Age and political leaning predict COVID-19 vaccination status at a large, multi-campus, public university in Pennsylvania: A cross-sectional survey.

INTRODUCTION: Vaccine hesitancy during the COVID-19 pandemic impacted many higher education institutions. Understanding the factors associated with vaccine hesitancy and uptake is instrumental in directing policies and disseminating reliable information during public health emergencies. OBJECTIVE: This study evaluates associations between age, gender, and political leaning in relationship to COVID-19 vaccination status among a large, multi-campus, public university in Pennsylvania. METHODS: From October 5-November 30, 2021, a 10-minute REDCap survey was available to students, faculty, and staff 18 years of age and older at the Pennsylvania State University (PSU). Recruitment included targeted email, social media, digital advertisements, and university newspapers. 4,231 responses were received. Associations between the selected factors and vaccine hesitancy were made with Chi-square tests and generalized linear regression models using R version 4.3.1 (2023-06-16). RESULTS: Logistic regression approach suggested that age and political leaning have a statistically significant association with vaccine hesitancy at the 5% level. Adjusted for political leaning, odds of being vaccinated is 4 times higher for those aged 56 years or older compared to the ones aged 18 to 20 (OR = 4.35, 95% CI = (2.82, 6.85), p-value < 0.05). The results also showed that adjusted for age, the odds of being vaccinated is about 3 times higher for liberal individuals compared to far-left individuals (OR = 2.85, 95% CI = (1.45, 5.41), p-value = 0.001). CONCLUSIONS: Age and political leaning are key predictors of vaccine uptake among members of the PSU community, knowledge of which may inform campus leadership's public health efforts such as vaccine campaigns and policy decisions.

Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Developmental/behavioral training innovation in a high-need, low-resource state: The child health and development promotion fellowship.

INTRODUCTION: Developmental and behavioral problems are prevalent in early childhood, whereas the workforce available to identify and address early problems is comparatively limited. Beyond workforce shortages, additional barriers to developing and training a highly skilled workforce in this area exist-particularly in rural, high-need, and underserved U.S. states. As the health care landscape emphasizes expertise in interdisciplinary care, training approaches that provide intensive learning opportunities for supporting a skilled early childhood developmental workforce necessitate novel training approaches. This Workforce Catalyst report summarizes the initial conceptualization, development, execution, and evaluation of a Child Health and Development Promotion (CHDP) postgraduate fellowship in a high need, underserved rural area. METHOD: Three cohorts totaling 15 trainees across fields including psychology, pediatric nursing, speech-language pathology, social work, and occupational therapy were recruited and cross-trained in an intensive postgraduate fellowship in early childhood development and behavior. RESULTS: The CHDP fellowship led to experiences across the care continuum and resulted in multiple clinical, educational, and scholarly products. Outcomes revealed a training program aligned with Infant and Early Childhood Mental Health competencies, high in-state retention (71%) and employment (93%) following training, and graduates who report leadership positions and sharing of specialty developmental-behavioral knowledge in organizations focused on early childhood. DISCUSSION: The CHDP Fellowship is a novel, immersive, and interdisciplinary training experience demonstrating positive initial training outcomes in Mississippi. The model and experience may serve as a roadmap for bolstering a skilled early childhood workforce in other underserved and high-need states. Aspects regarding scale of reach, funding, and accreditation are discussed as barriers. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Temporal concordance between pulse contour analysis, bioreactance and carotid doppler during rapid preload changes.

PURPOSE: We describe the temporal concordance of 3 hemodynamic monitors. MATERIALS AND METHODS: Healthy volunteers performed preload changes while simultaneously wearing a non-invasive, pulse-contour stroke volume (SV) monitor, a bioreactance SV monitor and a wireless, wearable Doppler ultrasound patch over the common carotid artery. The sensitivity and specificity for detecting preload change over 3 temporal windows (early, middle and late) was assessed. RESULTS: 40 preload changes were recorded in total (20 increase, 20 decrease). Immediately, the wearable Doppler had high sensitivity (100%) and specificity (100%) for detecting preload change with an area under the receiver operator curve (AUROC) of 0.98 for both velocity time integral (VTI, 10.5% threshold) and corrected flow time (FTc, 2.5% threshold). The sensitivity, specificity and AUROC for non-invasive pulse contour were equally good (9% SV threshold). For bioreactance, a 13% SV threshold immediately detected preload change with a sensitivity, specificity and AUROC of 60%, 95% and 0.75, respectively. After two SV outputs following preload change, the sensitivity, specificity and AUROC of bioreactance improved to 70%, 90% and 0.85, respectively. CONCLUSIONS: Carotid Doppler ultrasound and non-invasive pulse contour detected rapid hemodynamic change with equal accuracy; bioreactance improved over time. Algorithm-lag should be considered when interpreting clinical studies.

A novel, hands-free ultrasound patch for continuous monitoring of quantitative Doppler in the carotid artery.

Quantitative Doppler ultrasound of the carotid artery has been proposed as an instantaneous surrogate for monitoring rapid changes in left ventricular output. Tracking immediate changes in the arterial Doppler spectrogram has value in acute care settings such as the emergency department, operating room and critical care units. We report a novel, hands-free, continuous-wave Doppler ultrasound patch that adheres to the neck and tracks Doppler blood flow metrics in the common carotid artery using an automated algorithm. String and blood-mimicking test objects demonstrated that changes in velocity were accurately measured using both manually and automatically traced Doppler velocity waveforms. In a small usability study with 22 volunteer users (17 clinical, 5 lay), all users were able to locate the carotid Doppler signal on a volunteer subject, and, in a subsequent survey, agreed that the device was easy to use. To illustrate potential clinical applications of the device, the Doppler ultrasound patch was used on a healthy volunteer undergoing a passive leg raise (PLR) as well as on a congestive heart failure patient at resting baseline. The wearable carotid Doppler patch holds promise because of its ease-of-use, velocity measurement accuracy, and ability to continuously record Doppler spectrograms over many cardiac and respiratory cycles.

The Feasibility of a Novel Index From a Wireless Doppler Ultrasound Patch to Detect Decreasing Cardiac Output in Healthy Volunteers.

INTRODUCTION: Early hemorrhage is often missed by traditional vital signs because of physiological reserve, especially in the young and healthy. We have developed a novel, wearable, wireless Doppler ultrasound patch that tracks real-time blood velocity in the common carotid artery. MATERIALS AND METHODS: We studied eight healthy volunteers who decreased their cardiac output using a standardized Valsalva maneuver. In all eight, we simultaneously monitored the velocity time integral (VTI) of the common carotid artery (using the ultrasound patch) as well as the descending aorta (using a traditional pulsed wave duplex imaging system); the descending aortic VTI was used as a surrogate for left ventricular stroke volume (SV). Additionally, in a subset of four, we simultaneously measured SV using a noninvasive pulse contour analysis device. RESULTS: From baseline to peak effect of Valsalva, there was a statistically significant fall in descending aortic and common carotid VTI of 37% (P = 0.0005) and 23% (P < 0.0001), respectively. Both values returned to baseline on recovery. Additionally, a novel index from the carotid ultrasound patch (i.e., the heart rate divided by the carotid artery VTI) detected a 10% fall in aortic VTI with high sensitivity and specificity (100% and 100%, respectively); this novel index also accurately detected a 10% decrease in SV as measured by the noninvasive SV monitor. The mean arterial pressure, measured by the noninvasive pulse contour device, did not correctly detect the fall in SV. CONCLUSION: In summary, a novel index from a wireless Doppler ultrasound patch may be more sensitive and specific for detecting decreased cardiac output than standard vital signs in healthy volunteers.

A wearable carotid Doppler tracks changes in the descending aorta and stroke volume induced by end-inspiratory and end-expiratory occlusion: A pilot study.

BACKGROUND AND AIMS: To test the feasibility of a novel, wearable carotid Doppler ultrasound to track changes in cardiac output induced by end-inspiratory and end-expiratory occlusion tests. METHODS: We observed the pattern of Doppler change of the common carotid artery during a simulated end-inspiratory and expiratory occlusion test (sEIOT/sEEOT) in 10, nonventilated, healthy subjects. Simultaneously, we measured the Doppler signal of the descending aorta using duplex ultrasound (Xario, Toshiba Medical Systems) and stroke volume (SV) using noninvasive pulse contour analysis (Clearsight, Edwards Lifesciences, Irvine, California). RESULTS: During sEIOT, SV, maximum velocity time integral (VTI) of the descending aorta, and common carotid fell by 25.7% (P = .0131), 26.1% (P < .0001), and 18.5% (P < .0001), respectively. During sEEOT, SV, maximum VTI of the descending aorta, and common carotid rose by: 41.3% (P = .0051), 28.3% (P < .0001), and 41.6% (P < .0001), respectively. There was good correlation between change in aortic VTI and carotid VTI (r 2 = 0.79); SV and aortic VTI (r 2 = 0.82), and SV and carotid VTI (r 2 = 0.95).The coefficient of variation of the VTI measured by the Doppler patch was roughly 60% less than that of the duplex system. CONCLUSIONS: The pattern of SV change induced by a sEIOT/sEEOT in nonmechanically ventilated volunteers is reflected in the common carotid artery and descending aorta. The VTI variability of the Doppler patch was less than that of the traditional, duplex Doppler.

Diagnostic characteristics of 11 formulae for calculating corrected flow time as measured by a wearable Doppler patch.

BACKGROUND: Change of the corrected flow time (Ftc) is a surrogate for tracking stroke volume (SV) in the intensive care unit. Multiple Ftc equations have been proposed; many have not had their diagnostic characteristics for detecting SV change reported. Further, little is known about the inherent Ftc variability induced by the respiratory cycle. MATERIALS AND METHODS: Using a wearable Doppler ultrasound patch, we studied the clinical performance of 11 Ftc equations to detect a 10% change in SV measured by non-invasive pulse contour analysis; 26 healthy volunteers performed a standardized cardiac preload modifying maneuver. RESULTS: One hundred changes in cardiac preload and 3890 carotid beats were analyzed. Most of the 11 Ftc equations studied had similar diagnostic attributes. Wodeys' and Chambers' formulae had identical results; a 2% change in Ftc detected a 10% change in SV with a sensitivity and specificity of 96% and 93%, respectively. Similarly, a 3% change in Ftc calculated by Bazett's formula displayed a sensitivity and specificity of 91% and 93%. FtcWodey had 100% concordance and an R2 of 0.75 with change in SV; these values were 99%, 0.76 and 98%, 0.71 for FtcChambers and FtcBazetts, respectively. As an exploratory analysis, we studied 3335 carotid beats for the dispersion of Ftc during quiet breathing using the equations of Wodey and Bazett. The coefficient of variation of Ftc during quiet breathing for these formulae were 0.06 and 0.07, respectively. CONCLUSIONS: Most of the 11 different equations used to calculate carotid artery Ftc from a wearable Doppler ultrasound patch had similar thresholds and abilities to detect SV change in healthy volunteers. Variation in Ftc induced by the respiratory cycle is important; measuring a clinically significant change in Ftc with statistical confidence requires a large sample of beats.

A Carotid Doppler Patch Accurately Tracks Stroke Volume Changes During a Preload-Modifying Maneuver in Healthy Volunteers.

OBJECTIVES: Detecting instantaneous stroke volume change in response to altered cardiac preload is the physiologic foundation for determining preload responsiveness. DESIGN: Proof-of-concept physiology study. SETTING: Research simulation laboratory. SUBJECTS: Twelve healthy volunteers. INTERVENTIONS: A wireless continuous wave Doppler ultrasound patch was used to measure carotid velocity time integral and carotid corrected flow time during a squat maneuver. The Doppler patch measurements were compared with simultaneous stroke volume measurements obtained from a noninvasive cardiac output monitor. MEASUREMENTS AND MAIN RESULTS: From stand to squat, stroke volume increased by 24% while carotid velocity time integral and carotid corrected flow time increased by 32% and 9%, respectively. From squat to stand, stroke volume decreased by 13%, while carotid velocity time integral and carotid corrected flow time decreased by 24% and 10%, respectively. Both changes in carotid velocity time integral and corrected flow time were closely correlated with changes in stroke volume (r 2 = 0.81 and 0.62, respectively). The four-quadrant plot found a 100% concordance rate between changes in stroke volume and both changes in carotid velocity time integral and changes in corrected flow time. A change in carotid velocity time integral greater than 15% predicted a change in stroke volume greater than 10% with a sensitivity of 95% and a specificity of 92%. A change in carotid corrected flow time greater than 4% predicted a change in stroke volume greater than 10% with a sensitivity of 90% and a specificity of 92%. CONCLUSIONS: In healthy volunteers, both carotid velocity time integral and carotid corrected flow time measured by a wireless Doppler patch were useful to track changes in stroke volume induced by a preload-modifying maneuver with high sensitivity and specificity.

Building new twenty-first century medical school libraries from the ground up: challenges, experiences, and lessons learned.

The twenty-first century library at a newly opened medical school often differs from those at traditional medical schools. One obvious difference is that the new medical school library tends to be a born-digital library, meaning that the library collection is almost exclusively digital. However, the unique issues related to building a library at a new medical school are not limited to online collections. A unique start-up culture is prevalent, of which newly appointed directors and other library and medical school leaders need to be aware. This special paper provides an overview of best practices experienced in building new medical school libraries from the ground up. The focus is on the key areas faced in a start-up environment, such as budgeting for online collections, space planning, staffing, medical informatics instruction, and library-specific accreditation issues for both allopathic and osteopathic institutions.

System for Informatics in the Molecular Pathology Laboratory: An Open-Source End-to-End Solution for Next-Generation Sequencing Clinical Data Management.

Next-generation sequencing (NGS) diagnostic assays increasingly are becoming the standard of care in oncology practice. As the scale of an NGS laboratory grows, management of these assays requires organizing large amounts of information, including patient data, laboratory processes, genomic data, as well as variant interpretation and reporting. Although several Laboratory Information Systems and/or Laboratory Information Management Systems are commercially available, they may not meet all of the needs of a given laboratory, in addition to being frequently cost-prohibitive. Herein, we present the System for Informatics in the Molecular Pathology Laboratory (SIMPL), a free and open-source Laboratory Information System/Laboratory Information Management System for academic and nonprofit molecular pathology NGS laboratories, developed at the Genomic and Molecular Pathology Division at the University of Chicago Medicine. SIMPL was designed as a modular end-to-end information system to handle all stages of the NGS laboratory workload from test order to reporting. We describe the features of SIMPL, its clinical validation at University of Chicago Medicine, and its installation and testing within a different academic center laboratory (University of Colorado), and we propose a platform for future community co-development and interlaboratory data sharing.

Noninvasive Follicular Thyroid Neoplasms With Papillary-like Nuclear Features Are Genetically and Biologically Similar to Adenomatous Nodules and Distinct From Papillary Thyroid Carcinomas With Extensive Follicular Growth.

CONTEXT: - Proposed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs), formerly noninvasive encapsulated papillary carcinoma, follicular variant (PTC-FV), is an indolent tumor with follicular growth and frequent RAS mutations. OBJECTIVE: - To detect histologic and molecular differences separating NIFTP from follicular adenomas (FAs) and invasive carcinomas, particularly papillary carcinomas with extensive follicular growth (PTC-EFGs) and invasive encapsulated PTC-FV (IE-PTC-FV). DESIGN: - Sixty-one tumors were reviewed histologically and reclassified into 32 NIFTPs (52%), 4 IE-PTC-FVs (7%), 14 PTC-EFGs (23%), and 11 FAs (18%). Next-generation sequencing for mutations in 50 genes was performed. Clinical outcomes were recorded. RESULTS: - The NIFTPs and FAs were well circumscribed and unencapsulated. The FAs had bland nuclei, whereas the NIFTPs showed at least 2 of 3 (67%; sufficient) nuclear features (enlargement, irregular contours, chromatin clearing). The IE-PTC-FVs had follicular growth, sufficient nuclear features, and extensive capsular invasion. The PTC-EFGs had a median of 5% papillae with intrathyroidal invasion (broad-based, sclerotic, or small follicle growth patterns); intranuclear pseudoinclusions were present only in PTC-EFGs (9 of 14; 64%). Mutations included RAS in 20 of the 32 NIFTPs (62%), 4 of the 11 FAs (36%), and 3 of the 4 IE-PTC-FVs (75%); BRAF K601E in 1 NIFTP (3%); BRAF V600E in 5 PTC-EFGs (36%). No NIFTPs or FAs recurred or metastasized. All 4 IE-PTC-FVs (100%) had hematogenous metastasis. Two PTC-EFGs (14%) had lymphatic metastasis. CONCLUSIONS: - The morphologic similarity and RAS mutations in FAs, NIFTPs, and IE-PTC-FVs supports the genetic similarity of those follicular neoplasms in contrast to the unique presence of BRAF V600E mutations in PTC-EFGs. Using strict diagnostic criteria supported by molecular testing, tumors with extensive follicular growth can be classified into follicular type or RAS-like (FA, NIFTP, IE-PTC-FV) versus papillary type or BRAF V600E-like (PTC-EFG).

Exploratory Analysis of Single-Gene Predictive Biomarkers in HERA DASL Cohort Reveals That C8A mRNA Expression Is Prognostic of Outcome and Predictive of Benefit of Trastuzumab.

PURPOSE: The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2-positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs. METHODS: To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted. Disease-free survival (DFS) was used as the end point in a Cox regression model, with the interaction term between C8A mRNA and treatment as a categorical variable split on the cohort mean. RESULTS: A significant interaction between C8A mRNA and treatment was detected (P < .001), indicating a predictive response to trastuzumab treatment. For the C8A-low subgroup (mRNA expression lower than the cohort mean), no significant treatment benefit was observed (P = .73). In the C8A-high subgroup, patients receiving trastuzumab experienced a lower hazard of a DFS event by approximately 75% compared with those in the observation arm (hazard ratio [HR], 0.25; P < .001). A significant prognostic effect of C8A mRNA also was seen (P < .001) in the observation arm, where the C8A-high group hazard of a DFS event was three times the respective hazard of the C8A-low group (HR, 3.27; P < .001). C8A mRNA is highly prognostic in the Hungarian Academy of Science HER2+ gastric cancer cohort (HR, 1.72; P < .001). CONCLUSION: C8A as a single-gene biomarker prognostic of DFS and predictive of a benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer if validated by additional studies. Understanding the advantage of overexpression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer.

Risk factors, prevalence, and site concordance of human papillomavirus in high-risk Greek men.

The aim of this study was to determine the risk factors, genotype-specific prevalence, and concordance of human papillomavirus (HPV) infections at three anatomical sites in a cohort of high-risk Greek men. Patients were recruited from sexually transmitted infection and HIV clinics in Athens. Samples were obtained from oral, penile, and anal sites of 294 study participants and HPV testing was performed on 882 samples using next-generation sequencing. Patients also completed a questionnaire assessing risk factors for infection. The mean age of the participants was 33.1, 30% identified as men who have sex with men (MSM), and 21% were HIV positive. The prevalence of HPV was 49%; it was the highest at anal sites (33%) compared with 23% at penile sites (P=0.008) and 4% at oral sites (P<0.001). The most common HPV types in order of frequency were 6, 44, 16, 53, and 89. The genotype concordance rate was the highest between the penile and anal sites (7%), followed by 2% for anal-oral concordance. Identifying as MSM [adjusted odds ratios (aOR)=6.75, P<0.001] and being HIV positive (aOR=2.89, P=0.026) were significant risk factors for anal HPV infection, whereas alcohol use (aOR=0.45, P=0.002) was associated negatively with infection. The only significant risk factor for oral infection was an older age of sexual debut (aOR=1.32, P=0.038). Nearly half of our study participants tested positive in at least one of three anatomical sites. Using next-generation sequencing, we could identify high-risk types that are not covered by the current vaccine and would be missed by traditional HPV testing kits.

High prevalence of MiTF staining in undifferentiated pleomorphic sarcoma: caution in the use of melanocytic markers in sarcoma.

AIMS: The diagnosis of undifferentiated pleomorphic sarcoma (UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (MiTF) stains naevi and epithelioid melanomas, as well as some mesenchymal neoplasms. The aim of this study was to evaluate the prevalence of MiTF and melanocytic markers in UPS and a subset of atypical fibroxanthoma (AFX). METHODS AND RESULTS: MiTF, SOX10, Melan-A, HMB45 and S100 immunostaining was performed on resection specimens from 19 UPSs and five AFXs. Next-generation sequencing of 50 genes was performed in UPSs to exclude dedifferentiated melanoma. In 17 of 19 UPSs (89%), tumour cells showed nuclear positivity for MiTF that was not eliminated by casein block. Three showed focal nuclear staining for HMB45, which was eliminated by casein block. One showed focal nuclear vacuole staining for S100 with red but not brown chromogen. None expressed SOX10 or Melan-A. Mutational analysis of 15 UPSs with adequate DNA showed no mutations within hotspot regions of BRAF, KIT, or NRAS. Four of five AFXs (80%) stained with MiTF; other markers were negative. CONCLUSION: There is a high prevalence of nuclear MiTF expression in UPSs (89%) and AFXs (80%). Rare UPSs showed non-specific nuclear HMB45 or S100 staining. These findings argue against using MiTF in isolation to differentiate between UPS or AFX and melanoma, and caution in interpreting focal staining for a single additional melanocytic marker. Casein block may eliminate non-specific staining. MiTF should be used to support a diagnosis of melanoma only if multiple melanocytic markers are positive.

High Expression of FGD3, a Putative Regulator of Cell Morphology and Motility, Is Prognostic of Favorable Outcome in Multiple Cancers.

PURPOSE: Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. METHODS: Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. RESULTS: A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)-positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer-free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 (P = 3.8E-14) outperformed MKI67 (P = 1.06E-8) and AURKA (P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88E-5) outperformed MKI67 (P = .477) and AURKA (P = .820). CONCLUSION: FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker.

Clinical Validation of a Next-Generation Sequencing Genomic Oncology Panel via Cross-Platform Benchmarking against Established Amplicon Sequencing Assays.

Next-generation sequencing (NGS) genomic oncology profiling assays have emerged as key drivers of personalized cancer care and translational research. However, validation of these assays to meet strict clinical standards has been historically problematic because of both significant assay complexity and a scarcity of optimal validation samples. Herein, we present the clinical validation of 76 genes from a novel 1212-gene large-scale hybrid capture cancer sequencing assay (University of Chicago Medicine OncoPlus) using full-data comparisons against multiple clinical NGS amplicon-based assays to yield dramatic increases in per-sample data comparison efficiency compared with previously published validations. Using a sample set of 104 normal, solid tumor, and hematopoietic malignancy specimens, head-to-head NGS data analyses allowed for 6.8 million individual clinical base call comparisons, including 2729 previously confirmed variants, with 100% sensitivity and specificity. University of Chicago Medicine OncoPlus showed excellent performance for detection of single-nucleotide variants, insertions/deletions up to 52 bp, and FLT3 internal tandem duplications of up to 102 bp or larger. Highly concordant copy number variant and ALK/RET/ROS1 gene fusion detection were also observed. In addition to underlining the efficiency of NGS validation via full-data benchmarking against existing clinical NGS assays, this study also highlights the degree of performance similarity between hybrid capture and amplicon assays that is attainable with the application of strict quality control parameters and optimized computational analytics.

Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.

Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

IMPORTANCE: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). INTERVENTIONS: Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. MAIN OUTCOMES AND MEASURES: Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. RESULTS: Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. CONCLUSIONS AND RELEVANCE: Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045032.