tbuckley/cabot-search huggingface dataset:
Heart Transplantation in Adriamycin-Associated Cardiomyopathy in the Contemporary Era of Advanced Heart Failure Therapies
Authors: Bhavadharini Ramu, Maria Masotti, Ryan J. Tedford, Rebecca J. Cogswell
Journal: JACC CardioOncology (2021)

Adriamycin-associated cardiomyopathy (ACM) can lead to end-stage heart failure requiring advanced heart failure therapies.This study sought to provide post-cardiac transplant survival data in patients with ACM in the contemporary era of mechanical circulatory support and cardiac transplantation.Adults (≥18 years of age) who underwent first-time, single-organ heart transplantation were identified from the United Network for Organ Sharing between October 18, 2008, and October 18, 2018. Cardiomyopathy subtypes that could have been supported with a left ventricular assist device (LVAD) including ACM, dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM) were included. A multivariable Cox regression analysis was performed to determine the association between cardiomyopathy subtype and post-cardiac transplant survival.This analysis included 18,270 patients (357 with ACM; 10,662 with DCM; and 7,251 with ICM). Heart transplant recipients with ACM were younger, included more women, and had higher pulmonary vascular resistance at the time of listing. Patients with ACM had a lower percentage of durable LVADs at the time of transplant across all years of the study period. Patients with ACM did not experience an increase in post-cardiac transplant mortality compared to those with DCM (adjusted hazard ratio: 0.96; 95% confidence interval: 0.79 to 1.40; p = 0.764) or ICM (adjusted hazard ratio: 0.85; 95% confidence interval: 0.6 to 1.2; p = 0.304).Patients with ACM who received heart transplants between 2008 and 2018 had similar post-cardiac transplant survival to those with dilated and ischemic cardiomyopathy. Bridge-to-transplant LVAD use remains lower compared to other cardiomyopathy subtypes.
Abstract GMM-044: IDENTIFICATION OF A NOVEL CANDIDATE BIOMARKER FOR DIAGNOSIS AND THERAPEUTIC OVARIAN CANCER TARGET
Authors: Kyoungsook Park, Chaeyeon Son, Sang Yong Song
Journal: Clinical Cancer Research (2019)

Abstract Ovarian cancer is the most fatal gynecological cancer with high mortality. It still has no reliable diagnostic marker and effective treatment due to its high drug resistance and high recurrence. To develop a novel biomarker for diagnosis and therapeutic target of intractable ovarian cancer, we selected for an upregulated gene in serous ovarian tumors compared with normal ovary counterparts by microarray analysis and confirmed its elevated mRNA expression in ovarian tumors by RT-PCR. Consistent with its high mRNA level, tumor-specific preferential high expression of candidate protein was detected in the cytoplasm of the ovarian tumor tissues by immunohistochemistry. To our surprise, indirect immunofluorescence staining revealed an unexpected cytoplasmic subcellular localization of a candidate protein. Furthermore, forced expression of a candidate gene in cultured cells with no detectable level showed a marked inhibition of cell proliferation. To address these unexpected findings, we set out to identify a candidate interacting protein by yeast 2-hybrid screening to explore a novel function and its underlying mechanism. Among them, one of cell death associated protein was identified as a novel interacting partner of a candidate protein and their physical interaction in mammalian cells was confirmed by co-immunoprecipitation assay and confocal microscopy. Further domain mapping analysis should reveal critical domains for their interaction and would provide fundamental and pivotal information for a novel function and an underlying molecular mechanism of a candidate gene. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07047640). Citation Format: Kyoungsook Park, Chaeyeon Son, Sang Yong Song. IDENTIFICATION OF A NOVEL CANDIDATE BIOMARKER FOR DIAGNOSIS AND THERAPEUTIC OVARIAN CANCER TARGET [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-044.
Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study
Authors: Pamela R. Matías-García, Rory Wilson, Qi Guo, Shaza B. Zaghlool, James M. Eales, Xiaoguang Xu, Fadi J. Charchar, John Dormer, Haifa Maalmi, Pascal Schlosser, Mohamed A. Elhadad, Jana Nano, Sapna Sharma, Annette Peters, Alessia Fornoni, Dennis O. Mook-Kanamori, Juliane Winkelmann, John Danesh, Emanuele Di Angelantonio, Willem H. Ouwehand, Nicholas A. Watkins, David J. Roberts, Agnese Petrera, Johannes Graumann, Wolfgang Koenig, Kristian Hveem, Christian Jonasson, Anna Köttgen, Adam Butterworth, Marco Prunotto, Stefanie M. Hauck, Christian Herder, Karsten Suhre, Christian Gieger, Maciej Tomaszewski, Alexander Teumer, Melanie Waldenberger
Journal: Journal of the American Society of Nephrology (2021)

Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed.A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR.In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR.In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects
Authors: Emeline Dierge, Elena Debock, Céline Guilbaud, Cyril Corbet, Eric Mignolet, Louise Mignard, Estelle Bastien, Chantal Dessy, Yvan Larondelle, Olivier Feron
Journal: Cell Metabolism (2021)
IL-6 blockade for prophylaxis and management of immune-related adverse events (irAEs) with anti-PD-1 based immunotherapy.
Authors: Florentia Dimitriou, Sabrina A Hogan, Phil F Cheng, Reinhard Dummer, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2021)

9553 Background: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory irAEs. We sought to determine the activity of tocilizumab, an anti-IL6R monoclonal antibody (mAb), in treatment or prevention of auto-immune irAE in ICI-treated patients (pts). Methods: Institutional databases from 2 melanoma centers were reviewed for pts treated with ICIs and tocilizumab. Treatment and melanoma outcomes were prospectively assessed. Longitudinal assessment of c-reactive protein (CRP) and assessment of clinical improvement (defined as irAE resolution to grade ≤1 CTCAEv5) or prophylaxis (absence of flare, defined as ≥ grade 2) were utilized to evaluate the benefit of tocilizumab. Paired Wilcoxon rank test was used to compare CRP levels prior to ICI administration, at the onset of irAEs and after tocilizumab administration. Results: 22 pts were identified. 2 pts were treated prophylactically (pre-existing dermatomyositis [n = 1] and giant cell arteritis [GCA, n = 1]) before the administration of PD1. 20 pts were treated for management of irAEs due to PD1 +/-CTLA4 (multiple concurrent irAEs [n = 3], steroid refractory irAES [hepatitis &amp; pancreatitis, n = 2], steroid+anti-TNFα refractory colitis [n = 2], steroid+other immunosuppressive-refractory hepatitis [n = 1], cytokine release syndrome-related AEs [n = 6], musculoskeletal irAEs [n = 6]). 15 (68.2%) pts with irAEs required hospitalization and of those, 13 (86.7%) received tocilizumab whilst inpatient. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab administration 32 days (range 1-192). Median time to irAE resolution from tocilizumab administration was 7 days (range 1-799). Clinical improvement/benefit was demonstrated in 21/22 patients; one patient with ir-hepatitis did not respond. Median CRP prior to ICI administration was 32mg/L (range 0.3-99), at the onset of irAE 49.5mg/L (range 0.3-251, p = 0.055) and after the tocilizumab administration 18mg/L (range 0.3-18, p = 0.0015). Tocilizumab was well tolerated with self-limiting and transient toxicities in 17 (77.3%) patients. There were two grade 4 events; gastrointestinal tract perforation and Fournier gangrene, the latter unrelated to tocilizumab. Two (9%) patients died due to melanoma. From start of ICI, median progression-free survival (PFS) was 5.88 months and median overall survival (OS) was not reached. Conclusions: Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of a flare of pre-existing auto-immune disorders during ICI administration. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
Modification of intrinsic ovarian cancer tumor factors by Wnt-pathway agents influences macrophage recruitment and activity.
Authors: Jhalak Dholakia, Carly Bess Scalise, Ashwini A. Katre, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2021)

e14514 Background: The Wnt/B-catenin pathway is associated with a “cold” phenotype in the gynecologic malignancy tumor microenvironment (TME), resulting in immunosuppression. Research is limited regarding this pathway’s effects on TME myeloid cell populations. We aimed to characterize the impact of Wnt pathway modulation on macrophage activity in ovarian cancer. Methods: Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood. Ascites from 10 high grade serous epithelial ovarian cancer patients were treated with DKN-01 (Wnt activator) or CGX-1321 (Wnt inhibitor) for 48 hours; multiplex cytokine array was performed to determine changes in cytokine/chemokine expression. Lastly, we performed co-culture analyses on the effects of ID8par and ID8p53-/- isolated cell media on murine macrophage (RAW264.7) activity. Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.) In human ascites, DKN-01 increased macrophage colony stimulating factor (M-CSF) expression. Of note, ascites from a patient harboring a p53 mutation demonstrated an increase in M1 polarization cytokines IFNy and TNFa in response to DKN-01; CGX-1321 treatment resulted in increased M2 polarization cytokines IL-4 and IL-13. In co-culture analysis, ID8par isolated media increased RAW264.7 migration and polarization towards an M2 phenotype; ID8p53-/- isolated media polarized towards an M1 phenotype. Conclusions: Macrophage activity influences immune responses and tumor behavior. For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion. In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment. The ID8par model positively influenced M2 macrophage activity; ID8p53-/- cells positively influenced M1 macrophage activity. Importantly, DKN-01 treatment reverses the M2-dominant phenotype in ID8par model towards M1. These results suggest that p53 mutation and/or DKN-01 treatment in ovarian cancer influences M1 anti-tumor macrophage activity, and posits a novel targetable pathway. Further studies should investigate Wnt/B-catenin modulation on macrophage activity for immunotherapy in gynecologic malignancies.
Investigating the impact of immune related adverse events, glucocorticoids use and immunotherapy interruption on long-term survival outcomes.
Authors: Charline Lafayolle de la Bruyère, Julien Peron, Pierre Jean Souquet
Journal: Journal of Clinical Oncology (2021)

e14551 Background: It remains unclear whether immune related adverse events (irAEs) and glucocorticoids use could impact long term-outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). Methods: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric study. Objectives were to assess the impact of grade 3+ irAEs, glucocorticoids use and interruption of immunotherapy on progression free survival (PFS) and overall survival (OS). Data collection was performed retrospectively using a standardized data collection form. Adverse events were categorized as irAEs based on the judgement of the treating physicians, based on the common Terminology Criteria for Adverse Events, version 4.0. Only grade 3 and more irAEs were considered in this study. As irAEs might happen late during the follow-up and progression event or death might happen early, an immortal-time bias might occur as patients responding to ICI will receive the ICI and then be exposed to irAE for a longer period of time. The first occurrence of an irAE was then included in Cox models, as a time-varying covariate. Similar methods were used to evaluate the impact of glucocorticoids introduction or ICI interruption. Results: In this 828 patients’ cohort, 78 patients presented at least one grade 3+ irAE. The first occurrence of grade 3+ irAEs had no significant impact on PFS (HR 0,94; 95%CI 0.7-1.26; p = 0,70) or OS (HR 0.82; 95%CI 0.6-1,12; p = 0,21). 65% of patients with anti CTLA4 and 55% of patients with anti PD(L)1 requested glucocorticoids, which was associated with a significant shorter PFS (adjusted HR 3.0; 95%CI 1.6-5.4; p = 0.00040) and a trend toward shorter OS. Grade 3+ irAEs led to interruption of the ICI in 82 % of patients, which was associated with a significant shorter PFS (adjusted HR 3.5; 95%CI 1.7-6.0; p &lt; 0.00043) and shorter OS (HR 4.5; 95%CI 1.7-12.1; p = 0.0027). The use of glucocorticoids was statistically associated with immunotherapy interruption. Conclusions: In our population of patients treated with single agent ICI, grade 3+ irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade 3+ irAEs reported in other studies might then be explained by the management of the irAEs.
A phase 1 dose escalation and cohort expansion study of the safety and efficacy of allogeneic CRISPR-Cas9–engineered T cells (CTX110) in patients (Pts) with relapsed or refractory (R/R) B-cell malignancies (CARBON).
Authors: Joseph McGuirk, Carlos R. Bachier, Michael Russell Bishop, P. Joy Ho, Hemant S. Murthy, Michael J. Dickinson, Joseph E. Maakaron, Charalambos Andreadis, Armin Ghobadi, Edmund K. Waller, Mark Daniel Benton, Susanna Suh, Huansheng Xu, Ewelina Morawa, Farrukh Tauseef Awan, Paul Shaughnessy, Constantine Si Lun Tam, Nicolaus Kroeger, Richard T. Maziarz
Journal: Journal of Clinical Oncology (2021)

TPS7570 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL), and although &gt; 50% of pts achieve long-term remission with first-line therapy, pts with R/R disease as well as those with R/R grade 3b follicular lymphoma (FL), double-, or triple-hit high-grade lymphomas have poor long-term outcomes (Crump 2017; Kahl 2016; Jain 2012). Autologous (auto) chimeric antigen receptor (CAR) T cell therapy has provided additional options for pts with R/R disease, but only when leukapheresis and manufacturing prove feasible (Jacobson 2020). Allogeneic (allo) CAR-T cells were designed specifically to address these unmet needs by using healthy donor T cells to produce a readily available product and remove the need for bridging chemotherapy. We are currently investigating the safety and efficacy of CTX110, an allo anti-CD19 CAR-T cell product modified by using CRISPR/Cas9-editing to disrupt the endogenous T-cell receptor (TCR) alpha constant (TRAC) locus in order to remove TCR expression and disrupt β 2 -microglobulin, which eliminates major histocompatibility complex (MHC) class I expression. Disruption of the TCR should significantly reduce or eliminate risks of graft-versus-host disease and elimination of MHC class I expression may increase CAR-T cell persistence by mitigating CTX110 rejection. In addition, the anti-CD19 CAR transgene construct is precisely inserted into the TRAC locus. Methods: The Phase 1 CARBON trial (NCT04035434) is an open-label, multicenter, global study evaluating the safety and efficacy of CTX110 in pts ≥18 y with R/R DLBCL NOS, double- or triple-hit DLBCL, or transformed or grade 3b FL with ≥2 prior lines of therapy or who are ineligible for/refused prior auto hematopoietic stem cell transplant (HSCT). Pts who received prior auto CAR-T or allo HSCT are excluded. Pts will receive lymphodepleting chemotherapy with fludarabine 30mg/m 2 and cyclophosphamide 500mg/m 2 for 3 days, followed by CTX110 infusion. In part A, dose escalation will be performed using a 3+3 design. Upon completion of dose finding, the cohort will be expanded to further assess safety signals and efficacy including the primary efficacy endpoint of overall response rate. Key secondary efficacy endpoints include duration of response, progression-free survival, and overall survival. The trial is currently open and enrolling. Clinical trial information: NCT04035434.
IMMU-13. CUSTOMIZABLE MULTI-LAMELLAR RNA-NANOPARTICLES FOR PEDIATRIC GLIOMA
Authors: Hector Mendez-Gomez, James McGuiness, Adam grippin, Frances Weidert, Sheila Carrera-Justiz, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2021)

Abstract Background Since the preponderance of pediatric gliomas are mutationally ‘bland,’ immune checkpoint inhibitors are unlikely to mediate therapeutic benefit. Alternately, immunologic response can be induced de novo against pediatric gliomas with mRNA cancer vaccines. Messenger RNA represents a paradigm shift in vaccinology (i.e. COVID-19) given its flexibility, commercialization, and propensity to confer rapid protection with only a single vaccine. Objective We sought to develop a new mRNA platform with an optimized backbone for insertion of both personalized and/or “off the shelf’ (i.e. H3K27M) transcripts for rapid induction of anti-tumor activity against pediatric gliomas. Approach We synthesized an mRNA backbone with optimized 5’ and 3’ UTRs for delivery of gene transcripts pertinent to pediatric brain tumors using a lipid-nanoparticle (NP) delivery vehicle. This vaccine utilizes a novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” or multi-lamellar package. Results We demonstrate immunogenicity of RNA-NPs delivering either personalized glioma mRNA or H3K27M mRNA. RNA-NPs localize to myeloid cells in murine KR158b brain tumors and activate dendritic cells that supplant regulatory intratumoral myeloid populations inducing antigen-recall response with long-term survivor benefit. Our optimized mRNA backbone yielded significantly improved anti-tumor efficacy compared with commercial backbones. We have shown this approach can be refined for co-delivery of immunomodulatory RNAs (i.e. GM-CSF) and/or delivery of siRNAs targeting immunoregulatory axes (PD-L1) in murine brain tumors (GL261). We have since established safety of RNA-NPs in acute/chronic murine GLP toxicity studies without cross-reactivity to normal-brain, and launched a large-animal canine brain tumor trial which demonstrated RNA-NPs to be feasible, safe and immunologically active. Conclusion RNA-NPs reprogram the brain tumor microenvironment while inducing a glioma-specific immune response. We have since received FDA-IND approval for first-in-human trials (IND#BB-19304) in pediatric patients with high-grade gliomas (PNOC020 study, NCT04573140).
Different exposure duration of adjuvant icotinib in stage II-IIIA non-small cell lung cancer patients with positive EGFR mutation (ICOMPARE study): A randomized, open-label phase 2 study.
Authors: Chao Lyu, Rui Wang, Shaolei Li, Shi Yan, Yuzhao Wang, Jinfeng Chen, Liang Wang, Yinan Liu, Zhanlin Guo, Jia Wang, Yuquan Pei, Lei Yu, Nan Wu, Jun Chen, Yanheng Liu, Shanqing Li, Bing Han, Lieming Ding, Li Mao, Yue Yang
Journal: Journal of Clinical Oncology (2021)

8521 Background: EGFR-TKI has been widely used in the treatment for advanced non-small cell lung cancer (NSCLC). Previous studies, such as the EVIDENCE study and the ADAURA study, have confirmed that patients with EGFR-mutated NSCLC could benefit from adjuvant EGFR-TKI treatment. However, the optimal duration time of adjuvant EGFR-TKIs has not been clearly defined. Methods: In this multicenter, randomized, phase 2 trial, eligible patients with II-IIIA stage EGFR mutation-positive NSCLC after R0 resection were randomized in 1:1 to receive adjuvant icotinib for 1 year (group A) or 2 years (group B). The primary endpoint was disease-free survival (DFS). Results: Between September 2013, and September 2018, 109 patients from 8 centers were enrolled in this study, among whom 55 were randomized to group A and 54 to B. As of August 24, 2020 (data cutoff), the median follow-up was 44.1 months (95%CI 37.1-49.9), 31 (56%) of 55 patients in the 1-year group and 25 (46%) of 54 patients in the 2-year group had DFS events. The median DFS was 48.92 months (95%CI 33.15, 70.11) in 2-year group and 32.89 month (95%CI 26.61, 44.78) in 1-year group, respectively. 2-year icotinib significantly prolonged DFS (HR 0.521, 95%CI 0.278, 0.976; p = 0.039). OS events were observed in 20 patients, the OS was not mature yet. Icotinib was re-given for 32 patients with disease recurrence or metastasis as first-line treatment, objective response occurred in 66.7% of 30 patients with measurable disease. Treatment-related adverse events were recorded in 41 of 55 (75%) patients in 1-year group and 36 of 54 (67%) patients in 2-year group, and grade 3 or 4 treatment-related adverse events occurred in 4 (7%) of 55 patients in the 1-year group versus 3 (6%) of 54 in the 2-year group, respectively. No treatment-related deaths or interstitial lung disease were reported. Conclusions: 2-year adjuvant treatment with icotinib resulted in a significantly lower risk of recurrence than 1-year adjuvant icotinib in patients with stage II-IIIA NSCLC positive EGFR mutations and was not associated with increased toxic effects. Clinical trial information: NCT01929200.