tbuckley/cabot-search huggingface dataset:
A survey study of knowledge, attitude, and practice regarding oncofertility among health professionals in Uruguay.
Authors: Dana Kimelman, Maria Clara Rodriguez Palleiro, Matilde Boada
Journal: Journal of Clinical Oncology (2021)

e24041 Background: Oncofertility is a field dedicated to preserve fertility of children, adolescents, and young cancer patients'. For young cancer patients, fertility preservation (FP) has become an important concern that needs to be addressed before cancer treatment. This study aimed to evaluate the general knowledge, attitudes, and practice towards FP and pregnancy-related issues of health care professionals in Uruguay. Methods: We conducted an online survey distributed to physicians from multidisciplinary areas (Oncology, Radiotherapy, Hematology, Pediatric hematology-oncology, Gynecology, Urology) involved in daily medical care to young cancer patients. Results: 208 physicians from 16 geographical regions completed the survey. 53 % of the subjects were less than 40 years old, and 77.7% identified themselves as women. Most of the responders (99 %) agreed that FP counseling should be part of cancer treatment; however, only 49 % discusses FP and refers their patients in their daily clinical practice. Regarding referral of patients to an Oncofertility specialist, 36% do it occasionally, and 15% have never referred. Half of the responders (50%) stated that they know the available FP options for young cancer patients, 49% have an idea, and 1% are not aware. 37 % of participants consider that FP treatments would delay cancer treatment initiation, impacting their attitude towards FP recommendation and referral. Regarding FP coverage, 51.7 % were not aware of financial coverage for fertility preservation treatments availableness. 57% of physicians directly involved in breast cancer (BC) care agreed with the statement that oocyte cryopreservation is safe in BC patients with positive hormonal receptors, 35% are not sure, and 8% believe it is not safe, 46% believe pregnancy is safe after BC, 34% is not sure, while 20% consider it is unsafe. Conclusions: This study demonstrates the need to increase FP awareness in Uruguayan health care professionals. Moreover, several misconceptions on FP and pregnancy-related issues in BC patients have been identified. Focused research and education to improve physicians' knowledge and adherence to available international guidelines are urgently required to improve the care of young cancer patients who desire future fertility. Key Words: Oncofertility, fertility preservation, oocyte cryopreservation, breast cancer, pregnancy.
Abstract 15006: Non-White HIV Patients Suffer Worse Outcomes With Non-ST Elevation Myocardial Infarction: A Nationwide Inpatient Analysis
Authors: Sonu Gupta, Rupak Desai, Gurleen Kaur, Waleed Ali, Kartik Dhaduk, Anand Gupta, Hosseini Hosseni, Arnav Kumar
Journal: Circulation (2018)

Background: Human immunodeficiency virus (HIV) patients have shown higher rates of coronary artery disease (CAD) owing to anti-retroviral therapy. We analyzed trends of non-ST-elevation myocardial ...
LGG-13. PILOCYTIC ASTROCYTOMAS WITH NOVEL BRAF FUSIONS DEMONSTRATE MAPK PATHWAY ACTIVATION
Authors: Hannah Chatwin, Katherine Lind, John DeSisto, Bridget Sanford, Ahmed Gilani, Adam Green
Journal: Neuro-Oncology (2021)

Abstract Background Pilocytic astrocytomas (PAs) are the most common pediatric low-grade glioma subtype. Oftentimes, PAs demonstrate somatic genetic alterations, the most common being the BRAF-KIAA1549 fusion, which results in constitutive activation of the MAPK pathway. Better understanding of the effects of other RAF fusions is necessary to determine the potential utility of MAPK-targeting therapies. Methods Three patients presented to Children’s Hospital Colorado and were ultimately diagnosed with PAs harboring previously unreported gene fusions identified as FYCO-RAF1, CCTTNNBP2-BRAF, and SLC44A1-BRAF. Utilizing immunohistochemistry, we stained novel samples and controls for ERK and pERK (phosphorylated ERK) to assess the activation of the MAPK pathway. PAs with known BRAF-KIAA1549 fusions (4 samples) and normal brain tissue (5 samples) were used as positive and negative controls, respectively. We additionally performed RNA sequencing to better understand expression changes associated with these fusions, utilizing Metascape and GSEA (Gene Set Enrichment Analysis) for analysis. Results Immunohistochemistry of negative control samples demonstrated less p-ERK than ERK (ratios of 0.6–0.9, mean 0.8). All samples with novel fusions demonstrated statistically significantly higher p-ERK expression compared to negative controls (ratios of 1.3–1.7, mean 1.4). These experimental samples also all fell within the p-ERK to ERK expression range of the positive control samples, which demonstrated the widest range of expression (ratios of 1.1–4.5, mean 2.2). Our molecular analysis further confirmed these results, with GSEA demonstrating positively upregulated MAPK and ERK pathways in 2 positive controls and 1 novel fusion sample. Metascape analysis emphasized overall similar gene expression between these samples, demonstrating many shared genes and functional pathways. Conclusions We identified 3 previously unreported RAF fusions in PA that demonstrate activation of the MAPK pathway, although not as extensively as seen in some positive control samples with BRAF-KIAA1549 fusions. MEK inhibition may be a useful therapeutic strategy in these tumors if targeted therapy is indicated.
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Authors: Ferdinandos Skoulidis, Bob T. Li, Grace K. Dy, Timothy J. Price, Gerald S. Falchook, Jürgen Wolf, Antoine Italiano, Martin Schuler, Hossein Borghaei, Fabrice Barlesi, Terufumi Kato, Alessandra Curioni-Fontecedro, Adrian Sacher, Alexander Spira, Suresh S. Ramalingam, Toshiaki Takahashi, Benjamin Besse, Abraham Anderson, Agnes Ang, Qui Tran, Omar Mather, Haby Henary, Gataree Ngarmchamnanrith, Gregory Friberg, Vamsidhar Velcheti, Ramaswamy Govindan
Journal: New England Journal of Medicine (2021)

Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non–small-cell lung cancer (NSCLC).
A single-arm study on the efficacy and safety of regorafenib plus sintilimab as salvage-line treatments in non-MSI-H metastatic colorectal cancer.
Authors: Rui Liu, Xia Wang, Zhi Ji, Ting Deng, Le Zhang, Yuchong Yang, Tao Ning, Ming Bai, Shaohua Ge, Hongli Li, Jingjing Duan, Yi Ba
Journal: Journal of Clinical Oncology (2021)

e15560 Background: PD-1 blockade is particularly ineffective in patients with microsatellite stable (MSS) or mismatch repair (MMR)-proficient colorectal cancer (CRC). Regorafenib (R) has been shown to modulate anti-tumor immunity through different mechanisms, including the reduction of tumor-associated macrophages (TAMs) and lymphocyte activation or immunosuppressive cells, such as forkhead box P3 (Foxp3) + CD25 + regulatory T cells (Tregs). Synergy between R and anti–PD-1/PD-L1 antibodies has been demonstrated in pre-clinical models compared to that of either treatment alone. Accordingly, this study attempted to evaluate the combined activity of regorafenib with an immune checkpoint inhibitor. Methods: This trial was a prospective, open-label, monocentric, nonrandomized, single arm study. This study included patients with non MSI-H mCRC who received R (80 mg QD 3weeks/4) and sintilimab (S)(200 mg every 3 weeks).The primary endpoint was the confirmed objective response rate (ORR).The secondary endpoints were progression free survival (PFS),overall survival (OS),disease control rate (DCR) and safety. Results: As of January 8, 2021, 24 patients (median age 59 years) with mCRC were enrolled and received treatment with R+S. RAS wild type was 50% of all patients. In addition, 83.3% of patients received two prior lines of treatment, while 58.3% had liver metastases at enrollment. Of the 24 patients, the best response was observed to be stable disease(SD) in six patients (25%) and progressive disease (PD)in four patients (16.7%). Another nine (37.5%) patients have yet to be evaluated. In the 15 evaluated patients, the ORR(RECIST version 1.1) was 33.3% , the DCR was 73.3%. Additionally, among the 10 evaluated patients with liver metastases, the ORR was 30% , the DCR was 80%. Among the nine evaluated patients with wild-type populations of k-ras, the ORR and DCR was found to be 44.4% and 66.7%, which was higher than the mutation patients. The median PFS was 4.2 (95% CI, 2.5, NA) months, the median OS was not reached. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (4.2%), erythra (4.2%). No death was related to the treatment. Moreover, four (16.7%) patients were subject to at least 1 dose modification or treatment interruption. Conclusions: In this study, the combination of R+S achieved a similar ORR with REGONIVO. Furthermore, this combination was well tolerated and had a manageable safety profile. However, due to the limited sample size, some biases may be present. As a result, we will continue to expand the sample size for future verification. Clinical trial information: NCT04745130.
Pan-cancer analysis of <i>CD274</i> (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression.
Authors: Richard S.P. Huang, Brennan Decker, Karthikeyan Murugesan, Matthew Hiemenz, Douglas A. Mata, Gerald Li, James Creeden, Shakti H. Ramkissoon, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2021)

2605 Background: The effects of non-amplification short variant (SV) mutations in CD274 (PD-L1) on PD-L1 protein expression and immune checkpoint inhibitor (ICPI) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. Methods: FoundationOne CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n = 213) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Results: Overall, the prevalence of CD274 SV mutations was low (0.3%, 1,081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n = 51), R260C (n = 18), R125Q (n = 12), C272fs*13 (n = 11), R86W (n = 10), and R113H (n = 10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Ultraviolet exposure was likely a mechanism for CD274 SV mutations in cutaneous tumors with high frequencies of ultraviolet mutational signatures (cutaneous squamous cell carcinoma [84.6%, 11/13], cutaneous melanoma [93.8%, 30/32], and unknown primary melanoma [100%, 32/32]), and microsatellite instability (MSI) was likely a mechanism for development of CD274 mutations in non-serous endometrial adenocarcinoma. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. This difference in protein expression of these two mutations was significantly different (p = 0.036). It was notable that nearly all samples (88.9%, 16/18) with a clonal truncating variant (nonsense or frame shift indel) and PD-L1 testing showed a PD-L1 TPS score ≤1, whereas three of four samples with sub-clonal truncating variants had TPS scores ≥5. Conclusions: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.
Tumor mutation burden and PIK3CA mutations are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment.
Authors: Qiyun Shi, Juncheng Xuhong, Jia Ge, Feng Liu, Yang Lan, Yi Zhang, Tao Luo, Xiuwu Bian, Xiaowei Qi, Jun Jiang
Journal: Journal of Clinical Oncology (2021)

e12610 Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods: To date, a total of 96 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results: Among the cohort of 96 cases, a total of 32 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 18 of them achieved total pCR. The most frequently mutated driver genes were TP53 (75%), PIK3CA (44%), NBN (9%), RUNX1 (9%), FANCD2 (9%), ATRX (9%), MAP3K1 (9%) and NF1 (9%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (63%), MYC (22%), CCND1 (19%), CDK12 (16%) and FGF19 (16%), respectively. The median tumor mutation burden (TMB) of the 36 patients was 4.23 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had significantly higher median TMB (5.29 vs 3.17 mut/Mb, P = 0.025). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (88.9% vs 14.3%, P &lt; 0.001). Conclusions: Preliminary results suggested that HER2-positive breast cancer patients with higher TMB and activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate. *Qiyun Shi and Juncheng Xuhong contributed equally. #Co-corresponding author (Dr. Jun Jiang, jcbd@medmail.com.cn; Dr. Xiaowei Qi, qxw9908@foxmail.com). Clinical trial information: ChiCTR1900022293.
High-Sensitivity Cardiac Troponin Assay in Patients With Kidney Impairment
Authors: Keith C. Hemmert, Benjamin C. Sun
Journal: JAMA Internal Medicine (2021)

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Patient-reported benefits and burdens of direct oral-anticoagulants (DOACs) and low molecular weight heparins (LMWHs): The CANVAS pragmatic randomized trial (AFT-28).
Authors: Deborah Schrag, Hajime Uno, Ottavia Zattra, Angela Tramontano, Rachel Pam Greenerger Rosovsky, Cynthia Rutherford, Kristen Marie Sanfilippo, John L. Villano, Monic R Drescher, Nagesh H. Jayaram, Chris E. Holmes, Lawrence Eric Feldman, Christine Cronin, Ethan M. Basch, Anna Weiss, Jean Connors
Journal: Journal of Clinical Oncology (2021)

12112 Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWHs for preventing recurrent venous thromboembolism (VTE). However, patients’ perspectives have not been reported. Objective: CANVAS compared LMWHs to DOACs for preventing recurrent VTE in cancer patients. Key 2° endpoints were: 1) health-related quality of life (QOL); and, 2) treatment satisfaction. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial. Between 12/2016 and 4/2020, 671 participants were randomized and followed for 6-months. Patients were assigned 1:1 to receive either a DOAC or a LMWH. Physicians could select any DOAC or LMWH at standard dosing, and patients assigned to LMWH were allowed to transition to Warfarin. Patients from 67 US practices with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified intent-to-treat population, (all subjects who received assigned treatment). Key 2° endpoints were to establish: 1) non-inferior change in HR-QOL; 2) greater perception of benefit; and 3) lower perception of burden for participants receiving DOACs versus LMWHs. Participants reported QOL at 0, 3 and 6 months on the SF-12 survey. At 3 and 6 months, they also reported satisfaction via the Anti-Clot Treatment Scale (ACTS), which includes a burden and a benefit scale. A 2-point change was pre-specified as significant. Results: Neither QOL nor patients’ perceptions of treatment benefits differed between groups. However, patients on DOACs reported lower treatment burden compared to those assigned LMWHs. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in no difference in QOL but higher patient-reported satisfaction stemming from decreased perception of the burden of treatment. Clinical trial information: NCT02744092. [Table: see text]
High dimensional mapping of temporal evolution within the marrow microenvironment in response to FLT3 inhibitor therapy.
Authors: Matthew Newman, Sunil K. Joshi, Daniel Bottomly, Shannon McWeeney, Brian J. Druker, Evan Lind, Elie A. Traer
Journal: Journal of Clinical Oncology (2021)

7020 Background: The advent of genomic sequencing technologies has revealed underlying genetic alterations, such as FLT3 mutations, that can be targeted in acute myeloid leukemia (AML). However, development of resistance limits the durability of response. Recent data has implicated that factors from the bone marrow microenvironment mediate initial resistance to FLT3 inhibitors (FLT3i) in AML. We combined high dimensional characterization techniques, time-of-flight mass cytometry (CyTOF) and RNA sequencing, to examine sequential marrow stromal samples from a subset of patients with FLT3 mutated AML treated with the FLT3i gilteritinib. Here, we report on the heterogeneity and evolution of cell surface and secreted factors over time. Methods: RNA sequencing of primary FLT3-ITD stromal samples (N = 29) from pre-study and on-treatment patients enabled prioritization of candidate targets for CyTOF. Target-specific purified antibodies were purchased pre-conjugated to metal lanthanides or conjugated in house according to manufacturer protocols (after validation via traditional flow cytometry). Primary stromal cells were cultured ex vivo until confluent and were harvested and stained according to a standardized protocol, and subsequently run on a Helios (Fluidigm) mass cytometer. A computational approach was employed to compensate and visualize data via the CATALYST R package. A total of four pre-treatment and four post-gilteritinib timepoint isolates (N = 8) were analyzed. Results: A 36-target mass cytometry panel revealed protein level differences in patients before and after gilteritinib therapy. Dimensional reduction techniques such as MDS and UMAP showed that samples taken from later timepoints clustered together compared to their earlier counterparts with respect to global protein expression. Inflammatory mediators such as IL1-beta and MCP-1 were upregulated in patient stroma soon after gilteritinib treatment and therefore potentially contribute to early resistance. Novel markers previously implicated in early resistance to targeted therapies in AML such as FGF2 and FGFR1 similarly peaked earlier in treatment, mimicking the clinical course of expression observed in marrow stroma of patients treated with another FLT3 inhibitor quizartinib (Traer et al. Cancer Res. 2016). Conclusions: Our findings show that primary marrow stroma evolves during gilteritinib treatment, and that stromal proteins previously reported to promote early resistance to FLT3i are also upregulated during gilteritinib resistance. The heterogeneity of stromal cell isolates detected by mass cytometry highlights the utility of high dimensional tracking of disease course in patients, and may enable a better understanding of how the temporal evolution of the marrow microenvironment contributes to development of resistance to targeted therapies such as gilteritinib and other FLT3i over time.
Association between improvements in survival of metastatic NSCLC patients and targeted- and immuno-therapy.
Authors: Sreeram Ramagopalan, Thomas P. Leahy, Joshua Ray, Samantha Wilkinson, Cormac J. Sammon, Vivek Subbiah
Journal: Journal of Clinical Oncology (2021)

9090 Background: Significant improvements in mortality among NSCLC cancer patients in the US over the past two decades have recently been reported based on SEER data. The timing of these improvements led to suggestions that they are primarily a result of the introduction of new and innovative treatments, however few studies have directly investigated this. Methods: We utilised the US Flatiron Health database to identify a cohort of non-biomarker (EGFR/ALK/ROS1/BRAF) positive metastatic NSCLC (mNSCLC) patients and a separate cohort of ALK positive (ALK+) patients diagnosed between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilised to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. Results: We identified cohorts of 30,076 (54.7% Males) non-biomarker positive and 652 (45.4% males) ALK+ mNSCLC cancer patients in the database eligible for the analysis. Survival in both cohorts improved over time. After adjustment for differences in baseline characteristics the hazard of death in non-biomarker positive patients diagnosed in 2015, 2016, 2017, 2018 and 2019 was observed to be 14%, 13%, 16% 19% and 21% lower respectively than that in those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these innovative treatments. Similarly, decreases in the hazard of death were only observed in ALK+ patients diagnosed in 2018 and 2019 relative to 2012 and were no longer observed following adjustment for the use of ALK inhibitors. Conclusions: Our findings expand on the SEER data and provide direct evidence linking improvements in survival of NSCLC patients over the past decade with the introduction of innovative therapies.[Table: see text]