bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical experience with sunitinib (SU) in patients over age 65 with metastatic gastrointestinal stromal tumors (GIST): A retrospective study from the French Sarcoma Group (FSG).
Authors: Duffaud Florence , Ray-Coquard Isabelle , Marchal Frederic , Chaigneau Loic , Bouche Olivier , Huynh Thanh Khoa , Mancini Julien , Isambert Nicolas , Bompas Emmanuelle , Ryckewaert Thomas , Bertucci François , Le Cesne Axel , Landi Bruno , Rios Maria , Adenis Antoine , Blay Jean-Yves ,   French Sarcoma Group
Published: March 2020

10546 Background: Elderly GIST patients (pts) represent a consistent portion of all GIST pts, but are under-represented in clinical trials. Data on benefits, tolerance of SU in elderly GIST pts and their specific outcome are very limited. Methods: Charts of elderly pts (≥ 65 yrs)treated with SU in routine clinical practice from 11 Centres of the FSG were reviewed to evaluate the efficacy and safety of SU. Results: 71 elderly GIST pts were reviewed, with a median age of 74, [distributed as 65-74, n=36; 75-84, n=30; ≥ 85, n=5], 41 (57%) men, with median ECOG-PS= 1 (0-2), and median active comorbities of 1 (0-4). SU was administered after progression on first-line Imatinib (400 mg/d for 21 pts, 400 then 800 mg/d for 45 pts) or masitinib (5 pts). SU was started at 50 mg/d 4-wks-on/2 wks-off in 37 pts (52%), at 37.5 mg daily in 32 pts (45%), and at 25 mg daily in 2 pts. All but 2 pts experienced at least one adverse event (AE). Drug related AE were mainly of grade 1 or 2 (298/388, 76%), and medically manageable. Most frequent AE were fatigue (20%), diarrhea (11%), mucositis (7%), abdominal pain (7%), hand-foot syndrome (6%), neutropenia (6%), and hypertension (5%). Permanent dose reduction was reported in 33 pts (46%). In 17 pts (24%) SU was permanently stopped due to grade 3 or 4 AE. ; this occurred within 3 months after starting SU in 10 pts. At a median 36 months follow-up, 53 pts progressed, and 28 pts were alive. The median PFS and OS were 10.2 (0.2-54) and 21 (0.5-77) months, respectively. Univariate analysis showed that age (≤ 80), PS (<1), WBC (≤ 4 Giga/l), Hb and Albumin have a positive impact on OS (all p < 0.04) and PFS (all p < 0.05). In multivariate analysis, Albumin and Hb had an impact on OS and PFS, PS had an impact only on OS, and WBC only on PFS. A correlation was found between comorbidities and Grade 3/4 toxicities, but no correlation between any toxicities and outcome. Conclusions: Compared to data from clinical trials, SU yields similar rates of GIST control and OS in elderly pts despite frequent dose reductions or interruptions. Since comorbidities may increase the risks of AEs, careful follow-up to assess tolerance is particularly indicated in elderly GIST pts.
Impact of mutational status and other prognostic factors on survival in patients with advanced GIST treated with standard-dose imatinib (IM): Results from the BFR14 phase III trial of the French Sarcoma Group.
Authors: Domont Julien , Chabaud Sylvie , Ray Coquard Isabelle , Bui Binh , Adenis Antoine , Rios Maria , Bertucci François , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Emile Jean-François , Coindre Jean-Michel , Blay Jean-Yves , Le Cesne Axel 
Published: March 2020

10548 Background: Factors predicting progression free survival (PFS) and overall survival (OS) of patients (pts) with advanced GIST treated with 400 mg daily dose IM were investigated. As mutational status was a secondary objective of the BFR14 study, we wanted to evaluate the added value of these genomic profiles to conventional clinical prognostic factors. Methods: 434 pts were included in this prospective multicenter trial from June 2002 to July 2009. Prognostic factors for survival were investigated in the cohort where the mutational status was available. A multivariate Cox model including baseline characteristics statistically significant in univariate were included in a backward procedure to identify independent prognostic factors for PFS then OS. Results: Mutational analysis were available in 322 pts. Material was insufficient in 55 cases (12.5%), incomplete results were obtained in 39 pts (9%). There were 196 KIT genetic alterations (exon 11: 173 pts, exon 9: 22 pts, exon 17: 1 pt), 6 GIST with a PDGFRA mutations and 26 GIST WT. The analysis of prognostic factors was performed in all mutated and non-mutated GIST (221 pts) except for pts with a KIT exon 17 and PDGFRa mutation. As of January 2013, median follow-up was 73 months (m) (CI95%:63; 86), 147 progressions (67%) were notified and 84 deaths (38%) occurred. The median PFS and OS were 12.3 m (CI95%: 2.1;32.7) and 54.9 m (CI95%:16.5;83.8) for WT GIST, 12.6m (CI95%: 6.1;30.8) and 55m (CI95%:33.5;83.0) for KIT exon 9 and 39.4m (CI95%: 31.4;54.4) and not reached for KIT exon 11, respectively. An initial low tumour volume, gender (female), and CD34 positivity were the three independent prognostic factors of a higher PFS. A higher OS was independently predicted by PS, low neutrophil counts, KIT exon 11 alterations, normal lymphocyte count, lower tumor size and female’s gender. Conclusions: GIST pts harboring a KIT exon 11 mutations have the better outcome but the mutational status is not the only prognostic factor influencing the outcome of pts. The clinical (gender, PS, tumor size) and biological characteristics (lymphocytes and neutrophil counts) remain critical for OS.
Correlation of PTEN loss and PI3K/AKT/mTOR pathway upregulation with malignant peripheral nerve sheath tumor (MPNST) development and outcome.
Authors: Shurell Elizabeth , Vergara-Lluri Maria Espera , Li Yunfeng , Tran Linh M , Nakashima Jonathan , Barzan Kathleen , Tam Brenna , Bernthal Nicholas , Tap William D. , Eckardt Jeffrey , Eilber Frederick R. , Dry Sarah M , Wu Hong , Eilber Frederick C. 
Published: March 2020

10555 Background: MPNST is an aggressive soft tissue sarcoma often arising from preexisting neurofibromas (NF). Our previous study using murine models demonstrated that PTEN loss and PI3K/AKT/mTOR pathway upregulation is a potential mechanism of malignant transformation. The goal of this study is to determine whether a similar mechanism also drives human MPNST development. Methods: A tissue microarray was created from 144 surgical specimens (MPNST n=58, NF n=51, schwannoma n=11, and normal nerve n=24). Cores were stained in triplicate for PTEN and PI3K pathway-associated markers (PTEN, P-AKT, P-S6, GLUT1, SKP-2), other previously identified alterations (p53, p16, P-ERK and c-Myc) as well as tumor grade biomarkers Ki-67 and cleaved caspase 3. Density, intensity and subcellular localization of each marker were quantified and compared using linear regression and survival analysis was performed using Cox proportional hazards modeling. Results: Consistent with our mouse model study, P-S6, GLUT1 and SKP-2, downstream surrogate markers for PI3K pathway, are upregulated in MPNST compared to benign NF (p=0.002, p=0.000, p=0.016, respectively). Upregulated GLUT1 is notable as we have shown that FDG imaging can be used to stratify MPNST lesions from benign. In the 34 primary MPNST patients, PTEN protein expression correlated with improved disease specific survival (DSS) and disease free survival (DFS) (p=0.066 and p=0.014, respectively). In this cohort, large size (p=0.085), low PTEN (p=0.066), and low c-MYC (p=0.001) were associated with poor DSS. Large size (p=0.074), low PTEN (p=0.023), skp2 (p=0.097), p-AKT (p=0.086), and c-MYC (p=0.001) all correlated with poor DFS. NF-1 patients and spontaneous patients had different expression patterns associated with survival. NF-1 patients had improved DSS with high p53 (p=0.044) and smaller size (p=0.013), whereas spontaneous patients showed improved DSS only with increased c-MYC (p=0.008). Conclusions: PTEN loss and PI3K/AKT/mTOR pathway activation are important in MPNST development/prognosis and serves as a potential therapeutic target.
A phase Ib/II study of imatinab and everolimus in patients with PDGFRA+ synovial sarcoma.
Authors: Keohan Mary Louise , Tap William D. , Dickson Mark Andrew , D'Angelo Sandra P. , Carvajal Richard D. , Gounder Mrinal M. , Morales Rita Elena , Condy Mercedes M. , Hameed M , Ho Alan Loh , Vasuveda S , Qin Li-Xuan , Luke Jason J. , Takebe Naoko , Schwartz Gary K. 
Published: March 2020

10558 Background: Our group previously reported that PDGFRA is the most highly overexpressed kinase gene in synovial sarcoma. Our preclinical studies also demonstrated synergistic anti-tumor activity by inhibiting both PDGFRA and mTOR signaling with imatinib and rapamycin respectively in PDGFRA + synovial sarcoma cell lines. Based on these data, a phase Ib/II study to evaluate the toxicity and efficacy of imatinib and everolimus was undertaken. Methods: The primary endpoint of the phase 1b portion of the study was to determine the maximum tolerated dose (MTD) of everolimus administered with imatinib. Starting dose of everolimus and imatinib was 5 mg/day and 400 mg/day respectively. Response rate (RR) by RECIST was the primary end-point of the Phase II study. The phase II study used a Simon two stage design. 9 patients (pts) were to be accrued initially. If there were no responses, further accrual would be stopped and treatment declared ineffective. If there was at least 1 response, an additional 15 pts would be accrued for a total of 24. Key eligibility: metastatic disease, any number of priors. Pre and post treatment tumor biopsies were mandated. Results: 12 pts were treated.5 M and 7 F, median age 44 (range: 22-71), median priors 4 (range: 0 - 6). Two DLTs were observed at dose level 2 (10 mg everolimus /400 mg imatinib) with grade 3 transaminases and hypophosphatemia. Everolimus 5 mg/ imatinib 400 mg was the MTD in the phase II study. 10 pts evaluable for response, included 4 pts treated at the MTD in the Phase 1b study. There were no RECIST responses. Stable disease was observed in 3 pts (7, 7, 19 mos.). Western blot and IHC analysis of matched pair tumor biopsies indicate inhibition of p-AKT, p-S6 and decreases in Ki 67. Conclusions: Imatinib and everolimus failed to achieve its primary response endpoint. However, prolonged stable disease in 3 pts in association with inhibition of PDGFRA and mTOR suggest clinical benefit and biological effect for this drug combination. Clinical trial information: CTEP 8603.
A large retrospective analysis of trabectedin in 885 patients with advanced soft tissue sarcoma.
Authors: Le Cesne Axel , Ray-Coquard Isabelle , Duffaud Florence , Chevreau Christine , Penel Nicolas , Bui Binh , Piperno-Neumann Sophie , Delcambre Corinne , Rios Maria , Chaigneau Loic , Le Maignan Christine , Guillemet Cecile , Bertucci François , Bompas Emmanuelle , Linassier Claude , Collard Olivier , Even Caroline , Ducimetiere Francoise , Cousin Philippe , Blay Jean-Yves 
Published: March 2020

10563 Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed the RetrospectYon database with patients’ data treated with trabectedin between Jan 2008 - Dec 2011. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2 as a 24-h infusion every 3 weeks. Patients who achieved partial response (PR) or stable disease (SD) after 6 cycles could receive maintaining trabectedin treatment. Uni- and multivariate analyses of prognostic factors were performed. Results: 885 patients (486 women) from 26 centers in France with ASTS with a median age of 54 years (range 12-84) were included. Most had leiomyosarcoma (36%), liposarcoma (18%) or synovial STS (11%). At baseline, performance status (PS) was 0 in 26%, 1 in 47% and >1 in 27% of patients. A median of 4 trabectedin cycles (range 1-28) was given as a 2nd (41%), 3rd (39%) or ≥4th (20% of patients) treatment line. Toxic death and unscheduled re-hospitalization occurred in 0.5% and 8% of patients, respectively.The objective response rate was 15% (6 complete and 127 PR), and SD rate was 45.5% (n=403). After a median follow-up of 22.6 months (range 0.03-51.2), the patients who received trabectedin as 2nd, 3rd or ≥4th line had the median PFS of 4.3, 4.2 and 3.4 months, respectively, and the median OS of 12.9, 12.3 and 9.5 months. Multivariate analysis identified liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and trabectedin line as independent prognostic factors for PFS, and UPS, angiosarcoma, rhabdomyosarcoma, gender, PS and trabectedin line for OS. After 6 cycles, 205 of the 273 patients with non-progressive disease received trabectedin as maintenance treatment and obtained a superior PFS (median 11 vs. 7.2 months, p=0.0001) and OS (median 25.1 vs. 16.9 months, p<0.0001) that those who stopped trabectedin after 6 cycles. Conclusions: Patients with ASTS treated with trabectedin had PFS and OS comparable or better to those observed in phase II/III trials. Trabectedin maintenance beyond 6 cycles is associated with improved OS and warrants further exploration.
Efficacy and safety of hypofractionated preoperative radiotherapy in treatment of localized extremity/trunk wall soft tissue sarcoma (STS): Final results of the study.
Authors: Rutkowski Piotr , Kosela Hanna Melania , Kolodziejczyk Milena , Dziewirski Wirginiusz , Zdzienicki Marcin , Morysinski Tadeusz 
Published: March 2020

10564 Background: The primary treatment of STS is surgical resection combined with pre- or postoperative radiotherapy. Conventional fractionation in neoadjuvant radiotherapy is 50Gy (fractions: 2Gy/day). Radiobiological studies shown that alpha/beta ratios of some sarcoma cells are below 10Gy, what is rationale for hypofractionation. Aim of the study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in patients with STS treated in one institution. Methods: 220 patients (median age 54years) participated in this prospective study (2006-2010). Median follow up is 34 months. 140 patients (64%) had high grade (G3) tumors, median size -9cm (45% ≥10cm), 68% on lower limb. 137 patients (62.2%) had primary tumors. Preoperative radiotherapy 5x5 Gy per 5 consecutive days was applied, with immediate tumor resection. Results: R0 resection was possible in 79%. 61 patients died (3-year overall survival OS 72%), 91 (41%) had disease relapse. Local recurrence (LR) was found in 20% of the patients (3-year LR-free survival 80%). Negative prognostic factors for LR were: tumor size ≥10cm (p=0.037), grade 3 (p=0.0041) and primary vs. recurrent tumor with borderline significance. LRs had significant impact on OS (p=0.0001). 101 patients (46%) had any kind of complications, majority on lower limb (early: 17.2% prolonged healing of the wound >1month, 12.7% -wound dehiscence, 4% -prolonged punctures of lymph fluid, 2.7% -acute skin toxicity; late: 0.9% -severe fibrosis with contracture, 11% -prolonged edema. 2.7% -bone fracture), but only 6.3% required additional surgery. Conclusions: In this non-selected group of advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (80%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrants evaluation in randomized trial.
Targeted next generation sequencing of sarcomas for identification of therapeutic targets.
Authors: Ravi Vinod , Ali Siraj M. , Ramesh Naveen , Meric-Bernstam Funda , Palmer Gary A. , Hwu Patrick , Patel Shreyaskumar , Futreal Andrew 
Published: March 2020

10577 Background: Sarcomas are a diverse group of mesenchymal tumors with significant heterogeneity. Evolving personalized cancer care strategies require identification of recurrent genomic alterations that can be targeted therapeutically. Due to the rarity of these tumors and lack of fresh or frozen tissue in routine clinical practice, DNA sequencing has been a challenge. Objective: To demonstrate the feasibility of a next-generation sequencing (NGS) platform that utilizes archival formalin-fixed paraffin-embedded (FFPE) tissue to evaluate the spectrum of DNA alterations seen in sarcomas. Methods: Study population included 35 consecutive patients with advanced sarcoma presenting to the sarcoma center at MD Anderson Cancer Center beginning August 2012 with archival FFPE tissue available for NGS. DNA was extracted from FFPE samples and used for hybridization capture and NGS on the Illumina HiSeq 2000 platform. A total of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations. In the absence of an individual–matched normal control, germline variations were removed using dbSNP and the remaining variants were classified on the basis of current knowledge of specific variants from cancer databases such as COSMIC. Results: 35 patients (10 Angiosarcomas, 9 Leiomyosarcomas, 3 synovial sarcomas, 13 other subtypes) underwent DNA extraction with a median yield of 3376 ng tumor DNA. The average sequencing depth was >900X. 43% of patients had point mutations/indels previously described in COSMIC and/or in known mutation hotspots. 54% of patients showed structural variants such as amplifications, deletions or rearrangements. 68% of genomic alterations are in genes that are actionable. We identified an apparently novel variant in KDR T771R in 2/10 patients with angiosarcoma. KDR amplifications were identified in 20% of patients with angiosarcoma. Outcomes of matched targeted therapy of patients with actionable targets will be presented with more mature follow-up. Conclusions: Targeted NGS of DNA from archival FFPE tissue is feasible with the potential for identifying actionable targets and discovery of novel mutations.
Phase I and pharmacokinetic study of sorafenib in Kaposi sarcoma.
Authors: Uldrick Thomas S. , Wyvill Kathleen , Peer Cody , Polizzotto Mark Niccolo , O'Mahony Deirdre , Bernstein Wendy , Aleman Karen , Steinberg Seth M. , Venzon David J. , Pittaluga Stefania , Little Richard F. , Figg William Douglas , Yarchoan Robert 
Published: March 2020

10588 Background: Kaposi sarcoma (KS) is a multifocal angioproliferative disorder. VEGFR2-3, PDGFR and c-kit are implicated in KS pathogenesis and inhibited by sorafenib (So). KS is commonly HIV-associated. The antiretroviral drug ritonavir (R) inhibits CYP3A4, and may affect So metabolism and tolerability. Methods: We performed a phase I study of So in KS. HIV+ patients (pts) were eligible if on combination antiretroviral therapy (cART) for >3 months with progressive KS or >4 months with no KS regression. Dose level 1 for pts on R-containing cART (R1) was So 200 mg daily, for pts not receiving R (NR1) So 200 mg every 12 hours. Treatment cycles were 21 days. So pharmacokinetic assessment performed cycle 1 day 8. Adverse event (AE) grade (Gr) by CTCAE v3.0 (2006-10) and v4.0 (2011-12). KS response graded by modified ACTG criteria. Results: 10 pts, R1 (8), NR1 (2). Baseline characteristics: median (med) (range) age 49 (35-72), CD4 in HIV+ 500 cells/uL (35, 747), time on cART 9 months (3.5, 27), previous KS therapies 2 (0-5). 9 HIV-infected, 8/9 HIV viral load <50 copies/mL. 6 had KS-associated edema. Med number cycles 4 (1, 13). Common AE at least possibly attributable to So: anemia, AST/ALT elevation, lipase elevation, hypertension, proteinuria, fatigue, infection, voice alteration. Dose-limiting toxicities (DLT): R1- Gr3 asymptomatic elevated lipase (1), Gr4 thrombocytopenia (1, likely due to multicentric Castleman disease); NR1- Gr3 hand-foot syndrome not resolved by week 6 (1). Other Gr 3-4 AE: R1- hand-foot syndrome (1), Gr3 thrombocytopenia (1), Gr3 transient cerebral ischemia (1), Gr3 hypertension (1); NR1- Gr3 hypertension (2). Best response: partial response (PR) (2), stable disease (SD)(5), progressive disease (1), not evaluable (2). Med duration SD 12 weeks (5, 33). 5/6 with KS-associated edema had objective decrease in edema. R was not associated with clear difference in So CMax or AUC at steady state. Conclusions: Preliminary estimate of PR or better is 20%. Even in some cases where KS did not respond, KS-associated edema improved. However, So was relatively poorly tolerated, with DLT observed at R1 and NR1, and these doses did not yield better responses than established therapies. Additional studies evaluating R’s effect on So metabolites are warranted. Clinical trial information: NCT00287495.
Insurance status as a strong predictor of outcome in triple-negative breast cancer (TNBC): A multi-institutional retrospective study.
Authors: Biswas Tithi , Prasad Shreya , Zagar Timothy , Efird Jimmy , James Sarah E. , Walker Paul R. , Raab Rachel Elizabeth , Carey Lisa A. , Marks Lawrence B. 
Published: March 2020

1069 Background: TNBC accounts for about 15-20% of all breast cancer. TNBC has particularly aggressive clinical course and accounts for a disproportionate number of breast cancer relapses and deaths in early stage disease. TNBC also have worse prognosis especially in African American (AA) women compared with white women. This retrospective study aims to investigate various clinical and demographic prognostic factors in TNBC. Methods: 476 TNBC patients who were treated at Eastern Carolina University and University of North Carolina, CH between 4/96 and 9/11 were included in this analysis. We collected data on age, race, grade, lymphovascular invasion (LVI), stage, treatments including surgery, chemotherapy, radiation, chemotherapy drugs, insurance type and year of treatment. Overall Survival (OS) was computed from the date of diagnosis to the date of death or last FU. For disease free survival (DFS), patients were scored if they failed either locally or distally. The Cox proportional-hazards regression model was used to compute hazard ratios. Results: The median age was 52 years (21-88 years) with median FU of 3.7 years. 49% women were white race followed by AA 223 (47%) and Hispanic or other race (5%). Stage (p<0.001), grade (p=0.02), surgery (p<0.0001), adjuvant chemotherapy (p=0.025), LVI (p=0.05) and type of insurance were significant predictor of OS. Similarly, stage (p<0.0001), surgery (p<0.0001), LVI (p=0.03) and insurance were significant predictors for DFS. On multivariate analysis, stage, surgery and adjuvant chemotherapy remained statistically significant predictors. Medicaid vs. Private Insurance also remained a significant detriment of survival (OS: HR=3.6, p<0.0001; DFS: HR=2.8, p<0.0001) as did having No Insurance for OS (HR=2.0, p=0.0074). Conclusions: To our knowledge, this is a largest retrospective study showing type of insurance to be a strong predictor of outcome in this very specific breast cancer subtype which remained significant after adjusting all other variables. Further insight is needed to determine the cause of this finding.