bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camrelizumab in combination with doxorubicin, cisplatin, ifosfamide, and methotrexate as neoadjuvant therapy for osteosarcoma: A single-arm, exploratory phase II trial.
Authors: Tang Qinglian , Zhu Xiaojun , Song Guohui , Lu Jinchang , Wu Hao , Xu Huaiyuan , Zhang Xin-ke , Ai Fei , Zhang Yingchun , Wang Jin 
Published: June 2023

11526 Background: Tumor necrosis rate after neoadjuvant therapy is one of the strongest predictors of long-term outcome for patients with osteosarcoma. Patients with good response (tumor necrosis rate ≥90%) have a substantially better survival than those with poor response (tumor necrosis rate < 90%), with 5-year overall survival of 75-80% and 55-65%, respectively. However, treatments for osteosarcoma have not yet shown much progress since the introduction of perioperative chemotherapy in 1970s. New neoadjuvant combinations are required to explored for osteosarcoma. Methods: In this phase II trial (NCT04294511), patients aged 14-65 years with histopathologically confirmed osteosarcoma and Eastern Cooperative Oncology Group performance status of 0-1 received three 21-day cycles of neoadjuvant regimen (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2 of cycles 1 and 3; cisplatin 100 mg/m2 on day 2 of cycles 1 and 3; methotrexate 8-12 g/m2 on day 12 of cycle 1; and ifosfamide 3 g/m2 on days 1-4 of cycle 2). Surgery was scheduled 12-14 days after neoadjuvant therapy. Two weeks after surgery, patients received 6 cycles of adjuvant therapy (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 9-10 of cycles 1, 3, and 5; cisplatin 100 mg/m2 on day 10 of cycles 1, 3, and 5; methotrexate 8-12 g/m2 on day 2 of cycles 1, 3, and 5; and ifosfamide 3 g/m2 on days 1-4 of cycles 2, 4, and 6). The primary endpoint was good response (tumor necrosis rate ≥90%) rate after neoadjuvant therapy. Results: A total of 86 patients were screened and 75 patients signed informed consent from December 2019 to June 2022. By the data cutoff date on December, 2022, 8 patients did not complete neoadjuvant therapy and 2 patients refused surgery. 65 patients completed neoadjuvant therapy, one patient had disease progression before surgery, 64 received surgical resection and adjuvant therapy, and 44 completed adjuvant therapy. Thirty-one (48.4%, 95%CI: 36.6%-60.4%) of 64 patients showed good response. The most common grade 3-4 adverse events were decreased platelet count (44.0%), decreased white blood cell (37.3%), decreased neutrophil count (29.3%), oral mucositis (14.7%), increased alanine aminotransferase (12.0%), and increased aspartate aminotransferase (10.7%). Conclusions: Camrelizumab combined with doxorubicin, cisplatin, methotrexate and ifosfamide in the perioperative treatment of osteosarcoma patients were safe and tolerable. Postoperative good response rate was similar to previously reported results. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of patients with osteosarcoma. Clinical trial information: NCT04294511 .
Variations in the approach to lung metastases in osteosarcoma among pediatric and adult patients.
Authors: Wytiaz Victoria A , Rice John , Rao Rama , Schuetze Scott , Chang Andrew C. , Reddy Rishindra M , Angeles Christina Vadala , Chugh Rashmi 
Published: June 2023

11528 Background: Osteosarcoma (OS) is most common in the pediatric (ped) and young adult population but can occur at any age. Amongst other factors, older age confers a worse prognosis, and it is uncertain whether this is due to inherent biologic differences or treatment approaches. Lung-only metastases (mets) is common, and metastasectomy is performed frequently to improve overall survival. Little is known about the differences in lung-only metastatic OS and approaches to metastasectomies between ped and adult populations. Methods: A single-institution retrospective chart review using a free-text search engine and keywords “osteosarcoma, “lung mets” and “pulmonary mets”, generated 206 patients(pts) diagnosed from 2006-2021. Eligible pts had a diagnosis of lung-only metastatic disease, resection performed at the institution and at least one year of follow-up data. Data was analyzed in two cohorts based on age at OS diagnosis: ped (age<18) and adult (age > 18 years), as well as with age as a continuous predictor. Results: Fifty pts (27F/23M) with lung only mets were eligible for analysis with a median follow up of 10.4 years. Median age was 23 yrs (range 6-77); 20 pts (40% were ≤18 years old); 31 pts (16 ped, 15 adult) had an extremity primary site. Rates of metachronous (67% vs 60%) and bilateral (50% vs 40%) lung mets were similar in ped vs. adult pts, respectively. The median number of lung mets was 2 (range 1 to > 25) with 50% of patients (35) having 2-6 metastases (8 ped, 20 adult). The median size of lung metastasis was 1.2 cm (range 0.1-4.0 cm). 15 ped pts (75%) underwent metastasectomy, compared to 19 adult (63.3%) (OR 1.74, p = 0.39). Probability of metastasectomy decreased with age when used as a continuous predictor (p = 0.11). Ped pts were more likely to have an open procedure as compared to thoracoscopic (OR 12.75, p < 0.01). There was no significant difference in relapse-free survival between ped and adult pts who underwent metastatectomy (p = 0.84). Median overall survival following lung metastasis detection was 5.8 years for ped pts compared to 3 years for adult pts (p = 0.15 from Cox model). Conclusions: Multiple tumor and patient-specific factors affect the decision to undergo metastatectomy in lung-only OS. In our single-center study we learned that timing, pattern, and number of lung mets in ped vs. adult pts were similar, but younger pts were more likely to undergo an open procedure. Our data trended towards a lower chance of undergoing metastatectomy with older age. Larger studies are required to further understand decision-making and therapeutic outcome and a randomized study of open vs. thoracoscopic metastatecomy for lung-only OS mets is underway. In this small study, many patients with lung-only metastatic OS had long-term survival. We showed that relapse-free survival post-metastatecomy was similar in ped and adult patients.
Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study.
Authors: Trent Jonathan C. , Jones Robin Lewis , George Suzanne , Gelderblom Hans , Schöffski Patrick , von Mehren Margaret , Zalcberg John Raymond , Kang Yoon-Koo , Abdul Razak Albiruni Ryan , Attia Steven , Le Cesne Axel , Reichmann William , Sprott Kam , Achour Haroun , Sherman Matthew L. , Ruiz-Soto Rodrigo , Blay Jean-Yves , Heinrich Michael C. , Bauer Sebastian ,   on behalf of the INTRIGUE Investigators
Published: June 2023

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA (ctDNA) next-generation sequencing (NGS) analysis from INTRIGUE showed pts with second-line advanced GIST with primary KIT exon 11 mutations and secondary resistance mutations exclusively in KIT exons 17/18 derived clinical benefit from ripretinib but not sunitinib (Bauer S et al. J Clin Oncol. 2023; Abs 397784). Outcomes in pts with advanced GIST with ctDNA not detected (ctDNA-ND) had not been evaluated. Here, we present exploratory data from INTRIGUE in pts who had baseline ctDNA-ND vs ctDNA detected (ctDNA-D). Methods: INTRIGUE is an open-label, phase 3 study that enrolled pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and stratified by mutation according to local pathology report. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA NGS-based assay. Pts with ctDNA-D had ≥1 somatic alteration in the 74 genes analyzed. Results: Pts with ctDNA-ND (82/362, 22.7%) were younger (median: 55.5 vs 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11–459] vs 108.8 [15–418] mm) vs ctDNA-D (280/362, 77.3%). Progression-free survival (PFS) was longer in pts with ctDNA-ND vs ctDNA-D and numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND (Table). Pts with ctDNA-ND categorized as not having a KIT exon 9 mutation at randomization ( KIT exon 11, other KIT/PDGFRA, or KIT/PDGFRA wild-type; n = 71) had longer PFS with ripretinib vs sunitinib (median not estimable [NE] vs 11 months; HR = 0.56; 95% CI 0.28 to 1.12). Objective response rate (ORR) and overall survival (OS) were higher with ctDNA-ND vs ctDNA-D. Safety was similar between groups and consistent with the primary analysis. Conclusions: Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501 . [Table: see text]
Large versus limited molecular profiling panel screening program in patients with metastatic sarcoma: An exploratory subgroup analysis from the ProfiLER 02 trial.
Authors: Brahmi Mehdi , Tredan Olivier , Penel Nicolas , Chevreau Christine , Perrin Christophe , Firmin Nelly , Bompas Emmanuelle , Bertucci Francois , Attignon Valéry , Saintigny Pierre , Treilleux Isabelle , Chabaud Sylvie , Garin Gwenaelle , Pérol David , Blay Jean-Yves , Dufresne Armelle 
Published: June 2023

11545 Background: Profiler 02 (NCT03163732) is a multicentre, randomized molecular screening clinical trial aiming to evaluate the feasibility and the benefit of a large NGS (Next-generation sequencing) panel (FoundationOne Medicine NGS panel or FOne, 324 cancer-related genes) compared to a limited one (Control panel or CTRL, 87 cancer-related genes) in terms of clinical, quality of life and health economic outcomes. We present here the results of the patients with advanced/metastatic sarcoma included in the Profiler 02 trial. Methods: Patients (pts) were enrolled during their first-line of standard therapy for an advanced sarcoma. All sarcomas diagnosIs were performed within the RRePS network (French pathology network of reference for sarcomas) and a central pathological review confirmed if quality and quantity of material were acceptable for molecular analysis. Patients were randomized within the two study arms (FOne versus CTRL) and DNA was analysed using both panels. The primary objective of the study was to compare the proportion of patients for whom a genomically driven recommended therapy (RT) could be initiated based on the FOne versus CTRL panels. A dedicated Molecular Tumour Board (MTB) reviewed tumour genomics data of both panels independently to propose a RT. Results: From January 2018 to July 2019, 39 pts with sarcoma (20F, 19M), with a median age of 54 years [21-81], were randomized between FOne Arm (17 pts) and CTRL Arm (22 pts). Pathological subtypes per arm are presented in the the table. Overall, 19 pts (49%) had at least one genomically driven RT, 11 according to both panels and 8 according to FOne panel exclusively (McNemar’s test, p=0.01). Main RT were CDK4/6 inhibitors ( n=5), PI3K/AKT/mTOR inhibitors ( n=4), and immunotherapy ( n=4). After the MBT, a RT was initiated for seven patients, four according to FOne panel only and three according to both panels. Importantly, a complete response was observed for a metastatic MPNST (Malignant Peripheral Nerve Sheath Tumor) with a high tumour mutational burden (TMB) detected by the FOne panel (37 mutations per megabase) and treated with durvalumab (anti-PDL1) + tremelimumab (anti-CTLA4). Conclusions: Although from an exploratory subgroup analysis, these results suggest that a large molecular profiling panel including TMB (FOne panel) might increase the number of RT and the number of sarcoma patients treated. Studies of precision medicine in rare cancers such as sarcomas are feasible,this approach could benefit to patients. Clinical trial information: NCT03163732 . [Table: see text]
Aristolochic acid (AA) exposure and telomere maintenance mechanism in liver angiosarcoma (AS).
Authors: Chen Tom Wei-Wu , Hsu Chia-Lang , Wu Yu-Ching , Ou Da-Liang , Su Yung-Yeh , Cheng Ann-Lii , Hsu Chiun 
Published: June 2023

11551 Background: Liver AS has a grave prognosis and our previous study (Chen TW et al. Cancer 2022) showed that the incidence of liver AS is higher in Asia. We aimed to investigate the etiology of liver AS and its molecular characteristics. Methods: We performed whole exome (WES) and transcriptome sequencing (RNA-seq) of AS (liver 10, scalp 5, breast 2, trunk 1, heart 1) and hepatocellular carcinoma (HCC, 9) from National Taiwan University Hospital (NTUH) and re-analyzed WES & RNA-seq of AS from the Count Me In Project (CMI, 46). Somatic mutations and copy number alternation were called by Mutect2 and Sequenza from tumor-normal matched WES. Non-negative matrix factorization was used to determine mutational signature profiles and the contributions of each signature to each sample. Telomere length was estimated using TelSeq. Results: We identified four single-base-substitution (SBS) signatures using somatic mutations from 74 (AS/HCC 65/9) WES data. The dominated signature in liver AS had exceptionally high cosine similarity (93.08%) with COSMIC SBS22 (ver 3.2), which is related to AA exposure. The AA-mutation signature contributed significantly (adjusted p < 0.01) to the DNA mutations in 70% (7/10), 0% (0/9), 7% (3/46), and 56% (5/9) of liver AS (NTUH), nonliver AS (NTUH), CMI AS, and HCC (NTUH), respectively. TP53 (60% vs 22% vs 32%) and ATRX (40% vs 0% vs 11%) mutations were more common in liver than nonliver AS (NTUH) or CMI, while KDR mutation rates were similar (30% vs 44% vs 22%). Among TP53 mutations from liver AS with AA signature, 86% (6/7) showed the typical A:T > T:A mutation caused explicitly by AA-induced DNA damage. In liver vs nonliver AS, the median number of mutations and neoantigen burdens were 6.55 vs 0.98 (p = 0.0076) and 1572 vs 544 (p = 0.095), respectively. Although liver AS and HCC were highly associated with AA-mutation signature, liver AS had significantly longer telomeres in terms of tumor/normal telomere ratio (median 1.27 vs 1.16, p = 0.0009) but a significantly lower telomerase enzyme activity (p = 0.016). We did not find an association between ATRX mutation, or its mRNA expression level, with the extended telomere length in liver AS. Compared to nonliver AS, the activity of the telomere replication molecule BUB1 was significantly higher in liver AS (p = 0.0029). Conclusions: Our study is the first to connect AA exposure to the etiology of liver AS. The high mutation rate and distinct telomere maintenance mechanism of liver AS provides insights into future treatments.
Efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: A single-arm, phase 2 trial.
Authors: Liu Zengjun , Liu Mengyao , Xu Jing , Hu Wenyu , Zhu Dongyuan , Tao Rongjie , Xu Ni , Zhang Hui , Li Minghuan 
Published: June 2023

11553 Background: Anthracycline plus ifosfamide is the standard first line treatment regime for advanced soft tissue sarcoma (STS). Anlotinib, a multikinase angiogenesis inhibitor, has evolved as a standard second line treatment option in Chinese advanced STS patients. This study was performed to evaluate the efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in the first line treatment of patients with advanced STS. Methods: This prospective, open-label, single-arm, phase 2 trial was conducted in Shandong Cancer Hospital and Institute (ChiCTR2100054711). The key inclusion criteria included: (a) age was 18-70 years; (b) ECOG performance state of 0-1; (c) histologically confirmed high-grade STS; (d) unresectable or metastatic STS; (e) previously untreated, and sensitive to chemotherapy; (f) having measurable lesions according to RECIST 1.1. All patients received up to 6 cycles of anlotinib (12 mg QD on day1-14, 21 days per cycle) combined with anthracycline (epirubicin 40mg/m2/d on day 1-2, 21 days per cycle; or liposomal doxorubicin 30mg/m2/d on day 1, 21 days per cycle) and ifosfamide (2g/m2/d on day 1-3, 21 days per cycle) followed by anlotinib maintenance until disease progression, unacceptable toxicity or death. Pegylated recombinant human granulocyte colony-stimulating factor was administered following chemotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse effect (AE). Results: From December 2021 to December 2022, 31 patients (median [range] age, 53 [18-69] years; 20 [64.5%] male) were enrolled. 29 were evaluable for objective response, and the ORR and DCR were 31.03% (95%CI, 17.28-49.23%) and 82.76% (95%CI, 65.45-92.4%), respectively. With a median follow-up duration of 6.3 months (range, 0.8–14.0), the median PFS for all 31 patients was 6.9 months (95% CI, 2.62-11.17). The median OS was not reached. Treatment-related AEs of any grade occurred in all patients. The most common AEs included nausea/vomiting (88.46%), anemia (23.08%), leukopenia (19.23%), venous thrombosis (15.38%), hand-foot syndrome (11.54%) and elevated alanine aminotransferase or aspartate aminotransferase (11.54%). The most frequent ≥ grade 3 AEs were leukopenia (11.54%) and thrombocytopenia (7.69%). 2 serious AEs (1 left heart failure and 1 intestinal obstruction) were recorded. No treatment-related death occurred. Conclusions: This study suggested that anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance demonstrated encouraging efficacy with a manageable safety profile in the first line treatment of patients with advanced STS. Clinical trial information: ChiCTR2100054711 .
Novel MRI scoring system to assess osseous malignancy in patients with soft tissue sarcoma following radiotherapy.
Authors: Vijayakumar Gayathri , Jones Conor M. , Supple Stephen , Meyer John R. , Blank Alan T. 
Published: June 2023

11561 Background: Although radiotherapy is an important component of STS management, radiation induced changes such as radiation osteitis are commonly identified on magnetic resonance imaging (MRI). These imaging findings may be concerning for malignancy and sometimes require biopsy for investigation. This study proposes a novel MRI scoring system to assess osseous lesions and predict potential for malignancy based on MRI score in STS patients who received radiotherapy. Methods: The MRI score consisted of 3 parameters: morphology, signal intensity, and progression. Interobserver reliability between the total score of MRI examinations scored by two senior musculoskeletal radiologists were analyzed with Cohen’s kappa coefficient. Receiver operating curve (ROC) analysis was performed to determine a predictive MRI score for malignancy. Results: 156 MRI’s from 30 STS patients who received radiotherapy were retrospectively reviewed. Two (6.7%) patients developed regional osseous metastasis identified on MRI. The kappa coefficient of the scoring system was 0.785 demonstrating substantial interobserver agreement (p<0.001). ROC analysis demonstrated that the optimal cut-off value for malignant lesion on MRI was 5.5 (area under the curve 0.998 (95% CI 0.993-1.000) p<0.001). Conclusions: This novel MRI scoring system recommends lesions with a score of six and above to be biopsied to distinguish if malignancy is present. We believe this scoring system can be utilized by multidisciplinary care teams to guide clinical recommendations for patients with STS and MRI findings concerning for malignancy versus radiation induced changes.[Table: see text]
The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Analysis of overall survival in advanced synovial sarcoma.
Authors: Van Tine Brian Andrew , Ganjoo Kristen N. , Blay Jean-Yves , Valverde Claudia , Araujo Dejka M. , Abdul Razak Albiruni Ryan , Le Cesne Axel , Schuetze Scott , Wagner Michael J , Attia Steven , Forcade Edouard , Druta Mihaela , Pollack Seth , Bai Jane , Bayer Paige , Van Winkle Erin , Norry Elliot , McAlpine Cheryl , Williams Dennis , D'Angelo Sandra P. 
Published: June 2023

11563 Background: Afami-cel is an autologous, T-cell receptor (TCR) T-cell therapy to treat human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). The efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma are being evaluated in the Phase 2, two-cohort, open-label, SPEARHEAD-1 (NCT04044768) trial. Here we report interim overall survival (OS) data in the pts with advanced synovial sarcoma in Cohort 1. Methods: Pts who were HLA-A*02 positive with advanced synovial sarcoma (with evidence of clinical/radiological progression) positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The primary endpoint was overall response rate per RECIST v1.1 by independent review. Secondary endpoints included OS and progression-free survival (PFS), estimated utilizing the Kaplan-Meier method. Results: As of August 29, 2022, 44 pts with synovial sarcoma received afami-cel (2.68–9.99×109 transduced T-cells) in Cohort 1. The median age was 41 years (range: 19–73 years), 50% of pts were female, 89% of pts were white, 96% of pts were typed as HLA-A*02:01P, and median tumor MAGE-A4 expression H-score was 257 (132–300). Pts were heavily pre-treated with a median of 3 prior lines of therapy (range: 1–12). The median follow-up time at the data cut-off was 20.8 months. Median PFS was 3.8 months (95% CI: 2.8, 5.8) and 4.1 months (95% CI: 2.8, 6.9) by independent and investigator review, respectively. Median OS by independent review was 15.4 months (95% CI: 10.9, not estimable) with 52% of pts censored at the data cut-off. The 12-month OS probability was 60% and 24-month OS probability was 40%. Twenty-one pts received additional therapy during long term follow up (systemic therapy, n = 20; radiation, n = 6; other, n = 4). In the 17 pts who had a RECIST response by independent review, the median OS was not reached, the 12-month OS probability was 90%, and 24-month OS probability was 60%. Conclusions: Pts with advanced synovial sarcoma treated with afami-cel in SPEARHEAD-1 had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 .