tbuckley/cabot-search huggingface dataset:
RARE-19. NETWORK AND DEEP LEARNING INFERENCE IN SINGLE CELL RNA SEQUENCING REVEAL DETAILED TRANSCRIPTIONAL SIGNATURES CONGRUENT WITH MOLECULAR UNDERSTANDING OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Eric Prince, Tammy Trudeau, Oscar Chatain, Keanu Chee, Trinka Vijmasi, Susan Staulcup, Andrew Donson, Nicholas Foreman, Todd Hankinson
Journal: Neuro-Oncology (2021)

Abstract Adamantinomatous Craniopharyngioma (ACP) is a highly morbid, cellularly heterogeneous pediatric tumor arising in the sellar/suprasellar region of the brain. This cellular heterogeneity makes ACP an ideal candidate for study using single-cell RNA-sequencing (scRNA-seq). We collected a 10,000 cell scRNA-seq dataset on the 10X v3 platform, from 6 unique patients. Using the industry standard Seurat software package, we identified 34 unique cell clusters. By crossing the results of two separate expert curated cellular reference atlases (Azimuth and scHCL), we determined that 33 of these cell types were immune-related (e.g., T cells, monocytes, etc.) or histologically related (e.g., glial cells). The remaining 2,048 cells were inferred to be ACP driver cells. Rigorous statistical testing of third-generation graph topology-based network enrichment methods utilizing the Reactome database supported this conclusion. In order to identify effective antitumor therapies, it is critical to understand the temporal evolution of tumor cell behavior. Computational solutions that describe the potential lifecycle of tumor cells have been derived using scRNA-seq datasets. Using a well-established method, Monocle3, we generated a potential model of temporal evolution of the ACP driver cell population. To identify a specific transcriptional “point-of-no-return” for ACP driver cells, which may help define a rational target for intervention, we created a custom probabilistic Deep Learning framework in the form of a Convolutional Variational Autoencoder (CVAE). By applying this CVAE to our data, we identified 31 anomalous transcripts, each of which was aberrantly active at all times or demonstrated a temporal pattern of anomalous activity. Strikingly, this small list – representing roughly 0.15% of the protein coding genome – aligns closely with extant data describing the molecular behavior of ACP. This work provides a novel transcriptome benchmark for comparison of in vitromodels, a deeper understanding of ACP heterogeneity, as well as a generalizable approach for scRNA-seq analysis.
Epidemiology, clinical features, and histopathology of sarcomas managed in a Haitian cancer clinic.
Authors: Joseph Bernard, Thierry Alcindor, Lynn Gabrielle Alexis, Doukens Patrick Gilbert, Vincent DeGennaro
Journal: Journal of Clinical Oncology (2021)

e23515 Background: Sarcomas are among the least described cancers diagnosed in Haiti. Suboptimal surgery and the unavailability of radiation therapy make their management challenging. The main objective of this study was to present the epidemiology, clinical features and histopathology of sarcomas in the Haitian setting. Methods: A seven-year retrospective study was conducted in the cancer program of Innovating Health International (IHI). We included all patients with clinical or histological diagnosis of sarcoma enrolled from January 1, 2014 to December 31, 2020. Date of first visit, age, gender, stage, anatomical site, histology, outcome as of December 31, 2020 and date of death were the main variables selected for this chart review. Mortality rate and overall survival were also evaluated. Results: One hundred and twenty-two (122) patients with sarcomas were diagnosed and treated during the study period. Their mean age was 43.3 years [range: 15-88] and the sample was 62.3% women and 37.7% men. 49.2% of the patients were less than 40 years of age. Among the cases of sarcomas, 86.9% were soft tissue sarcomas and 13.1% bone sarcomas. The lower limbs (36.9%), abdomen (14.8%), head and neck (13.1%), upper limbs (12.3%) and breasts (7.4%) were the most common locations of the sarcomas. 81% of abdominal/pelvic sarcoma cases (n=21) were in women. The most common histological types (n=94) were fibrosarcoma (15.2%), liposarcoma (10.9%), dermatofibrosarcoma protuberans (8.7%), malignant histiocytofibroma (6.5%), rhabdomyosarcoma (5.4%) and gastrointestinal stromal tumor (5.4%). 19.6% of the patients had metastatic disease. The mortality rate for the study period was 53.3% and 17.2% of the patients were lost to follow-up. The median overall survival was 7.2 months for the cohort and 18.4 months for the treated patients (n=70). Conclusions: The sarcomas seen in this Haitian medical clinic mainly affect the soft tissues of limbs, abdomen and head and neck. There is a strong predominance of female patients and about half of the patients are aged less than 40. Despite a low metastatic presentation rate, the prognosis is poor, likely reflecting both the aggressiveness of this group of diseases and the disparities of outcomes between high-income and low-and-middle-income countries.
Daytime and outcomes after cardiac surgery: Systematic review and metaanalysis, insights from a large UK database review and post-hoc trial analysis
Authors: Daniel Paul Fudulu, Arnaldo Dimagli, Lauren Dixon, Manraj Sandhu, Lucia Cocomello, Gianni D Angelini, Umberto Benedetto
Journal: The Lancet Regional Health - Europe (2021)

Several studies have suggested a variation of myocardial tolerance to ischaemia depending on the daytime of surgery. To test this hypothesis, we conducted a three-level analysis: metaanalysis, national patient-level dataset analysis and a post-hoc trial analysis. We first performed a systematic review and metaanalysis of available studies comparing clinical outcomes following cardiac surgery performed in the morning (am) versus afternoon (pm). Then, we interrogated the UK national adult cardiac surgery audit database (NACSA) and analysed the am or pm outcomes of patients undergoing non-emergency aortic valve replacement (AVR) or coronary artery bypass grafting (CABG). In a post-hoc analysis, we further investigated the effect of time of surgery on serum troponin release and ventricular myocardial biopsy adenine nucleotide metabolism. A total of 18377 patients undergoing uncomplicated isolated CABG or isolated AVR on the same day am or pm were included in the metaanalysis. Meta-analytic estimates showed no difference in the risk of MI between patients operated in pm vs am (OR 1.02, 95% CI:0.79–1.32) and in the risk of mortality (OR 1.1, 95% CI:0.85-1.42). Outcomes of 91248 patients from the NACSA dataset were analysed according to the daytime of the procedure. Patient-level analysis showed no significant effect of daytime for both isolated AVR (p=0.094) and isolated CABG (p=0.425). Finally, we performed a post-hoc trial database analysis in 124 patients undergoing isolated AVR or CABG of serial cardiac troponin and nucleotides metabolism on ventricular myocardial biopsies. We found no significant diurnal changes in the perioperative cardiac troponin release or nucleotide metabolism in the AVR (p=0.30) or the CABG cohort (p=0.97). The present three-level analysis found no evidence that daytime influences clinical outcomes and myocardial injury in patients undergoing cardiac surgery.
MRI-based radiomics signature for the prediction of response of lung cancer brain metastases after whole-brain radiotherapy.
Authors: Ruizhe Xu, Ye Tian, Bo Zhang
Journal: Journal of Clinical Oncology (2021)

e21096 MRI-based Radiomics signature for the Prediction of Response of Lung Cancer Brain Metastases After Whole-Brain Radiotherapy Background: Local response prediction for brain metastases (BMs) from lung cancer after Whole-Brain Radiotherapy (WBRT) is challenging, as existing criteria are based solely on unidimensional measurements. This study sought to determine whether radiomic features of lung cancer BMs derived from pre-treatment magnetic resonance imaging (MRI) could be used to predict local response following WBRT. Methods: A total of 88 Lung Cancer patients with BMs treated with WBRT were analyzed. After volumes of interest were drawn, 944 radiomic features including first-order, shape, Gray Level Co-occurrence Matrix (GLCM), Gray Level Dependence Matrix (GLDM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), Neighborhood Gray Tone Difference Matrix (NGTDM), and Laplacian of Gaussian (LoG) features were extracted, using the baseline pre-treatment post-contrast T1 (T1c) and T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences, respectively. Local response status was determined by contrasting the baseline and follow-up MRI according to the RANO-BM criteria. The independent samples t test or Mann-Whitney U test, and then least absolute shrinkage and selection operator (LASSO) were used for dimensionality reduction and feature selection. An adaboost classifier was trained using the selected radiomic features and evaluated using the area under the receiver operating characteristic curve (AUC) in both the training and testing sets. Other discrimination metrics, including classification accuracy, positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity, were also calculated. Results: The optimal radiomics signature was developed based on a multivariable logistic regression with 4, 5, 6 radiomic features on T1c, T2 FLAIR and T1c+T2 FLAIR, respectively. The radiomics model based on T1c features presented the AUC of (0.920 vs. 0.805, respectively) for both the training and testing sets, followed by T2 FLAIR features (0.893 vs. 0.701, respectively), and T1c+T2 FLAIR features (0.971 vs. 0.857, respectively). The classification accuracy of the radiomics model also well predicted the local response of BMs for both the the training and testing sets (T1c: 82.9% vs. 77.8%, T2 FLAIR: 82.9% vs. 77.8%, T1c+T2 FLAIR: 90.0% vs. 77.8%, respectively). Conclusions: Radiomics holds promise for predicting local tumor response following WBRT in patients with lung cancer and brain metastases. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions.
A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Authors: Sarah A. Weiss, Dijana Djureinovic, Shlomit Jessel, Irina Krykbaeva, Lin Zhang, Lucia Jilaveanu, Amanda Ralabate, Barbara Johnson, Neta Shanwetter Levit, Gail Anderson, Daniel Zelterman, Wei Wei, Amit Mahajan, Ovid Trifan, Marcus Bosenberg, Susan M. Kaech, Curtis J. Perry, William Damsky, Scott Gettinger, Mario Sznol, Michael Hurwitz, Harriet M. Kluger
Journal: Clinical Cancer Research (2021)

Abstract Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. Patients and Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. Results: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23–443). Median cycles were 4.5 (range, 2–21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. Conclusions: This first in-human study of patients with anti-PD-1/PD-L1–resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.
Preliminary results of the efficacy and safety of all-trans retinoic acid combined with low-dose apatinib in the treatment of patients with recurrent/metastatic adenoid cystic carcinoma of the head and neck.
Authors: Lulu Ye, Lin Zhang, Rongrong Li, Guopei Zhu
Journal: Journal of Clinical Oncology (2021)

6026 Background: There is no standard treatment for recurrent/metastatic adenoid cystic carcinoma of the head and neck (R/M ACCHN). Moreover, MYB and/or NOTCH1 mutation can lead to worse prognosis. Currently, anti-angiogenic targeted therapy is a relatively effective treatment option, but the accompanied toxicities may hinder the continuous medication. All-trans retinoic acid (ATRA) induces differentiation and promotes apoptosis, enhancing the cytotoxicity of anti-tumor agents; on the other hand, inhibits c-MYB and/or NOTCH1 expression. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We reported the preliminary results of the efficacy and safety of ATRA combined with low-dose apatinib in patients with R/M ACC. Methods: In this exploratory study, patients with pathologically or histologically confirmed advanced, R/M ACC with measurable disease were screened. Patients who previously received anti-angiogenic therapy then withdrew due to toxicities could be recruited. ATRA was administered orally at a dose of 20 mg twice a day, and apatinib was administered orally at a dose of 250 mg once a day. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors v1.1. Results: Between March 2019 and April 2020, a total of 16 patients were enrolled. The median age was 53 years (range: 35-69), and 7 (44%) patients were male. Four (25%) patients received ATRA plus apatinib as the third-line therapy, while 12 (75%) received as the second-line therapy. Of 16 patients, 3 (19%) achieved partial response and 13 (81%) achieved stable disease (SD), with ORR of 19% and disease control rate of 100%, respectively. Among patients with SD, 12 (75%) showed tumor shrinkage (3%-28%) and 1 (6%) showed minor tumor enlargement (2%). The median follow-up time was 14.5 months (range: 8.1-22.1). Throughout the period, 5 (42%) patients developed disease progression. The 6-month and 12-month progression-free survival rates were 100% and 80%, respectively. Grade 3 adverse events included hand-foot syndrome (1 [6%]) and proteinuria (1 [6%]). No grade ≥4 adverse events occurred. Conclusions: ATRA combined with low-dose anti-angiogenic drug apatinib could be a potential treatment option for patients with R/M ACC, including those with pretreated advanced ACC after progression on or intolerance to other therapies. These encouraging results were worth further investigations, and a randomized phase 2 trial in ongoing (the Aplus study, NCT04433169).
Correlation of baseline circulating tumor cells (CTC) and associated genomic profile with survival outcomes in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in a real-world cohort.
Authors: Umang Swami, Taylor Ryan McFarland, Benjamin Haaland, Adam Kessel, Roberto Nussenzveig, Nicolas Sayegh, Andrew Warren Hahn, Nityam Rathi, Deepika Sirohi, John Esther, Haoran Li, Manish Kohli, Benjamin L. Maughan, Amir Goldkorn, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

5077 Background: We recently published, in the context of SWOG1216 trial in pts with mCSPC, that higher baseline CTC level were associated with inferior survival outcomes (Goldkorn. Agarwal, CCR, 2021). Here in, we validate these findings in a real world population of mCSPC and interrogate tumor genomic profile with respect to the CTC level. Methods: Eligibility criteria: new mCSPC receiving ADT without or with intensification (docetaxel or novel hormonal therapy) and enumeration of baseline CTCs by FDA cleared Cell Search CTC assay. Gene alterations were determined by comprehensive genomic profiling (CGP) of tumor tissue (Foundation Medicine). CTC counts were categorized as 0, 1-4 and ≥5/7.5 ml. Relationships between CTC counts and number (no.) of genes altered and individual gene alterations were assessed via Kruskal-Wallis and chi-squared tests, respectively. Relationships between progression-free survival (PFS), overall survival (OS) and individual mutations were assessed via log-rank tests. Relationships between CTC counts, PFS and OS were assessed by Cox proportional hazards models, both unadjusted and adjusted for multiple variables (Table). Results: Overall 103 pts were eligible. Median age: 67 yrs, Gleason score: 9, PSA at ADT initiation: 41 ng/mL. 67 (65%) pts had de-novo metastatic disease and 44 (43%) pts underwent ADT intensification therapy. Pts with greater CTC counts tended to have greater no. of altered genes (p=0.017), greater no. of total alterations (p=0.017) and higher rate of TP53 mutations (p=0.036). In univariate analyses (UVA) and multivariable analyses (MVA), both CTC counts and no. of genes altered were strongly associated with both PFS and OS (Table). CGP of tumors with respect to CTC counts will be presented in meeting. Conclusions: Herein, we validate our previous findings from SWOG1216 trial of association of higher CTC level with inferior survival outcomes in a real world mCSPC cohort. The CTC enriched population is associated with a distinct tumor genomic landscape, which may guide further drug development in this pt population at the highest risk of progression and/or death.[Table: see text]
ARID1A mutation to predict disease progression during first-line chemotherapy in biliary tract cancer patients.
Authors: Sung Hwan Lee, Jaekyung Cheon, Seoyoung Lee, Hye Jin Choi, Beodeul Kang, Hyeon-Su Im, Chan Kim, Sung Hoon Choi, Choong-kun Lee, Hongjae Chon
Journal: Journal of Clinical Oncology (2021)

4105 Background: Biliary tract cancer (BTC) is a retractable disease showing a dismal prognosis with therapeutic resistance. There are clinical unmet needs on predicting therapeutic response and precise strategy for the patient classification according to clinically relevant tumor biology in the patients with BTC. We aimed to identify clinically detectable genomic alteration predicting therapeutic response after first-line chemotherapy in BTC using real-world data. Methods: A comprehensive genomic analysis of multi-institutional cohorts of BTC cases was performed using next-generation sequencing (NGS) with targeted DNA panel and patients’ clinicopathologic data. Results: A total of 200 BTC patients with NGS panel tests from three cancer centers were included in this study. The genomic alteration of TP53 (55.5%), KRAS (23%), ARID1A (10%), and ERBB2 amplification (10%) were the most frequent alteration events in the BTC. Pathologically-proved BTC including extrahepatic (n = 52), ampulla of Vater (n = 4), gallbladder (n = 56), intrahepatic (n = 88) cancers showed a distinct pattern of genomic alterations in terms of ARID1A for extrahepatic BTC and ERBB2 amplification, RB1, ARID2 for GB cancer, and KRAS, IDH1, PBRM1, BAP1 for intrahepatic BTC respectively (chi-square test, P &lt; 0.05). The oncologic outcomes for progression-free and overall survival were significantly stratified according to the best response after the first-line chemotherapy (log-rank test, P &lt; 0.001). The logistic regression test revealed that ARID1A, BRCA2, and STK11 could significantly predict disease progression during first-line chemotherapy. ARID1A, especially, was the only independent predictive marker in the multivariate regression model in total BTC (OR 3.91, 95%CI 1.25-11.66, P = 0.015) and extrahepatic BTC (OR 5.71, 95%CI 1.23-28.98, P = 0.027). The predictive performance of significant genomic alteration was enhanced with the tumor marker CA19-9 (DeLong’s test, Z = 1.933, P = 0.053, AUC 0.73, 95%CI 0.623-0.837). Conclusions: Clinically available NGS test showed distinct genomic alterations in terms of different deterioration patterns for oncogenic molecular pathways according to the anatomic locations of BTC. Integrative analysis using the data for genomic alteration and therapeutic response for the first-line chemotherapy uncover that the patients with ARID1A mutation show a significant disease progression rate during initial treatment for BTC, especially in the extrahepatic BTC. Prospective translational studies revealing underlying biology and precision strategy should be followed to improve the therapeutic response of BTC.
Accurately estimating the homologous recombination deficiency based on low-pass whole-genome sequencing and target sequencing.
Authors: Fang Lv, Yiqian Liu, Yaxi Zhang, Xiaoli Liu, Pei Zhihua, Jianing Yu, Weizhi Chen, Ji He
Journal: Journal of Clinical Oncology (2021)

e15077 Background: Homologous recombination deficiency (HRD) is a promising biomarker for poly ADP-ribose polymerase (PARP) inhibitors. In the past, the HRD status was mainly estimated by summing the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) based on target sequencing. However, the heterozygous loci coverage and probe number are closely correlated to B allele frequency and copy number variations (CNVs). Here we developed a novel method to combine the data from low-pass whole-genome sequencing (WGS) and target sequencing to accurately estimate the genome-wide CNVs and allelic imbalance. Methods: We first performed low-pass WGS and target sequencing on 30 healthy controls, formalin-fixed and paraffin-embedded (FFPE) samples, and matched blood cell samples for 29 patients with breast cancer or ovarian cancer. Two HRD positive samples were diluted to 40%, 30%, 20%, and 10% tumor purity with matched blood cell samples, respectively. Each diluted sample was sequenced 20 times. The baseline for CNVs was built based on the sequencing data of healthy donors. To eliminate the artifacts resulted from the sequencing platform, models for each candidate single nucleotide polymorphism (SNP) in target regions were trained using the data from healthy donors. The mutations of BRCA1/BRCA2 of 29 patients were used to define the threshold of the HRD score. The numbers of LOH, LST, and TAI were evaluated by CNVs and B allele frequency. Results: We defined a cutoff of 42 for the HRD status based on the low-pass WGS and target sequencing data of 29 patients. Specifically, the original HRD scores for two selected HRD positive samples were 68 and 89. The median HRD scores for 40%, 30%, 20%, and 10% tumor purity samples were 69 and 88, 66.5 and 90, 61 and 68, 52 and 34.5, respectively. Conclusions: We developed a novel method for robustly inferring the HRD status using low-pass WGS and target sequencing with a limit of detection of 20%.
Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species
Authors: Ruoke Wang, Qi Zhang, Jiwan Ge, Wenlin Ren, Rui Zhang, Jun Lan, Bin Ju, Bin Su, Fengting Yu, Peng Chen, Huiyu Liao, Yingmei Feng, Xuemei Li, Xuanling Shi, Zheng Zhang, Fujie Zhang, Qiang Ding, Tong Zhang, Xinquan Wang, Linqi Zhang
Journal: Immunity (2021)