Genetic Profiling of African American Patients With Prostatic Adenocarcinoma Metastatic to the Lymph Nodes: A Pilot Study.

CONTEXT.­: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations. OBJECTIVE.­: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation. DESIGN.­: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated. RESULTS.­: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046). CONCLUSIONS.­: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Rule of four: an anatomic and value-based approach to stent-graft inventory for blunt thoracic aortic injury.

PURPOSE: As blunt thoracic aortic injury (BTAI) treatment has shifted from open to thoracic endovascular aortic repair (TEVAR), logistical challenges exist in creating and maintaining inventories of appropriately sized stent-grafts, including storage demands, shelf-life management and cost. We hypothesized that most injured aortas can be successfully repaired with a narrow range of stent-graft sizes and present a value-based anatomic approach to optimizing inventory. METHODS: CT-scans of all patients with BTAI admitted to our Level I trauma center from Apr 2010-Dec 2018 were reviewed. Patients with anatomy incompatible with TEVAR were excluded. For each patient, after aortic sizing a set of two stent-grafts most likely to be utilized was selected from a list of twenty commercially available GORE conformable TAG endografts based on manufacturer instructions. Stent-graft sizes were then ranked based on the number of cases they would be suitable for. MATLAB was utilized to determine the combinations of stent-grafts which would cover the most patients. RESULTS: Twenty-eight patients with BTAI were identified and three were excluded based on iliac diameter. Most patients were male (68%), mean age 42.3 ± 20.2 years, mean ISS 37.0 ± 9.8. Overall mortality was 25%. Of the 20 available stent-graft options, a combination of four stent-grafts would successfully treat 100% of the patients in this series. CONCLUSIONS: Based on actual CT-scan aortic measurements, we demonstrated that an inventory of four sent-graft sizes was sufficient to treat 100% of patients with BTAI. These data can be utilized as a value-based anatomic approach to aortic stent-graft institutional inventory creation and maintenance.

Emerging artificial intelligence applications in liver magnetic resonance imaging.

Chronic liver diseases (CLDs) are becoming increasingly more prevalent in modern society. The use of imaging techniques for early detection, such as magnetic resonance imaging (MRI), is crucial in reducing the impact of these diseases on healthcare systems. Artificial intelligence (AI) algorithms have been shown over the past decade to excel at image-based analysis tasks such as detection and segmentation. When applied to liver MRI, they have the potential to improve clinical decision making, and increase throughput by automating analyses. With Liver diseases becoming more prevalent in society, the need to implement these techniques to utilize liver MRI to its full potential, is paramount. In this review, we report on the current methods and applications of AI methods in liver MRI, with a focus on machine learning and deep learning methods. We assess four main themes of segmentation, classification, image synthesis and artefact detection, and their respective potential in liver MRI and the wider clinic. We provide a brief explanation of some of the algorithms used and explore the current challenges affecting the field. Though there are many hurdles to overcome in implementing AI methods in the clinic, we conclude that AI methods have the potential to positively aid healthcare professionals for years to come.

Physician Communication and Patient Understanding of Molecular Testing Terminology.

BACKGROUND: The use of molecular testing in oncology is rapidly expanding. The aim of this study was to determine how oncologists describe molecular testing and whether patients understand the terminology being used. MATERIALS AND METHODS: Sixty conversations between oncologists and patients about molecular testing were observed, and the used technical terms were noted by the researcher. Patients were interviewed post-conversation to assess their understanding of the noted technical terms. A patient understanding score was calculated for each participant. Comparisons of the terms were conducted using χ2 tests, Fisher's exact tests, or ANOVA when appropriate. RESULTS: Sixty-one unique technical terms were used by oncologists, to describe seven topics. "Mutation" was a challenging term for patients to understand with 48.8% (21/43 mentions) of participants correctly defining the term. "Genetic testing" and "Gene" were understood a little more than half the time (53.3%; 8/15 and 56.4%; 22/39 respectively). "DNA" was well understood (80%; 12/15). There was no correlation between the terms being defined by the oncologist in the conversation, and the likelihood of the patient providing a correct definition. White participants were significantly more likely to understand both "mutation" and "genetic testing" than non-White participants. Forty-two percent (n = 25) of participants had an understanding score below 50%, and a higher family income was significantly correlated with a higher score. CONCLUSION: Our results show that oncologists use variable terminology to describe molecular testing, which is often not understood. Because oncologists defining the terms did not correlate with understanding, it is imperative to develop new, improved methods to explain molecular testing. IMPLICATIONS FOR PRACTICE: The use of molecular testing is expanding in oncology, yet little is known about how effectively clinicians are communicating information about molecular testing and whether patients understand the terminology used. The results of this study indicate that patients do not understand some of the terminology used by their clinicians and that clinicians tend to use highly variable terminology to describe molecular testing. These results highlight the need to develop and implement effective methods to explain molecular testing terminology to patients to ensure that patients have the tools to make autonomous and informed decisions about their treatment.

Fix it while you can Mortality after umbilical hernia repair in cirrhotic patients.

BACKGROUND: We hypothesize that patients with compensated cirrhosis undergoing elective UHR have an improved mortality compared to those undergoing emergent UHR. METHOD: The NIS was queried for patients undergoing UHR by CPT code, and ICD-10 codes were used to define separate patient categories of non-cirrhosis (NC), compensated cirrhosis (CC) and decompensated cirrhosis (DC). RESULTS: A total of 32,526 patients underwent UHR, 97% no cirrhosis, 1.1% compensated cirrhosis, 1.7% decompensated cirrhosis. On logistic regression, cirrhosis was found to be independently associated with mortality (OR 2.841, CI 2.14-3.77). On subset analysis of only cirrhosis patients, elective repair was found to be protective from mortality (OR 0.361, CI 0.15-0.87, p = 0.02). CONCLUSIONS: In this retrospective review, cirrhosis as well as emergent UHR in cirrhotic patients were independently associated with mortality. More specifically, electively (rather than emergently) repairing an umbilical hernia in cirrhotic patients was independently associated with a 64% reduction in mortality.

Approach to Cataract Surgery in an Ebola Virus Disease Survivor with Prior Ocular Viral Persistence.

A 46-year-old patient with previously documented Ebola virus persistence in his ocular fluid, associated with severe panuveitis, developed a visually significant cataract. A multidisciplinary approach was taken to prevent and control infection. Ebola virus persistence was assessed before and during the operation to provide safe, vision-restorative phacoemulsification surgery.

Electronic charting of transfusion medicine consults: implementation, challenges and opportunities.

BACKGROUND: The Joint Commission lists improving staff communication (handoffs) as part of several National Safety Goals. In this study, we developed an electronic web-based charting system for clinical pathology handoffs, which primarily consist of transfusion medicine calls, and evaluated the advantages over a paper-based handwritten call log. MATERIALS AND METHODS: A secure online web browser application using Research Electronic Data Capture (REDCap) was designed to document on-call pathology resident consults. A year after implementation, an online survey was administered to our pathology residents in order to evaluate and compare the usability of the electronic application (e-consults) to the previous handwritten call log, which was a notebook where trainees hand wrote different components of the consult. RESULTS: The REDCap web-based application includes discrete fields for patients' information, requesting physician contact, type of consult, action items for follow-up and faculty responses, as well as other information. These components have eventually progressed to be an online consult call catalog. With approximately 1079 consults per year, transfusion medicine-related calls account for ~90% of the encounters, while clinical chemistry, microbiology and immunology calls constitute the remainder. The overall response rate of the survey was 96% (29 of 30 participants). Of the 16 respondents who experienced both call log systems, 100% responded that REDCap was an improvement over the handwritten call log (P < 0·0001). CONCLUSION: E-consult documentation entered into a web-based application was a user-friendly, secure clinical information access and effective handoff system as compared to a paper-based handwritten call log.

Caring for patients with Ebola virus disease: Are U.S. biocontainment centers ready for the next outbreak?

The 2014 West African Ebola virus disease (EVD) outbreak is the largest and deadliest EVD epidemic to date, resulting in fivefold more cases than all other outbreaks combined. This outbreak was particularly devastating to healthcare workers in West Africa and resulted in several EVD patients being medically evacuated for treatment in the U.S. and Europe. Governmental agencies provide recommendations for triaging and testing patients with EVD, however best laboratory practices are still unknown and are very resource dependent.

Risk Factors for Kidney Dysfunction With the Use of Gentamicin in Open Fracture Antibiotic Treatment.

OBJECTIVES: To evaluate all patients who received gentamicin for open fracture treatment and determine the incidence of, and risk factors for, kidney injury in this population. DESIGN: Retrospective, case control. SETTING: Single institution; Level 1 trauma center. PATIENTS/PARTICIPANTS: A retrospective chart review identified patients who received gentamicin for open fracture antibiotic treatment from January 2008 to December 2012. Overall, 371 patients met the inclusion criteria and were categorized into 2 groups using risk, injury, failure, loss of kidney function, and end-stage kidney disease criteria: normal kidney function (74.9%) versus abnormal kidney function (25.1%). INTERVENTION: Use of gentamicin in open fracture antibiotic treatment. MAIN OUTCOME MEASUREMENTS: Kidney function; injury and treatment characteristics (eg, mechanism of injury; Gustilo-Anderson classification; number of surgical debridements, timing of definitive wound coverage, and type of wound coverage); and patient information (eg, age, height, weight, and body mass index, tobacco use, diabetes mellitus, human immunodeficiency virus, hepatitis, and current chemotherapy treatment). RESULTS: Those with abnormal kidney function had lower baseline creatinine (P < 0.001) and higher injury severity scores (16.5 vs. 11.8, P < 0.001) and were more likely to require intensive care unit admission (P < 0.001) than the normal group. Female sex (P = 0.015), and higher weight (P = 0.004), ICU admission (P < 0.001), and use of CT contrasted imaging (P < 0.001) were independently associated with abnormal kidney function. Abnormal kidney function incidence also sharply increased with age. CONCLUSIONS: Females and heavier individuals are at-risk of kidney injury while receiving gentamicin. ICU admission and concurent CT contrasted imaging are strongly associated with kidney injury in patients receiving gentamicin for open fracture treatment, and gentamicin should be avoided in those >60 years of age. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Evaluation of Performance Characteristics of Panther Fusion Assays for Detection of Respiratory Viruses from Nasopharyngeal and Lower Respiratory Tract Specimens.

Accurate and rapid diagnosis is needed for timely intervention and clinical management of acute respiratory infections. This study evaluated performance characteristics of the Panther Fusion assay for the detection of influenza A virus (Flu A), influenza B virus (Flu B), respiratory syncytial virus (RSV), parainfluenza viruses 1 to 3 (Para 1 to 3), human metapneumovirus (hMPV), rhinovirus (RV), and adenovirus (Adeno) targets in comparison to those of the eSensor and Lyra assays using 395 nasopharyngeal (NP) and 104 lower respiratory tract (LRT) specimens. Based on the consensus positive result established (positive result in 2 of the 3 assays), the NP specimens for the Fusion and eSensor assays had 100% positive percent agreement (PPA) for all the analytes and the Lyra assays had 100% PPA for Flu A and Adeno analytes. A 100% negative percent agreement (NPA) was observed for all the Lyra analytes, whereas those for the Fusion targets ranged from 98.4 to 100% and those for the eSensor ranged from 99.4 to 100% for all the analytes except RV. For the LRT specimens, Fusion had 100% PPA and 100% NPA for all the targets except hMPV. There was a 100% PPA for eSensor analytes; the NPA ranged from 98 to 100%, except for RV. For the Lyra assays, the PPA ranged between 50 and 100%, while the NPA was 100% for all the targets except Adeno. The Fusion assay performed similarly to the eSensor assay for majority of the targets tested and provides laboratories with a fully automated random-access system to test for a broad array of viral respiratory pathogens.

Validation of a Customized Bioinformatics Pipeline for a Clinical Next-Generation Sequencing Test Targeting Solid Tumor-Associated Variants.

Bioinformatic analysis is an integral and critical part of clinical next-generation sequencing. It is especially challenging for some pipelines to consistently identify insertions and deletions. We present the validation of an open source tumor amplicon pipeline (OTA-pipeline) for clinical next-generation sequencing targeting solid tumor-associated variants. Raw data generated from 557 TruSight Tumor 26 samples and in silico data were analyzed by the OTA-pipeline and legacy pipeline and compared. Discrepant results were confirmed by orthogonal methods. The OTA-pipeline reported 22 variants that were not detected by the previously validated pipeline, including seven synonymous or intronic single-nucleotide variants, five single-nucleotide variants at frequency <5%, one insertion, and nine deletions. Variant allele frequencies reported by the two pipelines were highly concordant, although a few significant discrepancies were present. Analysis of in silico FASTQ files demonstrated a higher sensitivity of detecting complex insertions and deletions with the OTA-pipeline. The higher sensitivity came at a cost, because false-positive calls were increased in difficult-to-sequence regions. However, these calls were all flagged by our strand bias filter, distinguishing them from true variants. Our validation process provides a model for laboratories that want to establish an in-house bioinformatics pipeline for clinical next-generation sequencing.

Creation and Evaluation of a Laboratory Administration Curriculum for Pathology Residents.

OBJECTIVES: A clinical laboratory management (CLM) curriculum that can objectively assess the Accreditation Council for Graduate Medical Education pathology systems-based practice milestones and can provide consistent resident training across institutions is needed. METHODS: Faculty at Emory University created a curriculum that consists of assay verification exercises and interactive, case-based online modules. Beta testing was done at Emory University and Johns Hopkins. Residents were required to obtain a score of more than 80% in the online modules to achieve levels 3 to 4 in the milestones. In addition, residents shadowed a laboratory director, performed an inspection of a laboratory section, and completed training in human subjects research and test utilization. RESULTS: Fourteen residents took and evaluated the laboratory administration curriculum. The printed certificates from the modules were used for objective faculty evaluation of mastery of concepts. Of all the activities the residents performed during the rotation, the online modules were ranked most helpful by all residents. A 25-question knowledge assessment was performed before and after the rotation and showed an average increase of 8 points (P = .0001). CONCLUSIONS: The multimodal CLM training described here is an easily adoptable, objective system for teaching CLM. It was well liked by residents and provided an objective measurement of mastery of concepts for faculty.

Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

OBJECTIVE: We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. PARTICIPANTS AND METHODS: Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60≤PTTR<70%), or excellent (PTTR≥70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (≥60 vs. <60) and major hemorrhages, respectively. RESULTS: Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60≤PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60≤PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. CONCLUSION: Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.

Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array.

AIM: We conducted a genome-wide association study using the Illumina Exome Array to identify coding SNPs that may explain additional warfarin dose variability. PATIENTS & METHODS: Analysis was performed after adjustment for clinical variables and genetic factors known to influence warfarin dose among 1680 warfarin users (838 European-Americans and 842 African-Americans). Replication was performed in an independent sample. RESULTS: We confirmed the influence of known genetic variants on warfarin dose variability. Our study is the first to show the association between rs12772169 and warfarin dose in African-Americans. In addition, genes COX15 and FGF5 showed significant association in European-Americans. CONCLUSION: We identified some novel genes/SNPs that underpin warfarin dose response. Further replication is needed to confirm our findings.

Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy.

BACKGROUND: Genetic aberrations are well characterized in lung adenocarcinomas (LACs) and clinical outcomes have been influenced by targeted therapies in the advanced setting. Stereotactic body radiotherapy (SBRT) is the standard-of-care therapy for patients with nonoperable, early-stage LAC, but to the authors' knowledge, no information is available regarding the impact of genomic changes in these patients. The current study sought to determine the frequency and clinical impact of genetic aberrations in this population. METHODS: Under an Institutional Review Board-approved protocol, the records of 242 consecutive patients with early-stage lung cancers were reviewed; inclusion criteria included LAC histology with an adequate tumor sample for the successful use of next-generation sequencing and fluorescence in situ hybridization testing. Univariate analysis was performed to identify factors associated with clinical outcomes. RESULTS: LAC samples from 98 of the 242 patients were reviewed (40.5%), of whom 45 patients (46.0%) had genetic testing. The following mutations were noted: KRAS in 20.0% of samples, BRAF in 2.2% of samples, SMAD family member 4 (SMAD4) in 4.4% of samples, epidermal growth factor receptor (EGFR) in 15.6% of samples, STK1 in 2.2% of samples, tumor protein 53 (TP53) in 15.6% of samples, and phosphatase and tensin homolog (PTEN) in 2.2% of samples. The following gene rearrangements were observed: anaplastic lymphoma kinase (ALK) in 8.9% of samples, RET in 2.2% of samples, and MET amplification in 17.8% of samples. The median total delivered SBRT dose was 50 grays (range, 48-60 grays) over a median of 5 fractions (range, 3-8 fractions). The KRAS mutation was associated with worse local control (odds ratio [OR], 3.64; P<.05). MET amplification was associated with worse regional (OR, 4.64; P<.05) and distant (OR, 3.73; P<.05) disease control. CONCLUSIONS: To the authors' knowledge, the current series is the first to quantify genetic mutations and their association with clinical outcomes in patients with early-stage LAC treated with SBRT. KRAS mutations were associated with worse local control and MET amplification was associated with worse regional and distant disease control, findings that need to be validated in a prospective setting. Cancer 2017;123:3681-3690. © 2017 American Cancer Society.

Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma.

Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre-induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen. Modeling invasion in 3D, loss of Lkb1, but not p53, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched KLLenti tumors with FAK inhibitor monotherapy resulted in a striking effect on tumor progression, invasion, and tumor-associated collagen. Chronic treatment extended survival and impeded local lymph node spread. Lastly, we identified focally upregulated FAK and collagen-associated collective invasion in KRAS and LKB1 comutated human lung adenocarcinoma patients. Our results suggest that patients with LKB1 mutant tumors should be stratified for early treatment with FAK inhibitors.