bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global differences in chemotherapeutic regimens of soft tissue sarcoma (STS): Results of PALETTE, an EORTC 62072/GSK VEG110727 global network phase III trial of pazopanib versus placebo.
Authors: Marreaud Sandrine , Graaf Winette T.A. Van der , Blay Jean-Yves , Chawla Sant P. , Lee Jeeyun , Bui Nguyen Binh , Casali Paolo Giovanni , Aglietta Massimo , Staddon Arthur P. , Beppu Yasuo , Le Cesne Axel , Gelderblom Hans , Judson Ian Robert , Araki Nobuhito , Ouali Monia , Dewji Mohamedraza , Powell Alex , Demetri George D. , Hohenberger Peter 
Published: March 2020

10067 Background: The global PALETTE EORTC/GSK network study on advanced STS patients (pts) randomized 223 European (EU), 43 American (US), 81 Asian, and 22 Australasian (AUS) pts between pazopanib and placebo. Prior to study entry pts should have received at least one anthracycline containing regimen, and preferably, if pts’condition allowed, all available standard chemotherapy treatments for STS in their countries. We investigated the differences in chemotherapy pts received prior- and post-protocol at a global level. Methods: Pts were grouped by continent. Pre- and post-protocol chemotherapeutic treatments (txs) were analyzed. The number of prior lines of systemic tx for advanced STS was divided between 0-1 vs 2 or more. Chemotherapy was studied in detail between Asian and other countries. Fisher’s exact test was used for statistical analysis. Results: Data from all 369 pts were analyzed. (Neo-) adjuvant systemic tx was given in 21% of EU, 23% of US, 36 % of Asian and 41% of AUS pts. In advanced STS: 2 or more lines of prior systemic txs were administered in 60% of EU, 84% of US, 42% of Asian, 22% of AUS pts before study entry. Prior to study entry 68% of EU, 65% of US, 84% of Asian and 68% of AUS pts received ifosfamide(or analogs); after protocol 21 % of EU, 14% of US, 13% of Asian and 5% of AU pts. There were significant differences in chemotherapy between Asian (n=81) and other (n=288) pts: prior to protocol trabectedin was administered in 1 vs 21%; gemcitabine 19 vs 39 %; cisplatin: 36 vs 5%; etoposide 32 vs 4% (all p<0.001), and docetaxel: 17 vs 31 % (p=0.004) of pts. Post-protocol trabectedin was given to 4 vs 34% (p<0.001), gemcitabine both in 19%; cisplatin 10 vs 4% (p=0.01); etoposide 12 vs 6%, and docetaxel 20 vs 12 % (both, p=0.02) of pts. Conclusions: The PALETTE study showed considerable intercontinental differences in chemotherapeutic txs for advanced STS pre- and post study drug. These differences might be due to availability and reimbursement of drugs, clinical studies and the practice patterns of sarcoma specialists world-wide. This is of particular interest for the design of future randomised global clinical trials in advanced STS.
Multimodality therapy for pulmonary metastasis in sarcoma patients: Results of a single institution.
Authors: Vohra Nasreen A. , Tejiram Shawn , Chai Christy Yoon-Hee , Conley Anthony Paul , Reed Damon R. , Toloza Eric M. , Fontaine Jacques , Bui Marilyn M , Cheong David , Letson Douglas D , Kim Jongphil , Gonzalez Ricardo Jorge 
Published: March 2020

10070 Background: Pulmonary metastasectomy (PM) for sarcoma can result in significant long term survival in carefully selected patients (pts). We report our experience with pulmonary metastasectomy. Methods: After IRB approval, 120 pts who underwent PM for sarcoma at Moffitt Cancer Center from 1999 to 2011 were reviewed. Survival was calculated according to the Kaplan-Meier method with Cox proportional hazard univariate (UV) and multivariate (MV) models used to analyze relationships between clinicopathologic variables and overall survival (OS). P-value < 0.05 was considered significant. Results: Median age was 51 yrs, 95(79%) pts had soft tissue sarcomas with pleomorphic being most common. Of the 25(21%) osseous sarcomas, osteosarcoma was most common. 20(15%) had synchronous metastasis (mets); of the pts with local disease only, median time to recurrence from primary resection was 13 months (mo). OS from initial resection was 55 mo for pts with local disease only vs. 27 mo for pts with synchronous mets. On UV analysis, use of radiation, number of index lesions, presence of synchronous mets and time to recurrence achieved significance. On MV analysis, only shorter time to recurrence (p=.03) and presence of synchronous mets (p=.04) were independent predictors of poor survival. 63(52%) pts [26(22%) neoadjuvant, 19(16%) adjuvant, 18(15%) both] received chemotherapy for the primary tumor, while 57(48%) did not. There was a trend towards poor survival in pts receiving chemotherapy compared to pts receiving no chemotherapy (p=0.06, HR 1.59). In addition 40(34%) pts received chemotherapy prior to PM with no difference in OS compared to pts who did not get chemotherapy (p=0.1, HR 1.55). 71(59%) had 1 PM, 32(27%) had 2 and 17(14%) had 3 or more PM with OS being 17 mo, 37 mo and 34 mo in each group, respectively. A higher number of PM was associated with improved survival (p=.01). Conclusions: Pts with a shorter disease free interval have a decreased OS as do pts with synchronous mets. Pts undergoing multiple PM have a survival benefit likely resulting from favorable disease biology. Failure of chemotherapy to show a survival benefit may be a result of selection bias for patients with aggressive disease being treated with chemotherapy.
Study of the expression of integrin pathway's proteins as predictive markers of response to neoadjuvant chemotherapy in pretreatment biopsies of patients with high-grade osteosarcoma.
Authors: Cohen-Jonathan Moyal Elizabeth Laurence , Le Guellec Sophie , Filleron Thomas , Delisle Marie-Bernadette , Chevreau Christine , Rubie Herve , Castex Marie Pierre , Roche Henri Hubert , Sales De Gauzy Jerome , Bonneviale Paul , Brouchet Anne 
Published: March 2020

10076 Background: Up to now, chemosensitivity to neoadjuvant chemotherapy performed for patients with osteosarcoma is evaluated on the surgical resection by the evaluation of the percentage of necrotic cells. No predictive profile of chemotherapy has been described yet. Because we have previously shown that integrin pathway controls genotoxic-induced cell death and hypoxia via ILK, FAK and RhoB, we hypothesized that the expression of the proteins involved in this pathway in pre-treatment biopsies could be associated with sensitivity to chemotherapy in osteosarcoma. Methods: We studied by immunohistochemistry β1, β3, β5, integrins, ILK, FAK, GSK-3β, RhoB and Ang-2 expression in 36 osteosarcomas biopsies of patients obtained before treatment. All the patients were treated by the SFOP OS94 chemotherapy protocol and underwent wide conservative surgery. Response to preoperative chemotherapy was assessed on the surgical resection by the Rosen’s protocol. An immunoreactive score (IRS) was assessed, combining the percentage of positive tumour cells and staining intensity. We evaluated the correlation of the selected markers expression with response to preoperative chemotherapy and clinical outcome. Results: FAK expression was statistically linked with ILK expression (rho=0.43; p=0.020), β1integrin expression with FAK expression (rho=0.51); p=0.003), RhoB with ILK expression (rho=0.55; p=0.002), and β1 with β3integrin expression (rho=0.70; p<.001), suggesting that a regulation of the integrin pathway that we studied might exist in high grade osteosarcoma. Moreover, the combination of β5 integrin, FAK and GSK-3β discriminated good and poor responder to chemotherapy (89.9%; 95% CI= [77.4;1.00], yielding a sensitivity of 94.1%, a specificity of 85.7% and a diagnostic accuracy of 90.3%. Conclusions: We report for the first time a protein expression profile on pre-treatment biopsies associating β5 integrin FAK and GSK-3β related with a poor response to neoadjuvant chemotherapy. This profile could help to select patients for clinical trials using inhibitors of this pathway in association with chemotherapy.
Primary localized gastrointestinal stromal tumors (GIST) of the duodenum: Final results of a French Sarcoma Group (FSG) retrospective review of 110 patients (pts).
Authors: Huynh Thanh Khoa , Cassier Philippe A , Bachet Jean Baptiste , Boucher Eveline , Bouche Olivier , Le Cesne Axel , Landi Bruno , Mancini Julien , Marchal Frederic , Bay Jacques-Olivier , Bertucci François , Spano Jean-Philippe , Italiano Antoine , Collard Olivier , Chaigneau Loic , Isambert Nicolas , Lebrun-Ly Valerie , Blay Jean-Yves , Duffaud Florence ,   French Sarcoma Group
Published: March 2020

10078 Background: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes from small series. We conducted a retrospective analysis of primary localized duodenal GISTs over the past 18 years. Methods: Pts were identified in two ways: a group of 101 pts reported via survey from 20 FSG centers, and a group of 9 pts enrolled in the BFR14 trial. Results: Pts were:55 females, 55 males, with a median age of 57 years (30-84), and median ECOG 0 (0-3). Abdominal pain, anemia, and GI bleeding were the most common symptoms. Tumors (T) originated mainly in D2 (41%), or D3 (27%), with a median size of 5 cm (1.5-30). All pts except four had resection of the primary T. Surgical procedures were: local resection (LR) [segmental duodenectomy (n=31), wedge local resection (n=31), local excision (n=6)], and duodenopancreatectomy (DP, n=20). Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics included: KIT+ (n=100), CD34 + (n= 54), mitoses/50 HPF ≤ 5 (n= 70), or > 5 (n=24), Miettinen low-risk (n=37), and high-risk (n=19), necrosis (n=29), spindle cell (n=84). Genotype was evaluated in 36 cases: KIT exon 11 mutant (n=30), no mutation (n=4), and KIT exon 9 mutant (n=2). 12 pts received neoadjuvant imatinib (IM) therapy resulting in 6 PR, 3 SD, 1 PD. 17 pts received adjuvant IM therapy. With a median FU of 32 months (1-250), 95 pts (86%) are alive. Twenty-eight (26%) pts relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS rates were 89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%. Univariate analysis showed that: age and ECOG PS have an impact on OS (p= 0.008, p <0.001), necrosis, spindle-cell type, T size, mitoses/50 HPF, and Miettinen risk were predictive of relapse (p< 0.001). In multivariate analysis tumor size and mitoses/ 50 HPF only were predictive of relapse (p< 0.001). Conclusions: Pts with resected duodenal GIST have a reasonably favourable prognosis. LR rather than DP should be pursued if possible to preserve optimal pancreas function. Neoadjuvant IM may potentially allow a proportion of patients requiring DP to undergo LR. Adjuvant IM should be systematically discussed with a patient based on the individual-risk of recurrence.
Activity of MK1775, a selective Wee1 inhibitor, alone or in combination with gemcitabine, in sarcomas.
Authors: Kreahling Jenny , Reed Damon R. , Foroutan Parastou , Martinez Gary , Gillies Robert , Altiok Soner 
Published: March 2020

10084 Background: Sarcomas consist of more than 50 subtypes of mesenchymal tumors. Doxorubicin alone or in combination has been the primary therapy for treatment of sarcomas; however, the response rates are suboptimal in many of the more common adult subtypes of soft tissue sarcoma. Accordingly, new agents are needed for the treatment of this heterogeneous group of diseases. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Methods: MK1775 treatment of multiple sarcoma preclinical models at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death. In our current study we have investigated the therapeutic efficacy of MK1775 in sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo in a xenograft model of osteosarcoma both alone and in combination with gemcitabine. Results: In patient-derived bone and soft tissue sarcoma samples ex vivo treatments show MK1775 in combination with gemcitabine causes significant apoptotic cell death suggesting that this treatment may represent a novel approach in the treatment of sarcomas. The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 mutational status. Furthermore, in a patient-derived osteosarcoma xenograft mouse model we show the therapeutic efficacy of MK1775 in vivo by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods. Our data shows MK1775 in combination with gemcitabine dramatically slows tumor growth, increases apoptotic cell death and increases CDC2 activity. Cell viability, a clinically established prognostic indicator of survival, was lowest with the combination and very low in animals treated with MK1775 alone. This was mainly due to increased mineralization of the tumors. Caspase-3 was increased in MK1775 treated animals by immunohistochemistry as well. Conclusions: These results together with the promising safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent alone or in combination with gemcitabine in the treatment of both adult as well as pediatric sarcoma patients.
SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal tumors.
Authors: Nannini Margherita , Pantaleo Maria A. , Astolfi Annalisa , Urbini Milena , Formica Serena , Indio Valentina , Gnocchi Chiara , Saponara Maristella , Lolli Cristian , Pallotti Maria Caterina , Mandrioli Anna , Gatto Lidia , Maleddu Alessandra , Casadio Rita , Biasco Guido 
Published: March 2020

10087 Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on SDHB and SDHC and, more recently, we described mutations on SDHA using massively parallel sequencing approach. We sequenced SDHA and SDHB genes in a larger series in order to validate the data. Methods: SDHA gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT GIST patients by Sanger Sequencing method. DNA was extracted from tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and amplified with specific primer pairs designed to amplify exons but not SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy) and sequenced on both strands using the Big Dye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems). Sanger sequencing was performed on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene exons were sequenced on a total of 27 WT GIST patients, in particular on T, PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were sequenced on a total of 18 out of 27 patients, in particular on T, PB and both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found in 5 samples (18.5%). Besides those previously identified, 5 new SDHA mutations were found in other 3 samples: one sample harboured R171C and R589Q heterozygous missense mutation in exons 5 and 13 respectively. The other one harboured G419R and E564K heterozygous missense mutations in exons 9 and 13 respectively. The third sample harboured a delCAG immediately upstream of exon 5, in heterozygosis on PB and in homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was found on 1 PB sample. Conclusions: the presence of SDHA mutations has been confirmed in a subgroup of WT GIST patients. All subunits of SDH complex should be sequenced on WT GIST patients in order to explore the frequency and any linkage between each other and the pathogenetic and clinical significance.
Diagnosis and initial evaluation of patients with gastrointestinal stromal tumor (GIST): An observational study of 1,226 patients.
Authors: Trent Jonathan C. , von Mehren Margaret , Pisters Peter W. T. , Picus Joel , Keir Christopher Hunt , Magley Andrea , Blanke C. D. 
Published: March 2020

10088 Background: The GIST registry (reGISTry) is an observational database designed to determine diagnostic method and evaluation of GIST patients outside of clinical trials. We previously described differences in treatment of patients in community versus academic centers (Pisters, Ann Oncol 2011;22:2523-9). Herein we present distinct differences in the diagnosis and initial evaluation of patients with GIST. Methods: The analysis cutoff date was May 2010. Patient demographics, presenting symptoms, diagnostic methodology, and KIT and PDFGRA mutations were described. For localized tumors, size and mitotic index (MI) were collected. Results: 1226 patients were included in this analysis. Initial diagnosis was most commonly made by surgeons (54.6%) and gastroenterologists (15.7%). Primary management decisions were made at time of diagnosis by medical oncologists (53%) and surgeons (53%) (sum >100% due to ≥1 responses/site). 84% were symptomatic at diagnosis, while 16% were diagnosed incidentally. Diagnostic procedure was performed during surgery (75%) and/or by endoscopy (22%) or interventional radiology (11%) using percutaneous core biopsy or fine needle aspirate. Initial diagnostic imaging was by CT scan (76%), endoscopy (25%), ultrasound (12%), or a combination. Most primary GISTs were located in the stomach (55%) or small intestine (28%). At diagnosis, localized and metastatic disease was seen in 83% and 17% of patients, respectively, with metastases mainly in the liver (62%) and/or peritoneum (36%). KIT immunostaining was performed in 93% of patients, with 98% positive. Mutation analysis was carried out in 8% of cases (57% KIT exon 11 and 12% exon 9 mutations). Of localized primary tumors, 52% were >5 cm in size and 23% had >5 mitoses per 50 high-power fields. Conclusions: We found that initial diagnosis is made by several different modalities. The majority of GIST patients are managed by medical and surgical oncologists. Most patients with localized tumor were at intermediate risk of recurrence and would be considered for adjuvant imatinib therapy.
Single-dimension CT measurements with RECIST 1.1 to evaluate liver metastases in GIST patients on imatinib.
Authors: Schiavon Gaia , Ruggiero Alessandro , Sleijfer Stefan , Bekers Dave J. , van der Holt Bronno , Kloth Jacqueline S.L. , Krestin Gabriel P. , Schoffski Patrick , Verweij Jaap , Mathijssen Ron H.J. 
Published: March 2020

10091 Background: Tumor response assessment to therapy is crucial in oncology, both in daily practice and research.We analyzed the morphology of liver metastases (LM) in gastrointestinal stromal tumors (GIST). Aims were to 1) determine whether uni-dimensional measurements of tumor lesions (according to RECIST 1.1) are accurate reflections of their volumes and 2) estimate eventual bias in volume change calculations, as introduced by using only the longest diameter. Methods: 78 GIST patients with LM were evaluated at baseline (n=139 lesions), 3 (n=129), 6 (n=128), and 12 months (n=108) after imatinib therapy. LM were segmented semi-automatically on standard CT scans. All measurements at baseline were obtained by 2 independent investigators and agreement between observers was assessed with Bland-Altman plots. Values for segmented volume (Vs; mL), maximum transaxial diameter (MTD; mm), and elongation value (EV, defined as 1 - [width/length], where EV of 1 = fully ellipsoidal and 0 = fully spherical) were reported for each lesion at several time-points. A calculated volume (Vc) of each LM was also generated using the MTD, with the hypothesis that metastases were fully spherical. Results: At baseline, 44% (61/139) of the LM was spherical and 56% (78/139) was ellipsoidal. Their EV ranged from 0.08 to 0.94 (mean, 0.53±0.17). During treatment, overall 42% of the lesions kept their morphology (spherical or ellipsoidal) and the other half changed from spherical to ellipsoidal or vice versa. At baseline, there was strong inter-observer agreement in the determination of Vs, with mean inter-observer variability of 1.5% (95% CI, -14.5% to 17.5%). The difference between Vs and Vc was highly significant (P<0.0001). Vc overestimates the actual volume of 35% (95% CI, -26% to 95%). Conclusions: LM are not always spherical and can change their morphology during imatinib therapy. Therefore, a lesion's single largest trans-axial dimension, as used in RECIST 1.1, is not an accurate surrogate of its actual volume. Further studies are warranted to fully understand the clinical impact of these findings and to assess whether we should apply different criteria for response assessment to therapies in solid tumors.
A phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC).
Authors: Tolaney Sara M. , Duda Dan G. , Boucher Yves , Goel Shom , Martin John , Ancukiewicz Marek , Potler Hannah , Incio Jaoa , Ligibel Jennifer A. , Isakoff Steven J. , Fukumura Dai , Winer Eric P. , Krop Ian E. , Jain Rakesh K. 
Published: March 2020

1026 Background: Two recent preop studies evaluating bev showed conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive markers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BCs most likely to benefit from bev. To accomplish these goals, we conducted a unique preop trial with a run-in of single agent bev followed by ddACT with bev in two cohorts, one with HR+HER2– BC, and a smaller triple negative (TN) cohort. Methods: Pts with HR+, HER2– or TN BC were eligible if their tumor (T) was ≥1.5 cm and high grade, or had axillary LN involvement; or if T≥2.5cm and was low/intermediate grade. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84 pts with HR+ and 20 pts with TN breast cancer were enrolled. Amongst HR+ pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Several biomarkers were evaluated as predictors of response to bev. Baseline sVEGFR1 correlated with MP response to treatment among TN pts (p=0.015). Single-agent bev reduced the mean vascular density by 18.5% (p=0.049) in HR+ patients and the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The reductions in IFP correlated with higher levels of sVEGFR2 (p=0.003). The IFP decreased > 50% in 24/65 pts and did not change in others. Gene expression profiling by PAM50 is underway. Conclusions: The addition of bev to preop chemotherapy is well tolerated. Tumor grade appears to predict MP response in HR+ and TN tumors, and sVEGFR1 may be a predictor of MP response to bev in TN tumors. Further work for biomarker predictors of response to bev is ongoing.