bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imatinib for the treatment of aggressive fibromatosis (desmoid tumors) failing local treatment. A phase II trial of the French Sarcoma Group
Authors: Penel N. , Le Cesne A. , Bui B. , Tubiana-Hulin M. , Guillemet C. , Cupissol D. , Berthaud P. , Mahier C. , Pérol D. , Blay J. 
Published: March 2020

9516 Background: Background: Aggressive fibromatosis/desmoid tumors (AF/DT) are rare tumors with loco regional spreading. Few options are available when local treatments have failed. Although cytotoxic agents, hormonal treatment have been reported to induced responses and tumor control in some patients, only few prospective phase II trials have been reported in the literature. Recently, antitumor activity of imatinib in AF/DT was reported. We report a phase II trial of imatinib in AF/DT after failure of local treatment options. Methods: Pts ≥ 18 years with advanced AF/DT from all sites in whom neither surgery nor radiotherapy was possible were eligible. The principal inclusion criterias were: disease not amenable to surgery and/or radiation with curative intent, systemic pre-treatments allowed and presence of a measurable lesion with evidence of progression. Imatinib was given at the dose of 400 mg/d and increased to 800 mg/d if progression. Primary endpoint was the rate of progression free at 3 months. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, α=0.05 and 90% power. 18 pts were scheduled to be recruited in the first stage for a total of 35 evaluable pts. Results: Between 09/2004 and 10/2005, 40 pts were included in 15 centers. The median age was 40 years (range 20–72) with 26% males. Primary sites were extra abdominal, mesenteric, abdominal wall in 79, 15, and 6% respectively. 15% patients had not been operated previously and 17% undergone radiotherapy. Prior systemic treatments were: NSAID, hormonal therapy or chemotherapy in 34, 46 and 23%, respectively. Median treatment duration was 4 months (range 0–12). No G4 toxicity was reported. Toxicities (G1–3) were notified for 30 pts including asthenias (70%), nauseas (53%), diarrheas, oedema (40%). G3 toxicities were abdominal pain (10%), rash, nausea, vomiting and asthenia (7%). At 3 months, 22 pts (55%) were evaluable with 1 CR, 17 SD and 4PD. As of December 2005, 7 of the 40 pts had progressed. After progression, dose was stopped in 2 pts and increased to 800mg in 5 pts with 2 tumor control following dose-escalation. Conclusions: Imatinib induces prolonged disease stabilization in the majority of evaluable patients with AF/DT in whom no local treatment option was available. [Table: see text]
A multicentric prospective study of intensive induction chemotherapy (API-AI) in localized osteosarcoma patients: Results of a phase II trial coordinated by the French Sarcoma Group (FSG) and the FNCLCC BECT
Authors: Piperno-Neumann S. , Bui B. , Blay J. , Roché H. , Pichon F. , Peny A. , Duclos B. , Jimenez M. , Perol D. , Le Cesne A. 
Published: March 2020

9521 Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders <95% necrosis (PR) a salvage regimen of 3 cycles of etoposide 100 mg/m2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival. No significant financial relationships to disclose.
DNA repair functionality modulates the clinical outcome of patients with advanced sarcoma treated with trabectedin (ET-743)
Authors: Schöffski P. , Casali P. G. , Taron M. , Van Oosterom A. T. , Judson I. R. , Grosso F. , Blay J. Y. , Maki R. G. , Tercero J. C. , Jimeno J. M. , Rosell R. 
Published: March 2020

9522 Background and Methods: The sensitivity to trabectedin (Yondelis, ET-743) in experimental cancer models correlates with functional transcription-coupled nucleotide excision repair (TC-NER) and with deficient homologous recombination repair (HRR) activity. In order to assess the clinical relevance of this observation we have characterized the mRNA expression levels of ERCC1, XPD, BRCA1 and BRCA2 by RT-PCR in historical tumor samples from 92 sarcoma patients (pts) treated with the agent. Results: The overall objective response (CR+PR) rate to Yondelis in this group was 9%, which confirms the previous clinical experience with the compound in unselected, pre-treated patients with sarcoma. The Kaplan-Meier estimates for progression-free survival at 6 months (PFS6) was 23% and for median survival 8 months (mo). 26% of pts were alive at 24 mo. Correlative Study: Pts with high expression levels (> median) of ERCC1 had better PFS6 (32% vs 15%, p = 0.07) and better median survival (12 vs 7 mo) as compared to pts with low expression ( ≤ to median). Pts with low expression levels of BRCA1 had better PFS6 (33 vs 11%, p = 0.02) and superior median survival (15 vs 5 mo, p = 0.0003) than pts with high expression. Expression levels of XPD and BRCA2 (58 pts) had no significant impact on PFS and survival. The analysis of co-expression of ERCC1-BRCA1 identified a highly sensitive group of pts, characterized by high ERCC1 and low BRCA1 expression levels, with a PFS6 of 50% (p=0.0003) and median survival of 20.4 mo (p = 0.0005). A Cox regression analysis demonstrated that ERCC1 (HR=0.52, p = 0.02) and BRCA1 (HR=2.73, p = 0.0006) are independent variables for PFS, while BRCA1 (HR= 2.57, p = 0.0005) is also an independent variable for survival. Conclusion: This exploratory retrospective study supports the hypothesis that the sensitivity to Yondelis in pts with sarcoma correlates with a functional TC-NER and with deficient HRR. Prospective studies in sarcoma and other potentially sensitive tumor types are required to confirm and validate these findings. [Table: see text]
Pharmacodynamic case study of sunitinib/SU11248 in a gastrointestinal stromal tumor patient: Evidence toward a mechanism of effect
Authors: Seandel M. , Shia J. , Linkov I. , Maki R. G. , Antonescu C. , Dupont J. 
Published: March 2020

9526 Background: Despite abundant pre-clinical data, the mechanisms of action in humans of multi-targeted small molecule tyrosine kinase inhibitors against sarcomas remain unclear. Herein, we sought evidence from pre- and post-treatment biospies to suggest whether the primary mechanism of action of sunitinib/SU11248 is anti-angiogenic or rather a direct anti-tumor cell effect. Methods: We report data regarding a 59 year old woman with imatinib-resistant GIST who demonstrated a marked tumor response to sunitinib treatment. Her gastric primary GIST tumor was previously resected, followed by recurrence one year later. A complete remission lasting 24 months was then attained on imatinib therapy. After progression of disease, sunitinib was started at 50 mg orally per day. A major clinico-radiographic response was seen after 12 months of therapy, followed by resection. To assess the pharmacodynamic effects of sunitinib, we undertook immunohistochemical analysis of formalin-fixed tissue sampled immediately prior to treatment and just after completing sunitinib, using anti-CD117, anti-CD34, or anti-CD31 antibodies, respectively. Results: We found a dramatic effect of sunitinib on the tumor parenchyma. Whereas the pretreatment biopsy revealed viable, mitotically active, CD117+ and CD34+ tumor cells, the post-treatment specimen was >90% sclerotic and necrotic. The CD31+ blood vessels appeared robust both pre- and post-treatment. Vessel counts did not differ significantly before and after treatment by CD31 staining (3.3±2.0 per field vs. 1.8±1.3, p= 0.09). Thus, the tumor cells were largely eliminated with sunitinib treatment, while blood vessels were still present after 12 months of therapy. Conclusions: This observation supports the assertion that the mechanism of sunitinib in GIST is predominantly cytotoxic against the tumor by directly targeting KIT and that an anti-angiogenic effect, either through the VEGF-R2 in endothelium or through the PDGF-R in pericytes, may be secondary. [Table: see text]
Percutaneous tissue debulking and cement augmentation for advanced malignant vertebral compression fractures
Authors: Georgy B. , Wong W. 
Published: March 2020

9535 Background: Percutaneous cement injection procedures (eg vertebroplasty, kyphoplasty) are used successfully to palliate patients with painful osteoporotic vertebral compression fractures (VCFs). When VCFs occur because of malignant lesions however, treatment can be challenging; often by the time symptoms occur, the tumor has extended into the epidural tissue and is associated with posterior cortical disruption. As a result, patients have a higher likelihood of cement extravasation outside the vertebral body, thought to be associated with increased complication risk. This study was to investigate clinical viability and effectiveness of a technique designed to improve control of bone cement placement over standard methods when treating patients with symptomatic VCFs caused by malignancy. Methods: All patients had intractable pain determined to be associated with VCFs caused by metastasized malignancy. The procedure involved using a plasma-mediated radiofrequency-based device to debulk tissue and etch a void within the affected vertebral body and then filling the void and adjacent interstices with bone cement to stabilize the vertebral body and relieve pain. Results: 28 patients (36 vertebral bodies) with various types of metastatic lesions were treated. No evidence of cement extravasation outside the vertebral boundary was detected in 34/36 (94%) cases, even in cases with severe posterior cortical compromise and prominent epidural involvement pre-operatively. In the 2 observed cases, cement extravasation was clinically inconsequential. All treated patients reported marked pain relief. No patients were prevented from continuing other oncologic treatments. Conclusions: Tissue removal to create a void before injecting bone cement into a vertebral body compromised by malignancy may reduce the complication rate observed when injecting cement. This technique may redirect cement away from the spinal canal, notably in cases with posterior cortical defect and epidural extension, while also improving interdigitation of cement and decreasing risk of metastatic embolization. The resulting palliation potentially improves functionality and quality of life during and does not appear to affect the effectiveness of continued oncologic treatment. [Table: see text]
Pattern of progression and its impact on outcome in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: A retrospective multicenter long-term follow-up study
Authors: Hartmann J. T. , Heidel F. , Stoehlmacher J. , Duex M. , Izbicki J. R. , Elsaid A. , Wardelmann E. , Fischer T. , Jaeger E. , Al-Batran S. 
Published: March 2020

9541 Background: To investigate the clinical impact of the different types of disease progression (focal v extensive) in patients (pts) with metastatic gastrointestinal stromal tumors (GIST) after initial response to imatinib. Methods: Pts who received imatinib for metastatic GIST at three Cancer Centers and who have been followed up for at least 2.5 years were eligible for the study. Disease progression was classified as focal or extensive as defined by protocol. Responses were evaluated according to WHO criteria. Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier-method. In three pts with focal progressions, serial biopsies were obtained for mutation analysis. Results: Thirty-eight patients (21 men; mean age 58.4 years; range, 37–73 years) were included in the analysis. After a median follow-up of 31.8 mos, 25 of 38 (65.8%) patients had progressed. Nine of 25 progressions were classified as focal and 16 as extensive. Salvage therapies included dose escalation of imatinib with or without surgical resection. Median and 6- and 12-mos PFS were 11.3 mos, 89%, and 40% in pts with focal progression, and 2.5 mos, 39%, and 32%, in patients with extensive progression, respectively. The median OS was 22.8 mos in pts with extensive progression, and was not reached in pts with focal progression. Two subsequent focal progressions in one pt were associated with 2 different secondary KIT-mutations, whereas non-progressive disease harbored the original KIT-mutation alone. Conclusions: Imatinib resistance seems to be partial in a subset of progressing GIST pts. These pts may benefit from local treatment and imatinib continuation and further investigation of imatinib combinations with other compounds appears warranted. Extensive progression is associated with a dismal survival. No significant financial relationships to disclose.
A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)
Authors: Reichardt P. , Casali P. G. , Blay J. , Von Mehren M. , Schoffski P. , Hosseinzadeh S. , Tanaka C. , Gsponer T. , Veronese M. L. , Demetri G. D. 
Published: March 2020

9545 Background: Although imatinib induces durable clinical benefit in pts with metastatic GIST, resistance may emerge. AMN107 is a novel agent rationally designed to inhibit the PDGFR, KIT and Bcr-Abl tyrosine kinases. It has been shown to inhibit the proliferation of both imatinib-sensitive and imatinib-resistant GIST cells in vitro. Methods: Cohorts of imatinib-resistant GIST pts with radiological progressive disease (PD) were treated with AMN107 alone (400 mg p.o. bid) or with escalating doses of AMN107 (200 mg qd, 400 mg qd, or 400 mg bid) in combination with imatinib (400 mg p.o. bid). Pharmacokinetic (PK) analyses were performed for both AMN107 and imatinib. Serial tumor assessments included CT and 18FDG-PET scans. Results: As of 30 November 2005, 30 pts (13 women and 17 men), median age 51 yr (range 24–83) received AMN107 alone (n=18) or in combination up to 400 mg qd with imatinib (n=12) for 7 to 98 days (median 49 days). This study continues to accrue. Serious adverse events (SAE’s) reported in four patients deemed related to disease included abdominal pain, peritonitis and anemia. Grade 1/2 drug-related adverse events included hyperbilirubinemia, myalgias, peripheral edema and skin rash. Dose-limiting toxicity (Grade 3 elevated bilirubin) was reported in one pt on AMN107 alone. Efficacy data available for 18 patients show that three patients experienced progressive disease and 15 patients had stable disease, although the duration of follow-up was short. PK results in a limited number of patients showed that the effect of imatinib co-administration on AMN107 PK appears to be minimal, while AMN107 increases imatinib exposure on the average by 50%. Conclusions: AMN107 alone or in combination with imatinib has acceptable tolerability in patients with imatinib-resistant GIST. These initial data suggest there may be relevant activity of AMN107 alone and in combination with imatinib in imatinib-resistant metastatic GIST patients. [Table: see text]
Real-time reverse transcription-polymerase chain reaction for detection of SYT-SSX translocation in synovial sarcoma
Authors: Liu J. , Qu K. , Chai C. , Li H. , Sferruzza A. , Bender R. A. 
Published: March 2020

9553 Background: Synovial sarcoma is the most common non-rhabdomyosarcomatous soft tissue sarcoma in children and adolescents. A specific translocation, t(X;18), induces fusion of the SYT gene on chromosome 18 to an SSX gene on chromosome X. The resulting fusion gene consists of at least 2 subtypes with different breakpoints: SYT-SSX1(X;18)(p11.23;q11.2) and SYT-SSX2 (X;18)(p11.21;q11.2). Because t(X;18) transcripts occur in >90% of synovial sarcoma subtypes, this marker may be useful for diagnosis. We evaluated the accuracy of a multiplex real-time reverse transcription-polymerase chain reaction (RT-PCR) assay for detection of the primary SYT-SSX fusion transcript types in formalin-fixed, paraffin-embedded (FFPE) tissues and frozen tissues. Methods: 17 tumors (7 synovial sarcomas, 4 Ewing’s sarcomas, 5 rhabdomyosarcomas, 1 small round blue-cell tumor), 4 normal tissues, and 4 control samples were tested for SYT-SSX translocations using real-time RT-PCR. Results were compared to those obtained with gel electrophoresis detection of amplified transcripts; discrepant results were confirmed by sequencing. Results: Concordance between real time RT-PCR and gel electrophoresis was 100% (25/25) for internal control genes and SYT-SSX1, and 92% (23/25) for SYT-SSX2. Of the 2 samples with discordant SYT-SSX2 results, 1 was positive by real-time RT-PCR but not gel electrophoresis and 1 was positive by electrophoresis but not real-time RT-PCR; in both cases, DNA sequencing confirmed the real-time RT-PCR results. The minimum percentage of tumor to normal cells required for detection of SYT-SSX fusion transcripts by real-time RT-PCR was 6.25%. Conclusions: This real-time RT-PCR assay appears to provide greater accuracy than gel electrophoresis for identification of SYT-SSX translocation and fusion types. No significant financial relationships to disclose.
The HIV protease inhibitor ritonavir and the proteasome inhibitor bortezomib induce synergistic cytotoxicity on soft tissue sarcoma cells in vitro
Authors: Driessen C. , Kraus M. , Müller H. , Gogel J. , Kanz L. , Simon-Klingenstein K. , Koscielniak E. , Hartmann J. T. 
Published: March 2020

9566 Background: HIV-protease inhibitors like Ritonavir produces regressions in HIV-associated Kaposi‘s sarcoma, reportedly due to proteasome inhibition. We have here assessed the effect of Ritonavir and the proteasome inhibitor Bortezomib on the viability and proteasome activity of the soft tissue sarcoma cell lines RD (rhabdomyosarcoma) and A-673 (ewing‘s sarcoma) in vitro. Methods: Cytotoxixity was assessed by MTS-test. To directly dissect proteasome activity in viable sarcoma cells, we used a recently developed cell-permeable affinity label that for the first time allows to assess the individual activity profile of the different catalytically active proteasomal subunits in living cells (Berkers et al., Nature Methods, May 2005). Results: Both types of cells were resistant towards Bortezomib and Ritonavir monotherapy at therapeutic concentrations (20 nM for Bortezomib, 20μM for Ritonavir). Ritonavir induced cytotoxicity in sarcoma cell lines with an IC50 of 40μM. The combination of clinically meaningful concentrations of Ritonavir (20μM) with Bortezomib (10–20 nM) induced robust synergistic cytotoxicity in both sarcoma cell lines. Using affinity labelling of proteasome activity, we directly demonstrate that a) Botezomib abrogates beta5, but also beta1-proteosomal activity in sarcoma cells and b) that Ritonavir at 20μM does not affect proteasom activity. Conclusions: We here present the first analysis of active proteasomal subunits in living human sarcoma cell lines. Ritonavir and Velcade induce synergistic cytotoxicity at clinically meaningful concentrations in vitro, which is not mediated through a direct effect of Ritonavir on proteasome activity. Based on our data, the synergistic combination of Ritonavir and Bortezomib might warrant further clinical testing in soft tissue sarcoma in vivo. No significant financial relationships to disclose.
Semi-physiological pharmacokinetic/pharmacodynamic (PKPD) model for trabectedin-induced neutropenia
Authors: Hing J. , Perez Ruixo J. , Stuyckens K. , Zannikos P. , Soto-Matos A. , Lopez-Lazaro L. , Izquierdo M. A. , Pico C. , Yver A. , Chow A. 
Published: March 2020

9575 Background: Neutropenia was the trabectedin (T) dose limiting toxicity in phase I studies. The objective of the present study was to develop a semi-physiological PKPD model that describes the time course of the absolute neutrophil counts (ANC) in cancer subjects receiving trabectedin. Methods: A total of 704 subjects receiving intravenous T as monotherapy (dose range: 0.024 - 1.8 mg/m2) as a 1, 3 or 24 hr infusion every 21 days; 1 or 3 hr infusion on day 1, 8, 15 every 28 days; or a 1 hr infusion daily for 5 consecutive days every 21 days were used to develop (N=405, ANC=7253) and validate (N=299, ANC=4977) the model. The model comprised of a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC0), mean transit time in bone marrow (MTT), and a feedback parameter. T concentrations at the effect compartment were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to a sigmoid-EMax function. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency. Results: The mean (between subject variability, %) of the ANC0, MTT, T potency were estimated to be 4.4 × 109/L (39%), 3.99 days (40%), and 15.6 μg/L (58%), respectively. The feedback parameter, EMax and Hill coefficient were estimated to be 0.198, 154 and 1.48. Model validation procedure evidenced accurate prediction of the incidence of grade 3/4 neutropenia. Simulations indicated that T dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model predicted time course of the ANC confirmed that neutropenia is reversible, short-lasting, and non-cumulative. Conclusions: The extent and time course of neutropenia following five different dosing regimens of T were well predicted by the semi-physiological PKPD model. [Table: see text]