bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of systemic treatment after whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases: Differences depending on biological subtype
Authors: Niwinska A. , Murawska M. , Lemanska I. , Milewska J. 
Published: August 2020

1027 Background: The aim of the study was to analyze the efficacy of systemic treatment (chemotherapy [chth], endocrine therapy, targeted therapy) performed after WBRT in patients (pts) with breast cancer and brain metastases. Methods: The group of 222 consecutive breast cancer pts with brain metastases treated in one institution in the years 2003–2006 was divided into four biological subgroups based on ER, PR, and HER-2 receptors’ expression: HER-2(+++)ER/PR(-); HER-2(+++)ER/PR(+); ER(-)PR(-)HER-2(-); and ER/PR(+)HER-2(-). WBRT was performed in 219 (99%) pts. Systemic therapy after WBRT was continued in 160 (72%) pts. Clinically, patients with triple-negative breast cancer were more often in poor performance status (KPS<60%) than the others (51% vs. 28%, respectively). Survivals from brain metastases without and with systemic treatment were compared in four mentioned biological subgroups. Results: Median survival from brain metastases in the entire group was 7.5 months. In the group of ER/PR(+)HER-2(-) median survival without and with systemic therapy was 3 and 14 months, respectively (p = 0.007). In the group of HER-2(+++)ER/PR(+) median survival without further treatment, after chth and after chth with trastuzumab was 2, 8, and 13 months, respectively (p = 0.000) and in the group of HER-2(+++)ER/PR(-) median survival without further treatment, after chth and after chth with trastuzumab was 4, 8, and 10 months, respectively (p = 0.004). In triple-negative breast cancer patients median survival without and with chemotherapy was 3 and 4 months, respectively (p = 0.75). Conclusions: Systemic treatment (chth, endocrine therapy, targeted therapy) continued after WBRT in breast cancer pts with brain metastases prolongs survival in three of four biological subgroups. In the group of HER-2-positive breast cancer pts, trastuzumab added to chth had independent positive impact on survival. No benefit was observed in the subgroup of triple-negative breast cancer pts; it would be the result of refractory disease and the fact, that more pts were in poor performance status. No significant financial relationships to disclose.
Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors
Authors: Goldberg J. , Demetri G. D. , Choy E. , Rosen L. , Pappo A. , Dubois S. , Geller J. , Chai F. , Ferrari D. , Wagner A. J. 
Published: August 2020

10502 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. The drug has demonstrated a favorable safety profile and preliminary anti-cancer activity in three phase 1 studies. MiT tumors include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), and translocation-associated renal cell carcinoma (TLA RCC) and are linked biologically by a shared activated transcriptional mechanism which directly upregulates c-Met. Tumors with this type of chromosomal abnormality are generally resistant to all approved therapies and, in the absence of complete surgical resection, prove invariably fatal. Methods: This is a multi-center, single arm, two-stage phase 2 trial in patients (pts) 13 years of age or older with MiT tumors. Initially pts received 120 mg ARQ 197 orally twice daily (bid). The protocol was amended in August 2008 to increase the dose to 360 mg bid. If either a complete response (CR) or a partial response (PR) were to be observed in the 23 pts in stage 1, the study would be advanced to stage 2 where 16 additional patients will be enrolled. Tumor responses are measured in 8-week intervals per RECIST criteria. Results: To date, 28 pts (19 females, 9 males; median age = 21; 7 CCS, 17 ASPS, 4 RCC) have been treated. One pt with CCS demonstrated a confirmed PR, 15 pts (10 ASPS, 2 CCS, 3 RCC) demonstrated stable disease (SD) for durations up to 29+ weeks, and 4 pts progressed. An overall response rate of 5% and a disease control rate (CR+PR+SD) of 80% were demonstrated among 20 pts who were evaluable for efficacy. The most common drug-related adverse events (AEs) have been fatigue (35.7%), nausea (35.7%), vomiting (21.4%), decreased hemoglobin (10.7%). and cough (10.7%). To date, only 3 drug-related Grade 3 or 4 AEs have been reported including anemia (2) and decreased neutrophil count (1). No drug-related serious AEs or deaths have been reported. Conclusions: To date, ARQ 197 has demonstrated an extremely favorable safety profile and preliminary evidence of anti-cancer activity in these young pts. The criterion for advancing the study from stage 1 to stage 2 has been met. Stage 2 enrollment is ongoing. Updated data on both dose levels will be presented. [Table: see text]
Time to secondary resistance (TSR) after interruption of imatinib: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival
Authors: Duffaud F. , Ray-Coquard I. , Bui B. , Adenis A. , Rios M. , Bertucci F. , Chabaud S. , Perol D. , Blay J. , LeCesne A. 
Published: August 2020

10508 Background: We previously demonstrated that imatinib mesylate (IM, Gleevec/Glivec; Novartis Pharma) must not be interrupted after 1 and 3 years (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance. The impact of IM re-introduction at progression remains unknown regarding the impact of the interruption on the TSR. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 1, 3, and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM. Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of December 2008, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomized in the I and C arm. Pt characteristics were well balanced between the two arms. The median time to progression (TTP) were 7.3 months (m) (rate of relapse: 91% of pts) and 9.4 m (rate of relapse: 84%) in the I arms after 1 and 3 years of treatment. In contrast the median TTP were 31.4 m and not reached in the C arms after 1 and 3 yrs of IM treatment respectively. IM reintroduction in the I arm after a re-progression allowed again a tumor control in 93% (43/46) of pts. The median follow-up from randomization is 56 m and 25 m at 1 and 3 yrs respectively. TSR after randomization to IM (first progression in the C arm, 2nd progression in the I arm) was not significantly different between the two arms (the 2-yrs TSR is similar in both arms 63% and 62% in the I and C arm respectively for the 1-yr randomization, 83.5% and 84.3% for the 3-yr randomization) but the rate of secondary resistance decrease over time in both arms: 40% or relapse in the 2 yrs following the 1 yr randomization vs less than 20% or relapse in the 2 yrs following the 3-yrs randomization. Conclusions: The majority of responding pts relapsed when IM was stopped after 1 and 3 yrs of treatment but response is reinduced in 93% of patients after IM reintroduction. TSR was not significantly affected by treatment interruption in this series of pts. [Table: see text]
Chordoma of the mobile spine: A retrospective analysis on 146 patients from two reference centers
Authors: Stacchiotti S. , Lo Vullo S. , Mercuri M. , Mariani L. , Alberghini M. , Pilotti S. , Ferrari S. , Casali P. G. , Gronchi A. , Picci P. 
Published: August 2020

10517 Background: The natural history of chordoma is still poorly known. Methods: We reviewed a large series of patients (pts) from two major reference centers for chordoma. All pts presenting at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, over 25 years, were reviewed. Clinical and pathologic characteristics were recorded. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out. PDGFR and brachyury expression analysis is ongoing. Results: One hundred forty-six consecutive pts were identified (sacrum 79%, lumbar spine 15%, cervical-dorsal spine 6%; extension at diagnosis: localized 90%, locally-advanced 5%, metastatic 5%; median size 10 cm, IQ range: 6–14). Median follow-up was 140 months (IQ range: 80–205). The 5/10-year OS, local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) were respectively: 76/52%, 51/32%, 86/72%. For pts with primary disease, size independently predicted OS (p-value: 0.004), LRFS (p-value: 0.006) and DRFS (p-value: 0.02), while surgical margins independently predicted only LRFS (p-value: 0.0001) with a trend for OS (p-value 0.1007). Radiotherapy performed in 44 pts did not influence LRFS nor OS, but only 9 pts received >60 Gy. The 5/10-year OS, LRFS, DRFS after the first local relapse were 54/24%, 50/45%, 64/61%. Size of the recurrence and quality of surgical margins did not influence post-relapse OS. The 5/10-year OS after the second local relapse were 20/0%. The overall incidence of metastases was 32% (commonest site: lung). The 5/10-year post-metastases OS was 35/0% (median 3 years). Results on PDGFR and brachyury expression will be provided. Conclusions: Tumor size and surgical margins affected outcome only on initial presentation. Incidence of distant metastases was higher than expected, although with a more indolent course than generally supposed. In spite of its indolent behavior, long-term prognosis was poor, with 26% of pts being continuously disease-free at 10 years. This series may provide an external control for studies on novel targeted agents, which are proving effective in such a rare tumor. No significant financial relationships to disclose.
Correlation of gastrointestinal stromal tumor (GIST) gene expression signatures and response to imatinib mesylate in the Radiation Therapy Oncology Group phase II clinical trial S-0132
Authors: Rink L. , Skorobogatko Y. , Kossenkov A. , Belinsky M. G. , Pajak T. F. , von Mehren M. , Ochs M. F. , Eisenberg B. , Godwin A. K. 
Published: August 2020

10533 Background: Despite the known efficacy of imatinib mesylate (IM) in metastatic GIST, both primary and secondary drug resistance remain a clinical problem. Therefore, future management of GIST may benefit from further molecular characterization associated with IM treatment. Methods: A recently completed prospective phase II trial of neoadjuvant/adjuvant IM treatment for advanced primary and recurrent operable GISTs included gene expression profiling using oligonucleotide microarrays on tumor samples obtained before and after neoadjuvant IM therapy for 8 to 12 weeks. Fifty-two analyzable patients were classified according to changes in tumor size after IM based on CT scan measurements. A response was defined as >25% tumor reduction. Gene profiling data were then evaluated with SAM analysis (FDR = 10%) to identify differentially expressed genes (in pre-treatment GIST samples). In addition, a custom siRNA library was designed targeting these genes and a mid-throughput siRNA synthetic lethal screening approach was used to evaluate the ability of each to sensitize GIST cells to IM. Results: Thirty-eight genes were expressed at significantly lower levels in the pre-treatment samples of tumors that rapidly responded to IM. Eighteen of these genes encoded KRAB domain containing zinc finger (KRAB-ZNF) transcriptional repressors. Importantly, ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset of these predicted likely response to IM-based therapy in a naïve panel of GISTs. Further evaluation revealed that modifying in vitroexpression of genes via RNAi approaches within this predictive response signature enhanced the sensitivity of GIST cells to IM. Conclusions: Using clinical samples from a prospective neoadjuvant/adjuvant phase II trial we have identified a genetic signature which includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely rapid response to short-term IM treatment and which may provide a prognostic biomarker identifying patients who will benefit from it. [Table: see text]
Assessment of the heat shock protein 90 (HSP90) inhibitor IPI504 alone or in combination with the tyrosine kinase inhibitor (TKI) imatinib in mice carrying xenografts of human gastrointestinal stromal tumors (GIST)
Authors: Schoffski P. , Floris G. , Sciot R. , Stefan C. , Wozniak A. , Machiels K. , Normant E. , Debiec-Rychter M. 
Published: August 2020

10534 Background: Inhibition of HSP90 is a new strategy for treatment of GIST. IPI-504 is a potent i.v. HSP90 inhibitor. We assessed the activity of IPI-504 in imatinib-sensitive GIST xenografts, alone/combined with the TKI. Methods: Human GIST882 cells (KIT exon 13 mut.) were grafted in 43 nude mice, who were randomized to 4 groups: A (n=13; control); B (n=18; IPI-504 100 mg/kg 3x/wk p.o.); C (n=8; imatinib 50 mg/kg 2x/d p.o.); D (n=4; IPI-504+imatinib, dose/schedule as above) for 2 weeks. Histopathological assessment was done by H&E and KIT immunostaining, histological response (HR) was defined by magnitude of necrosis and myxoid degeneration [grade 1 (0–10%), 2 (>10% - ≤ 50%), 3 (> 50% - ≤90%), 4 (>90%)]. Expression/activation of KIT and its signaling (AKT, S6, MAPK) was assessed by Western blot. Results: IPI-504 alone significantly reduced tumor volume (41%) at day 14, further enhanced by adding imatinib (58%). Imatinib alone led to only a 5% reduction. IPI-504 induced grade 2 HR in 17/36 tumors, while the majority of tumors (13/15) treated with imatinib showed grade 1 HR. Grade 3/4 HRs were only seen with the combination. Mitosis decreased 3.3-fold, apoptosis increased 1.3-fold with IPI-504. Despite substantial reduction in mitotic activity in C and D (8.2- and 82-fold), apoptosis was virtually unaffected. In the IPI-504 arm, KIT levels were partially downregulated. Imatinib alone had no effect on KIT expression, while the combination produced a marked suppression of total KIT, accompanied by complete downregulation of the signaling. Loss of KIT in the combination arm was confirmed by immunostaining. Although KIT was not completely degraded with IPI-504, measurable effects on activation of AKT, S6 and MAPK were observed. Conclusions: IPI-504 has consistent antitumor effects in GIST xenografts, both histologically and on the molecular level. Combining IPI-504 with imatinib substantially enhances anti-tumor activity, providing a strong rationale for clinical trials of IPI-504 in GIST as single agent and in combination. [Table: see text]
Treosulfan-based high-dose chemotherapy with autologous stem cell transplantation in high-risk Ewing sarcoma
Authors: Juergens H. , Ranft A. , Paulussen M. , Kontny U. , Dilloo D. , Dirksen U. 
Published: August 2020

10546 Background: High-dose chemotherapy (HDC) is widely used in consolidation treatment of Ewing sarcoma patients with primary disseminated or recurrent disease. Standard busulfan-based regimens are not compatible with radiotherapy to central axis sites. Treosulfan is a newly-developed bifunctional alkylating agent that has been shown to be safe in current trials of the German Society for Pediatric Hematology and Oncology (GPOH) even in heavily pre-treated patients including axial radiation. Methods: Event-free survival (EFS) and overall survival (OS) for 21 patients with primary disseminated disease (PDD) and survival after relapse for 11 relapse patients recruited from the EURO-E.W.I.N.G.99 trial 1998–2007 were analyzed. PDD-patients had received VIDE induction prior to treosulfan-based HDC (treosulfan: 36g/m2; melphalan: 140mg/m2) followed by autologous stem cell transplantation. Median follow up was 1.72 yrs. Relapse patients had received appropriate second line chemotherapy regimens prior to treosulfan-based HDC. Median follow up after relapse was 2.26 yrs. Results: Seventeen of 21 (81%) PDD-patients had a central axis site of the primary tumor, 8 patients (38%) presented with a pelvic tumor. Metastatic sites were: bone (76%), bone marrow (22%), CNS (10%), liver (15%), lymphnode (29%), other (16%), and additionally lung metastases in 57%. 1y-EFS was 0.70 (SE=.10), 2y-EFS was 0.27 (SE=0.10), and 3y-EFS was 0.16 (SE=.09). 1y-OS was 0.84 (SE=.08), 2y-OS was 0.46 (SE=.13), and 3y-OS was 0.32 (SE=.12). In the cohort of 11 relapse patients two patients (18%) had a local relapse, 3 (27%) a combined relapse, and 6 (55%) a systemic relapse. Six of 11 (55%) relapse patients had a late relapse >2 yrs from diagnosis. Survival after relapse at 3yrs was 0.70 (SE=.15). Conclusions: Treosulfan-based HDC is an alternative approach in high-risk Ewing tumor patients especially after relapse to consolidate a second remission. Further investigation and comparison to other standard HDC regimens is needed. No significant financial relationships to disclose.
Microscopic margins of resection in gastrointestinal stromal tumor (GIST): An analysis of 122 patients
Authors: Di Battista M. , Saponara M. , Pantaleo M. A. , Catena F. , Santini D. , Lolli C. , Di Scioscio V. , Astorino M. , Maleddu A. , Nannini M. , Biasco G. 
Published: August 2020

10554 Background: The main treatment for localized GIST is complete surgical resection. The prognosis is strongly correlated with both tumor size and mitotic index. The aim of our study was to analyze retrospectively the outcome of patients affected by GIST related to microscopic margins of resection. Methods: The outcome of 122 patients surgically managed during the past 11 years, were evaluated. We analyzed the impact of R0 and R1 resection on DFS. Results: All patients but one, had a c-Kit positive GIST, 91% had primary disease without metastasis, 9% had metastasis. There were 46% high, 31% intermediate and 28% low risk GIST. The median age was 65 years (range 29–87). The most common sites of tumor origin were the stomach (54.9%) and the small bowel (36.9%). Sites of tumor metastasis were liver (18.2%), peritoneum (36.4%) or both (19.3%). R0 resection was achieved in 102 (83.6%) patients, while 16 pts (13.1%) had positive microscopic margins (R1). With a median follow up of 24 months (range 3–119), recurrence occurred in 34 (33.3%) R0 and in 9 (56.3%) R1 patients. The median DFS was 53.7 months and 35.6 months for the R0 and R1 group, respectively. The difference tested with univariate analysis using Long rank test, was not statistically significant (p= 0.228). Conclusions: In our series, the status of microscopic margins does not appear to be important for prediction of recurrence in patients affected by GIST. No significant financial relationships to disclose.
Sorafenib fourth-line treatment in imatinib-, sunitinib-, and nilotinib-resistant metastatic GIST: A retrospective analysis
Authors: Reichardt P. , Montemurro M. , Gelderblom H. , Blay J. , Rutkowski P. , Bui B. , Hartmann J. T. , Pink D. , Leyvraz S. , Schütte J. 
Published: August 2020

10564 Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors usually caused by mutations in the KIT or PDGFRA gene. Advanced disease generally cannot be cured by surgery nor by tyrosine kinase inhibitors (TKI), but TKIs have considerably improved outcome for patients (pts) with advanced GIST. Patients failing TKI treatment with imatinib (IM), sunitinib (SU) or nilotinib (NI) have a poor prognosis. Sorafenib is a multi kinase inhibitor that blocks not only receptor tyrosine kinases such as KIT, VEGFR and PDGFR but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway. Recently, clinical activity of sorafenib in third-line treatment in patients with GIST after IM and SU failure has been shown (Wiebe et al. ASCO 2008, #10502). Methods: We report herein preliminary data of 32 pts treated with sorafenib in nine European centers. Centers were selected based on their previous and known experience in GIST and reported all pts treated. Pts received sorafenib after failure of IM, SU and NI in fourth-line treatment. Baseline characteristics and treatment details have been retrieved via questionary. Results: Median age at sorafenib treatment start was 62 years (range 33–81 y), and the majority of pts were male (63 %). Primary tumor site was gastric or small intestine in 25% and 41% of pts, respectively. All pts had failed IM, SU, NI. 19 % of pts achieved partial remission and 44% disease stabilization. Approximately half of the pts had an improvement of symptoms and/or performance. Half of the pts were on treatment longer than 4 months (actuarial data) and 41% of pts continue to receive sorafenib. Median progression-free survival is 20 weeks and median overall survival 42 weeks (Kaplan-Meier), at a median follow-up of 22 weeks (range 3–54). Conclusions: This is the largest series assessing efficacy of sorafenib fourth-line treatment for IM, SU and NI refractory GIST reported yet. Sorafenib displays significant clinical activity in this heavily pretreated group of patients. [Table: see text]
Gastrointestinal stromal tumor associated with other primaries: A study of 154 patients
Authors: Pandurengan R. K. , Strom S. S. , Trent J. 
Published: August 2020

10567 Background: The objective of this study is to investigate the characteristics and survival rate of patients with Gastrointestinal Stromal Tumor (GIST) associated with other primary malignancies. Methods: 783 patients with GIST were treated at M. D. Anderson Cancer Center from 1995 to 2007. Multiple primaries included tumors that were not considered to be a metastasis, invasion or recurrence of GIST excluding non-melanoma skin cancer. Data on gender, age at diagnosis of cancer, follow-up time after diagnosis, and death rate were collected. Results: Of the 783 patients, 154 (20%) were identified with at least one other primary other than GIST (GIST+). The ratio of men and women was 1.5 and 1.3 in patients with GIST+ compared to those with GIST only, respectively. Median age at diagnosis of GIST was 57 for patients with GIST only whereas it was 68 in patients with GIST+. The stomach was the frequent site of occurrence in GIST only and GIST+. The total numbers of other primaries developed before the diagnosis of GIST was higher (134) than the primaries developed after the diagnosis of GIST (53). The most frequent primaries observed before the diagnosis of GIST were prostate (25), breast (12), esophagus (9), kidney (7) and melanoma (6). Lung (5) and kidney (5) were the most frequent type of primaries that developed after the diagnosis of GIST. The 5-yr survival was 68% for patients with GIST+ when the other primary occurred before GIST, 61% for patients with GIST+ when the other primary occurred after the diagnosis of GIST, 58% for patients with GIST only, and 49% for GIST++ patients with two or more other primaries (p=0.002). Conclusions: Superior survival in GIST+ patients may be due to the bias of early detection. The etiology and clinical implications of the association of other primaries in GIST patients should be further investigated. No significant financial relationships to disclose.