bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the presence of IGF1R overexpression in wild-type and kinase mutant GI stromal tumors
Authors: Corless C. L. , Beadling C. , Justusson E. , Heinrich M. C. 
Published: August 2020

10506 Background: Most adult GI stromal tumors have gain-of-function mutations in KIT (80%) or PDGFRA (5–7%). These pathogenetic mutations are the target for kinase inhibitor therapy. The pathogenesis of the 10–15% of GISTs lacking kinase mutations (WT GIST) is unknown; this includes most pediatric GISTs. Recently, Tarn et al. (PNAS 2008) identified IGF1R over-expression in all WT GIST in their series of cases, including one pediatric case. IGF1R may represent a novel therapeutic target for WT GISTs. Methods: We developed a quantitative RQ-PCR assay for IGF1R and GAPDH transcripts that is linear over 5 logs (R2 values of 0.99 and 0.98, respectively). We prepared cDNA from RNA isolated from 79 archival, formalin-fixed, paraffin-embedded GIST specimens and quantified IGF1R expression as the % ratio of IGF1R/GAPDH transcripts. We had previously genotyped the tumors to identify any kinase mutations. Results: Adult WT GIST had a 10–15 fold higher expression of IGF1R transcript than kinase mutant GISTs (WT GIST 13.7 ±18, n=35; KIT exon 11 mutant GIST 1.0 ± 1.1, n=26; PDGFRA mutant GIST 0.9 ± 1.0, n=8; KIT 9 or 13 mutation 0.8 ± 0.6, n=5). Interestingly, the WT GIST group could be further divided into tumors with low vs. high IGF1R expression. The low IGF1R expression group (mean 0.6, range 0.1–1.9, n=14), had similar IGF1R expression to kinase mutant GISTs. In contrast, the high expression group had more than 30-fold higher levels of IGF1R transcript (mean 22.5, range 7.3–76.5, n=21). We also examined IGF1R expression in 5 WT pediatric GISTs. The mean IGF1R expression in pediatric GISTs resembled that of the adult high expression group, with 4 of 5 cases showing IGF1R over-expression. Conclusions: WT GISTs are heterogeneous with regard to IGF1R expression and can be divided into two subgroups. One third of the WT GISTs overlap with kinase-mutant GISTs, while the remainder express IGF1R at more than 30-fold higher levels. These results have implications for evolving models of GIST pathogenesis and the clinical testing of IGF1R monoclonal antibodies for treatment of metastatic GIST. [Table: see text]
Masatinib mesylate in imatinib-naive locally advanced or metastatic gastrointestinal stromal tumor (GIST): Results of the French Sarcoma Group phase II trial
Authors: Le Cesne A. , Blay J. , Bui N. B. , Bouché O. , Adenis A. , Domont J. , Cioffi A. , Moussy A. , Hermine O. 
Published: August 2020

10507 Background: Masitinib mesylate (AB1010, AB Science, Paris, France) is a novel protein tyrosine kinase inhibitor which, in vitro, has greater activity and selectivity than imatinib mesylate against bith wild-type c-Kit receptor and its mutated form in the juxtamembrane region. Masatinib also inhibits PDGFR and FGFR3. This multicenter phase II study evaluated the efficacy and safety of masatinib as a first-line treatment of advanced GIST. Methods: Imatinib-naïve patients with inoperable, locally advanced or metastatic GIST received oral masatinib (7.5 mg/kg/day) until progression, refusal or toxicity. A Simon “minimax two stage” design was used. Efficacy variables included response rate at two months, best response according to RECIST, disease control rate (DCR), metabolic response rate and progression free survival (PFS). Results: 30 patients with a median age of 58 years (60% of males) were included from June 2005 to April 2007 in five French institutions. The most frequent relevant grade 3 toxicities were rash (10%), neutropenia (7%) and abdominal pain (7%). One patient presented a grade 4 skin exfoliation. Three patients discontinued treatment due to suspected toxicity. At two months, the response rate was 20% (6/30 patients) according to RECIST (DCR of 98.7%, 29/30 patients) and 84.6% (11/13 evaluable patients) according to FDG-PET response criteria. After a median follow-up of 23.7 months, there were 6.7% of CR, 43.3% of PR, 46.7% of SD and 3.3% of PD as best response (DCR of 96.7%). Mean time to response was 5.7 months (0.8 to 23.3 months). The median PFS was 27.2 months with PFS rates of 68.8% at 1 year and 60.2% at 2 years. Up to date, all but one patient are alive (one patient died of post-surgical complications, unrelated to treatment). Mutational analyses of the patients’tumors are ongoing. Conclusions: The results observed with masatinib compare favorably with those reported with imatinib in front-line treatment of advanced GIST both in term of safety and efficacy and support the initiation of a phase III randomized clinical trial. [Table: see text]
GEP01: A phase I study of lapatinib (L) and vinorelbine (VNR) in HER2 overexpressing (HER2+) locally advanced or metastatic breast cancer (LAMBC) patients (pts): A FNCLCC Group of early phase trials study
Authors: Brain E. , Dalenc F. , Lokiec F. , Dieras V. , Bonneterre J. , Rezaï K. , Mefti-Lacheraf F. , Roché H. , Jimenez M. , Fumoleau P. 
Published: August 2020

1051 Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN > 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies. [Table: see text]
Osteosarcoma of the jaw/craniofacial bones: Outcomes following multimodality treatment
Authors: Guadagnolo B. , Zagars G. K. , Raymond A. K. , Benjamin R. S. , Sturgis E. M. 
Published: August 2020

10511 Purpose: To evaluate outcomes for patients with osteosarcoma of the jaw/craniofacial bones treated with surgery or combined modality therapy (CMT) consisting of surgery and radiation therapy (RT). Methods: Retrospective analysis was performed on data for 119 patients with osteosarcoma of jaw/craniofacial bones who underwent definitive resection with or without RT between 1960 and 2007. Median age was 33 years (range, 7–77 years). Ninety-two (77%) underwent surgery alone while 27 (23%) were treated with CMT. Median RT dose was 60 Gy (range, 50–66 Gy). Kaplan-Meier method was used to calculate the actuarial curves for survival (OS), disease-specific survival (DSS), local recurrence (LR), distant metastatic relapse (DM), and complication rates; and the log-rank statistic was used to test for significance of differences between curves. Results: Median follow-up was 5.8 years (range, 0.25 to 44.5 years). The OS rates at 5 and 10 years were 63% and 55%, respectively. Corresponding DSS rates were 67% and 61% respectively. Surgical margin status (positive/uncertain vs. negative) was adversely prognostic for OS (p=0.0001) and DSS (0.0001). Stratified analysis by margin status showed that CMT compared to surgery alone improved OS (80% vs. 31%, p=0.02) and DSS (80% vs. 35%, p=0.02) for patients with positive/uncertain margins. Multivariate analysis showed that CMT for patients with positive/uncertain margins improved OS (p<0.0001). Forty-four patients (40%) experience LR and 25 (21%) developed DM. There was no difference in DSS if relapse was isolated LR vs. DM (26% vs. 29%, respectively at 5 years, p=0.48) Local control (LC) rates were 59% and 57% at 5 and 10 years, respectively. The use of CMT vs. surgery alone significantly improved LC for patients with positive/uncertain margins (75% vs. 24%, p=0.006). The rate of surgical complications was 28% at 5 years. Rates of RT-associated complications were 40% and 47% at 5 and 10 years, respectively. Conclusions: RT in addition to surgery improves OS, DSS, and LC for patients with osteosarcoma of the jaw/craniofacial bones who have positive/uncertain surgical margins. Complication rates from surgery and RT are high, but LR is lethal in this disease. Morbidity risks must be weighed against the need to eradicate disease with primary local managmement. No significant financial relationships to disclose.
Improving the detection of osteosarcoma tumor margins and metastasis using diagnostic nanoparticles
Authors: Dutour A. , Decouveleare A. , Josserand V. , Coll J. , Chotel F. , Rousseau R. 
Published: August 2020

10512 Background: The aim of osteosarcoma resection is the complete removal of the primary malignant lesion with adequate margins taking into account tumor control and functional reconstruction. To date, no intraoperative method is available to assist surgeons in precisely delineating tumor extension in the adjacent normal tissues. Thus, preoperative imaging and extended surgical resection remains the gold standard. We developed fluorescent nanoparticles RAFT-cRGD4-ICG’ targeting αVβ3 integrins on tumor neovessels and demonstrated their capacity to reveal tumor and its margins when exposed to near infrared (NIR) light. Methods: We evaluated in an orthotopic metastatic osteosarcoma in rats the potential of RAFT-cRGD4-ICG’ detected intra operatively by NIR illumination to improve margin resection without compromising local tumor control. Controls consisted of pathological margin analysis of the resected tumor/metastasis comparing ICG’ fluorescence with conventional tissue coloration, and pre operative magnetic resonance imaging. Results: We showed a significantly lesser extent of healthy tissue resection after surgical excision when assessing tumor margin intra operatively using RAFT-cRGD4-ICG’ and NIR camera compared to preoperative imaging studies and post operative conventional pathology coloration (p<0.01). Importantly, intraoperative NIR illumination of lungs revealed more metastases than by intraoperative manual lung palpation (p<0.01). Conclusions: Our preclinical data confirm the potential of intraoperative imaging for improved primary tumor and lung metastasis excision. We are now generating clinical-grade RAFT-cRGD4-ICG’ to further evaluate this approach as a mean to improve functional outcome after surgical excision while maintaining tumor control in patients with relapsed/metastatic osteosarcoma. No significant financial relationships to disclose.
Long-term follow-up (>20 years) for one of the original randomized prospective trials evaluating adjuvant chemotherapy in patients with high-grade operable osteosarcoma
Authors: Tap W. D. , Eilber F. R. , Rosen G. , Eckardt J. , Schwartz A. , Federman N. , Eilber F. C. 
Published: August 2020

10514 Background: Neoadjuvant and adjuvant chemotherapy is now standard practice for patients who present with localized osteosarcoma. We present the long-term follow-up (>20years) for one of the original prospective randomized trials that compared adjuvant chemotherapy to no treatment in patients with high-grade operable osteosarcoma. Methods: The original study was performed at UCLA from 1981 to 1984. During this time, 59 patients with high-grade, operable, non-metastatic osteosarcoma were randomized to receive adjuvant chemotherapy (MSKCC T-10B protocol)(N=32; 24 men, 8 women, median age 15 yrs) vs. expectant management (N=27; 20 men, 7 women, median age 18 yrs). All patients received one neoadjuvant course of intra-arterial doxorubicin hydrochloride (90mg) and radiation (1750cGy). At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free (55% vs. 20%, p<.01) and overall survival (80% vs. 48%, p<.01) for those who received immediate adjuvant chemotherapy. Upon recurrence, patients in the T-10B arm received salvage chemotherapy with doxorubicin hydrochloride and cisplatin while those in the expectant arm received the T-10B protocol. 27 years after the initiation of the trial, long-term follow-up was obtained on all patients. Results: Median follow-up time for survivors was 24 years. 18 patients in the adjuvant chemotherapy arm died of disease (DOD) while 14 have no evidence of disease (NED). 22 patients in the control arm DOD, 1 died of other causes and 4 have NED. The 5, 10, and 20 year disease specific survival (DSS) for the treatment arm (47%, 43%, 43% respectfully) was significantly better than that of the control arm (30%, 26%, 17% respectfully) (p=0.0254). Conclusions: Early administration of chemotherapy in patients with high-grade operable osteosarcoma provides a significant survival benefit that is maintained with long-term (>20 years) follow-up. These results support the idea that early systemic treatment offers the best opportunity to cure patients with this high-risk malignancy. No significant financial relationships to disclose.
A European treatment protocol for bone sarcoma in patients older than 40 years
Authors: Ferrari S. , Smeland S. , Bielack S. , Comandone A. , Dileo P. , Picci P. , Sundby Hall K. , Eriksson M. , Honegger H. , Reichardt P. 
Published: August 2020

10516 Background: EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) is the first prospective multicenter international study for patients 41 - 65 years old with high-grade bone sarcoma. Methods: Patients with HG Osteosarcoma (OS), HG sarcoma NOS (S), Fibrosarcoma, MFH, Leiomyosarcoma, Dedifferentiated Chondrosarcoma (DCh) were included. Chemotherapy: Combinations of cisplatin/doxorubicin (CDP 100mg/m2/ADM 60mg/m2), ifosfamide/CDP(IFO 6g/m2/CDP 100mg/m2) and IFO/ADM (IFO 6g/m2/ADM 60mg/m2) were repeated three times (9 cycles). Surgery was planned after 3 cycles. Methotrexate (8g/m2) was postoperatively added in poor responders. Immediate surgery was allowed and 9 cycles with CDP, ADM, IFO were postoperatively given. Results: In December 2007, 140 patients were registered (median age 51 years). OS (51%), S (16%), and DCh (11%) were the more frequent histotypes. Synchronous metastases in 30 (21%) patients, central location of tumor in 45 (32%). Surgical complete remission (SCR) was achieved in 84% of patients, (localized 91%, metastatic 37%) without difference among the histology groups. One surgical-related and one chemotherapy-related death were reported. Grade 4 WBC and PLT incidence was 55% and 17%.Renal toxicity and peripheral neurotoxicity were reported in 16% and 20% of patients. With a median follow-up of 25 months (4–68) 3 year OS was 58% (95%CI 48–68%) [7% (95%CI 0–19%) without SCR]. In patients with SCR, 3 year OS and EFS were 46% (95%CI 9–83%) and 0% in case of synchronous metastases and 69% (95%CI58–80%) and 45% (95%CI33–57%) for localized patients; 50% (95%CI 29–71%) and 40% (95%CI 20–59%) for patients with central tumor, 73% (95%CI61–85%) and 44% (95%CI31–57%) for those with extremity tumor; 68% (95%CI 52–83%) and 46% (95%CI 32–54%) for OS, 64% (95%CI 42–85%) and 48% (95%CI 25–71%) for S, 48% (95%CI 13–82%) and 27% (95%CI 1–54%) for DCh. Conclusions: The protocol is feasible, but the chemotherapy-related toxicity is remarkable. Surgical complete remission is the main factor influencing survival. Central location and synchronous metastases are negative prognostic factors, but 50% 3-year OS can be achieved with aggressive local and systemic treatment. Osteosarcoma and high-grade sarcoma NOS benefit from chemotherapy more than patients with dedifferentiated chondrosarcoma. No significant financial relationships to disclose.
Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma
Authors: Gardner K. , Judson I. , Leahy M. , Barquin E. , Marotti M. , Collins B. , Young H. , Scurr M. 
Published: August 2020

10523 Background: Alveolar soft part sarcoma (ASPS) is a rare entity making up <1% of soft tissue sarcomas (STS). It is typically indolent but with a high incidence of metastatic disease, usually to lungs, but also to sites such as the brain. Response to conventional chemotherapy is poor (overall response rates are approximately 7% [Reichardt P et al,Eur J Cancer.2003;39:1511–1516]). This is a preliminary report of the activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in this disease. Methods: Efficacy and tolerability data were collected for seven patients with ASPS. One patient was treated in a phase II randomized trial of cediranib ± prophylactic antihypertensive therapy and six were treated in a Phase II study in patients with imatinib-refractory gastrointestinal stromal tumors or other STS. Cediranib was administered orally, once daily at an initial dose of 45 mg. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors). Results: Median age at diagnosis was 39 years (range: 26–49). All patients had pulmonary metastases and two had additional sites of disease (brain, bone, intra-abdominal) at study entry. Adverse events were generally CTC grade 1–2 and manageable. The most common adverse events were fatigue (n = 6), diarrhea (n = 5), stomatitis (n = 4), headache (n = 3), and hypertension (n = 3). Four patients had a best response of partial response, two patients had a confirmed reduction in maximum tumor diameter of ≥10% and <30% and one patient experienced stable disease. As of November 2008, three patients remain on treatment with a median (range) time on study of 61 weeks (49–74). Time to progression and progression-free survival will be calculated and available at the time of presentation. Conclusions: These data demonstrate the promising preliminary activity and safety of chronic administration of cediranib in this disease. Further investigation is warranted, particularly as there is no effective systemic treatment for patients with advanced ASPS. [Table: see text]
A phase II study of intravenous (IV) wild-type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung
Authors: Mita A. C. , Sankhala K. , Sarantopoulos J. , Carmona J. , Okuno S. , Goel S. , Chugh R. , Coffey M. C. , Mettinger K. , Mita M. M. 
Published: August 2020

10524 Background: Reolysin is a Dearing strain, naturally occurring, ubiquitous human reovirus. The PKR (double stranded RNA-activated protein kinase) is inhibited and therefore the virus replicates specifically in transformed cells possessing an activated Ras pathway producing lysis. In vitro and in vivo studies with Reolysin in sarcoma cell lines revealed significant antitumor activity. Methods: This phase II open-label, single agent study was designed to characterize the efficacy and safety of Reolysin given IV every 28 days in patients (pts) with bone or soft tissue sarcoma with lung metastasis using a Simon two-stage design. 38 pts were accrued to the first stage. If 1 or more pts experience clinical benefit (prolonged SD > 6 months, partial or complete response) up to 52 pts could be accrued. The agent will be considered active if 3 or more responses or prolonged SD are observed. Results: Since July 2007, 43 pts age 19–76 (median 49) were enrolled (20 female) and received a total of 141 cycles (range 1–18). All pts had performance status 1 (29 pts) or 0 (14 pts). 38 pts received prior chemotherapy, radiotherapy, biological agents or combinations for their metastatic disease, 15 pts received more than 3 chemotherapy regimens. The sarcoma subtypes included: synovial sarcoma (13 pts), osteosarcoma (7 pts), leiomyosarcoma (7 pts), MFH (5 pts), Ewing/PNET (1 pt), chordoma (1 pt), others (9 pts). Side effects were mild to moderate (grade 1–2) and included constitutional symptoms fever, chills, fatigue. Two pts experienced respiratory side effects (cough and dyspnea) and 2 pts had diarrhea. Hematological side effects included grade 2–3 neutropenia (6 pts) and grade 2 thrombocytopenia (2 pts). One patient experienced grade 2 AST elevation. 33 pts are evaluable for response to date: 14 pts (42%) had SD for 2+ months including 5 pts having SD for more than 6 months. Conclusions: Utilization of single agent reovirus for treatment of sarcoma is a novel and unique therapeutic approach to date. Reolysin is well tolerated and shows promise for the treatment of metastatic sarcoma. Primary efficacy goals have been met. Accrual is ongoing to a total of 52 pts. [Table: see text]