bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving clinician knowledge of cancer-related anemia (CRA) and chemotherapy-induced anemia (CIA) through the execution of a hybrid educational initiative focused on the evolving role of intravenous iron.
Authors: Taylor Bryan Carson , Rodgers George M. , Gitzinger Susan H. , Trieu Tina , Carranza Vanessa , Hall Jessica , Weaver Rebecca 
Published: June 2022

e23001 Background: Anemia is an extremely common and robustly deleterious complication experienced by patients with cancer, with impacts ranging from patient-reported quality-of-life metrics, to functional capacity, to morbidity and mortality implications. Cancer-related anemia (CRA) and chemotherapy-induced anemia (CIA) arise from a complex pathogenesis and are often associated with multifactorial etiology, but iron deficiency (ID) is an especially prominent genesis in these patients and is a preeminent clinical focus for hematology/oncology clinicians, not only because of its frequency, but also because it is directly treatable and reversible. Recent positive data readouts examining intravenous iron as a mechanism to improve anemia outcomes in comorbid oncologic states illustrates a compelling and exigent need to educate the hematology/oncology clinicians managing patients with cancer. These clinicians are optimally positioned to ensure improved CRA/CIA patient outcomes. That was the formative objective of this educational initiative. Methods: We conducted a 180-minute symposium at the 2021 American Society of Hematology (ASH) Annual Meeting, with a panel of 5 hematology/oncology experts. The activity was delivered live, in-person in Atlanta, and was also live streamed to a national and international audience on a virtual basis; the session was then provided as an online on-demand offering for those couldn’t attend the live meeting. Clinician knowledge metrics were evaluated from pre-activity to post-activity via audience response software (in-person) and Zoom polling (virtual); all test questions were directly correlated with activity learning objectives. Results: Across all 3 delivery modalities, the educational initiative reached a vast audience of nearly 8,000 learners. Meaningful knowledge advancements were achieved across each of the following clinical topics of emphasis (statistics reflect differential between pre-test and post-test performance): Diagnosis of CRA/CIA using clinical signs, symptoms, and laboratory diagnoses (+17%). Differentiation of functional vs. absolute iron deficiency (+33%). Identifying how elevated hepcidin levels impact iron supplementation strategies (+37%). Knowledge of improved safety profiles of next-generation IV iron products (+75%). Correctly evaluating the benefits of IV iron given a real-world CIA patient case (+33%). Conclusions: Our outcomes illustrate both the relatively low baseline knowledge of hematology/oncology clinicians related to CRA/CIA management and the transformative impact of timely educational programming. Ongoing educational efforts focused on this clinical topic and target audience are warranted.
Surgical subtypes and survival in stage II osteosarcoma: A National Cancer Database (NCDB) analysis.
Authors: Eaton Vincent , Tupper Connor , McMahon Kevin , Silberstein Peter T. 
Published: June 2022

e23513 Background: Osteosarcoma (OSC) is the most common primary malignancy of bone and is most commonly diagnosed in its earlier stages (I and II). Standard of care involves a combination of chemotherapy and surgical resection and, to date, there are few reports examining different surgical subtypes in these patients. This study aims to analyze different surgical subtypes in OSC patients to assess survival, particularly in stage II. Methods: Using the NCDB, patients diagnosed with stage II OSC between 2004-2018 were identified using ICD-O-3 histology codes 9180-9193. The cohort was analyzed to determine if they received any of the following surgical subtypes: local tumor destruction/excision, partial excision, radical excision with limb salvage, limb amputation, and major amputation. Univariate analysis was performed assessing patient survival length for each surgical subtype. Data was analyzed using SPSS and statistical significance was set at α = 0.05. Results: A total of 3827 patients were analyzed. Patients who received surgery survived significantly longer than those who did not (p < .00001). Patients who underwent major amputations had shorter median survival times ranging from 24-74 months. Patients who received radical tumor excision with limb salvage had the longest survival of any surgical subtype with a mean of 130.1 months and survived significantly longer than patients receiving local tumor resection, partial resection, partial and total limb amputations, or any major amputation (p < .001). Patients with local tumor destruction survived similarly to those with local tumor excision (p > .05). Patients with partial or total limb amputation had significantly better survival than patients with major limb amputation (p < .01). Conclusions: We found numerous significant differences between the different surgical subtypes used to treat patients with OSC. Radical excision with limb salvage proved to yield the best survival outcomes, with significantly higher survival when compared to almost all other surgical subtypes (excluding local tumor destruction). Future studies should investigate additional parameters within each surgical subtype to assess the impact that variables like patient demographics and socioeconomic status, tumor characteristics, and surgical center may have on access to care and survival outcomes.[Table: see text]
The long-term analysis of prognostic role of mutational status in primary resectable gastrointestinal stromal tumors (GIST).
Authors: Sobczuk Pawel , Bylina Elzbieta , Klimczak Anna , Rutkowski Piotr 
Published: June 2022

e23517 Background: Radical surgery is the primary treatment for GIST, but up to 50% of patients relapse, mainly in form of hepatic and peritoneal metastases. GISTs are a group of tumors with various pathological and molecular features as well as different clinical courses. The aim of the study was the long-term analysis of prognostic role of mutational status in primary GIST after radical resection. Methods: The material consisted of a group of 304 patients with primary GIST diagnosed till 04/2012, with known mutational status and treated surgically with curative intend without adjuvant imatinib. Data were collected prospectively as part of the GIST clinical register. Relapse-free survival (RFS) was calculated from the date of GIST resection to the date of local recurrence, distant metastatic disease or last follow-up. Overall survival (OS) was calculated from the date of resection to the date of last follow-up or death. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate Cox regression was performed to asses impact of mutational status on RFS and OS. Results: The primary tumor (PT) locations were: gastric (57.6%) vs non-gastric (42.4%). The median of tumor size was 7cm (0.5-33 cm). Mitotic index was ≤5 in 54.3%, > 5 in 45.7%. Mutations in KIT gene exon 11 were as follow: del 557-558 in 22.7% or other (point mutations, other deletions or insertions) in 40.1% with similar rates in gastric and non-gastric GIST. KIT gene exon 9 dup 502-503 (7.2%) were more common in non-gastric vs gastric GIST (16.3% vs 0.6%). PDGFR D842V was observed in 26 patients (8.6%) while other mutations in PDGFRA gene in 17 (5.6%). The median follow-up was 25.1 months. Disease recurrence was observed in 124 cases (40.8%) resulting in median RFS of 84.4 (95%CI 48.3-120.5) months. The negative independent risk factors for RFS in univariate analysis were: primary tumor location, tumor size, mitotic index and KIT exon 9 dup 502-503 mutation (P < 0.05). In the multivariate analysis independent predictive factors for RFS were mitotic index > 5 (HR 4.38, 95%CI 2.82-6.78), PT location (HR 1.56, 95%CI 1.01-2.39). In multivariate analysis in patients with gastric GIST PDGFR D842V mutations were significantly correlated with better RFS (HR 0.16, 95%CI 0.04-0.61), what was not observed in non-gastric GIST. The median OS was 198.1 months. The negative independent risk factors for OS in univariate analysis were: primary tumor location, primary tumor size and KIT gene exon 9 dup 502-503 mutation. Mitotic index was also negative independent risk factors in a multivariate analysis (HR 1.70, 95%CI 1.15 -2.52). Conclusions: In the long-term analysis mutational status of primary resectable GIST is related to risk of relapse especially in gastric location, however it has no independent impact on overall survival. Genotype should be included in modern risk classification of GIST.
Multi-modal single-cell profiling of sarcomas from archival tissue reveals mechanisms of resistance to immune checkpoint inhibitors.
Authors: Caldwell Blake , Bose Sminu , Amin Amit Dipak , Tagore Somnath , Melms Johannes C , Berhe Simon , Ingham Matthew , Schwartz Gary K. , Izar Benjamin 
Published: June 2022

e23518 Background: Single-cell RNA-seq is an enabling technology that may inform the molecular underpinnings of drug response and resistance in patient biopsies. This method is difficult to implement in the study of rare diseases such as sarcomas due to specimen requirements and technical limitations. Methods: Here, we evolved novel methods that we recently reported in melanoma ( Wang, Fan, et al., bioRxiv, 2022), which enable single-nucleus RNA, T cell receptor (snRNA/TCR)-seq, and pool-matched whole-genome sequencing (WGS) from archival, frozen sarcoma tissue. Results: This enabled profiling of 75,716 cells and 788 matched TCR clonotypes from six patients with intimal sarcoma (INS) and undifferentiated pleomorphic sarcomas (UPS), including two matched pair samples from pre/post-immune checkpoint inhibitor (ICI). Our analysis revealed substantial transcriptional cancer cell heterogeneity driven by varying copy number alterations (CNAs). In one patient with INS with a complete response to ICI followed by an isolated recurrence, we identified a rare cancer cell clone defined by CNA (confirmed with WGS) and resulting transcriptional outputs that pre-existed and emerged during resistance. Furthermore, in a patient with UPS with intrinsic resistance to ICI, we find adequate T cell clonal expansion and activation, suggesting appropriate T cell response to ICI dampened by intrinsic mechanisms of ICI resistance within the cancer cells. Non-negative matrix factorization (NMF) analysis identified cell states associated with either intrinsic or adaptive resistance to ICI that was distinct from resistance to doxorubicin. These observations are consistent with those previously reported from sequential biopsies obtained from KEYNOTE-001 in metastatic melanoma ( Wang, Fan, et al., bioRxiv, 2022), which also revealed emergence of pre-existing populations of resistant clones defined by their underlying aneuploidy patterns. Conclusions: Together, these results demonstrate feasibility of implementing single-cell genomics from archival tissue to study sarcoma and propel our understanding of drug resistance. Conceptually, this work suggests that large-scale CNAs may drive cell sub-populations associated with ICI resistance in sarcoma and in other diseases.
Increased phosphorylation of RB and protein expression of Cyclin E confers resistance to CDK4/6 inhibitors in dedifferentiated liposarcoma.
Authors: Hsu Jocelyn , Seligson Nathan David , Hays John L. , Chen James Lin 
Published: June 2022

e23525 Background: Dedifferentiated liposarcomas (DDLPS) are malignant adipocytic cancers characterized by an amplification of the cell cycle regulatory gene, CDK4. Palbociclib, a CDK4/6-inhibitor, is a standard of care treatment; however, innate and acquired resistance to the drug limits efficacy in patients with DDLPS. Molecular mechanisms and biomarkers of palbociclib resistance have been posited in non-mesenchymal tumors but are poorly understood in DDLPS. To this end, we developed palbociclib-resistant DDLPS cell lines derived from several DDLPS patient samples to better characterize these phenotypic and genomic differences. Methods: Three human CDK4 amplified DDLPS cell lines (224A, 246, 863) and one control liposarcoma control cell line without CDK4 amplification and RB loss (LiSa2) were brought into culture. Each cell line was intermittently treated with palbociclib at their respective IC25 for 6 months to develop resistance in long-term treated cell lines. Surviving cells were allowed to recover for at least 2 weeks before retreatment. Parental lines were grown as controls in tandem with the developing resistant lines to compare molecular changes in response to palbociclib. Cell viability was measured by XTT, cell cycle analysis was measured with Flow cytometry using a PI stain, and protein expression was measured using whole cell lysates for Western blotting. Results: The four cell lines had IC50s to palbociclib ranging from 15.0, 14.8, 12.0, and 11.4 µM for LiSa-2, 224A, 246, and 863 cell lines respectively. Long-term treated strains demonstrated consistent reductions in the measured IC50s (8.99, 7.32, 8.27, and 7.08 µM respectively). After treatment with 10 µM of palbociclib for 48 hours, two parental cell lines showed a greater increase in cells in the G1 fraction than long-term treated cells: LiSa-2 (-2.4% increase in parental vs -16.5% increase in long-term treated) and 863 (16.2% vs 11.7%). 224A and 246 demonstrated the opposite where parental cell lines had fewer cells in G1 after treatment compared to long-term treated cell: 224A (12.6% vs. 20.5%) and 246 (12.6% vs. 21.6%). Western blots indicated that the initial response to palbociclib in parental cell lines decreased pRb protein levels and increased Cyclin E and CDK6. After 6 months of treatment for all cell lines, a significant increase in pRb and Cyclin E were observed in the long-term treated cell lines and no changes were seen in CDK4, Cyclin D, nor p16. Conclusions: Here we present the development of two novel, palbociclib resistant, DDLPS cell lines and two long-term treated cell lines. Our resistant cell lines indicated that the ability to bypass the G1/S-checkpoint in the presence of CDK4/6-inhibitors may result from increased phosphorylation of Rb and increased total of Cyclin E. Next generation sequencing of RNA expression in parental and resistant lines are underway.
Variation in survival rates among patients with angiosarcoma based on demographic and socioeconomic factors in academic versus non-academic settings: An NCDB analysis.
Authors: Creech Zachary , Truong Gia Thinh , Denny Regan , Hu Robert W. , Verplancke Kiana , Aurit Sarah J , Silberstein Peter T. 
Published: June 2022

e23537 Background: Angiosarcomas are malignancies of endothelial-cell origin representing 2% of soft-tissue sarcomas. Although the number of cases of angiosarcoma continues to rise, the prognosis is generally poor and treatment options remain limited. Due to the rarity of angiosarcoma and limited available literature, this study is intended to analyze the impact of demographic and socioeconomic factors on patients’ survival rates in academic versus non-academic settings. Methods: We performed a retrospective analysis of 5,544 patients diagnosed with angiosarcoma from the National Cancer Database (NCDB) between 2004-2017. Patients were stratified by facility type and compared via Kaplan-Meier analysis, log-rank test, chi-square analyses, and ANOVA. Additionally, a cox proportional hazards multivariate regression model was used. The following demographic factors were examined: age, sex, reported race and ethnicity, mean survival rates utilizing the Charlson Comorbidity Index, facility type where patients received treatments, and treatment modalities. Furthermore, the assumption of proportionality was tested for each variable. Data was analyzed using Statistical Analysis Software (SAS). Results: Higher rates of death were seen in those of male sex, African American race, increased age (> 72), and increasing Charlson-Deyo scores. There was an increased risk of death for older African American males with non-zero Charlson-Deyo scores. Additionally, patients from areas of increased income had decreased rates of death. After adjusting for most variables, patients who were treated at academic facilities had an 8.5% decreased risk of death compared with patients treated at non-academic facilities (95% CI: 1.5% to 15.0%; P = 0.019). Conclusions: Our study results indicate that certain demographic and socioeconomic factors may be linked to poorer survival outcomes in patients with angiosarcoma. Further investigation of socioeconomic barriers and prognostic factors for angiosarcoma may help to identify populations at risk for poor treatment outcomes and guide disease management.
Anlotinib rechallenge combined with immune checkpoint inhibitor for advanced soft tissue sarcoma after the failure of anlotinib.
Authors: Fu Yang , Jiang Yu 
Published: June 2022

e23541 Background: The anti-angiogenic tyrosine kinase inhibitor (TKI) anlotinib has been approved for the treatment of advanced clear cell sarcoma, alveolar soft-part sarcoma, and other anthracycline-failed advanced soft tissue sarcoma (STS) in China. However, the management of refractory STS is still an unmet medical need. The formation of immunosuppressive microenvironment is one of the resistance mechanisms of anti-angiogenic therapy. This retrospectively observational study investigated the efficacy and safety of anlotinib rechallenge combined with immune checkpoint inhibitor (ICI) for advanced STS after progression on anlotinib treatment. Methods: A cohort of STS patients who had progressed after the anlotinib treatment were prescribed with anlotinib plus ICI were enrolled. Other concurrent systemic treatments were not allowed. Demographic features and clinical outcomes were reviewed and analyzed. Results: A total of 10 STS patients were included. The median of previous systemic treatment regimens was 3 (range, 1-5). Two cases (20%) were observed a partial response, including anlotinib plus nivolumab for a leiomyosarcoma and anlotinib plus toripalimab for an angiosarcoma. Another 4 patients achieved stable disease lasting more than 6 weeks. The median progression-free survival (PFS) were 4.8 months (95% CI: NA-12.5 months). Three (30%) patients developed grade 3 or higher adverse events including toxicity of skin/mucosal(n = 2) and neutrophile granulocyte decreased(n = 1). Conclusions: ICIs plus anlotinib rechallenges maybe a potential treatment for advanced STS patients after progression on anlotinib with acceptable adverse events.
Insulin-like growth factor 1 and its binding protein-2 in tumor and peritumoral tissues as important factors involved in recurrence of soft tissue sarcomas in older men.
Authors: Sagatelyan Susan A. , Kaplieva Irina V. , Frantsiyants Elena M. , Goroshinskaya Irina A. , Vashchenko Larisa N. , Chernogorov Pavel V. , Ausheva Tatiana V. , Pogorelova Yulia A. , Kachesova Polina S. , Gusareva Marina A. , Atmachidi Dmitriy P. , Kit Oleg I. 
Published: June 2022

e23556 Background: The system of insulin-like growth factors (IGF) is involved in the pathogenesis of many malignant tumors. At the same time, the specificity of this system in recurrent soft tissue sarcomas is unknown. The purpose of this study was to analyze the IGF system in tumors and their peritumoral areas in men with recurrent soft tissue sarcomas. Methods: The study included 26 men aged 57.8±6.2 years with primary (n = 12, group 1, controls) and recurrent (n = 14, group 2, main group) soft tissue sarcoma of the extremities, T2bN0M0. Grade 1 tumors were diagnosed in 6 patients of group 1 and in 7 patients of group 2, while the other patients had G3 or G4 tumors. 95% of tumors were liposarcomas. All patients of group 2 had previously underwent surgical and radiation treatment for primary sarcomas and their relapses (up to 2 episodes), with the last surgery more than 1 year ago. Levels of the IGF system components were determined in tumor (T) and peritumoral (PT) tissues by ELISA, and ratios of IGF(T)/IGF(PT) were calculated. Results: Levels of the IGF system components in patients of group 1 were similar in T and PT. In group 2, levels of IGF1 and IGFВР2 in T were respectively 2.2 and 1.6 times (p < 0.05) lower than in PT, but did not differ significantly from the levels in group 1. The IGF1(T)/IGF1(PT) ratio in patients of group 2 was 1.8 times (p < 0.05) lower than in group 1. PT levels of IGF2 in group 2 depended on the tumor grade: they were 1.5 times (p < 0.05) higher in G1 than in G3-G4, while no such dependence was observed in T. Conclusions: The levels of the IGF system components in recurrent soft tissue sarcomas in older men had some peculiarities. Unlike primary sarcomas with similar levels of the studied components of the IGF system in tumors and in peritumoral tissues, recurrent tumors contained less IGF1 and IGFBP2 than the corresponding peritumoral areas. The levels of IGF2 in the peritumoral tissues of recurrent tumors depended on the tumor grade.
Sex dependence of hypothyroidism on malignant tumor growth.
Authors: Bandovkina Valeria A. , Frantsiyants Elena M. , Kaplieva Irina V. , Cheryarina Natalia D. , Surikova Ekaterina I. , Pogorelova Yulia A. , Arakelova Alina Yu , Salatova Ayna M. , Engibaryan Marina A. , Ulianova Yulia V. , Volkova Viktoriya L. , Rozenko Dmitry A. , Kit Oleg I. 
Published: June 2022

e23558 Background: Experimental data showed proliferative and anti-apoptotic effects of thyroxine (T4) and triiodothyronine (T3) on cancer cells which regulate gene expression and stimulate estrogen-like effects. The purpose of the study was to analyze effects of hypothyroidism on the development of malignant tumors in male and female rats. Methods: Female (n = 15) and male (n = 15) white outbred rats weighing 150 g and more received mercazolil (2.5 mg/100 g of weight) daily for 30 days (total dose of 75 mg/100 g of weight). Blood levels of T3, T4 and TSH were measured in all animals. When persistent hypothyroidism was observed, Guerin's carcinoma (GC, group 1) and sarcoma 45 (S45, group 2) were inoculated at a dose of 2 million cells in 0.5 ml of saline under the skin of the back to animals of both genders. The control group included rats of both genders with subcutaneous inoculation of Guerin's carcinoma and sarcoma-45 in the same dosage and volume but without preliminary reproduction of the hypothyroidism model. Results: Average tumor volumes in females with GC and hypothyroidism were less than in animals of the control group: after 4 days by 1.3 times (p < 0.05), after 7 and 10 days by 1.4 times (p < 0.05), after 14 days by 1.5 times (p < 0.05), after 18 days by 1.3 times (p < 0.05), and after 21 days by 1.4 times (p < 0.05). The survival of female rats in the main group was 1.6 times higher (p < 0.05) than in rats of the control group. Average tumor volumes in females with S45 and hypothyroidism were less than in animals of the control group: after 4 days by 1.4 times (p < 0.05), after 7 and 10 days by 1.6 and 3.2 times (p < 0.05), after 14 days by 3.9 times, and after 18 days by 4.8 times. The survival of female rats in the main group was 1.8 times higher (p < 0.05) than in rats of the control group. Average tumor volumes in males of the main group with GC and hypothyroidism after 18 and 21 days were similar to the values in animals of the control group. Their survival did not differ from the survival of control males. Average tumor volumes in males of the main group with S45 and hypothyroidism after 10 and 21 days were similar to the values in animals of the control group. Their survival did not differ from the survival of control males. Conclusions: Hypothyroidism in female rats with GC and S45 inhibited the growth of malignant tumors and improved the survival of animals, while in males no such inhibiting effect was observed.