenesis is undefined. Methods: We performed an affinity purification-/mass spectrometry-based analysis of endogenous mSWI/SNF (BAF) chromatin remodeling complexes in several primary cell types. Using these data in combination with protein biochemical methods, we discovered that SS18 is a dedicated, non-exchangeable subunit of these complexes with a binding affinity comparable to that of ribosomal subunits. Subsequent biochemical and functional investigations were performed to assess the oncogenic consequences of addition of 78aa of SSX to the SS18 subunit in SS. Results: We demonstrate that the SS18-SSX fusion incorporates into BAF complexes, evicting both wild-type (WT) SS18 and the tumor suppressor subunit, hSNF5 (BAF47), known to be biallelically inactivated in pediatric malignant rhabdoid tumors (MRTs). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and activating Sox2. Sox2, a pro-pluripotency transcription factor, is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of WT SS18 leads to reassembly of WT complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a region of only two amino acids of SSX, and hence provides a strong foundation for therapeutic intervention. Conclusions: These studies provide a novel oncogenic mechanism for SS tumors and inform strategies for therapeutic development in this intractable cancer.
An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.
Authors: Gelderblom Hans , Pérol David , Chevreau Christine , Tattersall Martin HN , Stacchiotti Silvia , Casali Paolo Giovanni , Cropet Claire , Piperno-Neumann Sophie , Le Cesne Axel , Italiano Antoine , Ferraresi Virginia , Duffaud Florence , Penel Nicolas , Dileo Palma , Bertucci François , Hassan Andrew Bassim , Kroep Judith R. , Denizot-Guillemaut Severine , Blay Jean-Yves 
Published: March 2020

10516 Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation resulting in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in patient (pts) with non resectable PVNS. Methods: In this open-label international, multicentric, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment (800 mg/day) in pts with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a futility stopping rule and a maximum sample size set to 50 evaluable pts, interim analyses (IA) were planned after the inclusion of 10 and then every 5 pts. Results: From December 2010 to September 2012, 56 pts with progressive disease were enrolled by 17 institutions from Europe and Australia. Successive previous IA led to positive results in favour of the study continuation. 47 pts (median age 37 y (range: 18-74), 51% of males) were evaluable at the time of the last IA, with a median follow-up of 11.2 months (range: 0.6-12.7). Median time since diagnosis was 2.5 years (range: 0.02-26). Primary tumour was mainly located on knee (25 pts, 53%), hip (6 pts, 13%), ankle (6 pts, 13%). 4 pts had already received imatinib, 76% of pts had undergone a previous surgery. The 12-w PFR was 93.6% (95%CI, 82.5%-98.7%), without any OR. PR were observed later (2 at w-24 and 1 at w-48). Nilotinib was well tolerated, with only 4 pts experiencing grade 3 adverse events (anorexia: 1 pt; prurit: 1 pt; diarrhea: 1 pt; hepatic failure: 1 pt). 8 pts (17%) had a dose reduction and/or temporary discontinuation of nilotinib due to toxicity. Final results will be further presented. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating. Clinical trial information: NCT01261429.
Preoperative chemoradiation therapy for localized retroperitoneal sarcoma (RPS): Final results of a phase II study from the Italian Sarcoma Group.
Authors: Gronchi Alessandro , De Paoli Antonino , Dani Carla , Merlo Domenico Franco , Quagliuolo Vittorio , Grignani Giovanni , Bertola Giulio , Navarria Piera , Sangalli Claudia , Dei Tos Angelo Paolo , Fiore Marco , Casali Paolo Giovanni 
Published: March 2020

10519 Background: To study the feasibility, safety and activity of the combination of high dose long-infusion Ifosfamide (HLI) and radiation therapy (RT) as preoperative treatment for resectable localized RPS. Methods: Patients received 3 cycles of HLI (14 g/m2). RT was started in combination with the onset of the 2nd cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. Primary end-point was 3-yr relapse free survival (RFS). The expected 3-yr RFS in the study population treated with surgery alone was 40%. The experimental treatment was aimed at achieving a relative reduction in relapses of at least 1/3, corresponding to a 3-yrs RFS of 55%. With 60 enrolled patients, the study would have had a 90% power to discriminate between the hypotheses of 3-yrs RFS of 40% (H0) and 55% (H1), using a 1-sided 10% level of significance. Results: Between December 2003 and 2010, 86 patients were recruited. 3 patients were ineligible after central pathological review. 63 were affected by primary tumor and 20 by local recurrence. The 3 main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%) and leiomyosarcoma (14/83, 17%). Median tumor size was 120 mm (IQ range= 82-160). The overall preoperative treatment was completed in 60 patients. CT was completed in 65 patients, while RT in 73. Five patients had progression before surgery (3 distant and 2 local) and were not operated. 78 patients underwent surgery. At a median follow-up of 4.8 years (IQ range=3-6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM) respectively; 30 patients died of disease. 3-yr and 5-yr RFS and overall survival were 56% and 44%, and 74% and 59%, respectively. Crude cumulative incidence of LR and DM at 5 yrs were 37% and 26%, respectively. Conclusions: The combination of preoperative HLI and RT was feasible in two thirds of patients, while pre-operative RT could be completed in most (73/83). The primary endpoint of the study was met. Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international Phase III trial is exploring the role of RT alone. Clinical trial information: ITASARC_*II_2004_003.
Using pegylated arginine deiminase (ADI-PEG20) for the treatment of sarcomas that lack argininosuccinate synthesase 1 expression.
Authors: Van Tine Brian Andrew , Bean Gregory R , Boone Phillip , Tanas Munir , Schulze Matthew B , Chen David Y , Bomalaski John S. , Rubin Brian 
Published: March 2020

10526 Background: To better understand the metabolism of sarcomas, we explored the role of argininosuccinate synthase 1 (ASS1), the rate-limiting enzyme in the conversion of citrulline to arginine in the urea cycle. When ASS1 is not expressed the amino acid arginine becomes an essential amino acid that must be delivered from the diet. The potential for therapeutic manipulation of this pathway with pegylated arginine deiminase (ADI-PEG20) was explored using metabolomic mass spectroscopy. Methods: Immunohistochemistry (IHC) of ASS1 expression on 701 patient specimens representing 45 subtypes of sarcoma was performed. Proliferation and cell death were analyzed in a panel of cell lines. Clonogenic assays were performed using ADI-PEG20 and chloroquine. Autophagy induction and inhibition was assessed. Xenograft models were tested. Metabolomic mass spectroscopy was performed in the presence and absence of ADI-PEG20. Results: lHC analysis demonstrated that ASS1 is not expressed in over 85% of sarcomas (619 of 701 patient samples). Treatment of a panel of LMS, synovial, ASPS, GIST, MPNST, chondrosarcoma, osteosarcoma, and Ewings sarcoma cell lines with ADI-PEG20 resulted in cell cycle arrest but not apoptosis when ASS1 expression was low (13/15 lines). Xenografts of the ASS1 low MNNG/HOS cells and SKLMS1 cells into nude mice followed by treatment with ADI-PEG20 +/- chloroquine demonstrated significantly slower tumor growth as compared to PBS or chloroquine treated controls. Treatment of sarcomas that lack ASS1 with ADI-PEG20 induced autophagy. Global analysis of metabolomic mass spectroscopy demonstrated alterations in PKM2, glutamine dependence, the Warburg effect, the TCA cycle and glutathione biology. Conclusions: This suggests that sarcomas may be sensitive to the arginine depletion therapy using ADI-PEG20. Autophagy induction has global metabolic consequences for sarcoma. Successful control of tumor burden by using arginine deprivation therapy and autophagy inhibition in our preclinical studies will help to orient clinical trials for this innovative treatment in patients with sarcoma that lack ASS1 expression.
Outcome and prognostic factors in localized primitive neuroectodermal tumors with uniform chemotherapy protocol: A single center experience of 224 cases.
Authors: Biswas Bivas , Rastogi Shishir , Khan Shah Alam , Agarwala Sandeep , Mohanti B. K. , Shukla N. K. , Deo S. V. S. , Sharma Dayanand , Sharma Mehar C , Vishnubhatla Sreenivas , Bakhshi Sameer 
Published: March 2020

10527 Background: Data on localized PNET with uniform protocol is minimal. Methods: This is single institutional patient review treated between June 2003-Nov 2011, and evaluated on intent-to-treat analysis. All patients received uniform chemotherapy (VAC/IE) as follows: neo-adjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by ACT. Results: 224/374 (60%) PNET patients were localized with median age 15 years (range: 0.1–55), tumor diameter 8 cm (range: 1.6-25) and symptom duration 4 months (range: 0.5-30). Regions were extremities 40%, thorax 25% and head & neck 14%. Post-NACT, CR was 32(14%); PR 152(68%) with ORR 82%. Ninety-nine patients underwent surgery (50/99 received adjuvant radiotherapy); 80 received radical radiotherapy as local therapy. There were no adverse tumor characteristics or poor NACT response in radical radiotherapy group versus surgery group. At median follow-up of 31.1 months (range: 1.3–113.4), 5-year EFS, OS and local control rate (LCR) were 34±3.5%, 52.5±4.7% and 59.5±4.8%, respectively. Multivariate analysis of prognostic factors is shown in the Table. Conclusions: This is largest data of localized PNET from Asia which identified unique prognostic factors. Localized PNET constituted 60% of entire cohort with delayed presentation. High WBC may be a marker of micrometastatic disease or an adverse paraneoplastic response. Skeletal primary and tumor diameter >8 cm predicted inferior OS and LCR; additionally radical radiotherapy predicted inferior LCR. All efforts should be made to resect primary tumor post-NACT as radical radiotherapy alone despite good NACT response results in inferior LCR. [Table: see text]
Gene expression of the MAPK pathway in osteosarcoma.
Authors: Lopes Luana Joyce Silva , Petrilli Antonio Sergio , Tesser-Gamba Francine , Alves Maria Teresa Seixas , Garcia-Filho Reynaldo Jesus , Toledo Silvia R. C. 
Published: March 2020

10534 Background: Osteosarcoma (OS) is the most common malignant bone tumor in adolescents. A feature of the OS is its high risk of lung metastasis. Unlike other sarcomas, OS does not have genetic markers. We suggest that abnormalities in the expression levels of genes involved in important cell signaling pathways, as MAPKs pathway, may contribute to OS progression and aggressiveness. In a recent study, we found an overexpression of MAPK7 gene in prechemotherapy specimens when compared to postchemotherapy specimens and when compared with normal bone. This previous study suggests that MAPK7 overexpression may be contributing to the worse response to treatment and therefore a poor overall survival. To understand the relationship between the OS genesis process and the MAPK pathway, we investigated the expression of genes involved in the regulation of MAPK pathway (MAP2K5, MAP2K6, MAP3K1, MAP3K3, MAP4K3 and DUSP1). Methods: Total RNA was extracted from 68 tumor samples obtained from 28 patients (28 prechemotherapy specimens, 28 postchemotherapy specimens and 12 metastasis specimens) and five normal bone tissues. cDNA was synthesized and expression of the six genes were determined by quantitative real-time PCR. Clinical variables were correlated with gene expression. Results: MAP2K6 and MAP4K3 had a similar gene expression profile. Both genes were overexpressed in postchemotherapy specimens and were strongly associated with important clinical parameters as presence of metastasis (P=0.0159 and P=0.0014, respectively), shorter overall survival (P=0.0040 and P=0.0040, respectively) and disease progression (P=0.0142 and P=0.0109, respectively). DUSP1 overexpression in postchemotherapy specimens was related with metastasis at diagnosis (P=0.0004), worse response to treatment (P=0.0009) and disease recurrence (P=0.0039). MAP2K5, MAP3K1 e MAP3K3 showed no significant correlations in the present study. Conclusions: The overexpression of MAP2K6, MAP4K3 and DUSP1 in postchemotherapy specimens presented a significant association with poor prognosis. The current study suggests that these genes could play an important role in OS tumorigenesis and may be in the future new therapeutic targets in OS treatment.
Relationship of the topography of KIT exon 11 alterations and predictive value for PFS in patients with advanced GIST: Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.
Authors: Emile Jean-François , Ray-Coquard Isabelle , Bui Binh , Adenis Antoine , Bertucci François , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Coindre Jean-Michel , Mir Olivier , Pérol David , Chabaud Sylvie , Blay Jean-Yves , Le Cesne Axel 
Published: March 2020

10542 Background: The mutations of KIT exon 11 are those most frequently observed in GIST, but there is a substantial level of heterogeneity in their nature and topography. We investigated the impact of the type of KIT exon 11 mutations on clinical presentation and outcome under imatinib in advanced GIST patients (pts) included in the BFR14 study. Methods: Among the 434 pts included, 167 were identified as having GIST with KIT exon 11 mutation (85% of all KIT mutations and 73% of all mutations available in the entire cohort). We analyzed the topography of the mutations and identified 3 groups (G) of mutations according to the first codon involved in the genetic alteration in which the precise topography was available (from codon 549 to 579). The distribution of these G in the different clinical presentations was investigated, as well as their predictive value for progression-free (PFS) and overall survival (OS). Results: Three G with distinct sites of altered codons were distinguished: G1 whose 1st mutated codon was <556 (n=41, 24.5%), G2 whose 1st mutated codon was 557 and 558 (n=74, 44.3%), including those with the deletion 557-558 (n=37, 22.1%), and G3 whose 1stmutated codon was 559 and beyond (n=52, 31.1%). All investigated parameters at inclusion, gender, tumor site and size, site of metastases, age, PS, CD34 expression, biological characteristics were well balanced between the three G of patients. Pts of G2 reached a statistically difference in terms of complete response under imatinib (p=0.028). In contrast, this G have the poorer PFS compared to the other two groups: the median PFS were 30.6 months (CI95%: 21.5;39.4), 49.4 months (CI95%: 33.5; 109.9) and 63.3 months (CI95%: 27.6; 84.7) for the G 2, 1 and 3 respectively (p=0.0176). OS was not significantly different in the 3 G of pts. Conclusions: Despite a favorable sensitivity to imatinib, GIST pts harbouring a genetic alteration initially involving the 557 and 558 codons develop statistically more secondary resistance than the others. These results deserve confirmation in other prospective series in advanced GIST and may be worth exploring in adjuvant series.
Imatinib plasma concentrations during long-term effective treatment of metastatic gastrointestinal stromal tumor.
Authors: Sawaki Akira , Inaba Kazuki , Hayashi Katsumi , Kanie Hiroshi , Owaki Toshihiro , Kimata Tsukasa , Suzuki Masato , Kawachi Aya , Orito Etsuro 
Published: March 2020

10543 Background: Imatinib concentrations at one month after the start of imatinib have shown an association with clinical benefit in pts with gastrointestinal stromal tumors (GISTs) and a significant decrease of 30% within twelve months. This retrospective study investigated imatinib plasma concentrations in pts with metastatic GISTs in a long-term (≥2 years) effective treatment. Methods: 31 metastatic GIST pts, who had been treated with imatinib for two or more years in our hospital, were enrolled in this study. 11 pts were excluded because of adjuvant setting (n=5) and rejection to concentration testing (n=6). 20 pts were included in this study. GISTs were immunohistochemically diagnosed, and radiologically assessed as effective GIST by Choi’s criteria without relapse. Results: 10 pts were male, median age was 63 years (range, 31-84), and median imatinib exposure time was 3.5 year (range, 2-12). The median plasma concentration was 1093 ng/ml (range, 417-2091) and minimal level after at least five years was 789 ng/ml. imatinib concentration has no significant correlation with age, gender, gastrectomy, leukocyte count, platelet count, serum albumin, serum creatinine, cholesterol, and duration of imatinib exposure. Body surface area (BSA) isn’t directly associated with imatinib dose; median BSA of pts taking 300mg imatinib was 1.560 m2 and that of 400mg 1.595 m2, but minimal BSA of 400mg imatinib was 1.560 m2, which is higher than the minimum of 300mg. Conclusions: Plasma concentrations of long-term (≥2 years) response pts was scattered, but one of longer-term (≥5 years) response pts were more than 789 ng/ml. Effective imatinib plasma level might be more than 789 ng/ml and 400mg imatinib may be recommended for a pt with BSA(≥1.56 m2).