Commercial Clinical Laboratory Research Articles

Role of CD47 gene expression in colorectal cancer: a comprehensive molecular profiling study

BackgroundIn patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new...

Antimicrobial use and combination of resistance phenotypes in bacteraemic Escherichia coli in primary care: a study based on Japanese national data in 2018.

Antimicrobial use (AMU) in primary care is a contributing factor to the emergence of antimicrobial-resistant bacteria. We assessed the potential effects of AMU on the prevalence of a combination of resistance phenotypes in bacteraemic Escherichia coli in outpatient care settings between primary care facilities ('clinics') and hospitals. Population-weighted total AMU calculated from the national database was expressed as DDDs per 1000 inhabitants per day (DID). National data for all routine microbiological test results were exported from the databases of a major commercial clinical laboratory, including 16 484 clinics, and the Japan Nosocomial Infections Surveillance, including 1947 hospitals. AMU and the prevalence of combinations of resistance phenotypes in bacteraemic E. coli isolates were compared between clinics and hospitals. The five most common bacteria isolated from patients with bacteraemia were the same in clinics, outpatient settings and inpatient settings in hospitals, with E. coli as the most frequent. Oral third-generation cephalosporins and fluoroquinolones were the top two AMU outpatient drugs, except for macrolides, and resulted in at least three times higher AMU in clinics than in hospitals. The percentage of E. coli isolates resistant to both drugs in clinics (18.7%) was 5.6% higher than that in hospitals (13.1%) (P < 10-8). Significant AMU, specifically of oral third-generation cephalosporins and fluoroquinolones, in clinics is associated with a higher prevalence of E. coli isolates resistant to both drugs. This study provides a basis for national interventions to reduce inappropriate AMU in primary care settings.

Comprehensive assessment of cortisol and cortisol metabolites provides insight into the complex relationship between HPA axis function and BMI

Aims/objectivesAlthough considerable effort, both experimental and theoretical, has been directed towards understanding the relationship between the HPA axis and weight regulation, no true consensus exists in the literature as to the nature of the relationship. The aim of this study was to explore potential correlations between BMI and measures of cortisol and cortisol metabolites using dried urine and saliva sampling in a large sample of individuals with BMIs ranging from underweight to obese. Materials and methodsA cohort of patients with data available from urinary and/or salivary measures of cortisol and cortisol metabolites who met inclusion criteria was extracted from the database of a commercial clinical laboratory. Pearson correlation coefficients were used to determine associations between variables; Student's t-test and one-way ANOVA were used to examine differences between groups, and the Jonckheere-Terpstra trend test was used to assess for trends by BMI category. A multivariable linear regression model was created to determine which variables explained the largest amounts of variance in BMI. ResultsA significant correlation was observed between the urinary cortisol metabolites and BMI (P < 0.0001). In addition, cortisol metabolites were associated with changes in BMI over time. No significant correlation was observed between urinary free cortisol and BMI, and correlations observed between BMI and other variables, with the exception of age, were either weak or not statistically significant. ConclusionsThe data presented in this study suggest that cortisol metabolism is a key component of weight regulation and that cortisol metabolite concentrations may potentially serve as informative biomarkers to characterize the relationship between the HPA axis and changes in BMI. The implications of this affect both clinical practice and the research and development of both prevention and treatment strategies aimed at either decreasing or increasing BMI.

A-327 Pre-analytical and Analytical Modifications to Improve the Quality of Pediatric Lead Tests

Abstract Background The recent decrease in the CDC Blood Lead Reference Value (BLRV) to 3.5 ug/dL has highlighted the need for systematic changes that some clinicians and laboratories need to implement to assure the quality of reported pediatric lead results. Building upon the recommendations of the Blood Lead Reference Value Workgroup, APHL has developed specific recommendations and resources designed to assist medical professionals and laboratory scientists in minimizing the likelihood of contamination when collecting and testing blood specimens. Also included are analytical practices that can improve precision, accuracy, and sensitivity of pediatric lead assays. Methods Evaluation of existing protocols and practices to identify potential sources of contamination and opportunities for process improvement. Results APHL will provide practical recommendations to systematically improve point of care and fixed laboratory testing to improve confidence in reported pediatric lead concentrations. These improved measurements will improve environmental health surveillance and inform public health intervention and patient care. Conclusion Rigorous pre-analytical practices including education, updated specimen collection guidance, pre-screening of collection materials, improvement of point of care technology and refinement of spectroscopic analytical methods result in less ambient contamination, improved sensitivity, precision and accuracy of pediatric lead testing. Clinician office practices, public health and commercial clinical laboratories will all benefit from implementing these strategies.

Serotype replacement and an increase in non-encapsulated isolates among community-acquired infections of Streptococcus pneumoniae during post-vaccine era in Japan

ObjectivesIt is feared that the serotype replacement of Streptococcus pneumoniae occurred by the introduction of pneumococcal vaccines as periodical inoculation leads to reduced efficacy of the approved vaccines and altered antimicrobial susceptibility. MethodsWe determined serotypes of 351 S. pneumoniae isolates collected at a commercial clinical laboratory in Hokkaido prefecture, Japan, from December 2018 to February 2019 by using the polymerase chain reaction procedure of the US Centers for Disease Control and Prevention. Antimicrobial susceptibility and resistance gene profiles were also examined. ResultsVaccine coverage rates were 7.9% for 13-valent conjugate vaccine, and 32.5% for 23-valent polysaccharide vaccine, respectively. Non-typable strains were 19.7%. cpsA-positive isolates (group I), and null capsule clade (NCC)1, NCC2 and NCC3 (group II) comprised 31.3%, 28.4%, 32.8%, and 7.5% of the 69 non-typable strains, respectively. No penicillin-resistant/intermediate isolates were found; however, serotypes 35B and 15A/F showed low susceptibility to β-lactams. Only five strains (1.4%) were levofloxacin-resistant, and all were from the older persons, and three strains were serotype 35B. ConclusionThe progression of serotype replacement in non-invasive pneumococcal infections has occurred during the post-vaccine era in Japan, and non-encapsulated isolates, such as NCC, have increased. Antimicrobial susceptibility is not worsened.

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

Patients with early-onset atrial fibrillation (AF) are enriched for rare variants in cardiomyopathy and arrhythmia genes. The clinical significance of these rare variants in patients with early-onset AF is unknown. To assess the association between rare variants in cardiomyopathy and arrhythmia genes detected in patients with early-onset AF and time to death. This prospective cohort study included participants with AF diagnosed before 66 years of age who underwent whole-genome sequencing through the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data were analyzed from February 26 to September 19, 2021. Rare variants identified in a panel of 145 genes that are included in cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. The primary study outcome was time to death and was adjudicated from medical records and the National Death Index. Multivariable Cox proportional hazards regression was used to evaluate the association of disease-associated variants with risk of death after adjustment for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term of age at AF diagnosis and disease-associated variant status. Among 1293 participants (934 [72%] male; median age at enrollment, 56.0 years; IQR, 48.0-61.0 years), disease-associated (pathogenic or likely pathogenic) rare variants were found in 131 (10%). During a median follow-up of 9.9 years (IQR, 6.9-13.2 years), 219 participants (17%) died. In univariable analysis, disease-associated variants were associated with an increased risk of mortality (hazard ratio, [HR], 1.5; 95% CI, 1.0-2.1; P = .05); the association remained significant in multivariable modeling when adjusted for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term between disease-associated variant status and age at AF diagnosis. The interaction demonstrated that disease-associated variants were associated with a significantly higher risk of mortality compared with no disease-associated variant when AF was diagnosed at a younger age (P = .008 for interaction). Higher body mass index (per IQR: HR, 1.4; 95% CI, 1.2-1.6; P < .001) and lower left ventricular ejection fraction (per IQR: HR, 0.8; 95% CI, 0.7-0.8; P < .001) were associated with higher mortality risk. There were 73 cardiomyopathy-related deaths, 40 sudden deaths, and 10 stroke-related deaths. Mortality among patients with the most prevalent genes with disease-associated variants was 26% (10 of 38 patients) for TTN, 33% (6 of 18) for MYH7, 22% (2 of 9) for LMNA, 0% (0 of 10) for MYH6, and 0% (0 of 8) for KCNQ1. The findings suggest that rare variants in cardiomyopathy and arrhythmia genes may be associated with increased risk of mortality among patients with early-onset AF, especially those diagnosed at a younger age. Genetic testing may provide important prognostic information for patients with early-onset AF.

MiR-141-3p Relative Expression Level from FFPE Samples as Biomarker of Prostate Adenocarcinoma Carcinogenesis in Yogyakarta, Indonesia

Globally, prostate cancer (PCA) is the second leading cause of male cancer-associated mortality. Micro-RNAs (miRNAs) are small non-coding RNAs considered promising biomarkers for diagnosis, prognosis, and treatment options. A miR-141 expression is frequently dysregulated and influences the development and progression of PCA. This study aimed to identify miR-141 expression level as a marker to differentiate PCA from another prostate anomaly, especially in Yogyakarta. Formalin-fixed paraffin-embedded (FFPE) tissues for each three groups: benign prostatic hyperplasia/BPH, high-grade prostatic intraepithelial neoplasia/HGPIN, and PCA (n=7/group) were stored in a commercial clinical laboratory in Yogyakarta. The total RNA was extracted from FFPE sections using miRNeasy FFPE kit, followed by the quantification of miR-141-3p expression level by RT-PCR. The result showed that miR-141 relative expression level on PCA was higher than other groups and significantly different (P&lt;0.05, Kruskal Wallis test). The mean of the miR-141 relative expression level of BPH, HGPIN, and PCA were 1.04±0.87, 6.44±7.8, and 7.06±8.83, respectively. The relative expression level of miR-141 can potentially be a prognostic biomarker in PCA and could differentiate aggressiveness in prostate anomaly, especially BPH, HGPIN, and PCA.

Clinical and genetic analysis of children with hearing loss and bilateral enlarged vestibular aqueducts

ObjectivesTo evaluate the clinical and genetic features of children with hearing loss associated with one of the most common malformations of the inner ear: bilateral enlargement of vestibular aqueducts (EVA). MethodsClinical and genetic features were investigated in 28 children with hearing loss diagnosed with bilateral EVA by computed tomography from January 2008 to September 2019. ResultsFourteen subjects had undergone newborn hearing screening (NHS). Nine subjects (64.3%) were referred in both ears, 4 subjects (28.6%) were referred in one ear, and one subject (7.1%) passed in both ears. Nineteen of 26 subjects (73.1%) who were followed for more than 3 years had hearing fluctuations, while 17 (65.4%) had hearing loss progression. Eleven of 28 subjects (39.2%) had vertigo attacks. Pathogenic variants were identified in two alleles of the SLC26A4 gene in 24 of 27 subjects (88.9%) by sequencing of all exons and flanking introns, leading to genetic diagnosis of Pendred syndrome/DFNB4. Our results indicate that genetic screening for specific SLC26A4 variants using a commercial clinical laboratory test in Japan would have achieved genetic diagnoses in 13 of the 27 subjects (54.2%). Although there was no statistically significance in the frequency of hearing fluctuation or progression depending on the presence or absence of the gene variant, mean hearing level was severe in subjects with two pathogenic variants in SLC26A4 gene. The most common variant detected in our subjects was p.His723Arg (13 alleles, 27.1%), followed by c. 919-2A > G (four alleles, 8.3%). Two novel variants were detected in this study: c.1544+1G > T and c.1614+5G > A. ConclusionsOur data suggest that some subjects may present with bilateral EVA that cannot be detected by NHS. We estimated that genetic diagnosis for SLC264 gene would not have been made in almost half subjects with the commercial genetic screening approach used in the present study in Japan. Although there were some limitations in this study, the subjects with pathogenic variants in two alleles of the SLC26A4 gene could have more severe hearing loss.

Homologous Recombination Deficiency Alterations in Colorectal Cancer: Clinical, Molecular, and Prognostic Implications.

Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown. Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided. Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm. HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.

The Landscape of Alterations in DNA Damage Response Pathways in Colorectal Cancer.

Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Although the mismatch repair system has been extensively studied, the clinical implications of other mechanisms associated with DDR alterations in patients with colorectal cancer remain unclear. This study aimed to understand DDR pathways alterations and their association with common clinical features in patients with colorectal cancer. Next-generation sequencing and whole-transcriptome sequencing were conducted using formalin-fixed paraffin-embedded samples submitted to a commercial Clinical Laboratory Improvement Amendments-certified laboratory. Samples with pathogenic or presumed pathogenic mutations in 29 specific DDR-related genes were considered as DDR-mutant (DDR-MT) and the remaining samples as DDR-wild type (DDR-WT). Of 9,321 patients with colorectal cancer, 1,290 (13.8%) were DDR-MT. The frequency of DDR-MT was significantly higher in microsatellite instability-high (MSI-H) cases than in microsatellite stable cases (76.4% vs. 9.5%). The DDR-MT genotype was higher in the right-sided, RAS-wild, BRAF-mutant, and CMS1 subgroups. However, these associations were primarily confounded by the distribution of MSI status. Compared with the DDR-WT tumors, the DDR-MT tumors had a higher mutational burden and gene expression levels in the immune-related pathway, which were independent of MSI status. We characterized a distinct subgroup of patients with colorectal cancer with tumors harboring mutations in the DDR-related genes. These patients more commonly had MSI-H tumors and exhibited an activated immune signature regardless of their tumor's MSI status. These findings warrant further investigations to develop personalized treatment strategies in this significant subgroup of patients with colorectal cancer.

Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020

Case-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely underestimates the true prevalence of infections. Large-scale seroprevalence surveys can better estimate infection across many geographic regions. To estimate the prevalence of persons with SARS-CoV-2 antibodies using residual sera from commercial laboratories across the US and assess changes over time. This repeated, cross-sectional study conducted across all 50 states, the District of Columbia, and Puerto Rico used a convenience sample of residual serum specimens provided by persons of all ages that were originally submitted for routine screening or clinical management from 2 private clinical commercial laboratories. Samples were obtained during 4 collection periods: July 27 to August 13, August 10 to August 27, August 24 to September 10, and September 7 to September 24, 2020. Infection with SARS-CoV-2. The proportion of persons previously infected with SARS-CoV-2 as measured by the presence of antibodies to SARS-CoV-2 by 1 of 3 chemiluminescent immunoassays. Iterative poststratification was used to adjust seroprevalence estimates to the demographic profile and urbanicity of each jurisdiction. Seroprevalence was estimated by jurisdiction, sex, age group (0-17, 18-49, 50-64, and ≥65 years), and metropolitan/nonmetropolitan status. Of 177 919 serum samples tested, 103 771 (58.3%) were from women, 26 716 (15.0%) from persons 17 years or younger, 47 513 (26.7%) from persons 65 years or older, and 26 290 (14.8%) from individuals living in nonmetropolitan areas. Jurisdiction-level seroprevalence over 4 collection periods ranged from less than 1% to 23%. In 42 of 49 jurisdictions with sufficient samples to estimate seroprevalence across all periods, fewer than 10% of people had detectable SARS-CoV-2 antibodies. Seroprevalence estimates varied between sexes, across age groups, and between metropolitan/nonmetropolitan areas. Changes from period 1 to 4 were less than 7 percentage points in all jurisdictions and varied across sites. This cross-sectional study found that as of September 2020, most persons in the US did not have serologic evidence of previous SARS-CoV-2 infection, although prevalence varied widely by jurisdiction. Biweekly nationwide testing of commercial clinical laboratory sera can play an important role in helping track the spread of SARS-CoV-2 in the US.

Association Between Vedolizumab Levels, Anti-vedolizumab Antibodies, and Endoscopic Healing Index in a Large Population of Patients with Inflammatory Bowel Diseases

BackgroundThe aim of this study was to assess the relationship between serum vedolizumab (VDZ) concentrations and antibodies to VDZ (ATV) in a large cohort of patients with inflammatory bowel diseases. Furthermore, we evaluated the association between serum VDZ concentrations and a novel serum-based biomarker panel designated as the endoscopic healing index (EHI), developed and validated for identifying mucosal inflammation in patients with Crohn’s disease (CD).MethodsRetrospective study where results from patient samples submitted to a commercial clinical laboratory were included. Serum VDZ and ATV levels were analyzed using a drug-tolerant assay. In CD patients for whom both VDZ and EHI were available, VDZ concentrations were correlated with EHI. serum VDZ threshold analysis was performed using ROC curves, and the serum VDZ concentrations that best differentiated EHI < 20 (previously associated with endoscopic remission) were chosen.ResultsA total of 9356 patients were included in the VDZ/ATV analysis. Detectable ATV was observed in 2.9% patients with significantly lower serum VDZ concentrations when compared to those with undetectable ATV [3.9 µg/mL (0–9.0) vs. 11.3 µg/mL (5.9–20.6), p < 0.0001]. Of the patients with serum VDZ result, 287 patients had a concomitant EHI test. An inverse correlation was observed between VDZ concentration and EHI (rho = − 0.20, p < 0.001). A serum VDZ concentration ≥ 15.7 µg/ml was best correlated wi th an EHI < 20 [AUROC: 0.67 (95% CI 0.57–0.77)].ConclusionsIncidence of ATVs was low, but significantly associated with lower VDZ levels. A serum VDZ concentration threshold of ≥ 15.7 µg/ml was associated with endoscopic remission as defined by an EHI < 20.

Application of the Whole Genome-Based Bacterial Identification System, TrueBac ID, Using Clinical Isolates That Were Not Identified With Three Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) Systems.

BackgroundNext-generation sequencing is increasingly used for taxonomic identification of pathogenic bacterial isolates. We evaluated the performance of a newly introduced whole genome-based bacterial identification system, TrueBac ID (ChunLab Inc., Seoul, Korea), using clinical isolates that were not identified by three matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems and 16S rRNA gene sequencing.MethodsThirty-six bacterial isolates were selected from a university-affiliated hospital and a commercial clinical laboratory. Species was identified by three MALDI-TOF MS systems: Bruker Biotyper MS (Bruker Daltonics, Billerica, MA, USA), VITEK MS (bioMérieux, Marcy l'Étoile, France), and ASTA MicroIDSys (ASTA Inc., Suwon, Korea). Whole genome sequencing was conducted using the Illumina MiSeq system (Illumina, San Diego, CA, USA), and genome-based identification was performed using the TrueBac ID cloud system (www.truebacid.com).ResultsTrueBac ID assigned 94% (34/36) of the isolates to known (N=25) or novel (N=4) species, genomospecies (N=3), or species group (N=2). The remaining two were identified at the genus level.ConclusionsTrueBac ID successfully identified the majority of isolates that MALDI-TOF MS failed to identify. Genome-based identification can be a useful tool in clinical laboratories, with its superior accuracy and database-driven operations.

MP07-03 ASSESSMENT OF BLADDER SENSATION AFTER YEAR-LONG LOWER SPINAL ROOT TRANSECTION AND SURGICAL REINNERVATION USING BEHAVIORAL MEASURES

INTRODUCTION AND OBJECTIVES:We aim to surgically reinnervate a lower motor neuron neurogenic bladder via obturator-to-pelvic and sciatic-to-pudendal nerve transfer. Behavioral observations provide the most global assessment of functional recovery. We sought to determine whether observed micturition postures disappear in decentralized animals and reappear after reinnervation.METHODS:Three groups of female canines were used: 1) Long-term survival (12 months) after transection of all ventral and dorsal sacral roots, the dorsal roots of L7 and hypogastric nerves, bilaterally (n=4); 2) Procedures described in Group 1, followed by obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfer (n=3); 3) Unoperated control animals (n=3). Micturition postures were monitored for 24 hours at monthly intervals via video recording. Bacteriuria was tracked midway through the study with urine Multistix test strip assays, body temperature, and cultured urine specimens by a commercial clinical laboratory. Awake cystomet...

Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities.

BackgroundThe phosphatidylinositol 3‐kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co‐alterations serving as potential resistance/attenuation mechanisms.MethodsConsecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment‐certified laboratory using comprehensive genomic profiling performed by next‐generation sequencing (315 genes). The co‐alterations evaluated included the Erb‐B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto‐oncogene tyrosine kinase (MET), and mitogen‐activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR). ResultsAlterations in any of 18 PI3K‐pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co‐occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co‐occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.ConclusionsComprehensive genomic profiling reveals altered PI3K‐related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co‐occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.

Frequency of frontotemporal dementia gene variants in C9ORF72, MAPT, and GRN in academic versus commercial laboratory cohorts.

Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia, and elucidating its genetic underpinnings is critical. FTLD research centers typically recruit patient cohorts that are limited by the center's specialty and the ways in which its geographic location affects the ethnic makeup of research participants. Novel sources of data are needed to get population estimates of the contribution of variants in known FTLD-associated genes. We compared FLTD-associated genetic variants in microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome nine open reading frame 72 (C9ORF72) from an academic research cohort and a commercial clinical genetics laboratory. Pathogenicity was assessed using guidelines of the American College of Medical Genetics and Genomics and a rule-based DNA variant assessment system. We conducted chart reviews on patients with novel or rare disease-associated variants. A total of 387 cases with FTLD-associated variants from the commercial (n=2,082) and 78 cases from the academic cohort (n=2,089) were included for analysis. In the academic cohort, the most frequent pathogenic variants were C9ORF72 expansions (63%, n=49), followed by GRN (26%, n=20) and MAPT (11%, n=9). Each gene's contribution to disease was similarly ranked in the commercial laboratory but differed in magnitude: C9ORF72 (89%, n=345), GRN (6%, n=24), and MAPT (5%, n=19). Of the 37 unique GRN/MAPT variants identified, only six were found in both cohorts. Clinicopathological data from patients in the academic cohort strengthened classification of two novel GRN variant as pathogenic (p.Pro166Leufs*2, p.Gln406*) and one GRN variant of unknown significance as a possible rare risk variant (p.Cys139Arg). Differences in gene frequencies and identification of unique pathogenic alleles in each cohort demonstrate the importance of data sharing between academia and community laboratories. Using shared data sources with well-characterized clinical phenotypes for individual variants can enhance interpretation of variant pathogenicity and inform clinical management of at-risk patients and families.

Reference standards for the detection of anti-mitochondrial and anti-rods/rings autoantibodies.

AbstractBackground:Anti-mitochondrial antibodies (AMA) are found in &gt;90% of primary biliary cholangitis patients. Anti-rods/rings antibodies (anti-RR) are most commonly associated with interferon-α and ribavirin treatment in hepatitis C patients. Clinical laboratories routinely screen for AMA and anti-RR using indirect immunofluorescence on HEp-2 cells (HEp-2-IFA). Therefore, we sought to establish reference materials for use in AMA and anti-RR testing.Methods:AMA-positive and anti-RR-positive human plasma samples (AMA-REF and RR-REF), identified as potential reference materials based on preliminary data, were further validated by multiple laboratories using HEp-2-IFA, immunoprecipitation (IP), western blotting, IP-western, line immunoassay (LIA), addressable laser bead immunoassay (ALBIA) and enzyme-linked immunosorbent assay (ELISA).Results:AMA-REF showed a strong positive cytoplasmic reticular/AMA staining pattern by HEp-2-IFA to ≥1:1280 dilution and positive signal on rodent kidney/stomach/liver tissue. AMA-REF reacted with E2/E3, E3BP, E1α and E1β subunits of the pyruvate dehydrogenase complex by IP and western blotting and was positive for AMA antigens by LIA, ALBIA and ELISA. RR-REF showed a strong positive rods and rings staining pattern by HEp-2-IFA to ≥1:1280 dilution. RR-REF reacted with inosine monophosphate dehydrogenase by IP, IP-western and ALBIA. RR-REF also produced a nuclear homogenous staining pattern by HEp-2-IFA, immunoprecipitated proteins associated with anti-U1RNP antibody and reacted weakly with histones, nucleosomes, Sm and nRNP/Sm by LIA.Conclusions:AMA-REF and RR-REF are useful reference materials for academic or commercial clinical laboratories to calibrate and establish internal reference standards for immunodiagnostic assays. AMA-REF and RR-REF are now available for free distribution to qualified laboratories through Plasma Services Group.

The Pathology Workforce and Clinical Licensure: The Role of the PhD Clinical Laboratorian in the United States

There has been a recent recognition of the need to prepare PhD-trained scientists for increasingly diverse careers in academia, industry, and health care. The PhD Data Task Force was formed to better understand the current state of PhD scientists in the clinical laboratory workforce and collect up-to-date information on the training and certification of these laboratorians. In this report, we summarize the findings of the PhD Data Task Force and discuss the relevance of the data collected to the future supply of and demand for PhD clinical laboratory scientists. It is clear that there are multiple career opportunities for PhD scientists in academic medical centers, commercial clinical laboratories, biotechnology and pharmaceutical companies, and the federal government. Certified PhD scientists have and will continue to form an important resource for our technologically advancing field, bringing training in scientific methods, and technologies needed for modern laboratory medicine. The data gathered by the PhD Data Task Force will be of great interest to current and future PhD candidates and graduate PhD scientists as they make decisions regarding future career directions.

Transforming Laboratory Utilization Review into Laboratory Stewardship: Guidelines by the PLUGS National Committee for Laboratory Stewardship.

Appropriate utilization of clinical laboratory services is important for patient care and requires institutional stewardship. Clinical laboratory stewardship programs are dedicated to improving the ordering, retrieval, and interpretation of appropriate laboratory tests. In addition, these programs focus on developing, maintaining, and improving systems to provide proper financial coverage for medically necessary testing. Overall, clinical laboratory stewardship programs help clinicians improve the quality of patient care while reducing costs to patients, hospitals, and health systems. This document, which was created by a new multiinstitutional committee interested in promoting and formalizing laboratory stewardship, summarizes core elements of successful hospital-based clinical laboratory stewardship programs. The core elements will also be helpful for independent commercial clinical laboratories.

Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers

BackgroundThe relation between testosterone (T) plasma concentration and cardiovascular (CV) risk is unclear, with evidence supporting increased risk in men with low and high T levels. Few studies have assessed CV risk as a function of plasma T levels using objective biomarkers. AimTo determine the relation between T levels and high-sensitivity CV risk biomarkers. MethodsTen thousand forty-one male patients were identified in the database of a commercial clinical laboratory performing biomarker testing. Patients were grouped by total T concentration and associations with the following biomarkers were determined: cardiac troponin I (cTnI), endothelin-1 (ET-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-17A, N-terminal pro–B-type natriuretic peptide (NTproBNP), high-density lipoprotein (HDL) cholesterol, high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), and leptin. OutcomesAssociation of CV risk markers with levels of T in men. ResultsThe median age of the cohort was 58 years (interquartile range = 48–68), and the median plasma T level was 420 ng/dL (interquartile range = 304–565); T levels did not vary with patient age. An inverse relation between plasma T levels and CV risk was observed for 9 of 10 CV markers: cTnI, ET-1, IL-6, TNF-α, NTproBNP, HDL cholesterol, hs-CRP, HbA1c, and leptin. Even after adjusting for age, body mass index, HbA1c, hs-CRP, and HDL cholesterol levels, the CV markers IL-6, ET-1, NTproBNP, and leptin were significantly associated with a T level lower than 250 ng/dL. Clinical ImplicationsMen with low T levels could be at increased risk for increased CV disease as seen by increased CV risk markers. Strength and LimitationsThis study was performed in a group of 10,041 men and is the first study to examine CV risk associated with circulating T levels using a large panel of 10 objective biomarkers. This study is limited by an absence of clinical data indicating whether men had pre-existing CV disease or other CV risk factors. ConclusionMen with low plasma T levels exhibit increases in CV risk markers, consistent with a potential increased risk of CV disease.Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. J Sex Med 2017;14:1095–1103.