tbuckley/cabot-search huggingface dataset:
One‐year mortality after implantable cardioverter‐defibrillator placement within the Veterans Affairs Health System
Authors: Marat Fudim, Matthew A. Carlisle, Srikant Devaraj, Tarek Ajam, Andrew P. Ambrosy, Sean D. Pokorney, Sana M. Al‐Khatib, Masoor Kamalesh
Journal: European Journal of Heart Failure (2020)

Abstract Aims Implantable cardioverter‐defibrillator (ICD) therapy reduces mortality in patients with heart failure and current guidelines advise implantation of ICDs in patients with a life expectancy of &gt;1 year. We examined trends in all‐cause mortality in patients who underwent primary or secondary prevention ICD placement in the Veterans Affairs (VA) Health System. Methods and results US veterans receiving a new ICD placement for primary or secondary prevention of sudden cardiac death between January 2007 and January 2015, who had heart failure with reduced ejection fraction (HFrEF) were included in the analysis. We assessed all‐cause mortality 1 year post‐ICD implantation. ICD implantation and HFrEF diagnosis were established with associated ICD‐9 codes. The VA death registry was utilized to identify mortality rates following ICD placement. Results were subsequently age‐stratified. There were 17 901 veterans with HFrEF with ICD placement nationwide. There was no statistically significant difference in 1‐year mortality from 2007 (13.1%) to 2014 (13.4%, P &gt; 0.05). There was a significant increase in 1‐year mortality in patients in the oldest age quartile (81.6 years, 32.3% mortality) compared to the youngest quartile (55.5 years, 7% mortality). The finding of diverging clinical outcomes extended to the 30‐day but also 8‐year mark. Conclusions Our data suggest there is a high 1‐year mortality in aging HFrEF patients undergoing primary and secondary prevention ICD placement. This highlights the importance of developing better predictive models for mortality in our ICD eligible patient population.
Time to second progression (PFS2) in patients (pts) from TITAN with metastatic castration-sensitive prostate cancer (mCSPC) by first subsequent therapy (hormonal vs. taxane).
Authors: Neeraj Agarwal, Simon Chowdhury, Anders Bjartell, Byung Ha Chung, Andrea Juliana Pereira de Santana Gomes, Robert W. Given, Álvaro Juárez Soto, Axel Stuart Merseburger, Mustafa Ozguroglu, Hirotsugu Uemura, Dingwei Ye, Anil Londhe, Angela Lopez-Gitlitz, Sharon Anne McCarthy, Suneel Mundle, Kim N. Chi
Journal: Journal of Clinical Oncology (2020)

82 Background: TITAN, a phase 3, randomized, double-blind study of apalutamide (APA) vs placebo (PBO) added to androgen deprivation therapy (ADT), demonstrated significant improvement in radiographic progression-free survival and overall survival in a broad pt population with mCSPC who received APA (Chi KN et al. NEJM 2019). This post hoc analysis evaluates whether type of 1st life-prolonging subsequent therapy (hormonal vs taxane) has an effect on PFS2 benefit shown with APA + ADT. Methods: PFS2 (the time from randomization to disease progression on 1st subsequent therapy for prostate cancer or death, whichever occurs first) was evaluated for pts from TITAN based on 1st subsequent life-prolonging therapy (hormonal vs taxane) after study treatment. Analysis censored all other 1st subsequent systemic therapies after start of treatment. Results: 277 pts (APA, 87; PBO, 190) received subsequent systemic therapy for prostate cancer; 86 pts (APA, 24; PBO, 62) received hormonal therapy (abiraterone acetate + prednisone or enzalutamide) and 99 (APA, 30; PBO, 69) received taxane (docetaxel or cabazitaxel) as 1st subsequent therapy. Baseline demographic and disease characteristics were generally similar between groups. The taxane group had a higher proportion of pts with high volume and pts with &gt; 10 bone metastases, and a lower proportion with prior docetaxel exposure when compared with the hormonal group. Median treatment duration with APA and PBO was 11.9 and 11.1 mos in the hormonal group and 11.0 and 11.3 mos in the taxane group. Regardless of subsequent therapy, PFS2 was significantly longer for APA vs PBO (HR 0.66 [95% CI 0.50-0.87], p = 0.0026). Pts in both groups who received APA had a significant reduction in risk of 2nd progression compared with PBO (hormonal: HR 0.68 [0.48-0.97], p = 0.0326; taxane: HR 0.67 [0.48-0.94], p = 0.0189; medians not reached). Safety analyses were not conducted; all pts had discontinued therapy, most due to disease progression. Conclusions: The addition of APA to ADT for treatment of mCSPC results in risk reduction of 2nd progression regardless of choice of hormonal or taxane as the 1st life-prolonging subsequent therapy. Clinical trial information: NCT02489318.
Apalutamide (APA) for metastatic castration-sensitive prostate cancer (mCSPC) in TITAN: Outcomes in patients (pts) with low- and high-risk disease.
Authors: Mustafa Ozguroglu, Simon Chowdhury, Anders Bjartell, Hirotsugu Uemura, Byung Ha Chung, Neeraj Agarwal, Axel Stuart Merseburger, Álvaro Juárez Soto, Angela Lopez-Gitlitz, Amitabha Bhaumik, Julie S. Larsen, Sharon Anne McCarthy, Kim N. Chi
Journal: Journal of Clinical Oncology (2020)

87 Background: TITAN showed that APA + androgen deprivation therapy (ADT) improves radiographic progression-free survival (rPFS) and overall survival (OS) in a broad group of pts with mCSPC (Chi et al. NEJM 2019). This post hoc analysis evaluates APA + ADT based on baseline (BL) prognostic risk as defined in LATITUDE (Fizazi et al. Lancet Oncol 2019). Methods: 1052 pts with mCSPC receiving ADT were randomized 1:1 to APA (240 mg/d; n = 525) or placebo (PBO; n = 527). Treatment cycles were 28 days. Risk included Gleason score ≥ 8, ≥ 3 bone lesions, or visceral metastasis. High risk was ≥ 2 risk factors, low risk was ≤ 1. Cox proportional hazards model was used to estimate HR and 95% CI for rPFS and OS. Results: Pt demographic and BL disease characteristics were similar between treatment groups (high risk: APA n = 289, PBO n = 286; low risk: APA n = 236, PBO n = 241). Median treatment duration was similar in the low-risk group with APA or PBO (21.8 mo and 20.3 mo, respectively). For the high-risk groups, treatment duration was longer with APA (APA 19.5 mo, PBO 14.7 mo). APA significantly reduced the risk of radiographic progression relative to PBO in both groups (Table). Risk of death (OS) was reduced by 38% in high-risk pts and 26% in low-risk pts with APA (Table). 24-mo survival rates: high risk, 76% APA, 63% PBO; low risk, 90% APA, 85% PBO. There were few deaths (≤ 33) in low-risk groups. Second PFS in APA pts: high risk, HR 1.9 (95% CI 1.2-3.0), p = 0.004; low risk, HR 2.2 (95% CI 1.5-3.2), p &lt; 0.0001. Regardless of risk category, the safety profile of APA remained consistent with previously reported overall results. Conclusions: Addition of APA to ADT for pts with mCSPC prolonged rPFS and OS with a consistent safety profile compared with PBO + ADT regardless of BL risk. Clinical trial information: NCT02489318. [Table: see text]
Association of clinical severity with FANCB variant type in Fanconi anemia
Authors: Moonjung Jung, Ramanagouda Ramanagoudr-Bhojappa, Sylvie van Twest, Rasim Ozgur Rosti, Vincent Murphy, Winnie Tan, Frank X. Donovan, Francis P. Lach, Danielle C. Kimble, Caroline S. Jiang, Roger Vaughan, Parinda A. Mehta, Filomena Pierri, Carlo Dufour, Arleen D. Auerbach, Andrew J. Deans, Agata Smogorzewska, Settara C. Chandrasekharappa
Journal: Blood (2020)
Results of the REALISE (Real-life Use and Safety of EPIT) Study: A Multicenter Blinded Randomized Controlled Trial Investigating the Safety of Epicutaneous Immunotherapy for Peanut Allergy in Peanut-Allergic Children
Authors: Jacqueline Pongracic, Remi Gagnon, Gordon Sussman, Dareen Siri, Roxanne Oriel, Terri Brown-Whitehorn, Todd Green, Dianne Campbell, Robin Mukherjee, Philippe Begin
Journal: Journal of Allergy and Clinical Immunology (2020)
Light‐chain and transthyretin cardiac amyloidosis in severe aortic stenosis: prevalence, screening possibilities, and outcome
Authors: Christian Nitsche, Stefan Aschauer, Andreas A. Kammerlander, Matthias Schneider, Thomas Poschner, Franz Duca, Christina Binder, Matthias Koschutnik, Julian Stiftinger, Georg Goliasch, Jolanta Siller‐Matula, Max‐Paul Winter, Anahit Anvari‐Pirsch, Martin Andreas, Alexander Geppert, Dietrich Beitzke, Christian Loewe, Marcus Hacker, Hermine Agis, Renate Kain, Irene Lang, Diana Bonderman, Christian Hengstenberg, Julia Mascherbauer
Journal: European Journal of Heart Failure (2020)

Abstract Aims Concomitant cardiac amyloidosis (CA) in severe aortic stenosis (AS) is difficult to recognize, since both conditions are associated with concentric left ventricular thickening. We aimed to assess type, frequency, screening parameters, and prognostic implications of CA in AS. Methods and results A total of 191 consecutive AS patients (81.2 ± 7.4 years; 50.3% female) scheduled for transcatheter aortic valve replacement (TAVR) were prospectively enrolled. Overall, 81.7% underwent complete assessment including echocardiography with strain analysis, electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), 99m Tc‐DPD scintigraphy, serum and urine free light chain measurement, and myocardial biopsy in immunoglobulin light chain (AL)‐CA. Voltage/mass ratio (VMR; Sokolow–Lyon index on ECG/left ventricular mass index) and stroke volume index (SVi) were tested as screening parameters. Receiver operating characteristic curve, binary logistic regression, and Kaplan–Meier curve analyses were performed. CA was found in 8.4% of patients ( n = 16); 15 had transthyretin (TTR)‐CA and one AL‐CA. While global longitudinal strain by echo did not reliably differentiate AS from CA‐AS [area under the curve (AUC) 0.643], VMR as well as SVi showed good discriminative power (AUC 0.770 and 0.773, respectively), which was comparable to extracellular volume by CMR (AUC 0.756). Also, VMR and SVi were independently associated with CA by multivariate logistic regression analysis ( P = 0.016 and P = 0.027, respectively). CA did not significantly affect survival 15.3 ± 7.9 months after TAVR ( P = 0.972). Conclusion Both TTR‐ and AL‐CA can accompany severe AS. Parameters solely based on ECG and echocardiography allow for the identification of the majority of CA‐AS. In the present cohort, CA did not significantly worsen prognosis 15.3 months after TAVR.
Expression of circulating miR375 and miR371 to differentiate teratoma and viable germ cell tumor in patients with post-chemotherapy residual disease.
Authors: Lucia Nappi, Marisa Thi, Nabil Adra, Ricardo Romao Nazario Leao, Bernhard J. Eigl, Kim N. Chi, Martin Gleave, Alan So, Peter C. Black, Robert James Hamilton, Siamak Daneshmand, Clint Cary, Timothy A. Masterson, Lawrence H. Einhorn, Craig R. Nichols, Christian K. Kollmannsberger
Journal: Journal of Clinical Oncology (2020)

414 Background: Viable germ cell tumors (vGCT) express high levels of certain circulating microRNAs, including miR-371a-3p (miR371) that has shown high specificity and sensitivity. However, neither tissue nor serum/plasma from patients with only teratoma are miR371 positive. miR375 is overexpressed in teratoma tissue, but detectability in blood is unknown. Methods: miR371 and miR375 expression was analyzed in 100 patients with various stages and histology of GCT. miR375 expression in teratoma was validated in patients with post-chemotherapy pathologically confirmed teratoma (PCPCT). The miRNAs expression was assessed by RT-PCR and quantified by ΔΔCT method. The optimal cut-off for miR375 expression was estimated by Youden index ( &gt; 20). Spike-in cel-miR-39-3p, miR-451 and miR-30b-5p were used as internal controls. Sensitivity, specificity, AUC of the ROC of miR375 in detecting teratoma was analyzed. Results: In the discovery cohort miR371 and miR375 were measured in 62 pts: 27 CSI NED, 15 chemo-naïve metastatic seminoma and 20 with PCPCT. miR375 was over-expressed in pts with teratoma compared to CSI and seminoma pts (p = 0.002), while miR371 was expressed in the seminoma pts and undetectable in the PCPCT and CSI pts (p &lt; 0.001). In the post-chemotherapy setting, 38 pts were analyzed: 21 PCPCT, 6 vGCT and 11 complete remission (CR). Also in this cohort, miR375 was over-expressed in pts with teratoma compared to the pts presenting vGCT and post-chemotherapy CR (p = 0.01), while miR371 was detectable only in the pts with vGCT (p &lt; 0.001). Overall, sensitivity and specificity of miR375 in identifying teratoma were 78% and 80%, respectively; the AUC was 0.7 (95% CI: 0.5490-0.8186; p &lt; 0.01). Conclusions: Pts with residual post-chemotherapy teratoma present higher plasma levels of miR375 compared to pts with vGCT in whom miR375 is low but miR371 is expressed at high levels. The simultaneous evaluation of miR371 and miR375 may be clinically useful to predict the histology of the GCT components in pts with post-chemotherapy residual disease to inform the best therapeutic options (surgery or chemotherapy). Further validation within larger studies is warranted.
Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC.
Authors: Alexandra Drakaki, Arash Rezazadeh Kalebasty, Jae-Lyun Lee, Juan Martin-Liberal, Miso Kim, Sang Joon Shin, Jane Shi, Sanjeev Mariathasan, Bo Ci, Viraj Degaonkar, Patrick Williams, Edward Cha, Julia Maltzman, Thomas Powles
Journal: Journal of Clinical Oncology (2020)

TPS591 Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.
Oncological outcomes following radical cystectomy for urothelial carcinoma of the bladder with positive lymph nodes.
Authors: Seyedeh Sanam Ladi Seyedian, Zhoobin Bateni, Shane Pearce, Saum Ghodoussipour, Azadeh Nazami, Jie Cai, Gus Miranda, Sumeet Bhanvadia, Hooman Djaladat, Anne K. Schuckman, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2020)

584 Background: To determine oncological outcomes among patients who underwent radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder with positive lymph nodes (LN). Methods: On a retrospective review of 4093 patients from our institutional IRB approved cystectomy database from Jan 1971 to Dec 2017, we identified 3284 patients who underwent RC for UC of the bladder. We included patients with positive LNs at the final pathology. The data was stratified into three groups based on number of positive LNs: 1, 2-9, and more than 10 positive LNs. Multivariable analysis was performed to identify prognostic factors for overall survival (OS) and recurrence-free survival (RFS). A subgroup analysis was performed to assess the oncological outcomes in cases that did not receive any chemotherapy (adjuvant or neoadjuvant). Results: 712 patients (22%) had positive LN after RC. Median age was 68 years and 76% of patients were male. 105 (15%) patients had clinical evidence of LN involvement on pre-operative imaging. Patient characteristics are provided in Table. Five-year (5-y) RFS for 1, 2-9 and 10+ positive LNs was 39%, 36% and 16%, respectively (p&lt;0.001). 5-y OS were 45%, 33% and 14%, respectively (p&lt;0.001). On multivariable analysis, more than 10 positive LNs pathologic tumor stage &gt;pT2, and neoadjuvant chemotherapy were associated with increased risk of recurrence and worse overall survival after radical cystectomy. Adjuvant chemotherapy was associated with decreased risk of recurrence and better overall survival after radical cystectomy. On subgroup analysis of patients with positive LNs without peri-operative chemotherapy, 5-y RFS for 1, 2-9 and 10+ positive LNs was 25%, 32% and 5%, respectively (p&lt;0.001). 5-y OS was 31%, 20% and 4%, respectively (p&lt;0.001). Conclusions: Only 15% of patients with positive LNs have clinical evidence of LN involvement prior to cystectomy. Oncological outcomes after radical cystectomy are associated with the number of involved LNs. Surgery alone can be curative in 20-30% of patients with less than 10+ LN.
Follow-Up of Food-Allergic Patients Transitioned to Daily Ingestion of Real Food Equivalents after Clinical Trial Participation
Authors: Amanda Cox, Mary Grace Baker, Jake Kattan, Marion Groetch, Allison Schaible, Roxanne Oriel, Angela Tsuang, Anna Nowak-Wegrzyn, Julie Wang, Scott Sicherer
Journal: Journal of Allergy and Clinical Immunology (2020)
Electronic Fetal Monitoring—Imperfect but Opportunities for Improvement
Authors: Aaron B. Caughey
Journal: JAMA Network Open (2020)

Cynthia M. Farquhar, MBChB, MD, MPH, FRANZCOG, FRCOG, CREI; Sarah Armstrong, MBBS, MRCOG; Vicki Masson, MPH; John M. D. Thompson, PhD; Lynn Sadler, MBChB, MPH
Online Bayesian Phylodynamic Inference in BEAST with Application to Epidemic Reconstruction
Authors: Mandev S Gill, Philippe Lemey, Marc A Suchard, Andrew Rambaut, Guy Baele
Journal: Molecular Biology and Evolution (2020)

Abstract Reconstructing pathogen dynamics from genetic data as they become available during an outbreak or epidemic represents an important statistical scenario in which observations arrive sequentially in time and one is interested in performing inference in an “online” fashion. Widely used Bayesian phylogenetic inference packages are not set up for this purpose, generally requiring one to recompute trees and evolutionary model parameters de novo when new data arrive. To accommodate increasing data flow in a Bayesian phylogenetic framework, we introduce a methodology to efficiently update the posterior distribution with newly available genetic data. Our procedure is implemented in the BEAST 1.10 software package, and relies on a distance-based measure to insert new taxa into the current estimate of the phylogeny and imputes plausible values for new model parameters to accommodate growing dimensionality. This augmentation creates informed starting values and re-uses optimally tuned transition kernels for posterior exploration of growing data sets, reducing the time necessary to converge to target posterior distributions. We apply our framework to data from the recent West African Ebola virus epidemic and demonstrate a considerable reduction in time required to obtain posterior estimates at different time points of the outbreak. Beyond epidemic monitoring, this framework easily finds other applications within the phylogenetics community, where changes in the data—in terms of alignment changes, sequence addition or removal—present common scenarios that can benefit from online inference.
Genetic Determinants of Peanut-Specific IgG4 in The Learning Early About Peanut Allergy (LEAP) Study
Authors: Kanika Kanchan, Ingo Ruczinski, Henry Bahnson, Meher Preethi Boorgula, Sameer Chavan, David Larson, Karen Cerosaletti, George DuToit, Gideon Lack, Kathleen Barnes, Gerald Nepom, Rasika Mathias
Journal: Journal of Allergy and Clinical Immunology (2020)
Differential expression of melanoma-associated antigen A3/6 and associated immune molecules prior to and post treatment with immune checkpoint inhibitors (ICI) in patients with mUC.
Authors: Izak Faiena, Samuel Aaron Funt, Stephanie H. Astrow, Tanya B. Dorff, Sabina Adhikary, Tristan Gorgan, Jonathan E. Rosenberg, David Elashoff, Allan J. Pantuck, Alexandra Drakaki
Journal: Journal of Clinical Oncology (2020)

433 Background: MAGE is an attractive target for IO given its expression restricted to carcinomas and the testes. Engineered T-cell targeting MAGE A3/6 has shown promise. However, successful treatment is dependent on circumventing the potentially hostile immune microenvironment in metastatic tumors. In this study, we aim to assess the effects of ICI on the immune microenvironment in patients who progressed on ICI. Methods: We obtained FFPE tissue from 16 patients with mUC across 3 institutions. Samples from the primary or metastatic tumor prior to treatment with PD1/PD-L1 inhibitors (ICI) were paired with samples from metastatic sites post-treatment. Differential mRNA expression was assessed using NanoString PanCancerIO360 panel for the main genes of interest ( MAGEA3/6, CD274, HLADP, HLAA, B2M and PDCD1) in addition to immune profiling of the tumor samples. Also, IHC was done on the paired samples to assess DE for the genes of interest using an H-score analyzed via the paired T-test. p-values &lt;0.05 were considered significant and FDR corrected. Results: MAGEA3/A6 mRNA expression was unchanged in the post-treatment samples. In addition, time to progression was not influenced by the mRNA DE. Similarly, IHC expression was not decreased post-treatment. The other genes of interest were also similarly expressed pre and post treatment. Immune cell localization genes CPA3,TPSAB1/B2, HDC, MS4A2 were significantly downregulated post treatment. Genes implicated in cancer cell killing ( MX1,KIT) were similarly downegulated whereas CD276, TLR1 were upregulated. Expression in the post treatment tissue of PTPN1, CES3, ACVR1C, and BAD were associated with increased progression. LY9, PTPRC, CTLA4, HLA-DMA, IL10RA, HLA-DMB, ITGAL, CD48 were associated with decreased progression. Conclusions: Prior ICI treatment does not decrease expression of MAGE A3/6, suggesting that salvage treatments targeting this antigen remain a viable strategy. Suggestion of immune microenvironment alterations were also noted. More work is necessary to understanding the tumor microenvironment in order to design rational treatment combinations and sequences.