Publications by authors named "Yu Shyr"

357 Publications

Development and Evaluation of a Method to Correct Misinterpretation of Clinical Trial Results With Long-term Survival.

JAMA Oncol 2021 Apr 15. Epub 2021 Apr 15.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: In immune checkpoint inhibitor (ICI) trials, long tails and crossovers in survival curves-which violate the proportional hazards (PH) assumption-are commonly observed, making cure or restricted mean survival time models preferable for analysis of ICI survival data. Cox PH analysis, however, still appears in major medical journals, leading to potential misinterpretation of clinical significance.

Objective: To convert inappropriate Cox hazard ratios (HRs) to appropriate PH cure model treatment-effect estimates (HR for short-term survivors and difference in proportions [DP] for long-term survivors) for more accurate interpretation of published ICI trials.

Design And Setting: This study uses the Taylor expansion technique to demonstrate the mathematical relationship between Cox PH and PH cure models for data with long-term survival, and based on this relationship, proposes the Cox-TEL (Cox PH-Taylor expansion adjustment for long-term survival data) adjustment method. The proposed Cox-TEL method requires only 2 inputs: the reported Cox HRs and Kaplan-Meier-estimated survival probabilities.

Results: Comprehensive simulations show the strength of the proposed method in terms of power, bias, and type I error rate; these results, which are close to PH cure model estimates, were further verified in a melanoma data set (N = 285; Cox HR = 0.71; 95% CI, 0.51-0.91; Cox-TEL HR = 0.83; 95% CI, 0.60-1.07; PH cure HR = 0.86; 95% CI, 0.61-1.11; Cox-TEL DP = 0.10; 95% CI, 0.01-0.23; PH cure DP = 0.10; 95% CI, 0.00-0.21). The magnitude of potential difference between reported and adjusted HRs using real-world ICI trial results is demonstrated. For example, in the CheckMate 067 trial (nivolumab/ipilimumab combination therapy vs ipilimumab), the Cox HR was 0.54 (95% CI, 0.44-0.67), and the Cox-TEL HR was 0.90 (95% CI, 0.73-1.11).

Conclusions And Relevance: The findings of this study suggest the need to revisit published ICI survival data analysis to address potential misinterpretation. The Cox-TEL method not only is designed for this purpose, but also is user friendly and easy to implement using published clinical trial data and a freely available R software package.
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http://dx.doi.org/10.1001/jamaoncol.2021.0289DOI Listing
April 2021

Clinical activity and safety of cediranib and olaparib combination in patients with metastatic pancreatic ductal adenocarcinoma without BRCA mutation.

Oncologist 2021 Mar 20. Epub 2021 Mar 20.

Medical Oncology, Yale School of Medicine, New Haven, CT, USA.

Lessons Learned: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation.

Background: Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib resulting in an objective response in mPDAC patients.

Methods: Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30mg daily and olaparib 200mg twice daily, orally. The primary endpoint was objective response (OR) rate.

Results: Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six due to clinical progression and one due to an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea.

Conclusion: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.
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http://dx.doi.org/10.1002/onco.13758DOI Listing
March 2021

Prediction models for breast cancer prognosis among Asian women.

Cancer 2021 Mar 11. Epub 2021 Mar 11.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Robust and reliable prognosis prediction models have not been developed and validated for Asian patients with breast cancer, a rapidly growing yet understudied population in the United States.

Methods: We used longitudinal data from the Shanghai Breast Cancer Survival Study, a population-based prospective cohort study (n = 5042), to develop prediction models for 5- and 10-year disease-free survival (DFS) and overall survival (OS). The initial models considered age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the addition of modifiable lifestyle factors (physical activity, soy isoflavones intake, and postdiagnostic weight change) improved the models. All final models have been validated internally and externally in the National Cancer Database when applicable.

Results: Our final models included age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status, PR status, 6-month postdiagnostic weight change, interaction between ER status and tamoxifen therapy, and interaction between age and TNM stage. The internal validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS, 10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity, 0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined.

Conclusion: We developed prediction models for breast cancer prognosis from a large prospective study. Our prognostic models performed very well in women from the United States-particularly in Asian American women-and demonstrated high prediction accuracy and generalizability.
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http://dx.doi.org/10.1002/cncr.33425DOI Listing
March 2021

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

Ann Otol Rhinol Laryngol 2021 Feb 25:3489421995283. Epub 2021 Feb 25.

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Objectives: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients.

Methods: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence.

Results: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression.

Conclusions: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.
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http://dx.doi.org/10.1177/0003489421995283DOI Listing
February 2021

Outcomes After Use of a Lymph Node Collection Kit for Lung Cancer Surgery: A Pragmatic, Population-Based, Multi-Institutional, Staggered Implementation Study.

J Thorac Oncol 2021 Apr 16;16(4):630-642. Epub 2021 Feb 16.

Department of Surgery, Washington University, St. Louis, Missouri.

Introduction: Suboptimal pathologic nodal staging prevails after curative-intent resection of lung cancer. We evaluated the impact of a lymph node specimen collection kit on lung cancer surgery outcomes in a prospective, population-based, staggered implementation study.

Methods: From January 1, 2014, to August 28, 2018, we implemented the kit in three homogeneous institutional cohorts involving 11 eligible hospitals from four contiguous hospital referral regions. Our primary outcome was pathologic nodal staging quality, defined by the following evidence-based measures: the number of lymph nodes or stations examined, proportions with poor-quality markers such as nonexamination of lymph nodes, and aggregate quality benchmarks including the National Comprehensive Cancer Network criteria. Additional outcomes included perioperative complications, health care utilization, and overall survival.

Results: Of 1492 participants, 56% had resection with the kit and 44% without. Pathologic nodal staging quality was significantly higher in the kit cases: 0.2% of kit cases versus 9.8% of nonkit cases had no lymph nodes examined; 3.2% versus 25.3% had no mediastinal lymph nodes; 75% versus 26% attained the National Comprehensive Cancer Network criteria (p < 0.0001 for all comparisons). Kit cases revealed no difference in perioperative complications or health care utilization except for significantly shorter duration of surgery, lower proportions with atelectasis, and slightly higher use of blood transfusion. Resection with the kit was associated with a lower hazard of death (crude, 0.78 [95% confidence interval: 0.61-0.99]; adjusted 0.85 [0.71-1.02]).

Conclusions: Lung cancer surgery with a lymph node collection kit significantly improved pathologic nodal staging quality, with a trend toward survival improvement, without excessive perioperative morbidity or mortality.
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http://dx.doi.org/10.1016/j.jtho.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012255PMC
April 2021

Biomarker Discovery and Validation: Statistical Considerations.

J Thorac Oncol 2021 Apr 2;16(4):537-545. Epub 2021 Feb 2.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

Biomarkers have various applications including disease detection, diagnosis, prognosis, prediction of response to intervention, and disease monitoring. In this era of precision medicine, having validated biomarkers to inform clinical decision making is more important than ever. In this article, we discuss best the practices and potential issues in biomarker discovery and validation. We encourage team science partnerships to bring cutting-edge discovery from bench to bedside, leading to improved patient care and outcomes.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012218PMC
April 2021

The design and analysis of non-randomized studies: a case study of off-label use of hydroxychloroquine in the COVID-19 pandemic.

Authors:
Derek Shyr Yu Shyr

Expert Opin Investig Drugs 2021 Feb 29;30(2):111-117. Epub 2020 Dec 29.

Department of Biostatistics, Vanderbilt University School of Medicine , Nashville, TN, USA.

: The COVID-19 pandemic has prompted researchers to conduct non-randomized studies in an effort to find an off-label drug that can effectively combat the virus and its effects. While these studies can expedite the drug approval process, researchers must carefully design and analyze such studies in order to perform rigorous science that is reproducible and credible. This article focuses on several key design and analysis considerations that can improve the scientific rigor of non-randomized studies of off-label drugs. : The aim of this article is to provide an overview of best approaches that should be considered for non-randomized studies on off-label drugs. We discuss these approaches in detail and use a non-randomized study by Rivera et al. in as an example of methods that have been undertaken for COVID-19. : While non-randomized studies are inherently biased, they may be unavoidable in situations such as the COVID-19 pandemic, where researchers need to find an effective treatment quickly. We believe that a well-formed experimental design, high-quality data collection, and a well-thought-out statistical and data analysis plan are sufficient to produce rigorous and credible results for making an optimal decision.
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http://dx.doi.org/10.1080/13543784.2021.1868435DOI Listing
February 2021

Scientific Rigor in the Age of COVID-19.

JAMA Oncol 2021 Feb;7(2):171-172

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

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http://dx.doi.org/10.1001/jamaoncol.2020.6639DOI Listing
February 2021

Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells.

Biochem Pharmacol 2021 02 4;184:114359. Epub 2020 Dec 4.

Department of Cellular and Molecular Medicine, University of Arizona Cancer Center College, Tucson, AZ, USA. Electronic address:

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.
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http://dx.doi.org/10.1016/j.bcp.2020.114359DOI Listing
February 2021

PheWAS-ME: a web-app for interactive exploration of multimorbidity patterns in PheWAS.

Bioinformatics 2020 Oct 14. Epub 2020 Oct 14.

Department of Biostatistics, Vanderbilt University, Nashville, TN.

Summary: Electronic health records (EHRs) linked with a DNA biobank provide unprecedented opportunities for biomedical research in precision medicine. The Phenome-wide association study (PheWAS) is a widely used technique for the evaluation of relationships between genetic variants and a large collection of clinical phenotypes recorded in EHRs. PheWAS analyses are typically presented as static tables and charts of summary statistics obtained from statistical tests of association between a genetic variant and individual phenotypes. Comorbidities are common and typically lead to complex, multivariate gene-disease association signals that are challenging to interpret. Discovering and interrogating multimorbidity patterns and their influence in PheWAS is difficult and time-consuming. We present PheWAS-ME: an interactive dashboard to visualize individual-level genotype and phenotype data side-by-side with PheWAS analysis results, allowing researchers to explore multimorbidity patterns and their associations with a genetic variant of interest. We expect this application to enrich PheWAS analyses by illuminating clinical multimorbidity patterns present in the data.

Availability: A demo PheWAS-ME application is publicly available at https://prod.tbilab.org/phewas_me/. Sample datasets are provided for exploration with the option to upload custom PheWAS results and corresponding individual-level data. Online versions of the appendices are available at https://prod.tbilab.org/phewas_me_info/. The source code is available as an R package on GitHub (https://github.com/tbilab/multimorbidity_explorer).

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa870DOI Listing
October 2020

Integrated Omics of Metastatic Colorectal Cancer.

Cancer Cell 2020 Nov 3;38(5):734-747.e9. Epub 2020 Sep 3.

CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; CAS Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address:

We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application.
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http://dx.doi.org/10.1016/j.ccell.2020.08.002DOI Listing
November 2020

What Constitutes a Valid Surrogate End Point in Cancer Clinical Trials?

Authors:
Yu Shyr Derek Shyr

JAMA Oncol 2020 09;6(9):1334-1335

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaoncol.2020.1847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780730PMC
September 2020

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Cancer Discov 2020 10 22;10(10):1514-1527. Epub 2020 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541683PMC
October 2020

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.

Chest 2020 10 15;158(4):1397-1408. Epub 2020 Jun 15.

Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.

Background: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.

Research Question: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.

Study Design And Methods: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.

Results: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).

Interpretation: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.
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http://dx.doi.org/10.1016/j.chest.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831876PMC
October 2020

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

Lancet 2020 06 28;395(10241):1907-1918. Epub 2020 May 28.

Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.

Methods: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.

Findings: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.

Interpretation: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

Funding: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.
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http://dx.doi.org/10.1016/S0140-6736(20)31187-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255743PMC
June 2020

Mortality of Cardiovascular Events in Patients With COPD and Preceding Hospitalization for Acute Exacerbation.

Chest 2020 Sep 14;158(3):973-985. Epub 2020 Mar 14.

Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Background: Acute exacerbation (AE) of COPD may be accompanied by the deterioration of cardiovascular comorbidities, as evidenced by the increased incidence of acute cardiovascular events.

Research Question: The goal of this study was to determine whether preceding AE might be associated with mortality of cardiovascular events.

Study Design And Methods: Using a health insurance research database in Taiwan, patients with COPD were identified who experienced first-time acute myocardial infarction (AMI; n = 26,442), ischemic stroke (n = 54,959), and intracranial hemorrhage (ICH; n = 14,893) over a 13-year period. In each cohort, 4,356, 6,655, and 1,727 patients, respectively, had been hospitalized for AE within the previous year prior to the index cardiovascular events, and patients with COPD but without hospitalization for AEs constituted the control subjects. ORs of 90-day mortality and hazard ratios (HRs) of overall mortality during follow-up in relation to hospitalization for an AE and the frequency of hospitalization for AEs (ie, 1 and ≥ 2 hospitalizations for AEs) were estimated with adjustment for potential confounders.

Results: Hospitalization for an AE was independently associated with 90-day mortality of AMI (OR, 1.33; 95% CI, 1.24-1.43), ischemic stroke (OR, 1.46; 95% CI, 1.36-1.56), and ICH (OR, 1.19; 95% CI, 1.06-1.32). Hospitalization for an AE was associated with overall mortality of AMI (HR, 1.23; 95% CI, 1.19-1.27), ischemic stroke (HR, 1.29; 95% CI, 1.26-1.33), and ICH (HR, 1.19; 95% CI, 1.13-1.26). In addition, compared with control subjects, patients with more frequent hospitalizations for AEs exhibited significant trends at higher risk of 90-day and overall mortality of AMI, ischemic stroke, and ICH. Finally, these results were consistent with propensity score matching-based estimates.

Interpretation: Preceding hospitalization for AEs is associated with 90-day and overall mortality of cardiovascular events in COPD.
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http://dx.doi.org/10.1016/j.chest.2020.02.046DOI Listing
September 2020

Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors.

Sci Transl Med 2020 03;12(534)

Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)-targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC. Here, we report that MYCN, an oncogene typically overexpressed in tumors of the nervous system or with neuroendocrine features, is heterogeneously expressed within a substantial fraction of primary and recurrent TNBC and is expressed in an even higher fraction of TNBCs that do not display a pathological complete response after neoadjuvant chemotherapy. We performed high-throughput chemical screens on TNBC cell lines with varying amounts of MYCN expression and determined that cells with higher expression of MYCN were more sensitive to bromodomain and extraterminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell lines and patient-derived xenograft (PDX) models. Our preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced MYCN-expressing TNBC.
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http://dx.doi.org/10.1126/scitranslmed.aaw8275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427123PMC
March 2020

Quantitative Analysis of Oncology Professional Learning Preferences.

JCO Oncol Pract 2020 02 7;16(2):e155-e165. Epub 2020 Jan 7.

Vanderbilt University School of Medicine, Nashville, TN.

Purpose: ASCO is the premier and largest global professional society for oncology care professionals. In 2015, ASCO launched a longitudinal Learning Cohort Pilot Project to catalog and better understand the learning behaviors and preferences of oncology health care providers. A secondary goal was to assess learner preferences and utilization related to ASCO's portfolio of educational resources.

Methods: The Learning Cohort Pilot Project was conducted between November 2015 and August 2016 with 49 ASCO members. Participants were selected via convenience sampling and stratified random sampling to generate a cohort that mirrored the demographic distribution of overall ASCO membership. Participants completed a different ASCO resource-specific feedback activity each month, which measured professional educational needs, sources sought, and preferences for educational resources. Responses were organized by demographic variables in our participant pool to identify trends in provider learning preferences. Fisher's exact test was used to assess the association between participant demographics and practice setting and responses. Holm's procedure was used to adjust for multiple testing.

Results: The Learning Cohort Pilot Project revealed statistically significant relationships between participant demographic variables and learning preferences. Age and practice setting were the demographic variables most consistently associated with the different preferences explored throughout the targeted activities.

Conclusion: The results of this pilot cohort reinforced the hypothesis that oncology care providers have different professional educational needs and preferences that can be potentially anticipated and met with tailored resources. Delivering solutions to meet these needs represents an opportunity for further research and resource development.
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http://dx.doi.org/10.1200/JOP.18.00731DOI Listing
February 2020

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

Oncologist 2020 08 14;25(8):669-679. Epub 2020 Jan 14.

Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Introduction: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy.

Materials And Methods: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.

Results: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.

Conclusion: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.

Implications For Practice: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
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http://dx.doi.org/10.1634/theoncologist.2019-0637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418359PMC
August 2020

TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR Metastatic Triple-Negative Breast Cancer.

Clin Cancer Res 2020 05 10;26(9):2111-2123. Epub 2019 Dec 10.

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.

Purpose: Preclinical data demonstrating androgen receptor (AR)-positive (AR) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR (≥10%) breast cancer.

Patients And Methods: Phase Ib patients [estrogen receptor positive (ER) or TNBC] with AR breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks.

Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, = 0.06), and increased PFS (4.6 vs. 2.0 months, = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel fusions and AR splice variants.

Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196503PMC
May 2020

Establishing and Evaluating an ASCO Learning Cohort: a Longitudinal Project Assessing the Learning Needs and Behaviors of Oncology Professionals.

J Cancer Educ 2019 Nov 18. Epub 2019 Nov 18.

Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.

Background: In 2013, the American Society of Clinical Oncology (ASCO)'s Continuing Education Committee recommended establishing an interprofessional, longitudinal cohort pilot project. The main goals of the cohort were to gain feedback from oncology providers on how they use resources to address their learning needs and gain insights into the utility of different ASCO educational activities.

Methods: The ASCO Learning Cohort Pilot Project included 49 ASCO members that were representative of the overall Society membership demographics and ran from November 2015 through August 2016. Participants documented monthly learning needs and completed monthly feedback activities focused on specific ASCO educational resources.

Results: The Learning Cohort Pilot Project proved a viable and innovative cohort model for analyzing the learning process for oncology healthcare professionals. The development, operations, and compliance required unique infrastructure to accomplish this project. Relationships between participant demographic variables and learning preferences are reported elsewhere.

Conclusion: The ASCO Learning Cohort Project is a unique educational project that demonstrated feasibility and has met its goals. This paper outlines the processes of establishing a learning cohort, including participant selection, project design, and participant feedback. We evaluate the project model as a means to better understand the learning needs and behaviors of oncology healthcare professionals.
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http://dx.doi.org/10.1007/s13187-019-01649-5DOI Listing
November 2019

Kidney Stone History and Adverse Outcomes After Percutaneous Coronary Intervention.

Urology 2020 Feb 4;136:75-81. Epub 2019 Nov 4.

Department of Urology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Objective: To determine whether kidney stone history is associated with adverse outcomes after percutaneous coronary intervention (PCI). Kidney stone formers have an increased risk of developing coronary artery disease; however, whether these patients have worse cardiac outcomes is unknown.

Materials And Methods: We identified adult patients who underwent first-time PCI in Vanderbilt University Medical Center (VUMC) Synthetic Derivative from 2008 to 2016 (n = 11,289) and in a nationwide database of Taiwan (NHIRD) from 2005 to 2012 (n = 155,762). Odds ratios (ORs) of 30-day in-hospital mortality and hazard ratios (HRs) of 1-year and 3-year adverse outcomes associated with kidney stone history were estimated using a propensity score approach.

Results: Overall, 294 and 12,286 stone formers undergoing PCI were identified in the VUMC and NHIRD, respectively. After matching, stone formers at VUMC were at higher risks of 30-day in-hospital mortality (OR 2.79, 95% CI 1.15-6.69) and 1-year (HR 1.59, 95% CI 1.13-2.24) and 3-year (HR 1.36, 95% CI 1.02-1.81) myocardial infarction. In the NHIRD, kidney stone history was associated with 1-year (HR 1.12, 95% CI 1.03-1.21) and 3-year (HR 1.14, 95% CI 1.06-1.22) myocardial infarction. In a sensitivity analysis, stone formers undergoing kidney stone surgery were marginally associated with 30-day in-hospital mortality (OR 1.21, 95% CI 0.99-1.48) and were associated with 3-year myocardial infarction (HR 1.13, 95% CI 1.02-1.25).

Conclusion: Kidney stone history is associated with poorer cardiac outcomes after PCI. Improving secondary cardiac prevention strategies after PCI may be necessary for patients with a history of kidney stone disease.
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http://dx.doi.org/10.1016/j.urology.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008077PMC
February 2020

Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis.

JAMA Otolaryngol Head Neck Surg 2020 01;146(1):20-29

Department of Otolaryngology-Head and Neck Surgery, Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio.

Importance: Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research.

Objective: To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease.

Design, Setting, And Participants: In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook.

Main Outcomes And Measures: The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications.

Results: Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk.

Conclusions And Relevance: In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.
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http://dx.doi.org/10.1001/jamaoto.2019.3022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824232PMC
January 2020

Outcomes of acute cardiovascular events in rheumatoid arthritis and systemic lupus erythematosus: a population-based study.

Rheumatology (Oxford) 2020 06;59(6):1355-1363

Department of Public Health, College of Medicine, National Cheng Kung University, Tainan.

Objectives: Patients with RA and SLE have an excess cardiovascular risk. We aimed to evaluate outcomes of acute cardiovascular events in these patients.

Methods: Using a nationwide database of Taiwan, we identified adult patients who experienced first-time acute myocardial infarction (n = 191 008), intracranial haemorrhage (n = 169 923) and ischaemic stroke (n = 486 890) over a 13-year period. Odds ratios (ORs) of in-hospital mortality and hazard ratios (HRs) of overall mortality and adverse outcomes during long-term follow-up in relation to RA and SLE were estimated with adjustment for potential confounders.

Results: In each cohort, 748, 410 and 1419 patients had established RA; 256, 292 and 622 patients had SLE. Among acute myocardial infarction patients, RA and SLE were associated with in-hospital mortality (RA: OR 1.61, 95% CI 1.33, 1.95; SLE: OR 2.31, 95% CI 1.62, 3.28) and overall mortality. Additionally, RA (HR 1.28, 95% CI 1.18, 1.38) and SLE (HR 1.46, 95% CI 1.27, 1.69) increased the risk of major adverse cardiac events. After intracranial haemorrhage, patients with RA and SLE had higher risks of in-hospital mortality (RA: OR 1.61, 95% CI 1.26, 2.06; SLE: OR 3.00, 95% CI 2.33, 3.86) and overall mortality. After ischaemic stroke, RA and SLE increased in-hospital mortality (RA: OR 1.45, 95% CI 1.15, 1.83; SLE: OR 2.18, 95% CI 1.57, 3.02), overall mortality and recurrent cerebrovascular events (RA: HR 1.10, 95% CI 1.002, 1.21; SLE: HR 1.31, 95% CI 1.14, 1.51), among which ischaemic stroke (HR 1.39, 95% CI 1.19, 1.62) was more likely to recur in SLE patients.

Conclusion: Both RA and SLE are consistently associated with adverse outcomes following acute cardiovascular events, highlighting the necessity of integrated care for affected patients.
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http://dx.doi.org/10.1093/rheumatology/kez456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849999PMC
June 2020

Bayesian Inference of Lymph Node Ratio Estimation and Survival Prognosis for Breast Cancer Patients.

IEEE J Biomed Health Inform 2020 02 24;24(2):354-364. Epub 2019 Sep 24.

Objective: We evaluated the prognostic value of lymph node ratio (LNR) for the survival of breast cancer patients using Bayesian inference.

Methods: Data on 5,279 women with infiltrating duct and lobular carcinoma breast cancer, diagnosed from 2006-2010, was obtained from the NCI SEER Cancer Registry. A prognostic modeling framework was proposed using Bayesian inference to estimate the impact of LNR in breast cancer survival. Based on the proposed model, we then developed a web application for estimating LNR and predicting overall survival.

Results: The final survival model with LNR outperformed the other models considered (C-statistic 0.71). Compared to directly measured LNR, estimated LNR slightly increased the accuracy of the prognostic model. Model diagnostics and predictive performance confirmed the effectiveness of Bayesian modeling and the prognostic value of the LNR in predicting breast cancer survival.

Conclusion: The estimated LNR was found to have a significant predictive value for the overall survival of breast cancer patients.

Significance: We used Bayesian inference to estimate LNR which was then used to predict overall survival. The models were developed from a large population-based cancer registry. We also built a user-friendly web application for individual patient survival prognosis. The diagnostic value of the LNR and the effectiveness of the proposed model were evaluated by comparisons with existing prediction models.
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http://dx.doi.org/10.1109/JBHI.2019.2943401DOI Listing
February 2020

Quantitative Assessment of Learning Behaviors for Oncology Providers.

J Cancer Educ 2021 Feb;36(1):25-32

Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.

How health care providers select topics and activities for learning is key to meeting their needs. The goal of this study was to investigate how oncology providers identify knowledge gaps and choose learning activities. An online focus group within a larger longitudinal study was conducted between November 2015 and August 2016. Participants were chosen by convenience and stratified random sampling of diverse types of oncology providers. Providers were asked monthly to identify learning needs, explain how they identified those needs, and describe the learning activity they chose to meet those needs. Thirty-two oncology providers recorded 201 learning needs via online journal entries (mean 6 entries per person). Needs were associated with practice setting and professional role (p < .05). Colleague recommendation predicted learning needs for advanced practice providers (APPs) (p = .003). Patient cases drove > 50% of identified learning needs across groups. Learning activity preferences were associated with practice setting (p < .05). Choice of learning activity was associated with practice setting, professional role, and geographic location. Colleague recommendation was important for APPs (p = .025). Over 75% of learner responses identify convenience and content quality as important factors in choosing an activity. This study represents a quantitative assessment of learning behaviors for oncology providers and shows that identification of learning needs and activity selection differ by provider demographics. Limitations include small size and underrepresentation of some groups. Our findings should be confirmed with larger samples. Future research should focus on assessment of cohort versus individual needs and learning priorities.
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http://dx.doi.org/10.1007/s13187-019-01593-4DOI Listing
February 2021

scRNABatchQC: multi-samples quality control for single cell RNA-seq data.

Bioinformatics 2019 12;35(24):5306-5308

Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.

Summary: Single cell RNA sequencing is a revolutionary technique to characterize inter-cellular transcriptomics heterogeneity. However, the data are noise-prone because gene expression is often driven by both technical artifacts and genuine biological variations. Proper disentanglement of these two effects is critical to prevent spurious results. While several tools exist to detect and remove low-quality cells in one single cell RNA-seq dataset, there is lack of approach to examining consistency between sample sets and detecting systematic biases, batch effects and outliers. We present scRNABatchQC, an R package to compare multiple sample sets simultaneously over numerous technical and biological features, which gives valuable hints to distinguish technical artifact from biological variations. scRNABatchQC helps identify and systematically characterize sources of variability in single cell transcriptome data. The examination of consistency across datasets allows visual detection of biases and outliers.

Availability And Implementation: scRNABatchQC is freely available at https://github.com/liuqivandy/scRNABatchQC as an R package.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954654PMC
December 2019

Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites.

Am J Hematol 2019 11 27;94(11):1200-1207. Epub 2019 Aug 27.

Department of Pharmacology, University of Iowa, Iowa City, Iowa.

Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.
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http://dx.doi.org/10.1002/ajh.25594DOI Listing
November 2019

Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations.

Mol Cancer Res 2019 09 11;17(9):1842-1853. Epub 2019 Jun 11.

Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.

Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726520PMC
September 2019

Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.

Nat Commun 2019 03 26;10(1):1373. Epub 2019 Mar 26.

Departments of Medicine, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA.

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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http://dx.doi.org/10.1038/s41467-019-09068-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435685PMC
March 2019