bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of tumor response to trabectedin (ET743) in myxoid liposarcomas
Authors: Grosso F. , Demetri G. D. , Blay J. Y. , Judson I. , Le Cesne A. , Spreafico C. , Jimeno J. , Pilotti S. , D’Incalci M. , Casali P. G. 
Published: March 2020

9511 Background: Trabectedin (T) is a marine-derived agent found to be active in ovarian cancer and sarcomas. Among sarcomas, activity has been notable in leiomyosarcomas and liposarcomas. Since liposarcomas are a heterogeneous group, including well/de-differentiated, pleomorphic, and myxoid/round cell subtypes, we have noted particularly interesting patterns of responsiveness to T in myxoid liposarcomas, which are associated with t(12;16)(q13;p11) or t(12;22)(q13;q12) chromosomal translocations, resulting in CHOP-TLS or CHOP-EWS fusion products. Methods: 15 cases of myxoid liposarcomas treated with T at the Istituto Nazionale Tumori, Milan, were retrospectively reviewed. In most cases, T was given as a 24-hr continuous infusion every 21 days, at dose levels from 1.0 to 1.5 mg/sqm. 108 courses were delivered, with a median of 5 courses per patient (range 2–20). Observations made in this series were shared with five other institutions having treated myxoid liposarcoma cases with T, all of which also report a significant response rate, for a total of 44 pts. A centralized radiological review of all pts is ongoing. Results: In the Milan series, early tissue alterations in tumors were observed in 14 patients, mainly with a decrease in tumor density on CT scan and/or decrease in contrast enhancement on MRI. These changes were followed by tumor shrinkage amounting to a conventional PR/CR in 8 (pending final review), while 3 others have responses which continue to evolve. Progression followed treatment interruption in one patient, with a minor response occurring at treatment restart. Treatment is continuing in 12 pts (median duration of therapy in excess of 5 months). Further results of the central radiological review from all centres will be reported. Conclusions: Tumor response to T seen in myxoid liposarcoma appears to be marked by early radiological alterations in tumor tissue, often preceding tumor shrinkage, which may be delayed. A selective mechanism of action for this chromosomal translocation-related sarcoma is suggested, and is being actively investigated at the moment. [Table: see text]
Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST)
Authors: Albritton K. H. , Rankin C. , Coffin C. M. , Ratner N. , Budd G. T. , Schuetze S. M. , Randall R. L. , Declue J. E. , Borden E. C. 
Published: March 2020

9518 Background: MPNSTs are rare soft tissue tumors (STS) that are relatively resistant to chemotherapy. 26% have epidermal growth factor receptor (EGFR) amplification. In preclinical studies, NF1/p53 murine MPNSTs in vitro are stimulated by EGF and inhibited by EGFR inhibitors. We proposed to assess response rate (RR) to erlotinib in adult patients with unresectable or metastatic MPNST. Methods: Patients (pts) were required to have measurable disease, Zubrod performance status (PS) <3, adequate organ function, no prior EGFR therapy, and centrally reviewed confirmation of diagnosis. Treatment was erlotinib 150 mg by mouth daily, in continuous 28 day cycles. Disease evaluation was performed every 2 cycles. Results: 24 pts enrolled in 22 months, from 13 institutions. 20 pts were deemed eligible. Median age was 45.3 years; 50% had neurofibromatosis. At enrollment, 15 had a PS of 0–1, 18 had metastatic disease, and 19 had unresectable disease. Pts were heavily pretreated: 9 pts had ≥ 2 prior regimens, 6 pts had 1 prior regimen, and 4 pts had no prior chemotherapy (1 unknown). 19 of 20 pts were assessable for toxicity: 6 pts had grade 3 toxicities; only 1 was hematologic (anemia). Mild rash (in 15 pts) and fatigue (in 8 pts) were the most common side effects. 20 pts were evaluable for response: 1 had stable disease after first evaluation and 19 had no response. Median progression-free survival was 2 months. 14 patients have died; median overall survival was 4 months. Because no objective responses were observed in the first stage of the study, it was closed to further accrual. Conclusions: We were able to accrue pts with a rare STS to a phase II histology specific study through a single adult cooperative group. In spite of preclinical promise of EGFR inhibition, erlotinib does not appear to be active in MPNSTs. To further understand the role of EGFR in MPNST, we are assessing EGFR expression immunohistochemically and performing quantitative PCR for genes altered by EGFR stimulation/inhibition on pt tumors. No significant financial relationships to disclose.
Evaluation of SRC-family kinases in gastrointestinal stromal tumors
Authors: Bauer S. , Demetri G. D. , Fletcher J. A. 
Published: March 2020

9529 Background: Inhibition of KIT oncoproteins by imatinib mesylate (IM) induces clinical responses in most GIST patients. However, many patients develop IM-resistance and novel KIT-Inhibitors show clinical benefit in only a minority of patients. SRC-family kinases (SFK) are important participants in kinase oncoprotein signaling pathways in ALL and CML, and dual-specificity SRC/ABL-inhibitors show promising activity in IM-resistant CML in vitro. However, little is known about SFK functional roles in IM-resistant GIST. Methods: GIST were analyzed for SFK expression and activation by western blotting. Biological consequences of KIT inhibition alone (IM), SFK inhibition (SU6656) and combined KIT/SFK inhibition (PP1, PP2, SU6656+IM) were determined by immunoblotting for protein activation, and—in GIST cell lines—by luminescence assays for cell proliferation. Results: Primary GIST and GIST cell lines showed weak SFK activation compared to Jurkat (T-cell ALL) controls. Variable expression of the SFK proteins FYN, LYN and SRC (but not BLK and LCK) was shown in the cell lines and primary GIST. Expression of SFK proteins HCK and FGR was found in 2 primary GIST only. KIT and KIT signaling pathways (pAKT, pS6, pSTAT3) were affected by IM and combined KIT inhibitors but not by SU6656 at 1μM in GIST882 (IM-sensitive cell line) and GIST48 (IM-resistant cell line). SRC phosphorylation (Y418) was not affected by IM or SFK-inhibitors at 1μM. IM showed superior inhibition of proliferation compared to PP1 and PP2 (1μM) in GIST882 (IM: 67%, PP1: 1%, PP2: 0%) and comparable inhibition in GIST48 (IM:30%, PP1: 29%, PP2: 29%). No effects on proliferation were seen with SU6656 alone or in combination with IM; no antagonistic effects were observed. Conclusions: Our analysis showed expression and weak activation of several SFK in GIST. Expression of heme-associated SFKs in primary GIST may be explained by lymphocellular infiltration. Biochemical inhibition of SFK alone does not have antiproliferative effects in GIST cell lines, and no synergies or antagonisms were found in combination with IM or with combined KIT/SFK inhibitors. Therefore, targeting of SFK may be of less therapeutic value in GIST than in kinase-driven haematological cancers. No significant financial relationships to disclose.
A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs) resistant to imatinib mesylate
Authors: Joensuu H. , De Braud F. , Coco P. , De Pas T. , Spreafico C. , Bono P. , Jalava T. , Laurent D. , Casali P. 
Published: March 2020

9531 Background: PTK787/ZK222584 (PTK/ZK) is a novel, oral selective inhibitor of certain receptor tyrosine kinases that may be important in the molecular pathogenesis of GIST (KIT, PDGFRs, VEGFR-1 and VEGFR-2). The efficacy and safety of PTK/ZK are not known in the treatment of imatinib resistant GIST. Methods: Pts who had histologically diagnosed, metastatic GIST that had progressed after at least 4 weeks of treatment with imatinib were eligible. Prior therapy with KDR inhibitor therapy was not allowed. PTK/ZK was administered orally 1,250 mg once daily until treatment failure. No concomitant systemic cancer treatments were allowed. Treatment response was monitored at 4 to 8 wk intervals and evaluated using the RECIST criteria. Adverse events (AE) were scored using the NCI/NIH Common Toxicity Criteria v. 2.0. A total of 15 pts were planned to be accrued as a 2-stage procedure. The highest prior imatinib dose: 400 mg, n=1; 600 mg, n=2; 800 mg, n=11; 1,000 mg, n=1. Prior response to imatinib: PR, n=8; SD, n=5; PD, n=1; unknown, n=1. Results: All 15 pts (M 12, F 3) enrolled were eligible. Two (13%) pts achieved PR, 8 (53%) had SD for 3 months or longer, and 5 progressed. The clinical benefit rate (PR+SD) was 67% (95% CI, 38% to 86%). The duration of the 2 PRs was 95 + and 225+ days and 8 SDs from 93+ to 346+ days. All PRs and SDs are ongoing to date. The median time to treatment failure (TTTF) has not been reached. PTK/ZK was well tolerated. The most frequently recorded AEs were dizziness (n=6), nausea/vomiting (n=6), abdominal pain/abdominal pain upper (n=4) and asthenia (n=4). All recorded AEs were either of grade 1 or 2 except for 2 events (grade 4 hypercalcemia, n=1; grade 4 pain, n=1). Conclusions: PTK787/ZK222584 showed signs of activity in this series of GIST patients who progressed during imatinib treatment. The dose of 1,250 mg o.d. is generally well tolerated. [Table: see text]
The criteria of aggressiveness and other prognostic factors for predicting relapses of primary tumors and imatinib (IM) treatment outcomes in advanced KIT immunopositive gastrointestinal stromal tumors (GIST): A report of the Polish Clinical GIST Registry (PCGR)
Authors: Rutkowski P. , Nowecki Z. I. , Michej W. , Debiec-Rychter M. , Limon J. , Siedlecki J. A. , Kakol M. , Gluszek S. , Osuch C. , Ruka W. 
Published: March 2020

9544 Background: The development of adjuvant treatment trials with imatinib in GIST has raised the debate about the accuracy of NIH risk criteria consensus and about the significance of other prognostic factors. Methods: We analyzed the criteria of aggressiveness and other clinico-pathological and genetic factors influencing disease-free survival (DFS) in patients with primary CD117-positive tumors (group I: 274 patients; median follow-up 29 months; calculated from primary tumor resection) and progression-free survival (PFS) in metastatic/unresectable GIST patients treated with IM (group II: 179 patients; median follow-up 19 months; calculated from the start of imatinib therapy) enrolled into PCGR. Results: In group I statistically significant (p<0.05) factors negatively influencing DFS both in univariate (log-rank test) and multivariate (Cox’s model) analysis were: primary tumor size > 5 cm, mitotic index > 5/50HPF, male gender, primary tumor R1 resection or tumor rupture, non-gastric primary tumor localization and intermediate/high risk group (3-year DFS for high, intermediate and low/very low risk group was: 28%, 75% and 99%, respectively). In group II we identified 5 factors negatively affecting PFS statistically significant both in univariate and multivariate analyses (p<0.05): tumor genotype indicating other than exon 11 KIT mutation, mitotic index > 10/50HPF, age below 45 years at diagnosis, high baseline pre-IM granulocyte count and poor WHO performance status ≥ 2. Conclusions: We validated the value of criteria of risk groups for the assessment of the natural course of primary GIST, but we also identified additional independent prognostic factors. For the prediction of PFS during IM therapy for advanced GIST we detected 5 different, independent biological and pathological factors. No significant financial relationships to disclose.
Patterns of PET response after long-term sunitinib therapy in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumors (GIST)
Authors: Raut C. P. , Van Den Abbeele A. , Ramaiya N. , Morgan J. A. , George S. , Quigley M. T. , Dollard A. M. , Bertagnolli M. M. , Baum C. , Demetri G. D. 
Published: March 2020

9547 Background: Sunitinib malate (previously known as SU11248) is an active therapy for GIST patients resistant to or intolerant of IM. During initial development, sunitinib was administered in 4–6 week cycles, with 2–4 weeks of drug dosing followed by 2 weeks off treatment. We previously reported suppression of tumor-related 18FDG avidity on PET imaging during sunitinib dosing, with rebound tumor uptake while off drug. This rebound, seen in 80% with initial PET suppression, did not correlate with lack of clinical benefit. We asked if this pattern persists in pts who benefited from long term (> 2 years) sunitinib therapy. Methods: Of 77 pts in our initial Phase I/II study, 7 remain on therapy with sunitinib for more than 2 years, 4 of whom had matched baseline PET and CT data to assess tumor metabolic activity on and off sunitinib dosing. PET scans were obtained at baseline, during initial treatment, during the off-treatment period, and again after > 2 years therapy. These 4 pts were followed for a median 39 months (range 35–45 months) and for a median of 35 cycles (range 27–47). Two achieved PR and two SD. Results: Initially, all 4 exhibited suppression of tumor FDG avidity with treatment followed by rebound during the off-treatment period. By 6 months, all showed complete suppression of FDG activity. After > 2 years on sunitinib, GIST lesions in 2 pts showed no activity on PET, even while off sunitinib, while GIST in 2 pts demonstrated rebound flare when off therapy. The GIST lesions have not progressed despite the transient metabolic rebound while off sunitinib. Conclusions: Metastatic lesions in pts with IM-resistant GIST benefiting from long-term sunitinib therapy display two patterns on PET imaging. GIST in certain pts who benefit from therapy demonstrates metabolic rebound of activity when off dosing, while lesions in other pts remain metabolically inert on PET even during the brief dosing breaks. Functional imaging may yield insights to differences in the underlying biology of GIST subtypes in different pts. [Table: see text]
Imatinib in locally advanced dermatofibrosarcoma protuberans (DFSP): A phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
Authors: Ugurel S. , Utikal J. , Mohr P. , Helmbold P. , Pfoehler C. , Schiller M. , Kellner I. , Schadendorf D. 
Published: March 2020

9561 Background: DFSP is known for its low metastatic potential but locally infiltrative growth, hereby enforcing extensive and often multiple surgical procedures. DFSP cells were recently shown to display chromosomal translocations of the regions 17q22 and 22q13, resulting in an autocrine growth stimulation loop via the platelet-derived growth factor (PDGF) pathway. The tyrosine kinase inhibitor imatinib blocks PDGF signal transduction, thus offering a new therapeutic option for DFSP patients. This multicenter phase II trial was aimed to investigate the efficacy of imatinib in locally advanced DFSP. Methods: The primary study endpoint was objective response, secondary endpoints were safety and relapse-free survival. Patients with histological proof of locally advanced primary or relapsed DFSP, measurable tumor parameters according to RECIST, and no evidence of distant metastases were eligible. Patients received imatinib 600 mg/d PO. Tumor measurements were performed at week 6 and 12, and every 8 weeks thereafter. At the end of imatinib treatment, at the earliest after week 12, residual tumors were surgically excised with histological proof of tumor-free margins. Results: By January 2006, nine out of 13 recruited patients were evaluable for response (per protocol, PP), three are still on treatment and one stopped treatment after 12 days due to side effects. Among the nine PP patients, seven partial responses, one stabilization, and one progression were observed. Five responders showed an ongoing tumor shrinkage until complete surgical excision, whereas two patients revealed an initial response at 6 weeks, followed by a disease progression at 12 weeks. None of the patients developed distant metastases under treatment or thereafter. Side effects were mostly mild to moderate (CTC grade 1–2). Severe side effects (CTC grade 3–4), reversible angina pectoris and septicemia, respectively, were observed in two patients. Conclusions: The study results indicate imatinib as a potent systemic treatment option in locally advanced DFSP. However, a subset of DFSP patients appeared resistant to imatinib, either primarily after treatment onset, or secondarily after showing an initial response. No significant financial relationships to disclose.
CXCR4, EGFR and HER2 expression in patients with high-risk synovial sarcoma (SS): A clinicopathologic study
Authors: Grisanti S. , Rossi E. , Ardighieri L. , Farisoglio C. , Ferrari V. D. , Bercich L. , Simoncini E. , Marini G. , Facchetti F. 
Published: March 2020

9580 Background: CXCR4 is overexpressed in many human tumors and plays important role in targeted metastasis. CXCR4 activation has been described in osteosarcoma, rhabdomyosarcoma and Ewing’s sarcoma both in vivo and in vitro, but its role has not been elucidated in SS yet. EGFR and Her2/neu, have been described to be overexpressed in patients with SS and proposed as potential therapeutic targets. Because CXCR4 and Her2 have been found to be functionally linked in breast cancer cell lines, we characterized SS in terms of CXCR4, Her2 and EGFR coexpression. Materials and Methods: Six patients sequentially observed at the Spedali Civili di Brescia from 1999 to 2005, with a diagnosis of synovial sarcoma were included in the study. The diagnosis of SS, a FISH analysis for t(X;18) was performed by using a commercial probe specific for the SYT gene breakpoint region (18q11) or by RT-PCR. Her2 and EGFR expression were determined by IHC and Her2 gene amplification by FISH analysis. CXCR4 expression was determined by IHC with anti-human CXCR4 monoclonal antibody (Clone 44716, R&D Systems) followed by incubation with the EnVision peroxidase kit (Dakocytomation, Glostrup, Denmark). Results: All patients were classified high-risk (stage III-IV) according to the AJCC/UICC VI Edition Staging System for soft tissue sarcomas. In all samples IHC analysis for Her2 was negative and no amplification was found by FISH. EGFR staining demonstrated positivity in 5 patients out of 6. CXCR4 reactivity was identified in 4 cases (nuclear staining in 3 and membrane staining in 1). CXCR4 and EGFR were coexpressed in 3 tumors. After a median follow-up of 24 months, 2 patients are dead of SS, 4 patients are alive, 3 of them are disease-free and one relapsed to the lung. The 3 patients alive and disease-free resulted positive for nuclear CXCR4 and EGFR while membrane CXCR4 was expressed in one dead patient. Conclusion: This study provides evidence that CXCR4 is expressed in cases of SS and is frequently coexpressed with EGFR but not with Her2. Due to the small size of this series it is not possible to establish any definitive prognostic or predictive value of CXCR4. However, nuclear expression of CXCR4 seems to be associated with a more indolent behaviour of the tumor and requires confirmation in larger series. No significant financial relationships to disclose.
Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial
Authors: Cunningham D. , Rao S. , Starling N. , Iveson T. , Nicolson M. , Coxon F. , Middleton G. , Daniel F. , Oates J. , Norman A. R. 
Published: March 2020

LBA4017 Background: The aim was to establish the potential use of the third generation platinum compound, oxaliplatin (O) & the oral fluoropyrimidine capecitabine (X) in untreated patients (pts) with advanced OG cancer. Methods: After stratification for PS and extent of disease, pts with histologically confirmed adenocarcinoma, squamous or undifferentiated carcinoma of the oesophagus, oesophago-gastric junction or stomach were randomised, in a 2 x 2 design, to 1 of 4 regimens; epirubicin, cisplatin, fluorouracil (ECF), EOF, ECX or EOX. Doses E 50 mg/m2, C 60 mg/m2 & O 130 mg/m2 IV 3 weekly; F 200 mg/m2 IV daily & X 625 mg/m2 twice daily PO continuously; for 8 cycles. The primary endpoint was overall survival. With 1000 pts (250 per arm) the study had 80% power to demonstrate non-inferiority of X over F and also O over C if the upper limit of the HR 95% CI excluded 1.23 (α = 0.05) in the per protocol population. Analysis was performed using the logrank test and Cox regression analysis. Results: 1002 pts were randomised from 61 centres. Demographics were balanced, 89% were PS 0–1, 77% metastatic, median age 63 (range 22–83), 81% were male and 40% gastric primaries. Histology: adenocarcinoma in 88% and 52% poorly differentiated. 11 pts were ineligible and 27 pts were withdrawn before treatment commenced. Median follow up was 17.1 months and 850 events have occurred. There were no significant differences in response rates comparing ECF to, EOF, ECX and EOX (41%, 42%, 46%, and 48% respectively); grade 3–4 non haematological toxicity 36%, 42%, 33% and 45%; and grade 3–4 neutropaenia 42%, 30% (p = 0.008), 51% (p = 0.043) and 28% (p = 0.001) respectively. Conclusions: Capecitabine may replace 5FU and Oxaliplatin may replace Cisplatin in triplet regimens used for the treatment of advanced OG cancer. [Table: see text] [Table: see text]