bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro activity of sorafenib against imatinib- and sunitinib-resistant kinase mutations associated with drug-resistant GI stromal tumors
Authors: Heinrich M. C. , Carden R. , Griffith D. , Liang C. , Marino-Enriquez A. , McKinley A. , Presnell A. , Fletcher J. A. 
Published: August 2020

10500 Background: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are targets of imatinib (front-line therapy) or sunitinib (second-line therapy). Resistance to imatinib (IM) or sunitinib (SU) is commonly associated with the acquisition of secondary kinase mutations. In phase II studies, sorafenib (SOR), which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in GIST patients after failure of IM and SU. We evaluated the in vitro activity of SOR against IM and/or SU resistant kinases. Methods: Kinase mutants were biochemically profiled for SOR, SU, and IM sensitivity by measuring inhibition of kinase phosphorylation after drug treatment in mutant-expressing CHO cells. We also tested the biochemical and cellular activity of SOR and IM against GIST cells derived from IM-resistant tumor clones. Results: SOR had superior potency to IM against IM-resistant KIT secondary mutations involving the ATP binding pocket (V654A, T670I) and the activation loop (D816H, D820A/G, N822K, Y823D). SOR and SU had similar potency against IM-resistant KIT secondary mutations involving the ATP binding pocket. In contrast, SOR had markedly increased potency, compared to SU, against IM-resistant KIT activation loop mutations. Both SOR and SU were more potent than IM against the isolated KIT exon 9 mutation. To confirm these observations in a GIST cellular context, we tested the relative potency of IM and SU against two previously described IM-resistant GIST cell lines (GIST430: exon 11 + V654A, GIST48: exon 11 + D820A). SOR was significantly more potent than IM against KIT in these cell lines. This also correlated with enhanced inhibition of downstream signaling pathways and cellular proliferation. Conclusions: SOR has superior in vitro potency compared with IM or SU against a panel of GIST-relevant mutant kinases. Notably, SOR, unlike SU, is active against most IM-resistant secondary mutations involving the KIT activation loop. Based on these results, we hypothesize that SOR might have superior clinical activity to SU in the setting of imatinib-resistant GIST and should be further evaluated for clinical efficacy in the second-line setting. [Table: see text]
Denosumab for the treatment of giant cell tumor (GCT) of bone: Final results from a proof-of-concept, phase II study
Authors: Thomas D. M. , Chawla S. , Skubitz K. , Staddon A. , Henshaw R. , Blay J. , Smith J. , Ye Z. , Roudier M. , Jun S. 
Published: August 2020

10510 Background: GCT of bone is a primary osteolytic bone tumor with low metastatic potential that is associated with significant skeletal morbidity. GCT is rich in stromal cells that express RANKL, a key mediator of osteoclast activation. In this open-label, study, we investigated whether denosumab, a fully human monoclonal antibody against RANKL, could have a potential therapeutic effect on giant cell histology for patients with GCT. Methods: In this single-arm study, 37 patients with measurable or unresectable GCT received denosumab 120 mg subcutaneously once monthly with loading doses on days 8 and 15 of month 1. The primary endpoint was the proportion of patients with a tumor response (≥90% elimination of giant cells or no radiographic progression of the target lesion) at week 25 as assessed by histology and CT or MRI. A sample size of 35 patients was planned. All 37 enrolled patients were evaluated for safety; 35 were eligible for efficacy evaluation (2 had insufficient histology or radiology data). Results: Thirty of 35 patients (86%; 95% CI 70%-95%) had a tumor response: 20 of 20 by histology and 10 of 15 by radiology. Of 31 patients with data for assessments of clinical benefit, 26 (84%%; 95% CI 66%-95%) reported reduced pain or improvement in functional status. Bone repair was reported in 9 patients (29%; 95% CI 14%-48%). Suppression of the bone turnover markers urinary N-telopeptide and serum C-telopeptide was seen as early as 28 days after the first dose and sustained for the duration of the study. Adverse events (AEs) were reported in 33 patients (89%). One death due to surgical complications (not treatment-related) occurred on-study. No patient experienced treatment-related serious AEs or developed anti-denosumab antibodies. Conclusions: In this study, 86% of patients with measurable or unresectable GCT experienced a tumor response with denosumab. Further clinical trials of denosumab as a new therapy for GCT are warranted. [Table: see text]
Evaluation of the safety and efficacy of pathotropic nanoparticles bearing a dominant negative cyclin G1 construct for chemoresistant osteosarcoma and other sarcomas: Phase I, II, and III studies
Authors: Chawla S. P. , Chua V. S. , Fernandez L. , Quon D. , Saralou A. , Blackwelder W. C. , Hall F. L. , Gordon E. M. 
Published: August 2020

10513 Background: (1) To evaluate the safety/anti-tumor potential of intravenous (i.v.) Rexin-G in chemotherapy-resistant sarcoma (Phase I/II), and (2) to confirm the efficacy/safety of i.v. Rexin-G in chemotherapy-resistant osteosarcoma (Phase II). Methods: Twenty patients in the Phase I/II study and 22 patients in the Phase II study received 1–2 × 10e11 cfu Rexin-G i.v., 2–3 times a week for 4 weeks. Treatment was continued if the patient had < Grade 1 toxicity. Results: Treatment-related adverse events included chills (n=1), presyncope (n=1), photophobia (n=1) of Grade 1 severity, and fatigue (n=4) of Grade 1–2 severity. In the Phase I/II sarcoma study, 3/6 patients had stable disease at Dose Level 0, median progression free survival (PFS) was 5 weeks, and overall survival (OS) was 14 weeks, while 10/14 patients had stable disease at Dose Level I-II, median PFS was 16 weeks and median OS was 34 weeks. Cox regression analysis showed a dose-response relationship between PFS/OS and Rexin-G dosage (p = 0.02 and 0.005, respectively). The Table below shows the results for evaluable patients (n=17) in the Phase II study for osteosarcoma. Kaplan-Meier analysis shows a dose-response relationship between overall survival and Rexin-G dosage in the combined Phase I/II sarcoma and Phase II osteosarcoma studies (p = 0.02; n=42). Two patients achieved surgical remissions which are sustained for >26 weeks. Conclusions: These studies suggest that (i) intravenous Rexin-G is safe and well-tolerated, and (ii) Rexin-G controls tumor growth and prolongs progression-free survival and overall survival in a dose-dependent manner in chemotherapy-resistant osteosarcoma and sarcoma. [Table: see text] [Table: see text]
Survival in high-grade osteosarcoma: Improvement in a 21-year period at a single institution
Authors: Picci P. , Mercuri M. , Ferrari S. , Alberghini M. , Briccoli A. , Ferrari C. , Pignotti E. , Bacci G. 
Published: August 2020

10515 Background: After the introduction of pre-operative chemotherapy in the early 1980s, treatment of osteosarcoma had not advantages from new drugs/modalities. Aim of this work is to analyze improvements in overall survival for patients treated over 21 years (1982–2002), with a 5-year minimum follow-up, in the largest series from a single institute ever reported, including all high grade osteosarcomas, despite histology varieties, age, site, and stage. Data are also analyzed in subgroups to define patients who benefited most. Methods: All diagnoses of high grade osteosarcoma were included. Of the 1,656 consecutive cases observed, 198 patients were excluded (41 consultation only, 129 low-grade varieties and 28 lost to follow-up). Within 1,456 included patients, 1,032 had characteristics to be enrolled in conventional clinical trials (classic histology, age < 41, localized and extremity disease). Results: Considering all patients, with a median follow-up of 12 years (5–25 yrs), 754 (51.7%) are alive, 613 continuously disease-free. Survival at 5, 10, and 15 years is 57%, 52%, and 51% respectively. Patients candidates for clinical trials have a survival rate of 68%, 64%, and 61% respectively. Survival for the other patients is 30%, 25%, and 24% respectively. Jointpoint Statistical Analysis at real 5-year follow-up shows a yearly statistically significant improvement in survival of 1.31% (95% CI 0.5–2.1), from 51% for patients treated in 1982 to 68% for those treated in 2002. Within the subgroups, survival statistically improved in patients candidates to protocols, those who relapsed, or presented with metastatic disease at diagnosis, or had axial tumors. Surgery was also analyzed, with a statistical significant increase in the percentage of limb salvage procedures without an increased rate of local recurrences. Conclusions: Despite the lack of new drugs for osteosarcoma, survival has statistically improved, especially for those patients with the worst outcome. Aggressive treatments are therefore recommended for all patients including those with poor prognosis. No significant financial relationships to disclose.
Cardiac cormorbidities in women with metastatic breast cancer treated with doxorubicin-based and non-doxorubicin-based chemotherapy
Authors: Watson G. J. , Kugel M. R. , Shih H. , Tak Piech C. , McKenzie R. S. 
Published: August 2020

1052 Background: Observational data are sparse regarding cardiac comorbidities in patients with metastatic breast cancer (MBC) newly initiated on chemotherapy. As some MBC treatments are associated with cardiac toxicity, such information would be useful in guiding treatment decisions. The objective of this analysis was to understand the frequency of cardiac comorbidities in MBC patients prior to chemotherapy initiation based on the Medicare 5% standard analytical file (SAF). Methods: The Medicare 5% SAF was used to investigate claims for women with breast neoplasm and > 1 distant metastatic site (based on ICD-9 diagnosis codes) that subsequently received chemotherapy (based on claims with a chemotherapy J code). Cardiac comorbidities [hypertension (HTN), coronary artery disease (CAD), myocardial function (MI), and congestive heart failure (CHF)] prior to initial chemotherapy were reported as non-mutually exclusive categories. The index quarter was based on chemotherapy initiation that occurred between 7/2001 and 12/2006. Patients were categorized based on receipt of non doxorubicin-based chemotherapy (non-DOX) vs DOX-based chemotherapy. Results: The study included 2,587 women with MBC that received cytotoxic chemotherapy subsequent to the diagnosis of MBC. The mean age was higher in the non-DOX group. Both groups reported a significant proportion of patients with cardiac comorbidities prior to chemotherapy, with greater proportions reported in the non-DOX group (table). Conclusions: Cardiac comorbidities were commonly reported in women with MBC prior to chemotherapy. Such information is useful to health care professionals when considering potential interventions for patients with MBC. [Table: see text] [Table: see text]
Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)
Authors: Schuetze S. , Rutkowski P. , Van Glabbeke M. M. , Rankin C. , Rubin B. P. , Lazar A. , Debiec-Rychter M. , Gelderblom H. , Hohenberger P. , van Oosterom A. T. 
Published: August 2020

10520 Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid. [Table: see text]
Role of trabectedin (T) in the management of advanced uterine leiomyosarcoma (U-LM)
Authors: Grosso F. , Sanfilippo R. , Jones R. L. , Collini P. , Morosi C. , Raspagliesi F. , Tercero J. C. , D'Incalci M. , Judson I. R. , Casali P. G. 
Published: August 2020

10530 Background: To explore the clinical impact of T in U-LM. T has been approved in Europe for second line treatment of advanced soft tissue sarcomas (STS). Efficacy is well established in liposarcoma and leiomyosarcoma. U-LMs display peculiar clinical and genetic features compared to other STS. These differences may be responsible for the sensitivity of this subtype to therapy, thus justifying an evaluation of the activity of T in a relatively homogeneous series of U-LM patients. Methods: From April 2000, 56 patients (pts) with advanced disease, previously exposed to a median of 3 chemotherapy lines (range 1–5), received T within an expanded access programme at two European referral institutions for sarcoma. The clinical records were reviewed focusing on response and treatment outcome. Two pts were excluded from the analysis having received only 1 course of T. Median age was 56 yrs (range 29–73), median number of metastatic sites was 2 (range 1–4), the most frequent metastatic site was lung (88%), 24 patients had a local relapse. Results: A total of 252 courses were delivered (median 3, IQR2–6) and 36% of patients received more than 5 courses of T. Fifty-two patients were evaluable for response. A partial response was observed in 11 patients and stable disease in 15, for a PR rate of 21% and a tumor control rate of 50%. The median progression-free survival was 3.6 months (CI95% 2.6–6.7), with 41% of patients free from progression at 6 months. Conclusions: These results compare favourably with other systemic treatments in advanced U-LMS and support their sensitivity to T. This should prompt further studies to prospectively evaluate the efficacy of T in U-LMS and elucidate possible biological predictive factors (e.g. DNA repair protein expression). [Table: see text]
Clival chordoma molecular subtypes and clinical behavior
Authors: Park D. M. , Prevedello D. M. , Gardner P. , Lee D. , Henry S. , Snyderman C. , Carrau R. , Horbinski C. , Hamilton R. L. , Kassam A. B. 
Published: August 2020

10538 Background: Chordoma is a primary bone cancer of the axial skeleton with predilection for local invasion. Primary treatment modalities consist of surgery and radiation therapy with limited role for chemotherapy. Because patients with chordoma exhibit heterogeneous clinical history and response to therapy, we investigated potential markers predictive of clinical behavior. Methods: This study analyzed 35 clival chordoma specimens with documented immunohistochemistry (IHC) staining for Ki-67 proliferation index from 29 patients. Detailed additional pathologic studies were performed prospectively on 12 consecutive patients. This consisted of the following: IHC for brachyury, cytokeratin, p53, and epidermal growth factor receptor (EGFR); fluorescent in situ hybridization (FISH) analysis for EGFR amplification and presence of 1p36, 9p21, and 19q13 loci; polymerase chain reaction based loss of heterozygosity analysis (LOH) of 1p, 9p, 10q, 17p, and 19p loci. Results: All confirmed chordoma specimens were positive for brachyury and negative for amplification of EGFR. Increase in Ki-67 index was associated with recurrence in 5 of 6 cases. Out of the 12 patients with detailed molecular pathologic studies, 5 had loss of 1p, 2 had deletion of 9p21 (p16), and 2 had loss of 10q (PTEN). The loss of 1p and 9p were detected via both FISH and LOH analyses. 3 of the 12 patients’ tumor specimens showed a Ki-67 index of greater than 10%; the remaining specimens were less than 5%. All 3 patients with high Ki-67 index had loss of either 9p (p16) or 10q (PTEN). The tumor specimen from these 3 patients also exhibited enhanced in vitro propagation. Conclusions: Subtyping of clival chordomas based on molecular phenotype may provide prognostic information. The prospective nature of this study in concert with assessment of residual disease after surgery may allow for identification of distinct subpopulations of patients at greater risk of disease recurrence for consideration of adjuvant therapy. The correlative in vitro study will provide an opportunity to evaluate targeted therapies customized to individual molecular subgroups. No significant financial relationships to disclose.
Prediction of tumor necrosis fraction using combined volumetric and metabolic indices derived from FDG-PET/CT in osteosarcoma patients receiving neoadjuvant chemotherapy
Authors: Park B. , Park H. , Min H. , Kang H. , Im H. , Kim S. 
Published: August 2020

10539 Background: Maximum standardized uptake values (mSUV) might not reliably reflect the chemotherapy response in osteosarcoma especially when treatment response within tumors is heterogenous. The purpose of this study was to compare the usefulnesses of various FDG PET/CT indices for predicting tumor response to neoadjuvant chemotherapy and to identify the most appropriate one in osteosarcoma. Methods: Thirteen patients with primary osteosarcoma (age 14±2.9 yrs, ranged 10–19 yrs) that had undergone FDG PET/CT scans before and after neoadjuvant chemotherapy were enrolled. The authors measured mSUV, metabolic tumor volumes (MTV), and total lesion glycolysis (TLG) in each PET/CT scan. MTVs were calculated by summing voxels with SUV greater than 1.5, 2, 2.5 and 3.0, and with % mSUV greater than 20%, 25%, 30% and 35%. Histopathologic necrosis fractions were compared with the above-mentioned PET/CT parameters and their pre- to post-treatment ratios (MTV ratio, rMTV; mSUV ratio, rSUV; TLG ratio, rTLG). Results: Histopathologic necrosis fractions ranged from 3% to 99% (62.2%±37.7%). rMTV and rTLG values were found to be correlated with histopathologic necrosis fractions (R2=0.45–0.65, p<0.05), whereas, mSUV and MR image volumes (MRV), both before and after treatment, rSUV values, and rMRV values were not. With regard to rMTV and rTLG values obtained using various MTV criteria, the highest correlation was observed for a rTLG value of 2.5 mg/ml (R2=0.65, p=0.001). Five patients were classified as responders and 8 as poor-responders to neoadjuvant chemotherapy defined as those with chemotherapy-induced necrosis fractions of ≥90% and <90%, respectively. The rSUVs of responders and poor-responders were not different, but rMTV and rTLG values showed a trend toward difference, although statistically not significant (p=0.110 and 0.106, respectively). The sensitivity and specificity of rTLG were 100% and 62.5%, respectively, at an SUV cut-off of 0.13. Conclusions: In our osteosarcoma patient population, TLG and MTV, which represent combined metabolic and volumetric indices, were found to predict tumor response better than pre- or post-treatment mSUV or rSUV. No significant financial relationships to disclose.
Role of MRI in osteosarcoma for chemotherapy response evaluation and prediction: Correlation with histological necrosis
Authors: Bajpai J. , Gamnagatti S. , Sreenivas V. , Phulia R. , Sharma M. , Khan S. A. , Rastogi S. , Safaya R. , Malhotra A. , Bakhshi S. 
Published: August 2020

10540 Background:Histologic necrosis (HN), the current gold standard for response evaluation in osteosarcoma (OS), is accessible only after neoadjuvant chemotherapy (NACT) and may get affected by confounding factors. Thus, it would be useful to have surrogate markers of response evaluation and prognostication using magnetic resonance imaging (MRI) to individualize therapy. Method:Thirty-one treatment naïve OS patients received 3 cycles of NACT followed by surgery during 2006–2008. All patients underwent baseline and post-NACT conventional(C), diffusion-weighted (DW) and dynamic contrast enhanced (DCE) MRI. Taking ‘Huvos grading’ (good response >/= 90% HN) as reference standard, various parameters of MRI were compared with it. Tumor considered as ellipsoidal; volume (V), average tumor plane (ATP) and relative(r)-ATP (ATP/body surface area) were calculated using standard formula for ellipse. Receiver operating characteristic curves were generated to assess the best threshold and predictability. Sensitivity and specificity were calculated along with 95% confidence limits. After deriving thresholds for each parameter in univariable analysis, multivariable analysis was carried out. Results: Both pre-and post NACT, absolute and relative size parameters were well correlated with HN, though post NACT change in parameters did not. Apparent diffusion coefficient (ADC), either pre-and post NACT measurements or change following chemotherapy were not correlating well. However, on adjusting for volume, significant correlation was found. Thus, we could derive a new parameter diffusion per unit volume (DV= ADC /V). Change in shape of time intensity curve did not show significant correlation. Conclusions: In OS, NACT response can be assessed and predicted by conventional and DW- MRI early in the disease course which correlates well with HN. DV seems to be a sensitive substitute for response evaluation. For DCE-MRI, more sophisticated models in future studies might be useful. [Table: see text] No significant financial relationships to disclose.