tbuckley/cabot-search huggingface dataset:
Association of post-transplant outcomes with induction intensity in patients with acute myeloid leukemia.
Authors: Melanie Rebechi, Kieran Sahasrabudhe, Ying Huang, Patrick Elder, Bradley Wayne Blaser, Jonathan Edward Brammer, Hannah Kyung Choe, Yvonne Adeduni Efebera, Ann-Kathrin Eisfeld, Samantha Jaglowski, Karilyn T.M. Larkin, Meixiao Long, Alice S. Mims, Sam L. Penza, Ayman A. Saad, Sumithira Vasu, Sarah Allison Wall
Journal: Journal of Clinical Oncology (2021)

e19026 Background: The USFDA has recently approved several oral targeted therapies for the treatment of acute myeloid leukemia (AML). The relative survival impact of these agents vs standard induction chemotherapy in the frontline setting is unknown, especially in patients who undergo allogeneic hematopoietic cell transplant (HCT). Methods: This is a retrospective, single-institution study of 125 patients with AML diagnosed 2015-2020 who received HCT. Patients were included if induced with high intensity chemotherapy (HiC) or lower intensity targeted therapy (LITT). HiC was defined as cytarabine + anthracycline given on a “7+3” based schedule. LITT was defined as venetoclax, gilteritinib, enasidenib, or ivosidenib alone or combined with hypomethylating agent. Patients receiving liposomal cytarabine-daunorubicin were excluded. Outcomes of interest were overall survival (OS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR). Between-groups analysis was conducted comparing receipt of any HiC to LITT only. OS was analyzed by Kaplan-Meier method and compared using log-rank test; NRM and CIR was estimated through cumulative incidence function and compared by Fine-Gray test. Results: Of 125 HCT recipients, 108 received any HiC and 17 LITT only. Two patients received HiC after suboptimal response to LITT. Median age at HCT was 61 years, 48% were female, and 90% were in complete remission at HCT. Population characteristics and outcomes as well as between-groups comparison are presented in the table. LITT only group was older with longer time to HCT and exclusively received RIC. With median follow-up of 23 months, median OS had not been reached. There were no statistically significant differences in median OS or one-year NRM or CIR between groups. Conclusions: Despite differences in age, conditioning regimen, and time to HCT in patients receiving any HiC vs LITT only, we have shown similar OS, CIR, and NRM. Difference in age is in contrast to lack of difference in HCT-CI and KPS, but is partially explained by limited access to LITT for younger patients. Longer time to HCT among LITT only recipients represents a major opportunity for pre-HCT optimization of recipient health. Prospective study from time of diagnosis will be important to understanding the appropriate use of LITT in HCT-eligible patients.[Table: see text]
Corrigendum to ‘Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q'
Authors: K.L. Jhaveri, X.V. Wang, V. Makker, S.-W. Luoh, E.P. Mitchell, J.A. Zwiebel, E. Sharon, R.J. Gray, S. Li, L.M. McShane, L.V. Rubinstein, D. Patton, P.M. Williams, S.R. Hamilton, B.A. Conley, C.L. Arteaga, L.N. Harris, P.J. O’Dwyer, A.P. Chen, K.T. Flaherty
Journal: Annals of Oncology (2021)

The authors regret that Dr Arteaga's disclosures were not complete in the original publication. Dr Arteaga's full disclosure should read as follows: CLA: grant support: Pfizer, Lilly, Radius, PUMA Biotechnology, Bayer, Takeda, Symphogen; honoraria: advisory board/steering committee: Daiichi Sankyo, ABBVIE, Novartis, Lilly, Sanofi, Radius, Taiho Oncology, PUMA Biotechnology, Merck, H3Biomedicine, Symphogen, OrigiMed, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex, Dr Arteaga receives compensation for his role in the Scientific Advisory Board of the Komen Foundation, unrelated to this work; stock options: Provista, Y-TRAP. LNH: patents, royalties, other intellectual property—Philips Healthcare. The authors would like to apologise for any inconvenience caused. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol QAnnals of OncologyVol. 30Issue 11PreviewThe National Cancer Institute—Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. Full-Text PDF Open Archive
ALK inhibitors for treatment of adult-onset neuroblastoma.
Authors: Jessica Stiefel, Brian H. Kushner, Ellen M. Basu, Stephen S. Roberts, Shakeel Modak
Journal: Journal of Clinical Oncology (2021)

2001 Background: Neuroblastoma (NB), a rare malignancy of the sympathetic nervous system, is a tumor of early childhood with &gt; 90% of cases diagnosed before 5 years of age. Adult-onset NB (AON) is extremely rare and differs significantly from childhood disease. AON, while more indolent, is usually metastatic at diagnosis, generally chemotherapy-resistant, and almost invariably lethal. Additionally, standard therapies for NB such as dose-intensive chemotherapy and anti-GD2 antibody are poorly tolerated by adults. Prior studies have shown AON is enriched for genomic aberrations especially ALK (Suzuki et al 2018). Although ALK inhibitors (ALKi) are effective for therapy of lymphoma and non-small cell lung cancer, their use in AON has not previously been reported. Methods: Retrospective review of patients &gt; 18 years old at diagnosis seen at Memorial Sloan Kettering Cancer Center (MSKCC) was performed after IRB approval. Response to ALKi was evaluated using International Neuroblastoma Response Criteria; objective responses were also noted. Progression-free (PFS) and overall survival (OS) was calculated using Kaplan-Meier methods. Results: Since 1979, 52 patients with AON were seen at MSKCC. Of 23 patients evaluated, 14 (61%), harbored somatic ALK mutations. Seven were treated with FDA-approved ALKi. One patient initially diagnosed at 12 years of age was treated with ALKi following a relapse 15 years later. Overall, all ALKi were well-tolerated; reported adverse events included grade 1-2 nausea and vomiting (n = 6), and neurologic symptoms including hallucinations, drowsiness, and dizziness (n = 1 patient each) which resolved after stopping ALKi. Four patients received &gt; 1 ALKi either due to progressive disease or intolerance. Most patients responded to the first ALKi with objective though partial response (n = 5) while one had progressive disease (PD). Median time to progression for initial ALKi was 15.5 months (10-45). One patient with no evaluable disease after four prior relapses was treated with alectinib for 36 months without PD. Of the patients treated with a second ALKi (n = 4), 1 had CR and 2 had PR after not having progressed previously, while the other had stable disease. Median OS from beginning treatment with first ALKi was 46.5 (17-74) months. Conclusions: AON is a rare disease which is a therapeutic challenge. Enrichment of ALK mutations permits consideration of targeted therapy. ALKi were well tolerated, often associated with significant responses, and treatment with serial ALKi led to ongoing benefit. Given this, ALKi should be considered for treatment in future AON cases.
Positive natural selection of N6-methyladenosine on the RNAs of processed pseudogenes
Authors: Liqiang Tan, Weisheng Cheng, Fang Liu, Dan Ohtan Wang, Linwei Wu, Nan Cao, Jinkai Wang
Journal: Genome biology (2021)

Abstract Background Canonical nonsense-mediated decay (NMD) is an important splicing-dependent process for mRNA surveillance in mammals. However, processed pseudogenes are not able to trigger NMD due to their lack of introns. It is largely unknown whether they have evolved other surveillance mechanisms. Results Here, we find that the RNAs of pseudogenes, especially processed pseudogenes, have dramatically higher m 6 A levels than their cognate protein-coding genes, associated with de novo m 6 A peaks and motifs in human cells. Furthermore, pseudogenes have rapidly accumulated m 6 A motifs during evolution. The m 6 A sites of pseudogenes are evolutionarily younger than neutral sites and their m 6 A levels are increasing, supporting the idea that m 6 A on the RNAs of pseudogenes is under positive selection. We then find that the m 6 A RNA modification of processed, rather than unprocessed, pseudogenes promotes cytosolic RNA degradation and attenuates interference with the RNAs of their cognate protein-coding genes. We experimentally validate the m 6 A RNA modification of two processed pseudogenes, DSTNP2 and NAP1L4P1 , which promotes the RNA degradation of both pseudogenes and their cognate protein-coding genes DSTN and NAP1L4 . In addition, the m 6 A of DSTNP2 regulation of DSTN is partially dependent on the miRNA miR-362-5p. Conclusions Our discovery reveals a novel evolutionary role of m 6 A RNA modification in cleaning up the unnecessary processed pseudogene transcripts to attenuate their interference with the regulatory network of protein-coding genes.
Tolerance of aromatase inhibitors in post-menopausal patients with early-stage hormone receptor positive (HR+) breast cancer: A real-world retrospective analysis in a large oncotype database.
Authors: Shana Berwick, Brittney Shulman Zimmerman, Sara Malin Hovstadius, Julia Blanter, Erin Moshier, Asem Berkalieva, Natalie S Berger, Shabnam Jaffer, Krystal Pauline Cascetta, Amy Tiersten
Journal: Journal of Clinical Oncology (2021)

e12532 Background: Aromatase inhibitors (AIs) compose the backbone of adjuvant endocrine therapy for early-stage HR+ breast cancer. Prior studies have demonstrated equivalence in efficacy between aromatase inhibitors in current clinical use. Thus choice of aromatase inhibitors is initially influenced by provider patterns and tailored based on adverse side effects. This study retrospectively evaluates the prevalence of intolerance to AIs warranting a change in therapy. Methods: We identified 181 post-menopausal patients with early-stage, HR+ breast cancer within a database of women who underwent oncotype testing at a large, urban medical center, with 167 (92%) receiving an AI. Patients were excluded if they had received chemotherapy. The Kaplan-Meier method was used to estimate median duration of endocrine therapy (ET). The Fisher’s exact test was used to compare proportions of patients requiring a switch in adjuvant AI and the Wilcoxon rank-sum test was used to compare age distributions. Results: Of the patients identified, 153 (90%) had stage IA disease with a median oncotype RS of 19. 167 (92%) patients received an AI as adjuvant therapy. Median duration of endocrine therapy (ET) was 83.5 months, with over 90% of patients on ET more than 5 years. Among the 152 patients with available data on ET interruptions, 52 (34%) patients had a change or interruption in their ET of these 40 (77%) were attributed to a medication side effect. The AI prescribed most frequently as initial therapy was anastrozole 138/165 (84%). 33 (24%) of patients who received anastrozole required a drug switch within the class, (no sig difference based on initial adjuvant therapy; p=0.4281). 12 (7%) patients required a switch from an AI to tamoxifen at some point during therapy. Changes in AI adjuvant therapy were most commonly attributed to joint pains 24 (46%), followed by hot flashes 2 (4%) and weight gain, 2 (4%). There was no statistically significant difference in median age between patients who interrupted ET due to medication side effect or other reason; p=0.2906. Conclusions: This study enforces previous findings that a significant proportion of women require a change in their adjuvant ET, most commonly due to adverse medication effects such as joint pain. The majority of the women in this database were initiated on anastrozole as initial adjuvant ET of whom 24% required a drug switch.[Table: see text]
Impact of race on the utilization and efficacy of CDK4/6i: Result from a real world database.
Authors: Shaheenah S. Dawood, Kaylen Brzozowski
Journal: Journal of Clinical Oncology (2021)

e13036 Background: The combination of the CDK4/6 inhibitors(CDK4/6i) and endocrine therapy has improved overall survival(OS) in patients(pts) with endocrine sensitive or resistant disease. Only 43 pts of black race were included in the first line trials making interpretation of results in this group difficult. The goal of this retrospective analysis of a real world database was to look at the clinical utilization and prognostic impact of CDK4/6i among pts of white and black race who have hormone receptor positive (HR+ve)/HER2-ve metastatic breast cancer(MBC). Methods: For this analysis, we utilized a federated network of de-identified health data representing approximately 64 million pt lives available through the TriNetX Platform. We identified 5400pts with information on race who had HR+ve/HER2-ve MBC diagnosed between 2015 and 2020. OS was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of survival, matching patients from two cohorts on secondary malignancy location (as noted in ICD-10 diagnosis coding)and age group. Results: 4182 white pts and 1199 black pts were identified, and 1,194 pts in each group remained after matching. Mean age at diagnosis was 57.2 and 58.3 yrs among white and black pts respectively. OS among pts of white and black race was significantly different (HR 1.4, 95%CI 1.12-1.70, p &lt; 0.0001), and 2-yr OS was 87.8% and 82.6% respectively. 599(20%) pts of white race and 148(18%) pts of black race received CDK4/6i therapy. The rate of uptake of use CDK4/6i was initially similar in 2015 however by 2020 some differences were observed with rate of uptake being 190 per 1000 and 264 per 1000 among pts of black and white race respectively. Pts of each race appeared to have a similar prevalence of CDK4/6i per line of treatment. OS among pts who received CDK4/6i and were of white and black race was not significantly different(HR 0.94, 95% CI 0.65- 1.38, p = 0.80), and 2-year OS was 69.9% and 69.5% respectively. Conclusions: Overall the proportional use of CDK4/6i was similar among pts of black and white and race. Although initial uptake appears to have been consistent between Black and White pts, further attention is necessary to assess potential disparities in use as time progresses. The use of CDK4/6i in the setting of HR+ve/HER2-ve MBC diminishes the differences in outcome between the two races.
Deep learning to identify and predict cardiotoxicities of anticancer drugs.
Authors: Mayur Sarangdhar, Venkatesh Kolli, William Seibel, John Peter Perentesis
Journal: Journal of Clinical Oncology (2021)

e15012 Background: Recent advances in cancer treatment have revolutionized patient outcomes. However, toxicities associated with anti-cancer drugs remain a concern with many anti-cancer drugs now implicated in cardiotoxicity. The complete spectrum of cardiotoxicity associated with anti-cancer drugs is only evident post-approval of drugs. Deep Learning methods can identify novel and emerging safety signals in “real-world” clinical settings. Methods: We used AERS Mine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 16 million patients. We identified 1.3 million patients on traditional and targeted anti-cancer therapy to analyze therapy-specific cardiotoxicity patterns. Cardiotoxicity training dataset contained 1571 molecules characterized with bioassay against hERG potassium channel and included 350 toxic compounds with an IC50 of &lt; 1μM. We implemented a Deep Belief Network to extract a deep hierarchical representation of the training data, and the Extra Tree Classifier to predict the toxicity of drug candidates. Drugs were encoded using 1024-bit Morgan fingerprint representation using SMILES with search radius of 7 atoms. Pharmacovigilance metrics (Relative Risks and safety signals) were used to establish statistical correlation. Results: This analysis identified signatures of arrhythmias and conduction abnormalities associated with common anti-cancer drugs (e.g. atrial fibrillation with ibrutinib, alkylating agents, immunomodulatory drugs; sinus bradycardia with 5FU, paclitaxel, thalidomide; sinus tachycardia with anthracyclines). Our analysis also identified myositis/myocarditis association with newer immune checkpoint inhibitors (e.g., atezolizumab, durvalumab, cemiplimab, avelumab) paralleling earlier signals for pembrolizumab, nivolumab, and ipilimumab. Deep Learning identified signatures of chemical moieties linked to cardiotoxicity, including common motifs in drugs associated with arrhythmias and conduction abnormalities with an accuracy of 89%. Conclusions: Deep Learning provides a comprehensive insight into emerging cardiotoxicity patterns of approved and investigational drugs, allows detection of ‘rogue’ chemical moieties, and shows promise for novel drug discovery and development.
Recent advances in nonalcoholic fatty liver disease metabolomics
Authors: Hwi Young Kim
Journal: Clinical and Molecular Hepatology (2021)

The clinical phenotypes of nonalcoholic fatty liver disease (NAFLD) encompass from simple steatosis to nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis or cirrhosis. Liver biopsy has been the standard to diagnose NASH. However, there has been strong need for precise and accurate noninvasive tests because of invasiveness and sampling variability of biopsy. Metabolomics has drawn attention as a promising diagnostic methodology in the field of NAFLD, particularly to unravel metabolic alterations which plays relevant roles in the progression of NASH. There have been numerous metabolomics researches to find new biomarker of NASH in the last decade, fueled by the recent advances in the metabolomics methodology. This review briefly covers recent research advances on the lipidomics, amino acids and bile acid metabolomics regarding continuing attempts to discover relevant biomarkers for NASH.
Spectrum of adipokines, batokines, myokines, and growth factors in blood serum of patients with various stages of lung cancer and with immunotherapy with PD-1/PD-L1 inhibitors.
Authors: Elena Yu. Zlatnik, Aleksandr B. Sagakyants, Oleg I. Kit, Oksana G. Shulgina, Elena A. Kalabanova, Maria A. Teplyakova, Liubov Yu Vladimirova, Anna E. Storozhakova, Inna A. Novikova, Dmitry A. Kharagezov, Anton G. Milakin, Yulia S. Konstantinova
Journal: Journal of Clinical Oncology (2021)

e21069 Background: Metabolites of the intestinal microbiota, including adipokines, batokins, and myokines, are involved in carcinogenesis, antitumor immune defense and ensuring the effectiveness of antitumor treatment, including chemotherapy and immunotherapy. Methods: The study included 100 patients with lung cancer (LC), 70% males and 30% females: stage I – 10%, II - 14%, III – 50%, IV – 26%. 21 patients (12 males and 9 females) received treatment with PD-1/PD-L1 inhibitors: stage I - 2 (9%), II - 1 (5%), III - 5 (24%), IV - 12 (62%). Therapy included atezolizumab and pembrolizumab – 9 patients each (43%), nivolumab – 3 (14%). Complete response was registered in 2 (9%), partial response in 5 (24%), stabilization - 4 (19%), progression - 8 (38%). One patient developed an immune-mediated adverse event (Guillain-Barré syndrome), so checkpoint inhibitors (CPI) were canceled. Serum levels of adipokines, myokines, batokines, and growth factors were determined by ELISA before and during treatment. The control group included 100 healthy donors. Results: Levels of VEGF and NGF were statistically significantly higher in patients with lung cancer than in donors, without differences in other parameters. Differences were revealed depending on the LC stage: leptin was higher in stages I and IV (Me 52.8 and 46.3 ng/ml, respectively) compared with stages II and III (Me 27.4 and 16.4 ng/ml, respectively) and with donors (Me 12.5 ng/ml). In stages III and IV, levels of VEGF increased (Me 504 and 473 pg/ml, respectively; in donors Me 239 pg/ml), while BDNF decreased (Me 2.7 and 0.4, respectively, in donors Me 12.6 μg/ml); NGF in stages I and II was not detected, unlike stages III and IV. Immunotherapy with CPI elevated levels of adiponectin (Me 12.5 and 16 μg/ml, respectively), and reduced levels of myostatin (Me 26.4 and 2.8 μg/ml, respectively) and NGF (Me 130 and 53 pg/ml, respectively). Only NGF could be regarded as a predictive factor of the response to CPI, since it was detected in high amounts only in patients with subsequent LC progression, while in patients with a positive response to treatment or stabilization, it was absent both before and after immunotherapy. Conclusions: Serum levels of some adipokines, myokines, batokins, and growth factors in LC patients differ depending on the cancer stage and the result of CPI immunotherapy; thus, NGF can be used as a predictor of the immunotherapy effectiveness. The study was performed with financial support from the Federal Medical and Biological Agency of Russia under contract No. 0373100122120000017 dated 20.05.2020.
PHYTOCHROME-INTERACTING FACTORs trigger environmentally responsive chromatin dynamics in plants
Authors: Björn C. Willige, Mark Zander, Chan Yul Yoo, Amy Phan, Renee M. Garza, Shelly A. Wanamaker, Yupeng He, Joseph R. Nery, Huaming Chen, Meng Chen, Joseph R. Ecker, Joanne Chory
Journal: Nature Genetics (2021)
Seroconversion rates following COVID-19 vaccination among patients with cancer
Authors: Astha Thakkar, Jesus D. Gonzalez-Lugo, Niyati Goradia, Radhika Gali, Lauren C. Shapiro, Kith Pradhan, Shafia Rahman, So Yeon Kim, Brian Ko, R. Alejandro Sica, Noah Kornblum, Lizamarie Bachier-Rodriguez, Margaret McCort, Sanjay Goel, Roman Perez-Soler, Stuart Packer, Joseph Sparano, Benjamin Gartrell, Della Makower, Yitz D. Goldstein, Lucia Wolgast, Amit Verma, Balazs Halmos
Journal: Cancer Cell (2021)