bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic analysis of novel tumor suppressor gene fusions in bone sarcomas.
Authors: Grachev Dmitrii , Ivanov Danil , Kushnarev Vladimir , Yong Sheila T. , Kotlov Nikita , Chernyshov Konstantin , Bagaev Alexander , Fowler Nathan Hale , Conley Anthony Paul , Cote Gregory Michael , Chawla Sant P. 
Published: June 2024

11523 Background: Despite the evolution of therapeutic strategies for sarcomas in the past four decades, survival in the metastatic setting remains poor. This underscores the urgent need to explore new diagnostic and treatment avenues to improve patient outcomes. Harnessing the capability of RNA sequencing (RNA-seq) to detect gene fusions de-novo, we analyzed treated bone sarcoma samples with the aim to uncover gene fusions and breakpoints that are potentially relevant as clinical biomarkers and treatment targets. Methods: We analyzed 83 formalin-fixed, paraffin-embedded tumor samples of treated bone sarcomas, including osteosarcomas, chondrosarcomas, chordomas, and Ewing sarcomas. These samples were subject to in-depth whole exome analysis and bulk RNA-seq. RNA-seq was employed to identify gene fusions, with STAR-fusion utilized for sequence calling. Quality control of all NGS samples was performed using FastQC, FastQ Screen, RSeQC, and MultiQC. Tumor purity was assessed via pathological and bioinformatics examination with the threshold set at 20%. Fusions involving tumor suppressor genes listed in the OncoKB database were investigated further. A comprehensive literature search on PubMed and Google Scholar as well as analysis of the FusionGDB and COSMIC databases were performed to verify candidates of novel gene fusions. We also compared our samples with those in the publicly available MSK sarcoma cohort and 11 osteosarcoma cell line datasets. Results: We detected 238 gene fusions in all samples analyzed. Among these fusions, 18 (16 previously unknown, 2 previously reported) involving known tumor suppressor genes were present in 14 samples (17%). Among the 16 previously unknown fusions, 8 were indicative of potential loss-of-function variants of tumor suppressors: TP53-NF1, TP53-CEMIP, CTNNBL1-RB1, PRPF40A-FBXW7, VAMP2-MSH3, and ETV6-ATM in osteosarcoma; BRD4-TP53 in unspecified bone sarcoma; and FBXW7-ZNF770 in Ewing sarcoma. Furthermore, we also uncovered a novel breakpoint combination in EWSR1-ETV4 in Ewing sarcoma that links exon 9 of EWSR1to exon 9 of ETV4. Conclusions: Our comprehensive transcriptomic analysis of treated sarcoma samples uncovered previously unknown gene fusions involving tumor suppressor genes and a unique breakpoint combination in an oncogene. These findings emphasize the crucial role of RNA-seq not only in advancing genomic research of sarcomas, but also in identifying potential biomarkers/targets and devising new treatment strategies for this rare cancer.
Personalized tumor-informed circulating tumor DNA analysis in monitoring recurrence following resection of high-risk stage II-III gastrointestinal stromal tumor.
Authors: Gao Zhidong , Cheng Baosen , Bao Yudi , Cui Peng , Du Haiwei , Fan Xuning , Peng Di , Yang Shuya , Wu Xin , Zhao Dongbing , Xing Zhaodong , Cao Feng , Zhang Wei , Li Bing , Li Chengcheng , Zhang Yuzi , Wang Guoqiang , Cai Shangli , Ye Yingjiang 
Published: June 2024

11534 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Radical resection is the standard treatment of localized GIST, yet the 5-year recurrence rate for high-risk GIST is more than 50%. It remains unclear whether detecting post-surgery molecular residual disease (MRD) via circulating tumor DNA (ctDNA) can predict the recurrence of high-risk locally advanced GIST. Methods: Patients with high-risk stage II-III GIST who underwent R0 surgery and following adjuvant imatinib/avapritinib were enrolled prospectively. Surgical tissue samples were collected. Blood samples were drawn pre-surgically, and at 7 days, 1 month, and every 3–6 months post-surgically. Tumor-derived variants were identified by whole-exon sequencing of the surgical tissues. Up to 50 highly ranked variants with a variant allele frequency 3.0% were selected for the personalized panel design, which was subsequently used to assess MRD status. Results: A total of 36 patients with a median age of 65 years were included in the current analysis (data cutoff on January 16, 2024). Most tumors (17/36, 47%) were located at the stomach or gastroesophageal junction, and 94.4% of patients (34/36) did not receive neoadjuvant treatment. The mean maximum diameter of tumors was 7.87 ± 2.87 cm. At present, 36 tissue samples, 34 pre- and 161 post-surgical blood samples were collected and analyzed. Tissue sample-based sequencing identified variants in KIT and PDGFRA in 31 (86%) and 4 (11%) patients, respectively. 98.4% (1003/1019) of tumor variants included in personalized panels were patient-specific. ctDNA was detected in 64.7% (22/34) of pre-surgical plasma samples. The ctDNA-positive rate at baseline was associated with tumor mutation burden (p < 0.05), rather than tumor size (p = 0.6). Landmark analysis at 1 week post-surgery showed that 12.1% of patients were positive for ctDNA. Up to now, 4 patients were identified with tumor recurrence based on imaging results. Among these patients, 3 patients (3/4) exhibited ctDNA positivity preceding radiological recurrence. Notably, a 71-year-old patient was ctDNA-positive at 1 week post-surgery. Longitudinal analysis revealed that his ctDNA became negative after adjuvant treatment but turned positive at 9 months post-surgery, with a lead time of 2 months prior to his radiological recurrence. Additionally, a patient tested positive for ctDNA at 3 months post-surgery but had negative imaging results. Follow-up visits are ongoing for this patient. Conclusions: The present study suggests that personalized tumor-informed ctDNA has the potential to inform recurrence in high-risk stage II-III GIST patients. Clinical enrollment is still ongoing.
Phase IB/II trial of durvalumab plus doxorubicin combination in patients with advanced soft-tissue sarcoma.
Authors: Cho Hee Jin , Sim Nam Suk , Shin Su-Jin , Yun Kum-Hee , Lee Young Han , Jun Hyun Jung , Rha Sun Young , Kim Hyo Song 
Published: June 2024

11552 Background: We conducted an open-label, phase IB/II study to determine the activity and safety of the standard-of-care, doxorubicin in combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in patients with anthracycline-naïve soft tissue sarcoma (STS) and identified patients who would likely benefit from combination treatment. Methods: In this trial (NCT03798106), we enrolled patients with metastatic and/or recurrent STS had not received anthracycline chemotherapy and PD-L1/PD-1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin [level 1 (75mg/m2) and level -1 (60 mg/m2)] in combination with durvalumab 1500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II assessed the efficacy, with the primary endpoint to detect a difference in objective response between 5% and 20%. Results: No DLTs were observed during the phase IB (n=3), therefore recommended phase II dose was defined at doses of 75/m2 doxorubicin and proceed the phase II part. Of 41 evaluable patients, 1 (2.4%) achieved complete response, 12 (29.3%) achieved confirmed partial response, yielding an objective response rate of 31.7%. The median progression free survival was 8.2 months (95% CI, 7.3-9.0) and median overall survival was 24.1 months (95% CI, 7.6-40.3). Treatment-related adverse events of grade 3 or 4 occurred in neutropenia (n = 23, 53.4%), thrombocytopenia (n=6, 13.9%), and anemia (n=5, 11.6%). The prespecified genomic analysis with targeted and transcriptomic sequencing will be available at the meeting. Conclusions: Durvalumab combined with doxorubicin demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. Clinical trial information: NCT03798106 .
Safety and toxicity evaluation of the combination of selinexor with atezolizumab in patients with soft tissue sarcomas.
Authors: Ahmed Jibran , O'Sullivan Coyne Geraldine Helen , Moore Nancy , Foster Jared C. , Gore Steven , Chen Helen X. , Juwara Lamin , Johnson Barry C. , Doroshow James H. , Chen Alice P. 
Published: June 2024

11557 Background: The U.S. Food and Drug Administration (FDA) recently approved the anti-PD-L1 antibody atezolizumab for alveolar soft part sarcoma (ASPS). Selinexor, a selective XPO1 inhibitor, demonstrated cytotoxic activity in ASPS-KY and ASPS-1 cell lines of ASPS and other sarcoma cell lines; it has been approved as a part of regimens to treat multiple myeloma and diffuse large B-cell lymphoma. Preliminary clinical data demonstrate acceptable safety profiles in patients with melanoma who received selinexor in combination with an anti-PD-1 antibody. Methods: We designed a randomized phase 2 study to evaluate atezolizumab with or without selinexor in adult patients with ASPS that included a safety run-in (SR) open to patients with soft tissue sarcoma (NCT05333458). Prior immune checkpoint inhibitor therapy was not allowed. During the SR, patients received selinexor (60 mg PO) on days 1, 8, and 15 of the 28-day cycle and atezolizumab (1200 mg flat dose IV) on day 8 at the Developmental Therapeutics Clinic. Protocol-defined treatment-related adverse events (TRAEs) occurring during cycle 1 would either expand accrual to the SR or close the study. Safety data were evaluated by the principal investigator and NCI CTEP (National Cancer Institute Cancer Therapy Evaluation Program). Results: Six patients were enrolled in the SR and were evaluated weekly during the first cycle of study treatment. All patients were female with a median age of 47 years (range: 22-71 years). Diagnoses included sclerosing epithelioid fibrosarcoma (n=2), dedifferentiated liposarcoma (n=1), metastatic leiomyosarcoma (n=1), metastatic angiosarcoma (n=1), and ASPS (n=1). No patients were removed from the SR due to AEs. Two patients experienced grade 3 TRAEs, including one instance each of neutropenia and lymphopenia (Table). Beyond cycle 1, there was 1 occurrence of grade 3 lymphopenia. No grade 4 or 5 AEs have occurred during the SR. Fatigue and nausea were the most prevalent TRAEs, but only one patient experienced grade 2 nausea; all other occurrences of nausea and fatigue were at grade 1. Conclusions: The safety run-in completed without any occurrences of protocol-defined treatment-related toxicity during cycle 1. The treatment was well tolerated. Based on these data, the randomized part of this study began accruing patients with ASPS across the ETCTN (Experimental Therapeutics Clinical Trials Network). Clinical trial information: NCT05333458 . [Table: see text]
Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in a phase 2 expansion cohort of patients (Pts) with synovial sarcoma (SS).
Authors: Cote Gregory Michael , Martin Broto Javier , Chawla Sant P. , Bockorny Bruno , Falcon Gonzalez Alejandro , López Pousa Antonio , Paz-Ares Luis G. , Verret Benjamin , Martinez Sara , Extremera Sonia , Cullell-Young Martin , Fudio Salvador , Kahatt Carmen Maria , Zeaiter Ali Hassan , Le Cesne Axel 
Published: June 2024

11560 Background: LUR has shown activity in several solid malignancies. Preclinical studies found synergism for LUR combined with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The recommended dose was defined at LUR 2.0 mg/m2 on Day (D) 1 + IRI 75 mg/m2 on D1, D8 q3wk with primary G-CSF prophylaxis. After observing 3 partial responses in SS pts during the phase 1b part, a phase 2 expansion cohort was implemented to explore this activity further. Methods: This cohort included pts with SS progressing after up to 2 prior cytotoxic-containing lines for advanced disease. The primary endpoint was overall response rate (ORR) per independent review committee (IRC)/investigator. Results: Thirty pts were enrolled and treated. Baseline characteristics were median age 41 y (range, 19-73), 57% males, 53% ECOG PS=1. Primary tumor location was mostly in the extremities (53%). Most common tumor metastatic sites at study entry were lung (83%), pleura (37%) and lymph nodes (23%). 60% had at least one lesion >50mm. The median number of prior lines was 2 (range, 1-5), and the median number of prior chemotherapy lines for advanced disease was 1 (range, 0-3). The median time from diagnosis was 32 mo (range, 2-160 mo). The best response to first-line therapy was stable disease in 50% of pts and progressive disease in 8%. Efficacy results are summarized (Table). Most common G3/4 events/abnormalities were neutropenia (60%), anemia (27%), thrombocytopenia (17%), diarrhea (10%), fatigue (10%) and febrile neutropenia (10%). 20% had treatment-related SAEs. No treatment-related discontinuations or deaths occurred. No evidence of drug-drug interaction was observed in the PK analysis. Conclusions: The LUR/IRI combination showed activity in pretreated SS with manageable toxicity. These results reinforce the rationale for assessing the activity of LUR combined with IRI in SS and other tumor types. Clinical trial information: NCT02611024 .[Table: see text]
Predictors of cardiotoxicity in patients with early breast cancer treated with doxorubicin and/or trastuzumab: Implications of race/ethnicity and insurance status.
Authors: Jahangier Shahzaad Khadeem , Qamar Rubina 
Published: June 2024

12021 Background: Approximately 4.1 million women in the US are living with breast cancer1. Cardiac dysfunction is a significant adverse effect of commonly used breast cancer therapies like doxorubicin (D) and trastuzumab (T). The cardiotoxicity (CTox) associated with these agents manifests as a reduction in left ventricular ejection fraction (LVEF) with or without signs and symptoms of heart failure. Purpose: Identify high-risk populations susceptible to developing CTox, with a focus on identifying individuals who could potentially benefit from the early initiation of empiric cardioprotective therapies. Methods: We investigated the relationship of race/ethnicity, insurance status, treatment regimen and comorbidities including hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), tobacco use, BMI, age, and radiation therapy on the development of CTox from D and/or T. A total of 133 newly diagnosed stage I-III invasive breast cancer patients were enrolled in a prospective clinical trial (2013-2017) and received standard of care D and/or T based systemic therapy. Echocardiogram data was collected every 6 months for two years and then based on clinical need for a total of six years. CTox was defined as a >10% drop in LVEF, and/or LVEF <50%. Results: Our study included a population of 133 patients comprising Black (22%), White (77%), and Hispanic (1.5%) individuals. Among these patients, 32 developed CTox (Black 41%, White 19%, Hispanic 50%). Of all patients, 29% had State insurance while 71% had Private insurance. Prevalence rates for comorbidities were as follows: HTN (41%), HLD (32%), DM (13%), and tobacco use (36%). In a univariate logistic regression model, race/ethnicity, HTN, insurance status, and tobacco use were most strongly associated with Ctox. When controlling for tobacco use and HTN, race/ethnicity was not significantly associated with Ctox. However, direct comparisons of levels of race/ethnicity showed that Black patients were more likely to develop Ctox when compared to White patients (OR 2.60, 95% CI = 1.01-6.65, P = 0.045). HTN patients were also more likely to develop Ctox, when controlling for ethnicity and tobacco use (OR 2.62, 95% CI = 1.10-6.43, P = 0.031). In a separate multivariate analysis, we examined insurance as a surrogate for socioeconomic status. State insurance was associated with an increased risk of developing CTox when controlling for race/ethnicity and HTN (OR 3.73, 95% CI = 1.47-9.58, P = 0.006). Furthermore, in all models, HLD, DM, BMI, age, and radiation field were not found to be significantly associated with increased CTox. Conclusions: In our well characterized population of patients with stage I-III breast cancer, who were prospectively followed and received standard of care systemic therapy, we observed an association between insurance status with increased risk of CTox from treatment regimen.
Using natural language processing to qualitatively assess goals of care conversations for patients with cancer.
Authors: Greene Melissa , Broadwater Gloria , Niedzwiecki Donna , LeBlanc Thomas William , Ma Jessica , Casarett David J. , Davidson Brittany Anne 
Published: June 2024

12035 Background: The importance of goals of care (GOC) discussions during end-of-life (EOL) care is well known. Institutions are increasingly tracking the frequency and timing of GOC documentation, but qualitative assessments of this content on a large scale have been limited given the person-power required and constraints of electronic health systems. Our aim is to use natural language processing to qualitatively assess the content of GOC documentation and associations with EOL care in patients who died with cancer. Methods: This is a retrospective review of patients with solid or hematologic malignancies who died between 2018-2022 with documented GOC notes in the last 12 months of life at a single academic National Cancer Institute-designated cancer center. Eight GOC components were identified based on prior literature: current understanding of patient’s illness, information preferences, disclosure of prognosis, goals, fears, acceptable function, trade-offs, and family involvement. GOC notes were extracted from the electronic health record and text annotation software Clinical Regex was utilized to search for the aggregate presence of these GOC components. Associations between these 8 components and receipt of aggressive EOL care (chemotherapy within 14 days of death, no hospice care, or hospice admission ≤3 days of death) were evaluated. Results: 2,031 patients met inclusion criteria. The most common disease sites were gynecologic (22.6%), gastrointestinal (20.3%), and thoracic (16.7%). The most common GOC components addressed were family involvement (75.0%), patient goals (72.0%), acceptable function, and decision making & information preferences (both 65.8%). Only 5.4% had all 8 components addressed in documentation the last 12 months of life. More comprehensive GOC notes were associated with lower rates of aggressive EOL care; 73.2% received aggressive EOL when 0/8 components were documented, compared to 56.8% and 50.3% when 6 or 7 components were discussed, respectively. In multivariate logistic regression, GOC components documented (≤6 vs ≥7), primary tumor site, and inpatient palliative care referral were independent predictors of aggressive EOL care (p-values <0.0001). Conclusions: GOC conversation documentation is largely not comprehensive. Increasingly comprehensive documentation is associated with a lower likelihood of receiving aggressive EOL care, suggesting opportunities to improve both the quality and documentation of GOC conversations may impact the EOL care for patients with cancer. Opportunities for increasing outpatient palliative care referrals may also improve the quality of the EOL experience for patients.[Table: see text]
Chemotherapy-induced peripheral neuropathy research: A National Institute of Health (NIH) grant portfolio analysis.
Authors: Altshuler Rachel D. , Minasian Lori M. , Schweppe Catherine , Kadan-Lottick Nina S. 
Published: June 2024

12064 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating cancer treatment-related toxicity associated with considerable discomfort, functional loss, and impaired quality of life both acutely and long-term. Unfortunately, limited prevention and treatment options for CIPN currently exist. In this portfolio analysis, we sought to describe the landscape of CIPN research and identify gaps and opportunities to meet the needs of patients with CIPN. Methods: Using the NIH Query View Report system to search all NIH-funded competitive grants awarded between fiscal years 2014-2023, we identified 660 grants containing text pertaining to CIPN in the Abstract or Specific Aims. Grants were then manually reviewed and 480 were excluded as not specifically addressing CIPN. We categorized the final 180 grants as preclinical, clinical, or preclinical/clinical, followed by ascertainment of preclinical model, clinical population, CIPN assessment techniques, and/or clinical trial design, as applicable. Results: Of the 180 grants, 119 were preclinical, 51 clinical, and 10 with both preclinical and clinical components. The larger number of CIPN grants (n=27) were awarded in fiscal year 2022 vs. the lowest number (n=10) in 2014. Among the preclinical grants, 89% of grants utilized rodent models of CIPN, of which 19% proposed tumor-bearing models. A large majority of preclinical grants investigated paclitaxel (71%), followed by oxaliplatin (23%); none proposed studies of newer immune therapies. Among clinical grants, 41% (n=21) were interventional trials, 38% were prospective observational studies, and 15% retrospective studies. Clinical grants most frequently focused on breast cancer patients (41%), followed by unspecified cancer diagnoses (33%) and colorectal cancer (18%). For age of eligibility, 11% included patients younger than 18 years, while a higher proportion included 18-39 (82%), 40-64 (88%), and ≥65 (89%). The 21 interventional study grants investigated behavioral interventions (44%), pharmacological agents (28%), and devices (28%). Conclusions: The number of CIPN grants awarded annually by NIH have generally increased since fiscal year 2014, indicating increased investment by NIH. However, multiple gaps and opportunities remain. At the preclinical level, in addition to current rodent models and the narrow range of treatment exposures, novel strategies to mimic human CIPN conditions may improve translatability. Clinical studies are needed in younger patients that can be impacted by CIPN long-term. Also, there are important gaps in the CIPN-associated cancer diagnoses and therapy exposures (including novel agents) in current studies. Addressing the highlighted gaps may identify avenues to study additional interventions that achieve the highest impact in the populations that most need them.