bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response of gastrointestinal stromal tumors (GISTs) to imatinib by Choi criteria and response evaluation criteria in solid tumors (RECIST) as surrogates for survival and time to progression
Authors: Benjamin R. S. , Choi H. , Macapinlac H. A. , Burgess M. A. , Patel S. R. , Chen L. L. , Podoloff D. A. , Chuslip C. 
Published: March 2020

9506 Background: Recent studies have demonstrated that RECIST is insensitive in evaluating GIST’s treated with imatinib. We have demonstrated in a small group of patients that a good response by Choi Criteria, i.e., a 10% decrease in unidimensional tumor size or a 15% decrease in tumor density on contrast-enhanced CT, correlated well with good response by PET (Proc. ASCO 22:819, 2003) and was more predictive of time to tumor progression (TTP) than response by RECIST (CTOS 2004). The aim of this study was to validate the correlation with disease-specific survival (DSS) and TTP with follow-up updated to 5-years. Methods: We evaluated 98 patients treated with imatinib for recurrent or metastatic GIST at our institution from December 2000 to September 2001 by RECIST and Choi criteria. All patients had pre-treatment and initial 2-monthly follow-up CT’s. DSS and TTP were analyzed by response category. Results: There were 28 (48%) good responders by RECIST and 30 (52%) poor responders. There were 49 (84%) good responders by Choi criteria, and 9 (16%) poor responders. Patients with good response by Choi criteria on CT at 8 weeks after treatment had significantly improved DSS (P = 0.04) in contrast to those with complete or partial response at any time by RECIST (P = 0.45). Similarly, TTP was significantly correlated with Choi response group (P = 0.01) but not with response group by RECIST (P = 0.74). Conclusions: Choi response criteria, incorporating tumor density and using small changes in tumor size on CT, are more sensitive and more accurate than RECIST in assessing the response of GISTs to imatinib mesylate and should be routinely incorporated into future studies of GIST therapy. Good response is detected earlier by Choi criteria and is a valid surrogate for DSS and TTP. We should desist using RECIST, at least in GIST. (Supported in part by NCI contracts U01-CA70172–01 and N01-CM-17003) [Table: see text]
Consequences of different approaches to local treatment of Ewing’s sarcoma within an international randomised controlled trial: Analysis of EICESS-92
Authors: Whelan J. , McTiernan A. , Weston C. , Douglas C. , Grimer R. , Cassoni A. , Paulussen M. , Jurgens H. , Craft A. , Lewis I. 
Published: March 2020

9533 Background: Two national clinical trial groups (NCTG 1 and 2) together undertook a randomised trial (EICESS-92) which addressed chemotherapy treatment options for Ewing’s sarcoma (ES). No significant differences were found in analysis of the randomised trial questions. A significantly greater use of surgery, with or without radiotherapy, to achieve local tumour control was noted in NCTG 1. The influence on overall outcome was investigated. Methods: Univariate and multivariate analysis of the trial data set was undertaken. Patient characteristics, recognised prognostic factors for ES and treatment factors were all examined. Results: In total, 647 patients (pts) were randomised (NCTG 1: 437 pts; NCTG 2: 210 pts). There were no differences between groups in patient characteristics, disease factors or in chemotherapy received. Surgery of the primary tumour (74.6% v 51%) and pre-operative radiotherapy (44.6% v 2.9%) were more commonly used by NCTG1. Radiotherapy alone was more commonly used by NCTG 2 (39% v 19.5%). Five year overall survival (OS) for the whole cohort was 62.1% (95%CI: 58.3 to 66.0). Five year OS was 66.5% (95% CI 62.0–71.1) for NCTG 1 and 54.3% (95% CI 47.3–61.4) for NCTG 2 (p=0.009). OS was best for those selected for surgery alone and worst for those treated with radiotherapy alone (p <0.001). OS was equivalent between groups for each modality of local treatment. Local recurrence rates for NCTG1 were 7.1% vs. 21.4% for NCGT2. Conclusions: Unexpected differences in OS can occur between patient cohorts recruited by study groups co-operating in international randomised trials. Higher rates of local recurrence and poorer survival were seen in NCTG 2. Failure to select or deliver appropriate local treatment modalities for ES may compromise chances of cure. No significant financial relationships to disclose.
Gene expression profiles classifies the responsiveness of human osteosarcoma to doxorubicin, cisplatin and ifosfamide
Authors: Bruheim S. , Xi Y. , Nakajima G. , Ju J. , Fodstad O. 
Published: March 2020

9534 Background: Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still succumb to their disease. Furthermore, ultra-aggressive combination chemotherapy is associated with considerable acute and long term toxicity. This is of particular concern in patients who may be cured by a simpler and less toxic regimens or do not have micrometastatic disease. Hence, further improvements in the management of osteosarcoma seemingly depend on diagnostic and prognostic tools that may allow for a more risk adapted and individualized treatment. Methods: We have used GE Uniset Human 20K microarrays to obtain gene expression profiles from a panel of ten unique human osteosarcoma xenografts. For each of the three drugs doxorubicin, cisplatin or ifosfamide the xenografts were grouped according to their response to chemotherapy, resistant, weakly sensitive or sensitive. For each individual drug, a one-way ANOVA test with a Benjamini and Hochberg multiple test correction allowing a false discovery rate of 5% (doxorubicin, cisplatin) or 2% (ifosfamide) was used to identify genes with significantly differential expression. In addition a 2-fold cut off was applied to exclude smaller but yet significant differences. Results: For doxorubicin and cisplatin, respectively 59 and 120 genes met these criteria. The expression levels of 25 genes overlapped between these two groups. For ifosfamide, 148 genes were selected, for 5 of them the expression overlapped with cisplatin sensitivity related genes. In the lists, genes involved in mediating and regulating apoptosis were abundant, such as regulators of TGF signaling, ubiquitin mediated protein degradation and members of the immediate early response protein family. Several genes which products interact with components of the cytoskeleton were also identified. Conclusion: We have used a unique strategy to screen for potential chemosensitivity markers by utilizing xenografts as training sets. No significant financial relationships to disclose.
Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is a useful radiological assessment to early predict the outcome of patients with gastrointestinal stromal tumors (GIST) treated with imatinib (IM)
Authors: Lamuraglia M. , Le Cesne A. , Chami L. , Bonvalot S. , Terrier P. , Tursz T. , Roche A. , Lassau N. 
Published: March 2020

9539 Background: DCE-US combined with perfusion software VRI (Vascular Recognition Imaging) and contrast agent injection (Sonovue-Bracco) is a simple and reproductible imaging technique that allows an early and accurate evaluation of IM activity in GIST patients (Lassau et al, ASCO 2004). The objective of this study was to correlate the results observed with DCE-US with the outcome of c-Kit-positive GIST pts treated with IM and to early detect secondary resistance to IM. Methods: 36 pts with advanced GIST were prospectively included in a monocentric imaging trial. DCE-US was performed before IM administration (d0) on days 1, 7, 14, 60, and then every 3 months up to 33 months. The percentage of contrast uptake was evaluated on each tumor target by two radiologists and results were compared to PFS. Results: A total of 371 examinations were performed. At d7, the good responders (GR: 25 pts) and poor responders (PR: 11 pts) presented a statistically significant difference in contrast uptake of DCE-US (p=0.004). There was no significant difference between the 2 groups in tumor volume modification (WHO and RECIST criteria at 2 months). After a median follow-up of 510 days, the median PFS of GR an PR were 602 days and 252 days respectively. A resumption of contrast uptake, before any increase in tumor volume was depicted 6 months before any modification of CT-scan in 7 patients. Conclusion: DCE-US is a new functional non invasive imaging technique that allows: 1) to predict after d7 the PFS 2) an early evaluation of secondary resistance to IM. No significant financial relationships to disclose.
Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors
Authors: Antonini Cappellini G. , Borczuk A. , Kim H. , Hesdorffer M. , Taub R. , Powell C. 
Published: March 2020

9549 Background: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm derived from cells lining serosal membranes. The characteristics of the epithelial (E) type MPM are distinct from those of the biphasic and sarcomatous (BS) type tumors. The goal of our study was to examine the molecular basis for this distinction. Methods: We used global molecular profiling with DNA microarrays to identify pathways associated with histologic subtype of 16 MPM tumor specimens acquired from patients entered into pilot multimodality protocols at our Institution. We performed immunohistochemistry on a tissue microarray and quantitative-real time PCR to validate the microarray results. Results: We performed average linkage agglomerative hierarchical clustering using microdissected MPM specimens and normal peritoneal tissue. The tumors segregated into two clades associated with histological subtype, which were distinct from the controls. 476 genes were differentially expressed between E and BS histologic classes (P < .001, with permutation test P value of .001). To identify biologically important differentially expressed genes and pathways, we examined the functional annotation of mesothelioma histologic subtype classifiers using the Pathway Comparison tool of BRB-Array. Among the differentially expressed categories was the ubiquitin-proteasome (UP) pathway, which was upregulated in BS tumors. Cytoxicity experiments by MTS assay indicated that, by the computation of combination indexes of activity, cells derived from BS tumors were exquisitely sensitive to sequential combination regimens containing the proteasome inhibitor (PI) bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of E tumor origin, was apoptosis. Conclusions: Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic and sarcomatous malignant peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients. No significant financial relationships to disclose.
Pediatric-type sarcomas in adult patients: Age is an independent prognostic factor in IRS group I/II
Authors: Uhm J. E. , Park J. O. , Lee J. , Park B. B. , Ahn J. S. , Ahn M. J. , Park Y. S. , Lim H. Y. , Im Y. H. , Kang W. K. , Park K. 
Published: March 2020

9552 Backgrounds: A number of pediatric sarcomas occur in adults, including Ewing’s sarcoma (EWS)/primitive neuroectodermal tumor (PNET) and rhabdomyosarcoma (RMS). However, these are rare in adult patients (pts) and differ from typical adult sarcomas in that they are generally considered as systemic disease. There is debate as to whether adults do worse than pediatric pts with the same stage of disease. This study was performed to investigate whether various clinical parameters such as tumor size, primary site, age at diagnosis and response to chemotherapy predict the outcome. Methods: 74 consecutive cases of previously untreated pts over 18 years who were diagnosed with EWS/PNET, RMS, and desmoplastic small round cell tumor (SRCT) between 1995 and 2005, were identified from the database at the Samsung Medical Center. Among them, 64 pts were reviewed retrospectively and 10 pts who were lost to follow up were excluded. All pts were treated by a multimodality therapeutic approach, including surgery, chemotherapy, and radiotherapy, based on the ongoing protocols at the time of diagnosis. Results: The median age of the patients was 28 years (range, 18 - 74 years) and the majority (62.5%) of patients was male. There were 35 (54.6%) cases of EWS/PNET, 25 (39.1%) of RMS and 4 (6.3%) of desmoplastic SRCT. 29 pts (45.3%) had metastatic disease and 42 pts (65.6%) were Intergroup RMS Study (IRS) groups III/IV at diagnosis. Median overall survival was 41.5 months (95% CI, 16.1–66.9 months) and 5 years-survival rates was 38.7% (95% CI, 26.7–50.6%) in all pts. In univariate analysis, age (p=0.015), IRS group (p=0.0007) and tumor size (p=0.044) were correlated with better survival. However, multivariate analysis showed that independent variables for better survival were age (p=0.017) and IRS group (p=0.016). In subset analysis, significant statistical correlation between age and overall survival was observed in pts with IRS group I/II. Notably, pts younger than 30 years showed favorable outcome. Conclusions: In this study, age at diagnosis and IRS group reflecting tumor burden were important prognostic factors. Therefore, it is necessary that adult pts with pediatric sarcomas should be included in pediatric protocols, whenever feasible, to provide proper management for the rare disease. No significant financial relationships to disclose.
Liposomal anthracyclines and ifosfamide in the first line treatment of advanced soft tissue sarcomas: A two cohort phase II study
Authors: Siehl J. M. , Thiel E. , Schmittel A. , Hütter G. , Keilholz U. 
Published: March 2020

9563 Objectives: The current first line standard chemotherapy for advanced soft-tissue sarcomas is the combination of doxorubicine and ifosfamide. Liposomal encapsulation is a strategy pursued to reduce toxicity and improve tumor uptake. There are so far only limited systematic data regarding the efficacy of liposomal anthracyclines in advanced soft-tissue sarcomas. We have previously reported on a phase II study with liposomal daunorubicine (L-Dauno) with ifosfamide, named IDx1. Here we report on an additional cohort of the phase II study using liposomal doxorubicine (L-Doxo). Methods: In a single-arm two cohort phase II study 55 patients with advanced soft-tissue sarcoma had received first line a maximum of 6 cycles (median 2 cycles) of ifosphamide (5 g/m2) and in cohort 1 L-Dauno (100 mg/m2, 40 patients) or in cohort 2 the approximate equivalent of L-Doxo (75 mg/m2, 15 patients). Cycles were repeated every 4 weeks in absence of disease progression. Primary study endpoint was response rate. Results: The overall response rate was 25% (n = 14). In the L-Dauno group the results were as follows: CR 3% (n = 1), PR 29% (n = 10), SD 17% (n = 6), PD 37% (n = 13), NED or intermittent death 14% (n = 5), and in the L-Doxo group: PR 20% (n =3), SD 26% (n =4) and PD 53% (n = 8). Interestingly, all three liposarcoma patients (two in the L-Dauno group, one in the L-Doxo group) responded, whereas liposarcoma usually carries a poor response rate. For both combinations toxicity was similarly tolerable with short episodes of hematotoxicity (leucocyte nadir on day 9, platelet nadir on day 11), 11 febrile episodes, no grade 3 or 4 mucositis, no cardiac toxicity and 5 episodes of grade 2 acute ifosfamide-related CNS-toxicity. Based on the hematotoxicity kinetics, three weekly regimens appear feasible. Conclusion: The combination of liposomal anthracyclines and ifosfamide is a safe and effective first line regimen in the treatment for advanced soft tissue sarcoma. Further evaluation in a randomized trial will be pursued. The unexpected high responsiveness of liposarcoma warrants further phase II investigation. 1Siehl JM et al. Cancer 2005. No significant financial relationships to disclose.
The mechanism of human angiosarcoma drug resistance
Authors: Ravi V. , Henry D. , Chen S. , Wong M. K. 
Published: March 2020

9567 Background: Angiosarcoma (AS) is a malignant neoplasm of endothelial cells. AS has an extremely poor outcome since it can metastasize widely and rapidly becomes chemoresistant. Understanding the mechanism of this resistance is important not only because of the critical need for new therapeutic strategies in sarcoma, but also since it sheds light on important pathways in endothelial growth that may help understand tumor angiogenesis. Methods/Results: We have established and characterized stable pre-chemotherapy (named B8) and chemotherapy-resistant (named D3) angiosarcoma cell lines from an individual patient with primary (non radiated) breast angiosarcoma prior to initiation of chemotherapy and later after development of resistance to adriamycin, ifosfamide, gemcitabine, docetaxel, paclitaxel, interferon, thalidomide and bevacizumab. D3 cells differ dramatically from B8s in morphology and function. Prechemotherapy B8 cells assume a polygonal morphology reminiscent of native endothelial cells, the D3 cells throw out long processes that span several cell lengths, and do not appear to contact-inhibit. Migration and invasion assays confirm the highly motile nature of these cells. Although it is not surprising that the D3 cells were doxorubicin resistant, we found that unlike the B8 cells, the D3 cells actively transcribe VEGF. In keeping with this, D3 cells are relatively more sensitive to growth inhibition by the anti-VEGF drug bevacizumab than chemonaïve B8 cells. Conclusion: These studies reveal two avenues to target chemoresistant human angiosarcoma; via agents affecting cell migration and those agents that target the VEGF pathway. No significant financial relationships to disclose.
Aromatase inhibitors (AI) are highly effective in uterine sarcomas (US) expressing estrogen receptors
Authors: Fayette J. , Ray-Coquard I. , Bompas E. , Zufferey L. , Tabone-Eglinger S. , Ranchère D. , Thiesse P. , Méeus P. , Sunyach M. , Blay J. 
Published: March 2020

9576 Background: US frequently recur despite adequate locoregional treatments. Estrogen (ER) and progesterone (PR) receptors are expressed by 43–88% of US, mostly in endometrial stromal sarcomas (ESS) without correlation with survival. Whether hormonal treatment may be useful in estrogenreceptor (ER) expressing connective tumors of the uterus and pelvis is not known. Here, we report on the clinical antitumor effect of aromatase inhibitors (AI) in patients with US. Methods: Since september 2002, 8 menopaused women relapsing uterine leiomyosarcoma, ESS or intravascular leiomyomatosis, (all of grade 1 or 2 in WHO grading) were treated with AI (letrozole, n=5 or anastrozole, n=3). Median age was 62 (41–84), 7/8 expressed ER and 8/8 progesterone (PgR). Progression free, overall survival, and response to AI in evaluable patients were analyzed. Results: After a median follow-up of 16.5 months [1–38], 6 patients are currently non progressive under treatment by AI, without toxicity. All 8 (100%) evaluable patients experienced tumor control with 2 complete response -CR- (1 after lung surgery 25+, 38+), 2 PR (21 and 17+) and 4 stabilizations -SD- (15 months and at 1+, 3+ and 9+ months). Time to response was 3, 5 and 6 months respectively. Two patients progressed after 15 and 21 months; 3 patients are currently treated after 17+, 25+ and 38+ months. At 2 years. Median survival was not reached. 2 years DFS is 60% currently. Conclusions: AI enables prolonged progression free survival in uterine sarcoma expressing hormonal receptors. A prospective study for treatment of relapses and later in adjuvant setting is needed in these rare diseases. No significant financial relationships to disclose.
Defining intracellular signaling targets in soft tissue sarcoma (STS) using immunohistochemical staining (IHC)
Authors: Forman D. A. , Scarlato M. , Brown R. E. , Amadio C. , Friedman E. L. , Berman S. , Robertson G. , Mosca P. , Nair S. G. 
Published: March 2020

9577 Background: Pathologic events pertaining to the intracellular cell signaling pathway are now being recognized to be directly or indirectly responsible for oncogenic transformation in a variety of malignancies. Many drugs are now available which can block key steps of these signaling pathways. We sought to use IHC stains of previously stored sarcoma specimens to determine if expression of potential molecular targets (mTOR, p 70 S6 Kinase, ERK1/2, NF Kappa B) is present. Methods: Using tumor registry data, our three most common adult STS histopathologic subtypes were identified, and paraffin embedded tissue blocks representing these histologies were retrieved. Each block was reviewed for tissue adequacy. The blocks were cut and then stained with the aforementioned phosphorylated IHC stains (Cell Signal Technologies). Slides were graded on intensity of stain uptake (0–3+) and percentage of cells staining. A particular IHC stain was considered positive if 10% or more cells were stained 1+ or greater in intensity. Results: Seventeen Malignant Fibrous Histiocytomas (MFH), 20 Leiomyosarcomas (LMS) and 7 Liposarcomas were stained for the presence of p-mTOR, p-p70S6 Kinase, p ERK1/2, and p-NF Kappa B. Data for NF Kappa B will be presented at the meeting. The results are summarized in the table below. Conclusions: Pathways involving ERK appear to be active in more frequently diagnosed Sarcomas. Slightly more than half of the MFHs we studied expressed phosphorylated ERK1/2. Further exploration of this pathway, as well as mTOR, as potential targets of therapeutic intervention is indicated in STS. [Table: see text] No significant financial relationships to disclose.
Cofilin regulates axon growth and branching of Drosophila γ-neurons
Authors: Sudarsanam Sriram , Yaniv Shiri , Meltzer Hagar , Schuldiner Oren 
Published: March 2020

ABSTRACT
The mechanisms that control intrinsic axon growth potential, and thus axon regeneration following injury, are not well understood. Developmental axon regrowth of Drosophila mushroom body γ-neurons during neuronal remodeling offers a unique opportunity to study the molecular mechanisms controlling intrinsic growth potential. Motivated by the recently uncovered developmental expression atlas of γ-neurons, we here focus on the role of the actin-severing protein cofilin during axon regrowth. We show that Twinstar (Tsr), the fly cofilin, is a crucial regulator of both axon growth and branching during developmental remodeling of γ-neurons. tsr mutant axons demonstrate growth defects both in vivo and in vitro, and also exhibit actin-rich filopodial-like structures at failed branch points in vivo. Our data is inconsistent with Tsr being important for increasing G-actin availability. Furthermore, analysis of microtubule localization suggests that Tsr is required for microtubule infiltration into the axon tips and branch points. Taken together, we show that Tsr promotes axon growth and branching, likely by clearing F-actin to facilitate protrusion of microtubules.