tbuckley/cabot-search huggingface dataset:
Real-world outcomes for patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with nivolumab: A Galician multicentric study (Spain).
Authors: Leticia Iglesias Rey, Rocio Vilchez Simo, Santiago Aguin Losada, Francisco Ramon Garcia Arroyo, Carolina Pena, Alberto Carral Maseda, Gerardo Huidobro Vence, Aurea Molina Díaz, Jesus García-Gómez, Marta Covela Rúa, Marinha Costa Rivas, Ana Medina
Journal: Journal of Clinical Oncology (2021)

e18002 Background: Nivolumab has demonstrated efficacy in clinical trials of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). These results have been corroborated in real world studies in different populations. We describe the outcomes of 116 patients with R/M SCCHN in our clinical practice treated with Nivolumab in the main hospitals of the Galician health network (Spain). Methods: This multicenter study was carried out in nine hospitals that belong to the Galician Group of Head and Neck Cancer (GGCC). A total of 116 patients with R/M SCCHN who received nivolumab were recruited between January 2017 and June 2019. These patients were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS) and the disease control rate (DCR) of the overall patient and specifically in the first, second and third lines, as well as toxicity, were evaluated. Results: Data from 116 patients were available. Most of them were males (91.37%) with a median age of 60 years (41-84 years). The primary tumor sites were oral cavity, oropharynx, hypopharynx and larynx. At first diagnosis, the majority of the patients had advanced disease (stage IV a/b/c 74.12%) and a performance status (PS ECOG) rate of 1 (64.65%). Owing to the real-world nature of the study, patients with poor performance status were also included (ECOG 2: 13.79% and ECOG 3: 0.86%). HPV and PDL1 status were not available for the majority of patients. The use of nivolumab in the first, second and third line was carried out in 20 (17.24%), 76 (65.52%) and 20 (17.24%) patients respectively. With a median follow-up of 14 months (1-69), in all patients (n = 116) the median progression-free survival (mPFS) was 2.30 months (95% CI 1.45 – 3.14) and the median overall survival (mOS) was 8.08 months (95% CI 5.93 – 10.23). DCR was 43% with 5% complete response (CR), 25% partial response (PR) and 15% stable disease (EE). The mPFS of the patients who received nivolumab in the first, second and third line was 3.9 (IC 95%1.01- 6.93), 3.6 (IC 95% 0.82-6.47) and 2.3 months (IC 95% 0.72-3.87) and the mOS was 6.8 (IC 95% 2.36-11.43), 8.5 (IC 95% 5,9 - 11.62) and 7.2 months (IC 95% 4.51-10.07) respectively. Drug-related adverse effects (grade 3/4) were observed in 21.27% and were controlled with steroid treatment. Conclusions: in this real-life study, the population is broader than the represented in the phase III CheckMate 141 trial, including patients with higher ECOG PS (0-3). These concordant results in the real-world setting in both efficacy and safety, support the use of nivolumab in this group of patients with R/M SCCHN.
Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth
Authors: Adi L. Tarca, Bálint Ármin Pataki, Roberto Romero, Marina Sirota, Yuanfang Guan, Rintu Kutum, Nardhy Gomez-Lopez, Bogdan Done, Gaurav Bhatti, Thomas Yu, Gaia Andreoletti, Tinnakorn Chaiworapongsa, Sonia S. Hassan, Chaur-Dong Hsu, Nima Aghaeepour, Gustavo Stolovitzky, Istvan Csabai, James C. Costello
Journal: Cell Reports Medicine (2021)

Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27–33 weeks of gestation).
Safety and efficacy of pralsetinib in patients with advanced <i>RET</i> fusion-positive non-small cell lung cancer: Update from the ARROW trial.
Authors: Giuseppe Curigliano, Justin F. Gainor, Frank Griesinger, Michael Thomas, Vivek Subbiah, Christina S Baik, Daniel Shao-Weng Tan, Dae Ho Lee, Daniel Misch, Elena Garralda, Dong-Wan Kim, Luis G. Paz-Ares, Julien Mazieres, Stephen V. Liu, Gregory Peter Kalemkerian, Yariv Houvras, Daniel W. Bowles, Aaron Scott Mansfield, Alena Zalutskaya, Anthonie J. van der Wekken
Journal: Journal of Clinical Oncology (2021)

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]
Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.
Authors: Josep M. Llovet, Amit G. Singal, Augusto Villanueva, Richard S. Finn, Masatoshi Kudo, Peter R. Galle, Chunxiao Wang, Ryan C Widau, Elena Gonzalez Gugel, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2021)

4146 Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG performance status (PS) ≤1, and prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or Placebo Q2W. Meta-analysis was conducted in patients with AFP ≥400 ng/mL (n = 542). Univariate (UV) and multivariate (MV) analyses were performed using a Cox proportional hazard regression model. MV used the cut-off p-value &lt; 0.1 from UV, irrespective of treatment arm. Overall survival (OS) was evaluated by Kaplan-Meier estimator and Cox models. To define predictors of RAM benefit, treatment-by-covariate interactions terms were evaluated. Results: In terms of prognosis assessed by MV analysis in patients with AFP ≥400 ng/mL, 6 variables among demographic and baseline disease characteristics were associated with poor OS in the RAM cohort (ECOG PS 1, AFP &gt; 1000 ng/mL, Child-Pugh &gt; A5, Extrahepatic site &gt; 1, neutrophil-to-lymphocyte ratio &gt; 3.2 and aspartate aminotransferase &gt; 57 U/L) with an additional 3 factors identified within the whole cohort (macrovascular invasion presence, etiology HCV vs. Other and alkaline phosphatase ≥146). RAM benefit was present across all subgroups, including patients with very aggressive HCCs (AFP &gt; 4000 ng/mL; HR: 0.64; 95% CI: 0.49-0.84) and those with nonalcoholic steatohepatitis /alcohol related aHCC (HR: 0.56; 95% CI: 0.40-0.79). Of note, two treatment-emergent (TE) events were the only factors that were significantly associated with improved RAM-related survival: TE-hypertension (p interaction = 0.0392) and TE-ascites (p interaction = 0.0001). However, these results should be interpreted with caution given that TE events are factors only observed after randomization. Conclusions: Several poor prognostic factors for OS were identified in patients with aHCC and elevated AFP. RAM provided an OS benefit irrespective of baseline prognostic covariates, with greater benefit observed in patients with aggressive HCC and those who experienced TE-hypertension or TE-ascites. Clinical trial information: NCT01140347; NCT02435433.
Abstract 5665: Assessment of Noninducibility after Catheter Ablation for Atrial Fibrillation: High Dose Isoproterenol vs Rapid Atrial Pacing
Authors: Thomas Crawford, Jean F Sarrazin, Michael Kuhne, Nagib Chalfoun, Darryl Wells, Sujoya Dey, Eric Good, Krit Jongnarangsin, Frank Pelosi, Aman Chugh, Frank Bogun, Fred Morady, Hakan Oral
Journal: Circulation (2008)

Background: Noninducibility of atrial fibrillation (AF) after catheter ablation of paroxysmal AF (PAF) identifies patients who are more likely to remain in sinus rhythm (SR). However, it is not clear whether assessment of noninducibility by rapid atrial pacing (RAP) is incremental to high dose isoproterenol (ISO) infusion. Methods and Results: There were 65 patients (age=56±13 years) with PAF who presented in sinus rhythm for catheter ablation. ISO was administered in escalating doses of 5/10/15/20 μg/min every 2 minutes prior to ablation. AF (or frequent PACs in 4) was inducible in 61/65 patients (94%) at a mean dose of 15±6 μg/min. Antral pulmonary vein (PV) isolation (APVI) was performed in all patients with complete isolation of all PVs. If AF did not terminate during APVI, complex fractionated atrial electrograms (CFAEs) were targeted in the left atrium (16) or coronary sinus (2) until AF terminated or all target sites were ablated. AF terminated during ablation in 41/65 (63%). Following conversion to sinus rhythm, 54 of the 61 patients (89%) who were initially inducible with ISO became noninducible during ISO re-challenge. Among these 54 patients who were noninducible by ISO, rapid atrial pacing (RAP) down to a cycle length of 180 ms (≥5 times) induced sustained AF (&gt;60 seconds) in 17 patients (31%). At a mean follow-up of 9±4 months after a single ablation procedure, 35/54 patients (65%) who were noninducible by ISO and 2/7 patients (29%) who were inducible were in sinus rhythm without antiarrhythmic drugs. However, 11/17 patients (65%) who were inducible by RAP and 26/37 (70%) who were noninducible by RAP were in sinus rhythm without antiarrhyhtmic drug therapy (P=0.8). Conclusions: Noninducibility of AF in response to high dose isoproterenol infusion identifies patients who are more likely to remain in sinus rhythm after catheter ablation. Rapid atrial pacing may still result in induction of AF in 30% of patients who are noninducible by isoproterenol. However, inducibility of AF by rapid atrial pacing in patients who are noninducible by isoproterenol appears to be a nonspecific observation.
Abstract GMM-028: VALIDATION OF RUNX3 AND CAMKIINα HYPERMETHYLATION AS PROGNOSTIC MARKER FOR OVARIAN CARCINOMA
Authors: Karolin Heinze, Lars Jansen, Leticia Oliveira-Ferrer, Barbara Schmalfeldt, Matthias Dürst, Ingo B Runnebaum, Norman Häfner
Journal: Clinical Cancer Research (2019)

Abstract INTRODUCTION: Ovarian cancer is still the most lethal gynecological malignancy with a low five-years-overall survival rate. Except for BRCA1/2 mutations there is no predictive nor prognostic marker available indicating whether a patient is in need and eligible for personalized therapy. In a previous genome-wide array study we identified different methylation patterns in type II epithelial ovarian cancer patients with either good or poor outcome (PFS &amp;lt; vs. &amp;gt; 3 years). Using methylation-specific PCR (MSP) five marker candidates showed high prognostic value whereby the marker combination RUNX3/CaMKIINα was the most promising one [Häfner et al., 2015]. Moreover, in vitro experiments provided evidence that a transcript variant of RUNX3 can mediate Cisplatin sensitivity, further underlining the clinical relevance of this gene [Heinze et al., 2018]. METHODS: In this study we aim to validate the previous described prognostic value of the five candidates, especially of RUNX3 and CaMKIINα via MSP. Therefore, 100 fresh-frozen primary type II EOC samples from two different surgical centers were tested. Furthermore, previously analyzed samples were retested to gain insight on the marker distributions throughout the tumor and possible heterogeneity. The DNA was isolated via phenol/chloroform or QiaAmp Kit, converted to bisulfite DNA and tested via optimized MSP. All samples had similar clinical parameter (histology, FIGO grade, chemotherapy). RESULTS AND DISCUSSION: By re-testing a subset of EOC samples previous results could been confirmed. Additionally, the methylation pattern was similar after renewed sectioning for DNA extraction pointing towards little tumor heterogeneity in the analyzed samples. Interestingly the methylation rate is not as high as expected from the initial analyses. Statistical analysis of the data is currently ongoing. REFERENCES Häfner N, Steinbach D, Jansen L, Diebolder H, Dürst M, Runnebaum IB. RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer, Int J Cancer. 2016 Heinze K, Kritsch D, Mosig AS, Dürst M, Häfner N, Runnebaum IB. Functional Analyses of RUNX3 and CaMKIINα in Ovarian Cancer Cell Lines Reveal Tumor-Suppressive Functions for CaMKIINα and Dichotomous Roles for RUNX3 Transcript Variants, Int J Mol Sci. 2018 Citation Format: Karolin Heinze, Lars Jansen, Leticia Oliveira-Ferrer, Barbara Schmalfeldt, Matthias Dürst, Ingo B Runnebaum, Norman Häfner. VALIDATION OF RUNX3 AND CAMKIINα HYPERMETHYLATION AS PROGNOSTIC MARKER FOR OVARIAN CARCINOMA [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-028.
Characterization of long-term responders following treatment with talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 embraca trial.
Authors: Johannes Ettl, Hope S. Rugo, Sara A. Hurvitz, Miguel Martin, Henri Roche, Kyung-Hun Lee, Annabel Goodwin, Tiziana Usari, Silvana Lanzalone, Carolin Guenzel, Joanne Lorraine Blum, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2021)

1029 Background: In the EMBRACA trial (NCT01945775), the poly(ADP-ribose) polymerase inhibitor (PARPi) TALA significantly improved progression-free survival (PFS) versus PCT in patients (pts) with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (BC) (8.6 vs 5.6 months [mo]; hazard ratio [HR, 95% CI] 0.54 [0.41-0.71]; P &lt; 0.0001). Predictive markers for response to PARPi, other than germline BRCA1/2 mutational status, are largely unknown. A previous analysis investigated biomarkers associated with long and short responders in EMBRACA. Here, we report the clinical characteristics of long and short responders. Methods: Pts were randomized 2:1 to TALA or PCT. In this retrospective analysis, pts in the intent-to-treat (ITT) population were mapped into two groups based on response: LONG (pts in TALA arm with overall survival [OS] ≥30 mo and duration of treatment ≥24 mo; pts in PCT arm with OS ≥30 mo); SHORT (pts in either arm with a PFS event [progressive disease by Independent Radiological Facility or death] ≤12 wks). Data cutoff date was Sept 30, 2019. Results: Of 431 pts randomized, 412 pts were treated (286 received TALA; 126 received PCT). In the ITT population, 37 pts receiving TALA and 34 pts receiving PCT were identified as LONG responders; 40 pts receiving TALA and 32 pts receiving PCT were SHORT responders. The Table shows a summary of pt characteristics for LONG and SHORT responders. More pts with HR+ BC and no prior CT for ABC were associated with LONG response; more pts with TNBC and ≥2 prior CT regimens or platinum were associated with SHORT response (Table). Median treatment duration for LONG responders (n = 37, TALA; n = 31, PCT) was 33.5 (24.0-61.4) mo for TALA and 7.6 (1.1-36.3) mo for PCT; 51.4% receiving TALA and 91.2% receiving PCT had subsequent therapy. In SHORT responders, median treatment duration was 2.0 (0.1-5.5) mo (TALA) and 1.4 (0.2-5.6) mo (PCT); 67.5% and 68.8% received subsequent therapy following TALA or PCT, respectively. Conclusions: In this clinical characterization of responders from the EMBRACA study, a higher number of LONG responders had HR+ BC and received no prior CT for ABC. A greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens or platinum. Further investigation is warranted in a larger number of pts. Clinical trial information: NCT01945775 .[Table: see text]
Analyzing signaling activity and function in hematopoietic cells
Authors: Tobias Kull, Timm Schroeder
Journal: The Journal of Experimental Medicine (2021)

Cells constantly sense their environment, allowing the adaption of cell behavior to changing needs. Fine-tuned responses to complex inputs are computed by signaling pathways, which are wired in complex connected networks. Their activity is highly context-dependent, dynamic, and heterogeneous even between closely related individual cells. Despite lots of progress, our understanding of the precise implementation, relevance, and possible manipulation of cellular signaling in health and disease therefore remains limited. Here, we discuss the requirements, potential, and limitations of the different current technologies for the analysis of hematopoietic stem and progenitor cell signaling and its effect on cell fates.
Dynamic nanoassemblies for imaging and therapy of neurological disorders
Authors: Lingxiao Zhang, Heng Sun, Jing Zhao, Jiyoung Lee, Liang Ee Low, Linji Gong, Ying Chen, Nan Wang, Chaojie Zhu, Peihua Lin, Zeyu Liang, Min Wei, Daishun Ling, Fangyuan Li
Journal: Advanced Drug Delivery Reviews (2021)
YB1 regulates miR‐205/200b‐<i>ZEB1</i> axis by inhibiting microRNA maturation in hepatocellular carcinoma
Authors: Xiumei Liu, Di Chen, Huan Chen, Wen Wang, Yu Liu, Yawei Wang, Chao Duan, Zhen Ning, Xin Guo, Wuxiyar Otkur, Jing Liu, Huan Qi, Xiaolong Liu, Aifu Lin, Tian Xia, Hong‐xu Liu, Hai‐long Piao
Journal: Cancer Communications (2021)

Y-box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non-coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.The biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR, dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull-down and coimmunoprecipitation experiments. The cellular co-localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays.YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b-ZEB1 axis partially in a Snail-independent manner. YB1 suppressed miR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR-205 and miR-200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b-ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.