bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficiency of anlotinib in osteosarcoma with chemoresistance: Exploratory therapy based on PDX models and next-generation sequencing.
Authors: Long Zuoyao , Fu Zhanli , Yunus Aikebaier , Lu Yajie , Li Minghui , Chen Guojing , Li Jing , Zhang Hong-Mei , Wang Zhen 
Published: June 2022

11527 Background: It’s urgent to find a new approach for the treatment of progressed osteosarcoma in neoadjuvant chemotherapy. Using patient-derived xenograft (PDX) models and next-generation sequencing (NGS), we have explored the efficiency of anlotinib in these patients. Methods: Frozen osteosarcoma tissues were used to establish PDX models. Ten samples of each PDX model were randomized to treatment or control group. The treatment group were gavaged at a volume of 0.1 ml/10g body weight for 4 weeks, while the control group were administered with vehicle at the same dose orally. Tumor volume and body weight were measured every 3 days, and the tumour were removed and weighed after 28 days. The number of mitotic cells and tumor necrosis rate were detected by Hematoxylin-Eosin (HE) staining. Immunohistochemistry (IHC) was used to evaluate the number of apoptotic cells and the expression of VEGFR-2, PDGFR-β, FGFR-1, c-Kit and their phosphorylated proteins, CD 31. Additionally, patients who had progressed during neoadjuvant chemotherapy (NAC) were treated with combination of anlotinib. After four cycles NAC, we performed salvage surgery and maintained with anlotinib. The change of tumor size was evaluated for tumor response. We used IHC and NGS to analyze the expression of drug targets. Results: 21 PDX models were established successfully from 43 samples. Tumor specimens from patients, who had pulmonary metastasis, local recurrence or chemoresistance, were easier to establish PDX models (P < 0.001, P = 0.046, P = 0.013). Six models were selected randomly for anlotinib. After anlotinib administration, the tumor inhibition rates were 18.82%, 45.98%, 85.86%, 83.38%, 84.57% and 86.42%. Anlotinib could not only inhibit the mitosis, induce tumor cell apoptosis and necrosis, but also decrease the expression of drug targets. The expression of VEGFR-2, PDGFR-β and CD31 were positively associated with tumor response. Five patients had received anlotinib during NAC. Four patients had tumor regression (69.4%, 28%, 19%, 8.7%), including two with high expression of VEGFR-2 mRNA or/and PDGFR-β and one with medium expression. Conclusions: Based on the results of PDX models and NGS, we suggested that osteosarcoma with high expression of VEGFR-2 or/and PDGFR-β was sensitive to anlotinib, which was alternative for patients progressed during NAC.
Real-world experience of tyrosine kinase inhibitors in patients (pt) with recurrent bone tumours (BT): A CanSaRCC study.
Authors: Vora Tushar Shailesh , Peretz Soroka Hagit , Noujaim Jonathan Christopher , Marcoux Nicolas , Alcindor Thierry , Karachiwala Hatim , Alvi Saima , Shaikh Furqan , Abdul Razak Albiruni Ryan , Gupta Abha A. 
Published: June 2022

11530 Background: Survival after relapse in osteosarcoma (OST), Ewing Sarcoma (ES) and chondrosarcoma (CS) remains dismal. Recent reports suggest a role of tyrosine kinase inhibitors (TKI) including regorafenib (R) and cabozantinib (C). We conducted a retrospective multi-centre pan-Canadian study to assess real-word outcomes with these novel treatments in recurrent BT. Methods: After ethics approval, data from pts treated in 7 different institutions was extracted from the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) Database. Pt characteristics, treatment and outcomes were analyzed. Response was assessed per RECIST 1.1. PFS, OS were estimated using Kaplan-Meier. TTP was defined as time from TKI start to progression. Results: From June 2018-Dec 2021, 44 pts received R or C and best response by histology are listed in Table, with an overall clinical benefit rate of 63.6%. Median time to best response was 2.3 mo (range 1 – 17). 15 pts (34.1%) required dose reduction; most common reasons were hand-foot syndrome (13.6%), mucositis (9.1%) and hypertension (9.1%). At median FU of 6.4 mo (range 1.6 – 29), 25 pts (56.8%) died, 19 (43.2%) were alive with disease (AWD). Median PFS was 4.1 mo (95%CI 2.9 – 5.7), for OST was 5.0 (N = 25, 95%CI 2.6 – 10.6), for ES was 4.1 (N = 10, 95%CI 2-5.9), and for CS 4.0 (N = 9, 1 Progressed). Median OS was 10.5 mo (95%CI 7 – 14). By univariate analysis, age, line of therapy, gender, location of primary, or R vs. C did not correlate with PFS. Conclusions: Consistent with previous published studies, our pan-country real-world analysis shows that TKI have meaningful activity in the setting of recurrent BT with acceptable toxicities. Inclusion in earlier lines of treatment and/or maintenance therapy could be questions for future research. [Table: see text]
Discontinuation of imatinib in patients with oligo-metastatic gastrointestinal stromal tumor who are in complete radiological remission: A prospective multicenter phase II study.
Authors: Hompland Ivar , Boye Kjetil , Papakonstantinou Andri , Røsok Bård , Joensuu Heikki , Bruland Øyvind 
Published: June 2022

11535 Background: Life-long tyrosine kinase inhibitor (TKI) treatment is recommended for patients (pts) with metastatic GIST. We investigated whether highly selected pts with metastatic GIST may remain in durable complete remission after imatinib discontinuation. Methods: In this 1-group, prospective, multicenter phase II trial (NTC02924714) selected pts with overtly metastatic GIST discontinued imatinib treatment. Eligible pts had been treated with imatinib > 5 yrs for oligo-metastatic (≤3 metastases) disease, had no GIST progression and had undergone either R0/R1 resection or radiofrequency ablation (RFA) of all metastases, and had no longer detectable metastases on CT/MRI imaging, The primary endpoint was 3-yr progression-free survival (PFS), overall survival was a secondary endpoint. We estimated to achieve an improvement from 15% to 35% in 3-yr PFS compared to pts treated in the BRF-14 trial with a sample size of 31 pts. Results: The trial closed early due to slow accrual. Between January 5, 2017, and June 5, 2019, 12 pts (males, 7) with a median age of 67 yrs (range, 50-85) were enrolled. All pts had their primary tumor surgically removed (stomach, 4; small bowel, 6; large bowel/rectum, 2). Seven pts had KIT exon 11 mutation, 2 KIT exon 9 mutation, 1 PDGFRA exon 12 mutation, 1 had no mutation in KIT/PDGFRA, and 1 pt had unknown GIST mutational status. Eight pts had liver metastases, 3 peritoneal metastases, and 1 had both. Prior to enrollment all pts were in macroscopic complete remission after surgical metastasectomy (n = 7), RFA (n = 2), or both (n = 1), and 1 pt achieved complete radiological response with imatinib. At enrollment, 8 pts had imatinib 400 mg/d and 4 had < 400 mg/d. The median time of imatinib treatment before study entry was 8 yrs (range, 5-17). After imatinib discontinuation 7 (58%) pts progressed; the median time to progression was 10 mos (range, 2-31 mos). Five (42%) patients were progression-free after a median follow-up time of 42 mos (range, 30-59 mos). Median PFS was 23 mos and the estimated 3-year PFS 39%. Patients who progressed all achieved a second remission after restarting imatinib and were alive after a median follow-up time of 48 mos (range, 32 to 61 mos). Conclusions: The findings suggest that discontinuation of imatinib is safe in highly selected patients with oligo-metastatic GIST and that such patients may survive without detectable GIST progression for several years. The findings need to be viewed with caution due to the small pt numbers. Further study on imatinib discontinuation seem warranted. Clinical trial information: NCT02924714.
Second primary malignancies (SPM) in patients with gastrointestinal stromal tumors (GIST): 10-year experience from the Ottawa Hospital (TOH).
Authors: Alfagih Abdulhameed , Alshamsan Bader , AlJassim Abdulaziz , Alqahtani Nasser , Asmis Timothy R. 
Published: June 2022

11536 Background: The secondary malignancies in patients with GIST are relatively high. We present our 10-year experience of SPM in patients with GIST from a regional Cancer Centre in Canada. Methods: A retrospective cohort study was performed in all GIST patients treated at TOH between January 2011 and December 2021. Patients were identified using ICD-10 codes and electronic medical records reviewed. Clinicopathological data were analyzed. Logistic regression analysis was used to evaluate associated factors with SPM. Survival analysis was estimated with the use of the Kaplan-Meir method and compared by log-rank test. Results: In total, 248 patients with GIST were identified. Of these patients, 61 (25%) had SPM; synchronous (9, 15%) and metachronous (52, 85%). Nine patients had two additional primary cancers other than GIST, and four patients had three additional primary cancers. The median age at diagnosis was 70 (range 44 – 90) years, and males were (59%). The most common SPMs were skin cancer (14, 17%), melanoma (5), and non-melanoma (9), followed by prostate cancer (13, 16%) and breast cancer (12, 15%). Colorectal cancer and hematological malignancies were found in (5, 11%) patients each, while RCC was found in (4, 6%). Thyroid cancer, lung cancer, neuroendocrine tumor, bladder cancer, thymoma, and other types of cancers were collectively found in 15 patients (24%). The majority (57%) of SPM diagnosed before GIST, 30% after GIST. The most common primary GIST locations were in the stomach (62%), followed by the small bowel (30%), and the most common histology was spindle cell (69%), followed by mixed histology (13%). The majority of GIST were localized (46 patients, 75%). Based on Miettinen risk classes for non-metastatic GIST, 74% had zero to low-risk disease, while 26% had moderate or high-risk disease. There was no association between SPM and GIST primary site (p = 0.4), TNM stage (p = 0.8), histology (p = 0.2), Mitosis (p = 0.5), and Miettinen risk class (p = 0.6). The median follow-up time was 53 months (range 1 – 132), and four patients lost follow-ups. Five years overall survival of SPM group vs. non SPM, 79.8% vs. 94.1%, (p = 0.03). Cox regression did not reveal a significant association with the covariants Conclusions: We observed that one out of four GIST patients have SPM. Skin, prostate, breast cancers were the most common SPM associated with GIST. Molecular studies are needed to explore the association/underlying mechanisms of GIST with these malignancies.
Selective internal radioembolization (SIRT) allows to control liver metastases of gastrointestinal stromal tumors (GIST) failing treatment with tyrosine kinase inhibitors (TKI).
Authors: Hohenberger Peter , Rathmann Nils , Buesing Karen , Menge Franka , Reichardt Peter , Schoenberg Stefan O. , Diehl Steffen 
Published: June 2022

11540 Background: The liver and the peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH (‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients Methods: From 1/2008 to 1/2018, 2^6 pts (12f, 14m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 7), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 33.6 mos (range, 12-108mos) and all patients were followed until death Results:.The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 10.7-23.8 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p < 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in earlier treatment lines.
Serum glycoproteomic signatures and association with survival in patients with bone and soft tissue sarcoma treated with immune-checkpoint inhibitor therapy.
Authors: Serie Danie , Pickering Chad , Rice Rachel , Wong Maurice , Huang Hector , Kansara Maya , Thavaneswaran Subotheni , Ballinger Mandy L. , Sebastian Lucille , Thomas David Morgan , Lindpaintner Klaus 
Published: June 2022

11546 Background: Glycosylation is one of the most ubiquitous and functionally important forms of post-translational modification. The role of differential glycosylation in serum proteins has so far been limited by the technical complexity inherent in generating and interpreting this information. InterVenn has built a novel platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine, allowing for highly scalable and reproducible interrogation of glycoproteins with site- and glycan-specificity. Methods: Using this platform, we interrogated 519 glycopeptide (GP) biomarkers derived from 70 serum proteins in pre-treatment samples from a cohort of 103 individuals (56 females, 47 males, age ranging from 18 to 84 years) presenting with one of 20 solid cancer types. All patients were treated with durvalumab and tremelimumab immune checkpoint inhibitor (ICI) therapy. Median follow-up for overall survival (OS) was 11.4 months, with 70 events total observed. OS associations were assessed for individual GPs via Cox regression models and leave-one-out-cross-validation (LOOCV) was employed to generate penalized multivariable prediction scores. Notably, 43 patients had a primary diagnosis of bone and soft tissue sarcoma, and stratified analyses were carried out in this population. Results: We identified 154 biomarkers significantly associated with OS in the full dataset after adjusting for multiple comparisons (FDR < 0.05). Of these, 7 were statistically significant at p < 0.01 in the sarcoma-only subset. LOOCV models built in all cancer types resulted in held-out scores that discriminated those likely to exhibit long-term survival post-ICI therapy from those unlikely to benefit (HR = 4.0, p = 4.91E-08, with 4 GPs included in the final model). Furthermore, LOOCV models including only sarcoma patients demonstrated even stronger predictive attributes (HR = 8.22, p = 2.10E-05, employing 2 glycopeptides). All 9 sarcoma patients with extreme glycosylation signatures for prediction of poor survival displayed quick clinical progression with little benefit from ICI therapy. Relative signal strength and comparative analyses demonstrated strong histotype-specificity inherent in the biomarkers employed for sarcoma vs all cancers. Conclusions: Our results indicate that glycoproteomic liquid biopsy holds potential as a predictive biomarker for identifying sarcoma patients who will derive the greatest benefit from ICI therapy.
Distinct oncogenic signatures in malignant PEComa and leiomyosarcoma identified by integrative RNA-seq and H3K27ac ChIP-seq analysis.
Authors: Giannikou Krinio , Azim Ahmad-Abdel , Adib Elio , Schaefer Inga-Marie , Kesten Nikolas , Taing Len , Zhu Zachary , Hornick Jason , Hirsch Michelle S. , Long Henry , Wagner Andrew J. , Hemming Matthew Louis , Kwiatkowski David J. 
Published: June 2022

11552 Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make their diagnostic distinction challenging. We aimed to characterize the transcriptional and epigenetic landscape of PEComa and LMS to identify distinguishing features. Methods: We performed whole transcriptome RNA-sequencing on 19 PEComas and compared their gene expression profile to 259 sarcomas from The Cancer Genome Atlas (TCGA) including 104 LMS. ChIP-sequencing for H3K27ac, a histone modification associated with activation of nearby genes/open chromatin, was conducted on 9 malignant PEComas and 12 LMS and were compared with publicly available data from 4 other sarcoma subtypes (chordoma; osteosarcoma; undifferentiated pleomorphic sarcoma; rhabdomyosarcoma; n = 29 tumors). Results: Genome-wide epigenetic and transcriptional analyses revealed overlapping patterns between PEComa and LMS, which were distinct from other sarcomas. However, we also identified a set of highly expressed and epigenetically distinct transcripts which may represent diagnostic?biomarkers: e.g., DAPL1, MLANA, SULT1C2, GPR143, and CHI3L1 for PEComa; and MYOCD, WDFC2, DES, MYH11, and CNN1 for LMS; each of which showed >17x fold higher expression for each tumor entity by DESeq2 (FDR<0.0001). Gene Set Enrichment Analyses (GSEA) demonstrated enrichment in the KEGG Lysosome pathway for PEComa (FDR=0.11), whereas myogenesis and smooth muscle contraction pathways were enriched in LMS (FDR=0.09). Integrative transcriptomic and epigenetic analyses revealed a unique set of master core transcription factors for each tumor type including among others MYOCD for LMS; MITF for PEComa, which require further functional investigation. Twelve selected genes including new as well as known and standard diagnostic markers (e.g., DAPL1, MLANA, GPR143, PNL2, CHI3L1, DES, MYH11, ER, CD68, PU.1, pS6 and CNN1) were validated by immunohistochemistry (IHC) in multiple sections from PEComa and LMS (n = 26). The combination of three melanocytic markers (HMB45, MLANA, PNL2) and pS6 can distinguish LMS from PEComas (**** p<0.0001). IHC for CD68 and PU.1 macrophage markers did not show any difference regarding the degree of immune infiltration in PEComa vs. LMS. Conclusions: Our studies revealed novel epigenetic signatures translating into lysosomal and melanocytic proteins for PEComa and myogenic proteins for LMS, which may serve as useful diagnostic biomarkers in the distinction of these two sarcoma subtypes.
Phase 1b study of weekly split-dose selinexor in soft tissue sarcoma (STS).
Authors: Salawu Abdulazeez , Gupta Abha A. , Al-Ezzi Esmail Mutahar , Genta Sofia , Malone Eoghan Ruadh , Vora Tushar Shailesh , Watson Geoffrey Alan , Vornicova Olga , Wang Lisa , Arones Limore , Phillips Madeline J. , Lee Jasmine , Abdul Razak Albiruni Ryan 
Published: June 2022

11563 Background: Selinexor has demonstrated clinical activity in a variety of tumors including STS. Selinexor dosing at 60mg twice a week or 80mg once a week in later phase trials was associated with gastrointestinal and hematologic toxicities requiring frequent dose interruption and reduction. Preclinical in vivo studies show that selinexor use in a split-dose regimen or sustained-release formula is associated with less toxicity. This phase 1b study aimed to evaluate the safety and tolerability of split-dose selinexor in patients (pts) with advanced STS. Methods: Eligible pts with advanced STS of any histologic subtype, and ECOG performance status (PS) ≤ 1 were treated with split-dose selinexor (40mg, 20mg, 20mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15 and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. Antiemetic prophylaxis (oral dexamethasone and ondansetron) was given to all pts. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAE) by CTCAE v5.0. The secondary endpoint was assessment of quality of life (QoL) using the EORTC QLQ-c30 tool v3. Descriptive analyses of Global Health Status (GHS) QoL scores at screening (baseline) and cycle 2 day 1 (C2D1) were performed. Radiologic tumor assessments (by RECIST v1.1) were performed every 8 weeks while on treatment. Results: Nineteen pts [12 female and 7 male; ECOG 0/1, 8/11; median age 61 years (range 41 – 83)] were enrolled. The most frequent of 12 STS subtypes was leiomyosarcoma (n = 7, 37%). Among 18 patients evaluable for toxicity, there were no grade ≥ 3 TRAE. The most common grade ≤ 2 TRAE were dysgeusia (n = 11, 61%), nausea (n = 11, 61%), fatigue (n = 10, 56%) and vomiting (n = 10, 56%). Grade ≤ 2 hematologic TRAE were thrombocytopenia (n = 6, 33%), neutropenia (n = 4, 22%) and anemia (n = 1, 6%). Dose reduction was required in 3 pts (17%) due to intolerable grade 2 TRAE (fatigue, nausea, thrombocytopenia). No serious adverse event due to selinexor was noted. QoL scores were evaluable for 15 pts. The mean (± SEM) change in GHS QoL score from baseline to C2D1 was -10.6 (± 4.8). Among 16 pts evaluable for radiologic response, the best response was stable disease (SD) in 10 pts (63%), and progressive disease (PD) in 6 pts (37%). Durable clinical benefit (SD for > 16 weeks) was seen in 5 pts (31%; 95%CI 11.0 – 58.7%) The median PFS was 3.6 months (95%CI 1.7 – 7.3). Conclusions: Split-dose selinexor was well tolerated in this heterogeneous group of pts with advanced STS and warrants further interrogation. Updated toxicity, safety, efficacy and QoL data will be presented at the meeting. Clinical trial information: NCT04811196.