bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weekly paclitaxel in metastatic angiosarcoma. A FNCLCC French Sarcoma Group (GSF-GETO) phase II trial
Authors: Penel N. , Bui Nguyen B. , Bay J. O. , Cupissol D. , Ray-Coquard I. , Piperno-Neumann S. , Kerbrat P. , Fournier C. , Mahier C. , Blay J. Y. 
Published: March 2020

10002 Background: Angiosarcomas (AS) are unfrequent tumors with aggressive metastatic spreading. Although no prospective clinical trial has been so far specifically dedicated to these advanced tumors, their treatments are usually anthracyclin-based. However, a single institution-based retrospective study has suggested that paclitaxel (P) may have some efficacy in metastatic AS [Fata F et al. Cancer 1999, 86, 2034–7]. The aim of the following phase II study is to prospectively evaluate the efficacy and tolerance of weekly P in metastatic AS. Methods: Eligible patients were as follows: =18 years-old, measurable histologically-proven metastatic AS, and either naïve or pretreated patients (pts). Pts were planned to receive P 80 mg/m2 on day 1, 8 and 15, every 28 days until progression or severe toxicity. The primary endpoint was the objective response rate after 2 cycles, according to RECIST. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, a=0.05 and 80% power. Results: From 04/2005 to 10/2006, 30 pts were included in 12 centers. There were 19 female and 11 male, and the mean age was 63 (range 23–85). Main primaries were breast, skin or scalp, liver and kidney in 8, 8, 3 and 2 cases, respectively. 33% (10/30) of these AS occurred in irradiated fields (9 for breast adenocarcinoma). Seventy three per cent of the pts (22/30) had previous surgery and 47% (14/30) previous chemotherapy, including anthracyclin in all cases. The number of pts who received 3, 4, 5 and 6 cycles of P were 15, 11, 6 and 4, respectively. Grade (G) 4 toxicity was reported in 1 case (neutropenia). G2 and 3 toxicities were notified for 27/30 pts including myalgias in 15 cases (55%), leuco-neutropenia in 14 cases (51%), infections in 6 cases (22%), and anemia in 4 cases (15%). As of 12/2006, 23 pts were evaluable for response, with 4 (14%) PR, 14 (56%) SD and 7 (30%) PD. The overall tumor- control rate (PR+SD) was 16/23 (70% (95% CI:50–88%). Conclusions: Weekly paclitaxel induces a significant tumor control with manageable toxicity for metastatic AS. No significant financial relationships to disclose.
Change in quantitative FDG-PET was significantly more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high grade soft tissue sarcomas
Authors: Evilevitch V. , Weber W. A. , Tap W. D. , Chow K. , Allen-Auerbach M. , Nelson S. D. , Eilber F. R. , Eckardt J. J. , Czernin J. , Eilber F. C. 
Published: March 2020

10017 Background: Change in size by RECIST (Response Evaluation Criteria in Solid Tumors) has been the standard to assess response to therapy in non-GIST soft tissue sarcomas (STS). Although recent studies have demonstrated that Positron Emission Tomography with F18-fluorodeoxyglucose (FDG-PET) may be used to assess response, there has not been a direct comparison between these modalities. The aim of this study was to prospectively evaluate whether a change in quantitative FDG-PET or a change in size [computed tomography(CT)] was more accurate at predicting histopathologic response to neoadjuvant therapy in patients with high grade STS using a combined FDG-PET/CT scan. Methods: From 1/05 - 12/06 58 patients with resectable biopsy proven high grade STS scheduled to undergo neoadjuvant chemotherapy were prospectively enrolled in this study. Patients underwent FDG-PET/CT prior to and after neoadjuvant treatment (prior to surgery). Tumor FDG-uptake was quantified by standardized uptake values (SUV). Changes in tumor size were quantified according to RECIST. Following tumor resection, response was assessed histopathologically. Patients with = 10% viable tumor cells were classified as responders. To date, 36 patients have completed the study and are the subject of this analysis. Results: In histopathologic responders (n=10, 28%), reduction of tumor FDG-uptake was significantly greater (-64%) than in histopathologic non-responders (-37%), (p=0.005). Using a 50% decrease in tumor SUV as a threshold value resulted in a sensitivity of 90% and a specificity of 58% for assessment of histopathologic response (p=0.01). Response assessment per RECIST showed no significant correlation with histopathologic response (sensitivity 20%, specificity 89%, p=0.4). There was no correlation between changes in tumor size and histopathologic response (area under the ROC curve = 0.6, p=0.1). Conclusions: In patients with high grade STS, quantitative FDG-PET was significantly more accurate than size based criteria for assessment of histopathologic response to neoadjuvant therapy. FDG-PET should be considered as a modality to monitor treatment response is patients with high grade STS. No significant financial relationships to disclose.
Genomic of circulating tumor cells in metastatic breast cancer
Authors: Reuben J. M. , Lee B. N. , Li C. , Broglio K. R. , Valero V. , Jackson S. , Ueno N. T. , Krishnamurthy S. , Hortobagyi G. N. , Cristofanilli M. 
Published: March 2020

1002 Background: Metastatic breast cancer (MBC) is an incurable condition and palliative treatments are selected by considering pre-treatment prognostic and predictive factors. Recently, we reported the detection of CTCs to be predictive of prognosis and treatment efficacy and reasoned they might also be used to assess biological characteristics of the patient’s tumor to improve on treatment selection. Methods: Twenty patients with newly diagnosed MBC were enrolled in a prospective clinical trial designed to assess the baseline value of CTCs, evaluate the expression of selected genes in CTCs, and compare the expression of same biomarkers in the primary tumor (PT) and/or metastatic site (MS), as determined by standard IHC and FISH. CTCs were assessed by CellSearch, and subjected to real-time PCR (qPCR) for the expression of transcripts for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2), notch-1, and mammaglobin (MGB) using commercial primers. Results: Sixteen of patients had =1CTCs. With respect to biomarkers of PT, 17 were ER+, 11 PR+, and 3 HER-2 amplified. Among the 15 patients with MS, the biomarkers were as follows: 9 ER+, 7 PR+, and 2 HER-2 amplified. There were significant associations between the primary and metastatic tumors with respect to the presence of ER (χ2 = 6.516, P = 0.0107), PR (χ2 = 5.529, P = 0.0187), and HER-2 (χ2 = 3.938, P = 0.0472). The qPCR of CTCs detected transcripts: ER in 3 patients (15%); PR in none (0%); MGB and HER-2 in 2 (10%) and 11 patients (55%), respectively. Notch-1 transcripts were detected in 13 patients (65%). CTCs with detectable transcripts of HER-2 were more likely to co-express notch-1 transcripts (χ2 = 4.295, P = 0.038). Of the 4 samples without detectable CTCs, one was HER-2 positive, and three had notch- 1 transcripts. Conclusions: This study demonstrated a significant concordance in biomarkers expression between the tumor cells of the primary tumors and the metastatic site. Furthermore, it suggests that CTCs differ significantly from those tumor cells with regards to the expression of hormone-receptor and HER-2 status. Thus, CTCs may represent a unique and heterogeneous cell population which phenotype and “homing” properties should be further investigated. [Table: see text]
Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial
Authors: Demetri G. D. , George S. , Morgan J. A. , Wagner A. , Quigley M. T. , Polson K. , Pokela J. , van den Abbeele A. , Adams J. , Grayzel D. 
Published: March 2020

10024 Background: Prior work from our team demonstrates that inhibition of the Hsp90 chaperone protein results in preferential destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. To translate this into clinical application, we are conducting a phase I trial of IPI-504, a novel Hsp90 inhibitor, for patients (pts) with metastatic TKI-resistant GIST. Methods: Pts with metastatic TKI-resistant GIST were eligible to enter and receive IPI-504, IV in 250 cc of normal saline over 30 mins, on days 1, 4, 8 and 11 of a 21 day cycle. Serial monitoring with 18FDG-PET/CT imaging at baseline, day 11, and day 21, as well as PK profiling of IPI- 504 and its major active metabolites (17-AAG and 17-AG), were performed on all pts. Results: 21 pts with progressive GIST after both prior imatinib and sunitinib have been entered at 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [3], 225 [3], 300 [3], 400 [6]); 18 are now evaluable. The maximal tolerated dose has not been reached, and enrollment is ongoing. AEs possibly related to IPI-504 include Grade 1–2 elevation of alkaline phosphatase, fatigue, and headache; one DLT was observed in the 1st and 5th dose levels. PET demonstrated decreases in tumor FDG avidity in 1/6 pts, 1/3, 3/3, 1/3, and 2/3 at the respective dose levels in this schedule (3 patients were inevaluable by PET). Reactivation of tumor FDG uptake by PET was seen during the planned 10-day breaks in IPI-504 administration with reinduction of decreased tumor FDG avidity upon re-treatment with IPI-504. Although no RECIST-defined “anatomic responses” were noted, stable disease has allowed 7 pts to continue on study treatment for ≥ 4 cycles. Conclusions: Targeting Hsp90 is a novel therapeutic strategy in TKI-resistant GIST. IPI-504 has been well-tolerated overall, and the activity seen with decreased FDG avidity of GIST lesions, as well as the induction of SD in pts with documented prior progression, is promising with this non-TKI agent. Reactivation of PET signal in lesions during breaks in IPI-504 dosing is similar to flares with TKI discontinuation. To address this, a new schedule of continuous BIW dosing of IPI-504 has been added to optimize drug exposure. No significant financial relationships to disclose.
Immunohistochemical expression of ezrin correlates with Event-free and overall survival in osteosarcomas
Authors: Salas S. , Deville J. , Bartoli C. , Gaudart J. , Bollini G. , Curvale G. , Gentet J. , Duffaud F. , Figarella-Branger D. , Bouvier C. 
Published: March 2020

10035 Background: Ezrin is a cytoskeleton linker protein that is actively involved in the metastatic process of cancer cells. We have searched for a pronostic value of ezrin and some of its partners: a-smooth actin and CD44H in 37 patients with an osteosarcoma. Methods: Automate immunohistochemistry (IHC) with anti-ezrin, a-smooth actin and CD44H antibodies was performed in 37 biopsies before chemotherapy, 16 resected tumors of “poor” responders and 13 metastases. In addition the mRNA levels of ezrin of 13 frozen biopies and 4 metastases were evaluated by real time quantitative RT PCR. All results were correlated to the following clinical data: response to chemotherapy, onset of metastasis, event-free survival (EFS) and overall survival (OS). Results: Ezrin expression by IHC was found in 62% of 37 biopsies in the different histological subtypes especially chondroblastic osteosarcomas while chondrosarcomas were negative. A good correlation was found between positive or negative samples by IHC and mRNA levels. Ezrin expression was recorded in 84.5% of metastastic samples. The mean expression of ezrin was higher in metastases than biopsies (mean expression 38.1% versus 17.32%; p=0.024) but the onset of metastasis was not statistically correlated to ezrin positivity on biopsy (p = 0.183). In multivariate analysis, ezrin was an independent prognostic marker for EFS and OS with p<0.001 and p=0.003 respectively and a-smooth actin for OS only (p=0.024). No prognostic value was found for CD44H. Conclusions: We have shown that ezrin is expressed in the different subtypes of osteosarcomas especially chondroblastic osteosarcomas. Other studies are required to confirm that ezrin could be a useful tool for differential diagnosis with chondrosarcoma. Ezrin was an independent prognostic factor for event-free and overall survival rate in multivariate analysis and its partner a-smooth-actin was also an independent prognostic factor for overall survival only. These data confirm the role of ezrin signalling pathway for tumor dissemination in osteosarcomas in vivo. This also might be of interest for therapeutic strategy to select patient for dose intensification or to use new anticancer agents such as rapamycin which reduces experimental lung metastases through an ezrin-related pathway. No significant financial relationships to disclose.
Expression of cell cycle, angiogenesis and metastases associated factors in osteosarcoma - immunohistochemical analysis of tissue array in 35 patients
Authors: Chen W. , He M. , Aisner S. , Benevenia J. , Patterson F. , Hameed M. 
Published: March 2020

10036 Background: Osteosarcoma is the most common, non-haemopoietic primary malignant tumor of bone. A variety of biological markers have been investigated for their prognostic value with variable results. This study is aimed to assess the prognostic and biological value of biological markers involved in cell cycle checkpoint regulation (p53 family, p16, and PTEN), cell adhesion, motility and invasion (ezrin and beta catenin), angiogenesis (VEGF and PlGF) in tumor samples of osteosarcoma patients. Methods: Thirty-five patients were chosen for the study (ages 6–74 years, median age - 15 years). Among them, 32 were high-grade conventional intramedullary osteosarcoma, and 3 were Paget osteosarcomas. Eight patients presented with metastases. Immunohistochemical analysis was performed on a tissue array of tumor samples with standard protocol. Clinical outcome was measured as events (metastasis or death), chemo-response (stage), and survival by multivariate analysis. Analysis also included our previous reported results of p53, p63 and p73. Results: Staining was assessed based upon semi-quantitative manual scoring. Appropriate staining (nuclear or cytoplasmic) of >5% in tumor cells was considered as positive for all markers. The percentage positivity for the markers is as follows: p53 =29%, p63 =37%, p73= 9%, p16 =60%, PTEN=83%, ezrin =77%, beta catenin =91%, VEGF= 86% and PlGF =54%. There was no association of marker expression with specific subtype or location. Statistical analysis revealed no significant association between the positivity of these markers with clinical outcomes. Expression of ezrin was observed in all eight patients with metastases, although this finding did not approach statistical significance (P = 0.15). There was significant association between ezrin and P63 (P < 0.05). Conclusions: 1. Expression of p53 family proteins, p16, PTEN, ezrin, beta catenin, VEGF, and PlGF are not significant predictors of clinical outcome in osteosarcoma patients. 2. Ezrin may be essential for osteosarcoma metastases. 3. No significant association between VEGF, PlGF and metastases. 4. The positive association between ezrin and P63 is interesting and need to be evaluated further. No significant financial relationships to disclose.
Trabectedin (T) in metastatic Ewing's family tumors (EFT) patients (pts) progressing after standard chemotherapy
Authors: Dileo P. , Grosso F. , Casanova M. , Jimeno J. , Marsoni S. , Sanfilippo R. , Podda M. , Ferrari S. , Bertulli R. , Casali P. G. 
Published: March 2020

10040 Background: T is a formerly marine-derived agent which is active in human cancers, such as ovarian cancer and adult soft tissue sarcomas (STS). Efficacy of T in pts with unresectable/metastatic pretreated advanced STS was demonstrated in phase II settings. Leiomyosarcoma and liposarcoma were shown to be sensitive, with myxoid liposarcoma being exceedingly responsive. Data are lacking on “small round blue cell” sarcomas, including EFT. In 2000 a phase II study was launched by SENDO in a sarcoma population including EFT. At Istituto Nazionale Tumori, Milano, Italy, some EFT pts were treated after the completion of this study. We analyzed treatment efficacy in EFT pts treated within these two settings. Methods: Overall 15/29 of the pts were female, and age ranged from 15 to 55 years. Pts received T at a starting dose between 1,650 and 1,100 mcg/sqm every 3 weeks as 24-hour or 3-hour infusion. Each pt received at least 2 cycles of treatment, except in case of disease progression or unacceptable toxicity. Tumor response was assessed by RECIST criteria after the first 2 cycles and then every other cycle. Dose reductions were based on the worst toxicity (hematological or non-hematological) in the previous cycle. Results: As of December 2006, 20 pts were treated in the Phase II study, and 9 on a compassionate use basis. Two pts were still on therapy. A total of 79 treatment cycles (2–14 per pt) were administered. Three pts (10.3%) demonstrated a partial response, 3 had a minor response (10.3%), and 4 (13.7%) stable disease. PFS rate at 6 months was 25%. The most common all-causality AEs were acute reversible liver toxicity, fatigue, and myelosuppression. Following the introduction of steroid pre-medication, thrombocytopenia and fatigue were less frequent. Conclusions: In this cohort, T was overall well tolerated and showed antitumor activity in pts with advanced EFT. This calls for further evaluation of this compound, alone or in combination, in pts suffering from EFT. No significant financial relationships to disclose.
A multiplex assay for detection of common pediatric sarcoma tumor markers
Authors: Bender R. A. , Liu J. Y. , Li H. , Qu K. Z. , Sferruzza A. D. , Sanders H. R. 
Published: March 2020

10041 Background: Molecular assays for tumor markers have become an important component in diagnosing pediatric sarcomas and small round cell tumors. We developed a multiplex assay to detect 7 common translocations associated with synovial sarcoma (SYT/SSX1, SYT/SSX2), Ewing's sarcoma (EWS/FLI1, EWS/ERG), rhabdomyosarcoma (PAX3/FKHR, PAX7/FKHR), and small round cell desmoplastic tumors (SRCDT) (EWS/WT1). Methods: 27 samples were analyzed with the multiplex assay: 13 formalin-fixed paraffin-embedded tumor samples, 5 fresh frozen tumor samples, 2 commercial RNA samples (SYT/SSX1, SYT/SSX2), 3 cell line samples (EWS/FLI, EWS/ERG, PAX3/FKHR), 1 synthetic control (PAX7/FKHR), and 3 negative controls. After RNA extraction, RT-PCR was performed using the SuperScript III One-Step RT-PCR System with Platinum Taq DNA Polymerase (Invitrogen, Carlsbad, CA). 12 primers were added to a single master mix to amplify all 7 translocations and an internal control; 1 primer from each pair was fluorescently labeled. After RT-PCR, the PCR products were separated on a genetic analyzer and the translocations identified based on the size of the PCR products and their signal intensity. Samples were also analyzed by our current assay (real-time RT-PCR or standard RT-PCR/gel electrophoresis). Results: The results of our current and multiplex assays were positive for all synthetic controls, cell lines, and commercial RNA samples and were concordant for 15/18 tumor samples: 2/7 synovial sarcoma samples were positive for SYT/SSX1 and 3/7 for SYT/SSX2; 2/6 Ewing's sarcoma samples were EWS/FLI1-positive; 1/1 SRCDT sample was EWS/WT1-positive; and 4/4 rhabdomyosarcoma samples were negative. The 3 discordant samples tested negative with our current assay; the new multiplex assay detected EWS/FLI1 in 1 of these and SYT/SSX2 in 2, in agreement with the histological classification. Conclusions: This multiplex assay can detect 7 translocations commonly found in pediatric soft tissue tumors in a single-tube reaction, with increased clinical sensitivity relative to our current methods. No significant financial relationships to disclose.
Kit-stem cell factor (kit ligand) axis in GIST patients treated with imatinib
Authors: McAuliffe J. C. , Lazar A. , Steinert D. , Patel S. , Benjamin R. , Trent J. C. 
Published: March 2020

10046 Background: Gastrointestinal stromal tumors (GISTs) represent the majority of GI mesenchymal neoplasms. Imatinib (Gleevec; STI571; Novartis, Basel, Switzerland) has marked efficacy in the management of GIST; however, little is known of its exact mechanism in GIST. We sought to elucidate expression patterns of stem cell factor (SCF, Kit ligand) and the Kit receptor tyrosine kinase in GIST and tumor-associated endothelial cells (TECs) from patients treated with imatinib. Methods: We constructed a 54 GIST specimen tissue array from patients with GIST surgically resected who received 400–800 mg/day adjuvant imatinib. Arrays were stained for SCF by immunohistochemistry and scored for expression as 0 (none), 1 (weak), or 2 (strong). Expression was correlated to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. In a second study we collected pre-imatinib core needle biopsies from 15 patients on a phase II prospective, randomized clinical trial of neo-adjuvant and adjuvant imatinib (600mg/day) for the treatment of primary or advanced, resectable GIST. Specimens were stained for phosphorylated-Kit and CD31 and visualized by immunofluorescence and confocal microscopy. Co-localization of markers was correlated to radiographic response by positron emission tomography (PET) and dynamic computed tomography (dCT). Results: 47 of 54 tumors (87%) expressed SCF but there was no significant correlation between SCF expression or intensity with PFS and OS. Interestingly, the majority of GIST tissue from patients on the prospective clinical trial contained pre-imatinib TECs expressing phosphorylated-Kit. 69% and 79% of patients receiving 3–7 days of imatinib responded by PET scan or dCT, respectively. Conclusions: The majority of GISTs express SCF while pre-imatinib TECs were found to express phosphorylated-Kit. Therefore, our results suggest that within the tumor microenvironment there may be Kit/SCF crosstalk between tumor cells and TECs. Whether disruption of this crosstalk plays a role in tumor response or anti-vascular efficacy requires additional investigation. No significant financial relationships to disclose.