bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of soluble KIT (sKIT) as a potential surrogate marker for TTP in sunitinib malate (SU)-treated patients (pts) with advanced GIST
Authors: Blackstein M. , Huang X. , Demetri G. D. , Casali P. G. , Garrett C. R. , Schöffski P. , Shah M. H. , Verweij J. , Baum C. M. , DePrimo S. E. 
Published: March 2020

10007 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, approved multinationally for the treatment of imatinib (IM)-resistant/-intolerant GIST. Preliminary analysis in a SU phase I/II GIST study suggested that a decline in plasma sKIT levels may correlate with measures of clinical benefit. We evaluated the potential of sKIT as a surrogate marker for TTP using samples obtained in a randomized, double-blind, placebo-controlled phase III study of SU in pts with IM-resistant/-intolerant GIST, clinical results of which have been reported previously. Methods: 312 pts were randomized (2:1) to receive SU 50 mg (n=207) or placebo (n=105) daily in 6-wk cycles (4 wks on treatment, 2 wks off), respectively. The primary endpoint was TTP as per RECIST. Levels of sKIT in plasma samples were measured in cycle 1 on days 1, 14 and 28 and in cycles 2 and 3 on days 1 and 28 using a performance-validated ELISA. Prentice Criterion, Cox models and the Proportion of Treatment Effect (PTE) were used to analyze the results (PTE of 1 = ideal surrogate). Results: Numbers of pts with matched pairs of baseline and on-study plasma samples varied from 228 pts at cycle 1, day 14 to 106 pts at the end of cycle 3. After 4 wks of treatment (cycle 1, day 28), plasma sKIT levels began to exhibit a significant decrease (P<0.0001) in response to SU treatment; at the same time, changes in the level of sKIT (decreases vs. increases) also became indicators of TTP (HR=0.53; 95% CI, 0.37–0.75; P=0.0003), with decreases associated with longer TTP. This trend continued throughout the sampling period, with the effect persisting off treatment. Although the impact of SU on plasma sKIT levels continued to be seen after 2 cycles, sKIT changes became a better indicator of TTP than initial treatment group by cycle 2, day 28 (PTE = 0.62; HR=0.51; 95% CI, 0.38–0.69; P<0.0001), and at cycle 3, day 1 (PTE = 0.64; HR=0.42; 95% CI, 0.29–0.60; P<0.0001). Conclusion: These preliminary findings suggest that circulating sKIT may be a surrogate marker for TTP in GIST pts after 2 cycles of SU treatment. Further studies are warranted to confirm these findings and to establish whether sKIT can be used as a general surrogate marker of clinical outcomes in GIST pts with SU or other therapies. [Table: see text]
Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial
Authors: Woll P. J. , van Glabbeke M. , Hohenberger P. , Le Cesne A. , Gronchi A. , Hoekstra H. J. , Radford J. A. , van Coevorden F. , Blay J. ,   EORTC Soft Tissue & Bone Sarcoma Group
Published: March 2020

10008 Background: The impact of adjuvant CT on survival for resected STS remains uncertain. In a 1997 meta-analysis, doxorubicin-based CT significantly improved local and overall relapse free survival (RFS), but not overall survival. Many of the CT regimens used would now be considered suboptimal. We therefore undertook a multicentre randomised trial of intensive CT in patients with excised high grade STS. Methods: Patients with macroscopically resected, Trojani grade II-III STS at any site, no metastases, performance status (PS) <2 and age = 70 were eligible within 4 weeks of surgery. Patients were randomised to observation or CT with 5 cycles of doxorubicin 75 mg/m2, ifosfamide 5 g/m2q 21 days and lenograstim. Patients in both arms received radiotherapy (RT) if the resection was marginal or the tumor recurrent. Stratifications were for institution, disease site, tumor size, planned RT and isolated limb perfusion therapy. Results: Between 1995 and 2003, 351 patients were recruited. 9.5% were ineligible and 4.8% did not receive the allocated treatment. Patient characteristics were evenly distributed between the two arms: 47% > 50 years; 54% male; 33% PS 1. The commonest pathological subtypes were leiomyo- 15%, lipo- 13%, MFH 11%, synovial sarcoma 11%. 60% were grade III. 66% were extremity tumors. Of 175 patients allocated CT, 163 started and 127 completed 5 cycles. 38% had dose reductions or delays, mostly for hematologic toxicity or infection. 88% of patients received RT. An interim analysis for futility has been performed, because survival in the observation arm was better than expected: estimated 5-yr RFS was 52% in both arms and OS 69% (observation arm) and 64% (CT arm). The hypotheses that adjuvant CT improves RFS and OS (with hazard ratios = 0.621) can both be rejected. Conclusions: This is the largest study of adjuvant CT with ifosfamide and doxorubicin ever undertaken in STS. It fails to show a survival advantage for adjuvant CT. Improved survival over previous studies might be due to better surgery and increased use of adjuvant RT. Further analysis of this study will allow more detailed assessment of the role of adjuvant CT in resected STS and will contribute to an updated meta-analysis. [Table: see text]
Response assessment using dynamic MR imaging in non-metastatic osteosarcoma
Authors: Reddick W. E. , Hoffer F. A. , Billups C. A. , Jenkins J. J. , Wu J. , Daw N. C. 
Published: March 2020

10018 Background: Conventional static imaging methods are of limited utility in assessing osteosarcoma (OS) response to neoadjuvant chemotherapy primarily due to the lack of significant change in tumor size. Methods: We prospectively evaluated the utility of dynamic contrast-enhanced MR imaging (DEMRI) in assessing tumor response as part of a phase II trial of multiagent chemotherapy for treatment of OS from 1999 to 2006. Forty-two subjects (median age, 13.5 years) with non-metastatic OS of the extremity (27 femur, 10 tibia, 3 humerus, 1 fibula, and 1 ulna) underwent one or more DEMRI examinations and had histological assessment of tumor response. DEMRI was performed at baseline (before course 1 of chemotherapy [week 0]), at week 9 (after 3 courses of chemotherapy), and at week 12 (after 4 courses of chemotherapy before definitive surgery). Quantitative DEMRI measures reflecting rate and intensity of enhancement (dynamic vector magnitude [DVM]) and regional contrast transfer between the plasma and extracellular/extravascular spaces (kep) were analyzed in relation to histological response. Nonparametric Wilcoxon signed-rank test was used to compare DEMRI parameters during preoperative chemotherapy with baseline. Logistic regression was used to examine the association between DEMRI parameters and histological response at each time point. Results: Both DEMRI parameters at week 9 and at week 12 of preoperative chemotherapy were significantly decreased from baseline (p<0.001). Patients with lower DVM or lower kep at week 9 or at week 12 ( Table ) were significantly more likely to have good histological response (>90% tumor necrosis). Conclusions: DEMRI is a non-invasive method that can be used to assess tumor response to neoadjuvant chemotherapy in OS. A slower rate of contrast accumulation in the extracellular/extravascular space corresponds to increased tumor necrosis. [Table: see text] No significant financial relationships to disclose.
RECIST and Choi criteria for response assessment (RA) in patients with inoperable and metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate. Cambridge GIST study group experience
Authors: Bulusu V. R. , Jephcott C. R. , Fawcett S. , Cook N. , Hatcher H. , Moyle P. , Carroll N. , Earl H. , Save V. , Hardwick R. 
Published: March 2020

10019 Background: Imatinib Mesylate (IM) induces an overall response rate of 84% in patients (pts) with metastatic GISTs. Standard RA is by RECIST criteria. This may underestimate the true benefit of IM in such pts. Choi et al observed ↓ in size (10%) and or density (D) (15%) correlated well with disease specific survival. We report our experience using both RECIST and Choi criteria for RA in GIST pts on IM. Methods: Between 2003 and 06, 24 pts with metastatic or inoperable GISTs were treated with IM. 50 lesions (Liver 20, Omentum 21, Primary 9) were identified at presentation on contrast CT (Siemens multi slice CT, IV Niopam, GE PACS system). 3 monthly CT was used for RA until tumour progression (PD) or death. Parameters recorded were: 1.Largest dimension 2. Lesion density (Mean Hounsfield units, HFU) 3.New lesions 4.Any new features. RECIST and Choi criteria were both applied for RA. Results: N=50. At 3 months (m) only 16% of the lesions achieved partial response (PR) by RECIST and 24% increased in size by a mean of 22.5% (Range 3–150%). RA as measured by Choi criteria revealed 88% of lesions had either a 10% ↓ in size or a 15% ↓ in D at 3 m. Mean ↓ in D was 29% (95% CI 24.6–33.4). At 18 m 50% of the lesions achieved PR and 20% had PD by RECIST criteria, and with Choi criteria 68% RR was recorded. Calcification, haemorrhage and perforation within the lesions spuriously altered the mean D value in 15% of the lesions which made assessment by Choi criteria difficult. In 5 pts new hepatic cystic lesions (range 2–22) appeared with a mean D of 16 HF. None were detected in extra-hepatic sites. 4 pts showed new calcifications within lesions 3–18 m on IM. Enhancing nodules within lesions were seen in 4 pts predating clinical PD by 6–18 m. Conclusions: Choi criteria were found to be reproducible in our pts. RRs at 3 months using Choi criteria (88%) were far greater than by RECIST criteria (16%). RRs were more similar at 18 m (68% Choi vs 50% RECIST).Using density for RA can become unreliable in the presence of perforation, calcification and haemorrhage. These criteria should be evaluated by a radiologist experienced in assessing the response to IM in GISTs with awareness of their limitations. No significant financial relationships to disclose.
Subpopulation analyses in a worldwide treatment-use trial of sunitinib (SU) in GIST patients (pts) with resistance or intolerance to prior imatinib (IM) therapy
Authors: Reichardt P. , Kang Y. K. , Ruka W. , Seddon B. , Baum C. M. , Demetri G. D. 
Published: March 2020

10022 Background: SU is an oral, multitargeted TKI of KIT, PDGFRs, VEGFRs, RET and FLT3, approved multinationally for the treatment of IM-resistant/-intolerant GIST. The aims of this study are to provide access to SU to GIST pts who were ineligible for SU clinical trials or for whom SU is unavailable prior to regulatory approval in their country, and to collect safety/efficacy data in a large number of GIST pts. Methods: In this ongoing open-label study, pts with advanced GIST and prior IM failure receive SU at a starting dose of 50 mg/d in 6-wk cycles (4 wks on treatment, 2 wks off). Assessments include safety/tolerability measures, response (per local standard of care) and OS. Because of the variability of response evaluations, treatment duration (TD; time from first dose to the earlier of termination date or 2 wks after last dose) was analyzed as a surrogate efficacy measure. Results: As of March 1, 2006, 768 pts enrolled at 96 centers in 33 countries had received =1 dose of SU (ITT population). Of these, 362 had discontinued treatment (lack of efficacy: 25%; AE: 12%). Median TD (ITT population) was 126 d (range: 1–618); 55% of pts had received =3 mos of treatment; 32%, =6 mos and 16%, =9 mos. Median TD was similar for pts irrespective of tumor histological subtype (epithelioid: 125 d, n=85; spindle cell: 127 d, n=414; mixed: 126 d, n=100; other subtypes: 114 d, n=158; P=0.17). Median TD was longer in pts with ECOG PS 0/1 (127 d, n=637) vs 2 (84 d, n=96; P<0.0001) and pts aged <65 (127d, n=486) vs =65 yrs (97d, n=281; P=0.011). Median OS has not been reached. The impact of baseline factors on survival will be presented. The most common AEs of any cause were fatigue (42%), diarrhea (38%) and nausea (32%), which were usually grade 1/2. The most common grade =3 AEs of any cause were abdominal pain (4%), vomiting (3%) and dehydration (2%). 3% of pts have demonstrated hypothyroidism. Hematologic AEs (total, grade 3/4) included anemia (56%, 5%), thrombocytopenia (35%, 5%) and neutropenia (22%, 10%). Conclusions: In this ongoing study of a large, relatively heterogeneous population of IM-resistant/-intolerant GIST pts, SU demonstrated acceptable tolerability and clinical efficacy that is highly consistent with prior studies. No significant financial relationships to disclose.
A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update
Authors: Von Mehren M. , Reichardt P. , Casali P. G. , Blay J. , Debiec-Rychter M. , Dumez H. , Cheung W. , Feifel B. , Veronese M. , Demetri G. D. 
Published: March 2020

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.
Identification of therapeutic targets in angiosarcoma
Authors: Ravi V. , Kim S. , Dim D. , Hicks D. , Aggarwal C. , Hostetter G. , Cheney R. T. , Bittner M. , Trump D. L. , Wong M. K. 
Published: March 2020

10030 Background: Human angiosarcoma is an aggressive malignancy with ability to invade locally and metastasize widely. Even with a multimodality approach, the local recurrence rate is 81% and 5 year disease-free survival is 17% for all comers. Durability of the responses to treatment options such as paclitaxel is 4 to 5 months. Our previous work shows that enhanced cell migration and invasion are integral to the chemoresistant angiosarcoma phenotype. However the molecular mechanism of this is unknown. Methods: In order to address this and to identify new therapeutic strategies, we analyzed formalin fixed paraffin embedded (FFPE) archival angiosarcoma specimens from 17 consecutive patients at our institution to identify aberrations at the DNA level that were highly prevalent. DNA was extracted from FFPE angiosarcoma specimens using the proteinase K method. Good quality DNA with an yield more than 5 micrograms was obtained from 10 out of 17 patients and these samples were assayed for DNA dosage differences compared to genomic reference DNA using array comparative genomic hybridization. High density 244K Agilent arrays were used to evaluate these specimens to enhance the precision of the estimates in this rare disease. Results: Statistically significant (p<0.001) aberrations with prevalence greater than 50% were noted in several genes including NOTCH2, MAML1 (notch signaling intermediate), oncomodulin, calnexin, sequestosome1, zinc finger proteins and ADAMTS2. This is particularly important since Notch and its ligand Jagged are developmental genes critical to tumorigenesis and there is emerging evidence of their role in endothelial activation. Conclusions: Aberrations involving the notch signaling pathway occur with a high prevalence in angiosarcomas and may serve as a target for therapeutic intervention. No significant financial relationships to disclose.
Perioperative sunitinib dosing around extensive resections of imatinib-resistant metastatic gastrointestinal stromal tumors
Authors: Raut C. P. , Morgan J. A. , Quigley M. T. , George S. , Wagner A. J. , Demetri G. D. , Bertagnolli M. M. 
Published: March 2020

10044 Background: Sunitinib malate (SU) is the primary therapy for metastatic gastrointestinal stromal tumor (GIST) resistant to imatinib mesylate (IM). Its inhibition of multiple receptor tyrosine kinases (TK) raised concerns that SU may impair healing after cytoreductive procedures more than IM. We reviewed our experience to compare the spectrum of postoperative complications after SU v. IM therapy. Methods: All patients (pts) with IM-resistant metastatic GISTs enrolled in phase II/III SU protocols at our institution were reviewed. The control group underwent cytoreduction on IM. Perioperative SU dosing and complications after surgery and after resumption of SU were recorded. Complications related to healing included wound/fascial dehiscence, anastomotic leak, and fistula. Complications not attributed to wound healing included hemorrhage, abscess, seroma, and ileus. Results: We treated 188 pts with IM-resistant metastatic GISTs with SU. Twenty-six pts on SU and 46 pts on IM underwent 28 and 53 operations for disease resection, respectively ( Table ). SU was stopped a median of 5 days (range 0–26) prior to surgery and resumed a median of 33 days (range 12–183) after surgery and 20 days (range 7- 178) after hospital discharge, generally during the first postoperative clinic visit. There were 17 complications after 14 (50%) of 28 procedures on SU and 23 complications after 20 (38%) of 53 procedures on IM (p=NS). Dehiscence, leaks, or fistulas, were identified after 2 (7%) procedures on SU and 4 (8%) procedures on IM (p=NS). These 2 pts with complications on SU stopped the drug 9 and 22 days prior to surgery. No wound healing complications were noted among the 18 pts who stopped SU less than 9 days before surgery. Conclusions: Wound healing complications were not more common after extensive resections on SU than on IM, despite SU's inhibition of a wider spectrum of TKs. Our current practice is to continue SU until 1–2 days prior to surgery and to resume SU at the first postoperative visit. [Table: see text] No significant financial relationships to disclose.
Pathological significance of deletions involving codons 557 and 558 of KIT gene in localized resected gastrointestinal stromal tumors (GIST) of intermediate and high risk: A study by the Spanish Group for Sarcoma Research (GEIS)
Authors: Romero I. , Poveda A. , Martin J. , Lopez-Pousa A. , Gomez C. , Safont M. , Andres R. , Guillem V. , Llombart-Bosch A. , Lopez-Guerrero J. 
Published: March 2020

10051 Background: Approximately 60 to 85% of GISTs harbour activating mutations of the KIT or PDGFRA tyrosine kinase genes. Deletions affecting codons 557–558 of KIT are relevant to prognosis of resected GIST (Martin J, et al. J Clin Oncol. 2005, 23:6190). Methods: GIST of high or intermediate malignant risk according to Fletcher classification (Hum Pathol. 2002;33; 459) with a complete (R0) or microscopic residual (R1) resection were prospectively evaluated. Central pathology review was carried out. The mutational analysis of exons 9, 11, 13 and 17 of KIT and exons 12 and 18 of PDGFRA was undertaken from DNA extracted from paraffin-embedded tissue. The purpose of this study was to explore the correlation between deletion mutation involving 557–558 codons within KIT gene and known prognostic factors in GIST: mitotic count and size. Results: Of the 33 GIST, 19 were gastric, 13 of small bowell and one of other location. Median tumor size was 10.4 cm (1.9–22 cm), and median mitotic count was 2 (1–32). All cases showed an immunostaining with diffuse cytoplasmic pattern of c-kit (CD117). An 82% (27) presented either a KIT (23) or a PDGFRA (4) mutation. Eleven deletions affecting codons 557–558 of KIT were observed. KIT mutations were associated to spindle type histology and PDGFRA mutations to epithelioid histology. No statistical association between tumor size and KIT mutations, including patients with deletions 557–558, was found. Tumors carrying a deletion of codons 557–558 of KIT presented a different median of mitotic count (8 mit × 50 hpf) than the rest (2 mit × 50 hpf), this difference was statistically significant (p = 0,029) in the Mann-Whitney U test. Conclusions: Deletions affecting codons 557–558 of KIT define a group of cases with a high proliferative potential. The prognostic and predictive significance of these findings are waiting for a longer follow-up. No significant financial relationships to disclose.
Loss of CXCR4 nuclear immunoreactivity in synovial sarcoma (SS) correlates with poor survival
Authors: Grisanti S. , Facchetti F. , Dei Tos A. P. , Rossi E. , Ardighieri L. , Ferrari V. D. , Amoroso V. , Bercich L. , Ippolito V. , Marini G. 
Published: March 2020

10069 Background: The chemokine receptor CXCR4 has been found to be expressed in mesenchymal neoplasms including osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma and SS. Gene products of the HER oncogenic family, such as EGFR and HER2, have been described to be overexpressed in SS and we previously demonstrated coexpression of CXCR4 and EGFR but not HER2 in SS patients. In this study we analysed CXCR4 expression in terms of subcellular localization and extended results to 15 SS patients. Methods: Fifteen SS patients were included in the study. In all cases morphological diagnoses were confirmed molecularly by FISH or RT-PCR specific for t(X;18). HER2 and EGFR expression were determined by immunohistochemistry (IHC) while HER2 gene status was assessed by FISH analysis. CXCR4 expression was determined with an anti-human CXCR4 monoclonal antibody (Clone 44716, R&D Systems, Minneapolis, USA) followed by incubation with the EnVision peroxidase kit (Dakocytomation, Glostrup, Denmark). CXCR4 nuclear vs cytoplasmic expression was correlated with outcome. Results: In all samples IHC analysis for HER2 was negative and no amplification was found by FISH. EGFR expression was observed in 13/15 patients. CXCR4 immunoreactivity was identified in 9/15 cases. CXCR4 and EGFR were coexpressed in 8/15 tumors. Follow-up ranged from 9 to 127 months. After a median follow-up of 39 months, 7 patients were dead of SS, 8 patients were alive (7 of them are disease-free and one has evident disease in the retroperitoneum). All alive and disease-free patients showed nuclear CXCR4 expression whereas 6/7 dead patients expressed cytoplasmic or membrane CXCR4 (p = 0.0008). Conclusions: Loss of nuclear CXCR4 expression is associated with fatal course and may represent a novel prognostic factor. CXCR4 is frequently coexpressed with EGFR but not with HER2. In contrast with previous reports HER2 seems not involved in the carcinogenesis of SS. No significant financial relationships to disclose.