tbuckley/cabot-search huggingface dataset:
Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions
Authors: Jennifer E. Ho, Emily K. Zern, Luke Wooster, Cole S. Bailey, Thomas Cunningham, Aaron S. Eisman, Kathryn M. Hardin, Giovanna A. Zampierollo, Petr Jarolim, Paul P. Pappagianopoulos, Rajeev Malhotra, Matthew Nayor, Gregory D. Lewis
Journal: Circulation (2019)

Background: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. Methods: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. Results: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg -1 ·min -1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. Conclusions: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.
Case 17-1977
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Jean D. Wilson, Robert E. Scully, G. Richard Dickersin
Journal: New England Journal of Medicine (1977)

Presentation of CaseA 68-year-old woman was admitted to the hospital because of diarrhea.One year earlier she came to this hospital because of episodes of weakness and was found to have ventricular irritability with runs of ventricular tachycardia that required lidocaine, procainamide, phenytoin sodium, propranolol and potassium chloride infusions for control. The urea nitrogen was 10 mg, and the glucose 105 mg per 100 ml. The sodium was 145 meq, the potassium 1.4 meq, the chloride 94 meq, and the carbon dioxide 31 meq per liter. A specimen of arterial blood, drawn while the patient was breathing room air, . . .
Investigation of the efficacy of imidazolyl ethanamide pentandioic acid (IEPA) to reduce chemotherapy-induced myelosuppression (CIM) in breast cancer patients.
Authors: Frank Mayer, Dirk Pleimes, Marcus Schmidt, Peter A. Fasching, Christian Jackisch, Kathrin Flunkert, Corinna Asang, Florence Razoux, Volker Moebus
Journal: Journal of Clinical Oncology (2019)

e23098 Background: Neutropenia is a major toxicity of myelosuppressive chemotherapy (CTX). Treatment and prophylaxis of CTX-induced neutropenia with granulocyte colony-stimulating factors is mainly recommended in patients with high risk of febrile neutropenia. IEPA, a hemoprotective small molecule for oral use, may constitute a safe alternative. The main objective of the study was to assess the efficacy of IEPA in reducing CIM in breast cancer patients. Methods: Randomized, double-blind, placebo-controlled, parallel group study in female adults diagnosed with invasive breast cancer receiving epirubicin/cyclophosphamide CTX. Patients took one tablet daily of IEPA 100 mg or placebo starting 5 days prior to the first CTX cycle until 3 days prior to the second CTX cycle. Two batches of study medication were used sequentially in the study. Hematologic and other variables were tightly measured during the first CTX cycle. Results: After no significant treatment effect was observed in the total study results, post-hoc analyses revealed a significant batch effect. Treatment with Batch 1 IEPA was superior to placebo in treating CIM (Table). Conclusions: Although the presence of a batch effect precludes final conclusions and calls for a formulation optimization of the compound, the efficacy of Batch 1 IEPA in reducing CIM consistent with prior non-clinical and clinical studies invites further investigation of the hemoprotective properties of IEPA. Area over the curve (AOC) integrates extent and duration of decreased absolute neutrophil counts [(ANC/nL)*days] below thresholds corresponding to grade 1 (ANC &lt; 2.0x10^9/L) and 3 neutropenia (ANC &lt; 1.0x10^9/L); CI: confidence interval; LS: least squares; DN3: duration of grade 3 neutropenia in [days]. Clinical trial information: NCT02692742. [Table: see text]
Use of nivolumab as salvage therapy in heavily pretreated patients with gynecologic malignancies.
Authors: Heather Williams, Jennifer Wang, Lynn Tran, Sara Mobley, Bunja Jane Rungruang, Sharad A. Ghamande
Journal: Journal of Clinical Oncology (2019)

5593 Background: There are limited effective treatments for gynecologic cancer patients who have been previously treated with multiple lines of chemotherapy. Immune checkpoint inhibitor (ICI) therapy has demonstrated significant activity in certain cancers but has been inconclusive in most gynecologic malignancies. The objective of this study was to determine the impact of salvage ICI therapy in heavily pretreated gynecologic oncology patients. Methods: An IRB approved retrospective study was performed of women with gynecologic cancer treated with nivolumab on a compassionate use program between October 2015 and January 2018. Patient demographics, disease characteristics, pathology and treatment history were collected. Survival probabilities were calculated. Results: Twenty-eight women were identified. Median age at start of treatment was 63 years with a median of 4 prior lines of chemotherapy. Median ECOG status was 2. Disease site was evenly distributed among uterus, ovary and cervix. 67.9% of patients completed 3 or more cycles of treatment. Median PFS of all patients was only 2.6 months however when comparing patients who received 2-3 cycles (n = 13) with those who received 4 or more (n = 9), median PFS was statistically significant 2.4 months vs 6.4 months (p = 0.0005). When looking at treatment response, 7 patients had partial response/stable disease after 3 cycles (25%). Median PFS of the 7 “responders” was 6.6 months vs 2.5 months of the non-responders (p &lt; 0.001). Only 1 of 9 patients with uterine cancer had a disease response and that patient’s tumor was MSI high. Five patients had low grade serous ovarian cancer. Four of them had a treatment response with a median PFS of 6.1 months (range 3.8 – 25 months). Adverse events were experienced by 68% of patients; most commonly being fatigue (46.4%), arthralgia (25%), and anemia (21.4%). Only 1 patient experienced a grade 3-4 event (a diffuse maculopapular rash). Conclusions: In patients with heavily pretreated gynecologic malignancies with suboptimal performance status, immune checkpoint inhibitor therapy may prolong survival without significant toxicity. Also, there may be a role for ICI in patients with historically chemo resistant low grade serous ovarian cancers.
Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621.
Authors: Mark J. Ratain, Toshihiko Doi, Maja J. De Jonge, Patricia LoRusso, Martin Dunbar, Manoj Chiney, Monica Motwani, Jaimee Glasgow, Adam Matthew Petrich, Drew W. Rasco, Emiliano Calvo
Journal: Journal of Clinical Oncology (2019)

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for &gt; 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]
Educational attainment in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Lisa Bashore, Zahra Merchant, Philip Lupo, Allison A. King, Tyler Hamby, Deokumar Srivastava, Rebecca M. Howell, Todd M. Gibson, Kevin C. Oeffinger, Gregory T. Armstrong, W. Paul Bowman, Kevin R. Krull
Journal: Journal of Clinical Oncology (2019)

10063 Background: Diagnosis and treatment of childhood cancer place survivors at risk for lower educational attainment, the increased burden of chronic conditions on attainment has not been examined. Methods: Participants included 16724 survivors (48% female; mean diagnosis age 9.1 years, current age 36.2 years, time since diagnosis 26.6 years) and 4098 siblings (mean current age 39.3 years) Educational attainment was categorized as college graduation (yes/no) among survivors ≥ age 25 years. Chronic conditions occurring before age 25 years of age were graded using Common Terminology for Adverse Events 4.3. Modified Poisson regression models estimated relative risks (RR) and 95% confidence intervals (CI) of treatment exposures and chronic conditions on education attainment, adjusting for age at diagnosis and sex. Results: College graduation was reported by 8391 (51%) survivors and 2410 (59%) siblings. Survivors of all diagnoses were more likely to not graduate compared to siblings (all p’s &lt; 0.05), with survivors of CNS tumor (RR1.36, CI 1.25-1.49), leukemia (RR 1.17, CI 1.07-1.28), and Hodgkin lymphoma (RR 1.17, CI 1.07-1.29) being at higher risk than survivors of neuroblastoma. Compared to survivors with no history of cranial radiation therapy (CRT), higher risk of not graduating college was seen in those who received 20-30Gy (RR 1.16, CI 1.09-1.25), 30-50Gy (RR 1.37, CI 1.26-1.49) and ≥50Gy (RR 1.35, CI 1.28-1.42). Among survivors not exposed to CRT, dexamethasone had a protective effect on college education (RR 0.88, CI 0.80-0.97) compared to no corticosteroid exposure. Male sex and older age (≥ 5 years) at diagnosis were associated with being more likely to not graduate college. survivors reporting any serious/life threatening chronic condition prior to age 25 years (grades 3-4) were more likely to not graduate college (RR 1.14, 95% CI 1.10-1.18) compared to no or mild/moderate conditions (grades &lt; 3). Conclusions: Survivors reporting chronic conditions are less likely to complete a college education by age 25 years and may need additional early educational or vocational resources.
The study of the significance and prognosis of the differential expressed miRNAs and their target genes associated with biological in colorectal cancer.
Authors: Mingyun Wang, Mi Yang
Journal: Journal of Clinical Oncology (2019)

e15088 Background: MicroRNAs (miRNAs) have been related to prognostic indicators (such as stage and survival) in colorectal cancer. This study aimed to identify differentially expressed miRNAs and their target genes associated with biological significance and prognosis in colorectal cancer. Methods: The colorectal cancer, colorectal adenoma, and normal samples were obtained from the gene expression profile of GSE71187. A union of differentially expressed genes (DEGs) in the three groups was identified. The significantly different modules with highly interconnected DEGs were identified using weighted correlation network analysis (WGCNA) and were enriched to the KEGG pathway and GO function. Subsequently, the protein-protein interaction (PPI) network for DEGs in the module and the integrated regulatory network of miRNA-DEGs were constructed. In addition, the relationship of target DEGs and prognostic information was analyzed. Results: Three significantly different modules were identified, such as the brown, turquoise, and grey modules. The turquoise module including LTC4S, KLRK1, UNC5C, etc., which was mainly enriched to cell adhesion, cytokine−cytokine receptor interaction, and chemokine signaling pathway, inhibited the development of colorectal cancer. Subsequently, PPI network was constructed with the 678 DEGs in the three modules. Moreover, the miRNA-DEGs network was constructed with the 17 target DEGs (CXCR1, LTC4S, BTK, IGF1, etc.) and 14 miRNA (hsa-miR-335-5p, etc.). Finally, the overexpressed LTC4S was a good prognostic biomarker for colorectal cancer. Conclusions: The hsa-miR-335-5p might have potential prognosis value by targeting LTC4S and CXCR1 in colorectal cancer.
Phase 1b/2 study of enzalutamide (ENZ) with LY3023414 (LY) or placebo (PL) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone.
Authors: Christopher Sweeney, Ivor John Percent, Sunil Babu, Jennifer Cultrera, Bryan Allyn Mehlhaff, Oscar B. Goodman, David Morris, Ian D. Schnadig, Costantine Albany, Neal D. Shore, Paul R Sieber, Susan Guba, Minmin Wang, Suhyun Kang, Volker Wacheck, Gregory P Donoho, Anna M. Szpurka, Sophie Callies, Boris K. Lin, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2019)

5009 Background: Preclinical and phase 1 results suggest PI3K/mTOR pathway inhibition may enhance androgen receptor inhibition. We report the results of a double-blind, placebo-controlled, randomized Phase 1b/2 study of ENZ±LY (a dual PI3K/mTOR inhibitor) in pts with mCRPC who progressed on abiraterone. Methods: Phase 1b pts received single-agent LY 200 mg twice daily (BID) for 1 wk prior to starting LY+ENZ. Phase 2 pts were randomized 1:1 to 160 mg daily ENZ with PL or 200 mg BID LY on a 28-d cycle. The primary objective was progression-free survival (PFS: serological, radiographic [rPFS], or death) by PCWG2 criteria. Secondary objectives were rPFS, safety, decline in PSA, and PK. Exploratory biomarker analyses included outcomes by presence of androgen receptor variant 7 (AR-V7). 92 primary PFS events were needed for the study to have at least 80% power at one-sided alpha=0.20. Results: LY+ENZ was tolerable during Phase 1b with 1 dose limiting toxicity observed in 13 enrolled pts. Mean LY exposures remained in an efficacious range despite a 30% average decrease when combined with ENZ. In Phase 2, 129 pts were randomized to LY+ENZ (N=65) and PL+ENZ (N=64) (Table). Median PCWG2-PFS was 3.7 mos (LY+ENZ) vs 2.9 mos (PL+ENZ) (HR 0.66, 95% CI 0.43, 0.99; p-value 0.0208). Conclusions: Combination LY+ENZ had a clinically manageable safety profile. The primary end-point of PCWG2-PFS was met and is supported by a clinically meaningful delay in rPFS in AR-V7 negative pts. The biomarker data provide important insights to inform future development strategies. Clinical trial information: NCT02407054. [Table: see text]
Development of a PD-L1 multiplex immunofluorescence assay with advanced visual analysis for understanding the tumor microenvironment.
Authors: Sean Downing, Aditi Sharma, Courtney Hebert, Jamie Buell, Douglas Wood
Journal: Journal of Clinical Oncology (2019)

e14283 Background: Current PD-L1 Immunohistochemistry (IHC) assays utilizing conventional brightfield, chromogenic 3,3′-Diaminobenzidine (DAB) staining modalities are the norm in both translational and clinical research. With the rise of immuno-oncology, multiplexed immunofluorescence (mIF) has the potential to revolutionize pathology research as it enables the identification of complex cell phenotypes and their potential interactions in the tumor microenvironment (TME). Ultivue has developed a mIF assay for profiling PD-L1, CD8, CD68, pan-Cytokeratin, and Sox10 enabling whole-slide imaging and data analysis in a single workday. Methods: With an expanding number of biomarkers being interrogated, the complexity of the data analysis and visualization tasks increase exponentially. For N markers, a total of 2 N phenotypes are possible. To address this problem and reveal the biologically relevant information embedded in the data, we have developed software tools to reduce the complexity, visualize, and quantify spatial distributions of cells across the full spectrum of possible phenotypes. In this study we demonstrate the utility, robustness, and ability to derive meaningful biological insights by validating the accuracy, precision, sensitivity, and specificity of the PD-L1 multiplex immunofluorescence assay. Results: Here we present results that identify all distinct binary phenotypes within cohorts of lung cancer and melanoma samples using qualitative pathology review and an image processing technique called Phenotypic Surface Density Mapping (PSDM). Important features of this quantitative technique are robustness, use of real physical units (e.g. cells/µm 2 or intensity/µm 2 ), and data generation in an unbiased fashion to reveal information about every possible phenotype. Conclusions: Applying the pathology review and PSDM to the cohorts of samples confirmed a high level of concordance demonstrating sensitivity and specificity with high degrees of confidence above 85%. Analysis of intra-run, inter-run, and inter-technician runs revealed that cell counts were within a CV less than 15% across all markers. Data presented here indicates the potential for use in a high throughput testing laboratory to aid in collection and interpretation of meaningful biological insights.
Comparative effectiveness of surgery versus external beam radiation with/without brachytherapy in intermediate and high-risk localized prostate cancer.
Authors: Ming Yin, Paul Monk, Amir Mortazavi, Monika Joshi, Edmund Folefac, Steven K. Clinton
Journal: Journal of Clinical Oncology (2019)

e16602 Background: Radical prostatectomy (RP) and definitive radiation with androgen deprivation therapy (ADT) are both standard of care options for intermediate and high-risk localized prostate cancer (PCa). It remains controversial if the two modalities produce equivalent outcomes because the PROTECT trial (2016) and three recent retrospective studies (2018) drew inconsistent conclusions. Methods: The Surveillance, Epidemiology and End Results (SEER) database was queried from 2004 to 2015 for localized PCa (TxN0M0) who received upfront surgery or who were recommended for surgery but instead received external beam radiation (EBRT) with or without brachytherapy boost to control selection bias. The Kaplan-Meier method was used to generate overall survival (OS) curves and the Cox regression analysis was performed to compare survival outcomes. Results: A total of 175,349 patients were eligible with a median age of 62 years old (age range: 26 to 99). 167,234 patients had upfront surgery and 8,115 patients had upfront radiotherapy, including 7,099 EBRT and 1,016 EBRT with brachytherapy. Overall, upfront surgery was associated with a better OS, compared with patients who received radiotherapy (all patients: adjusted HR [adjHR], 0.79; 95% CI, 0.74–0.83, P &lt; 0.001). The survival benefit is more pronounced in patients of intermediate-risk group (adjHR, 0.61; 95% CI, 0.57–0.66, P &lt; 0.001; N = 112,816), and remains significant in patients of high-risk group (adjHR, 0.91; 95% CI, 0.84–0.98, P = 0.02; N = 62,533). However, in elderly high-risk PCa patients (age ≥ 70), surgery was associated with a significantly inferior OS, compared with radiotherapy (adjHR, 1.16; 95% CI, 1.06–1.28, P = 0.002). Conclusions: Compared with upfront radiation therapy, definitive surgery was associated with overall survival benefit in intermediate- and high-risk localized PCa, except patients with old age and high-risk features, who should be considered for radiation therapy.
Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression
Authors: Qingsong Hu, Youqiong Ye, Li-Chuan Chan, Yajuan Li, Ke Liang, Aifu Lin, Sergey D. Egranov, Yaohua Zhang, Weiya Xia, Jing Gong, Yinghong Pan, Sujash S. Chatterjee, Jun Yao, Kurt W. Evans, Tina K. Nguyen, Peter K. Park, Jiewei Liu, Cristian Coarfa, Sri Ramya Donepudi, Vasanta Putluri, Nagireddy Putluri, Arun Sreekumar, Chandrashekar R. Ambati, David H. Hawke, Jeffrey R. Marks, Preethi H. Gunaratne, Abigail S. Caudle, Aysegul A. Sahin, Gabriel N. Hortobagyi, Funda Meric-Bernstam, Lieping Chen, Dihua Yu, Mien-Chie Hung, Michael A. Curran, Leng Han, Chunru Lin, Liuqing Yang
Journal: Nature Immunology (2019)