Publications by authors named "Lori J Sokoll"

123 Publications

Quality Improvement in Critical Value Delivery at a Tertiary Care Center.

J Appl Lab Med 2021 Apr 27. Epub 2021 Apr 27.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Prompt notification of critical laboratory values to providers is essential for effective patient care. To improve the delivery of these critical values, a quality improvement project was initiated to determine the obstacles to prompt notification and to identify possible interventions to improve this process.

Methods: Critical value call logs were retrieved, and delivery time, patient location, test name, and call time were abstracted and analyzed. All critical values with delivery times greater than 60 min were reviewed by 2 authors for 1 representative month in both the pre- and postintervention period.

Results: Based on the results of the data review, a modification to the laboratory information system call center color-coded alerts was introduced to address delays attributable to the laboratory. The overall rate of calls greater than 60 min decreased from 3.4% ± 0.8% in the preintervention study period to 1.3 ± 0.3%, postintervention. The average number of values not delivered within 60 min decreased by 64% across all locations, following with an 82% decrease for values originating from inpatient locations, and a 39% decrease for outpatient values.

Conclusions: Low complexity interventions to critical value callback protocols can significantly increase the efficacy of communication between the laboratory and providers.
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http://dx.doi.org/10.1093/jalm/jfab002DOI Listing
April 2021

Prevalence of Detectable Biotin in Five US Emergency Department Patient Cohorts.

Clin Biochem 2021 Mar 24. Epub 2021 Mar 24.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The objective of this study was to estimate the prevalence of biotin supplementation in United States emergency department patients using a multi-site, geographically distributed sampling model.

Methods: Biotin was measured using an Abbott ARCHITECT Biotin research use only assay in 7118 emergency department patient serum or plasma samples from five US medical centers. Samples with biotin ≥10 ng/mL underwent additional LC-MS/MS confirmatory testing for biotin and its primary metabolites. The overall and site-specific prevalence of detectable biotin was determined using the screening assay while biotin speciation (i.e., prevalence of detectable metabolites) was determined using LC-MS/MS.

Results: Of 7118 samples screened, 291 (4.1%) had biotin ≥10 ng/mL and were considered positive. Across five medical centers, the fraction of positive samples ranged from 2.0% to 5.4%. The maximum biotin concentration observed was 355 ng/mL. Of the 285 positive screens that underwent additional LC-MS/MS testing, 89 (31%) showed detectable biotin, bisnorbiotin, and/or biotin sulfoxide. Biotin, bisnorbiotin, and biotinsulfoxide were detected in 82/89 (92.1%), 61/89 (68.5%), and 18/89 (20.2%) samples, respectively; biotin was detected in the absence of either metabolite in 18/89 (20.2%) samples.

Conclusions: Using a screening assay, 4.1% of emergency department patient samples were found to be potentially susceptible to interference from biotin. Confirmatory testing showed detectable biotin and/or biotin metabolites in 31% of positive screens (1.3% overall). The prevalence of biotin ≥10 ng/mL varied 2-3-fold across US emergency department patient cohorts. Biotin metabolites were observed in 80% of samples confirmed to have detectable biotin species by LC-MS/MS, suggesting that rigorous assessments of assay susceptibility to biotin interference, often performed using in vitro studies, should consider the potential role of biotin metabolites present in vivo.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.03.009DOI Listing
March 2021

Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation.

medRxiv 2021 Jan 12. Epub 2021 Jan 12.

Background: Neurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.

Methods: Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.

Results: CSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.

Conclusion: The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

Funding: This work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.
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http://dx.doi.org/10.1101/2021.01.10.20249014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814842PMC
January 2021

Urinary glycoproteins associated with aggressive prostate cancer.

Theranostics 2020 25;10(26):11892-11907. Epub 2020 Oct 25.

Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21231, USA.

There is an urgent need for the detection of aggressive prostate cancer. Glycoproteins play essential roles in cancer development, while urine is a noninvasive and easily obtainable biological fluid that contains secretory glycoproteins from the urogenital system. Therefore, here we aimed to identify urinary glycoproteins that are capable of differentiating aggressive from non-aggressive prostate cancer. Quantitative mass spectrometry data of glycopeptides from a discovery cohort comprised of 74 aggressive (Gleason score ≥8) and 68 non-aggressive (Gleason score = 6) prostate cancer urine specimens were acquired via a data independent acquisition approach. The glycopeptides showing distinct expression profiles in aggressive relative to non-aggressive prostate cancer were further evaluated for their performance in distinguishing the two groups either individually or in combination with others using repeated 5-fold cross validation with logistic regression to build predictive models. Predictive models showing good performance from the discovery cohort were further evaluated using a validation cohort. Among the 20 candidate glycoproteins, urinary ACPP outperformed the other candidates. Urinary ACPP can also serve as an adjunct to serum PSA to further improve the discrimination power for aggressive prostate cancer (AUC= 0.82, 95% confidence interval 0.75 to 0.89). A three-signature panel including urinary ACPP, urinary CLU, and serum PSA displayed the ability to distinguish aggressive prostate cancer from non-aggressive prostate cancer with an AUC of 0.86 (95% confidence interval 0.8 to 0.92). Another three-signature panel containing urinary ACPP, urinary LOX, and serum PSA also demonstrated its ability in recognizing aggressive prostate cancer (AUC=0.82, 95% confidence interval 0.75 to 0.9). Moreover, consistent performance was observed from each panel when evaluated using a validation cohort. We have identified glycopeptides of urinary glycoproteins associated with aggressive prostate cancer using a quantitative mass spectrometry-based glycoproteomic approach and demonstrated their potential to serve as noninvasive urinary glycoprotein biomarkers worthy of further validation by a multi-center study.
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http://dx.doi.org/10.7150/thno.47066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667684PMC
October 2020

Myocardial Injury in Severe COVID-19 Compared With Non-COVID-19 Acute Respiratory Distress Syndrome.

Circulation 2021 02 13;143(6):553-565. Epub 2020 Nov 13.

Divisions of Cardiology (T.S.M., A.S.B., M.J.C., A.G.H., C.J.L., E.D.M., W.S.P., J.R.R., D.R.T., J.C.T., R.K.H.), Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19.

Methods: We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19.

Results: Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (<0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex, and multisystem organ dysfunction. Compared with patients with ARDS without COVID-19, patients with COVID-19 were older and had higher creatinine levels and less favorable vital signs. After adjustment, COVID-19-related ARDS was associated with lower odds of myocardial injury compared with non-COVID-19-related ARDS (odds ratio, 0.55 [95% CI, 0.36-0.84]; =0.005).

Conclusions: Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age, and multisystem organ dysfunction, similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864609PMC
February 2021

Prostate Health Index and multiparametric magnetic resonance imaging to predict prostate cancer grade reclassification in active surveillance.

BJU Int 2020 09 2;126(3):373-378. Epub 2020 Jun 2.

Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: To identify the value of combining the Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI), tools which have previously been shown to be independently predictive of prostate cancer (PCa) grade reclassification (GR; Gleason score >6), for the purpose of predicting GR at the next surveillance biopsy to reduce unnecessary prostate biopsies for men in PCa active surveillance (AS).

Patients And Methods: Between 2014 and 2019, we retrospectively identified 253 consecutive men in the Johns Hopkins AS programme who had mpMRI and PHI followed by a systematic ± targeted biopsy. PHI and PHI density (PHID) were evaluated across Prostate Imaging-Reporting and Data System version 2.0 (PI-RADSv2) scores and compared to those with and without GR. Next, the negative predictive value (NPV) and area under the receiver operating curve (AUC) were calculated to compare the diagnostic value of PI-RADSv2 score combined with PHI, PHID, or prostate-specific antigen density (PSAD) for GR using their respective first quartile as a cut-off.

Results: Of the 253 men, 38 men (15%) had GR. Men with GR had higher PHI values (40.7 vs 32.0, P = 0.001), PHID (0.83 vs 0.57, P = 0.007), and PSAD (0.12 vs 0.10, P = 0.037). A PI-RADSv2 ≤3 alone had a NPV of 91.6% for GR (AUC 0.67). Using a PHI cut-off of 25.6 in addition to PI-RADSv2 ≤3, the NPV and AUC were both increased to 98% and 0.70, respectively. Using a PSAD cut-off of 0.07 ng/mL/mL with PI-RADSv2 had an AUC of 0.69 and NPV of 95.4%. PHI and PI-RADSv2 together could have avoided 20% of biopsies at the cost of missing 2.6% of GRs.

Conclusions: The combination of PHI and mpMRI can aid in the prediction of GR in men on AS and may be useful for decreasing the burden of surveillance prostate biopsies.
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http://dx.doi.org/10.1111/bju.15101DOI Listing
September 2020

Trichomonas vaginalis infection and prostate-specific antigen concentration: Insights into prostate involvement and prostate disease risk.

Prostate 2019 10 2;79(14):1622-1628. Epub 2019 Aug 2.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Background: The protist Trichomonas vaginalis causes a common, sexually transmitted infection and has been proposed to contribute to the development of chronic prostate conditions, including benign prostatic hyperplasia and prostate cancer. However, few studies have investigated the extent to which it involves the prostate in the current antimicrobial era. We addressed this question by investigating the relation between T. vaginalis antibody serostatus and serum prostate-specific antigen (PSA) concentration, a marker of prostate infection, inflammation, and/or cell damage, in young, male, US military members.

Methods: We measured T. vaginalis serum IgG antibodies and serum total PSA concentration in a random sample of 732 young, male US active duty military members. Associations between T. vaginalis serostatus and PSA were investigated by linear regression.

Results: Of the 732 participants, 341 (46.6%) had a low T. vaginalis seropositive score and 198 (27.0%) had a high score, with the remainder seronegative. No significant differences were observed in the distribution of PSA by T. vaginalis serostatus. However, slightly greater, nonsignificant differences were observed when men with high T. vaginalis seropositive scores were compared with seronegative men, and when higher PSA concentrations were examined (≥0.70 ng/mL). Specifically, 42.5% of men with high seropositive scores had a PSA concentration greater than or equal to 0.70 ng/mL compared with 33.2% of seronegative men (adjusted P = .125).

Conclusions: Overall, our findings do not provide strong support for prostate involvement during T. vaginalis infection, although our suggestive positive findings for higher PSA concentrations do not rule out this possibility entirely. These suggestive findings may be relevant for prostate condition development because higher early- to mid-life PSA concentrations have been found to predict greater prostate cancer risk later in life.
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http://dx.doi.org/10.1002/pros.23886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715535PMC
October 2019

Development of a glycoproteomic strategy to detect more aggressive prostate cancer using lectin-immunoassays for serum fucosylated PSA.

Clin Proteomics 2019 6;16:13. Epub 2019 Apr 6.

1Department of Pathology, Johns Hopkins Medicine, Smith Bldg 4013, 400 N. Broadway, Baltimore, MD 21287 USA.

Background: Prostate-specific antigen (PSA) is commonly used as a serum biomarker for the detection of prostate cancer. However, levels of PSA in serum do not reliably distinguish aggressive prostate cancer from non-aggressive disease. Therefore, there is an urgent need for biomarkers that can differentiate aggressive prostate cancers from non-aggressive phenotypes. Fucosylation is one of the glycosylation-based protein modifications. Previously we demonstrated increased levels of serum fucosylated PSA in patients with aggressive prostate cancer using lectin selection followed by PSA immunoassay.

Methods: We developed two lectin-immunoassays, Lens culinaris agglutinin (LCA) and Aleuria aurantia lectin (AAL) followed by clinical PSA immunoassay and investigated the levels of PSA and its fucosylated glycoforms in serum specimens from prostate cancer patients with different Gleason scores. First, we developed standard curves for lectins enrichment, which were applied to lectin-immunoassay for fucosylated PSA-LCA and PSA-AAL quantification in serum samples.

Results: Our results showed that both LCA- and AAL-immunoassays detected elevated fucosylated PSA and were correlated with higher Gleason scores but only AAL-immunoassay detected an increased percentage of fucosylated PSA in patient serum with higher Gleason scores.

Conclusion: We have developed quantitative lectin-immunoassays for serum fucosylated PSA. Our data demonstrated that fucosylated PSA-AAL, % fucosylated PSA-AAL and fucosylated PSA-LCA levels could be effective biomarkers to differentiate aggressive prostate cancer [especially Gleason 7 (4 + 3) or above] from non-aggressive disease. We believe that application of these lectin-immunoassays to a larger patient population is needed to evaluate the clinical utilities of fucosylated PSA using AAL-PSA and LCA-PSA for aggressive prostate cancer.
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http://dx.doi.org/10.1186/s12014-019-9234-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451306PMC
April 2019

A multiplex immunoassay of serum biomarkers for the detection of uveal melanoma.

Clin Proteomics 2019 5;16:10. Epub 2019 Mar 5.

1Center for Biomarker Discovery and Translation, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.

Background: Approximately 50% of uveal melanoma (UM) patients develop metastases preferentially in the liver leading to death within 15 months. Currently, there is no effective treatment for metastatic UM, in part because the tumor burden is typically high when liver metastases are detected through abnormal liver function tests (LFTs) or imaging studies. The use of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity, and better tests are needed for early diagnosis of the primary tumor as well as its metastatic spread. To evaluate serum biomarkers for the early detection of UM, multiplex immunoassays were developed.

Methods: Magnetic bead-based multiplex immunoassays were developed for the selected serum biomarkers using a Bio-Plex 200 system. The dynamic ranges, lower limits of detection and quantification, cross-reactivity, and intra- and inter-assay precision were assessed. All proteins were analyzed in sera of 48 patients diagnosed with UM (14 metastatic, 9 disease-free (DF) ≥ 5 years, 25 unknown) and 36 healthy controls. The performance of the biomarkers was evaluated individually and in combination for their ability to detect UM.

Results: A 7-plex immunoassay of OPN, MIA, CEACAM-1, MIC-1, SPON1, POSTN and HSP27 was developed with negligible cross-reactivity, recovery of 84-105%, and intra-assay and inter-assay precision of 2.3-7.5% or 2.8-20.8%, respectively. Logistic regression identified a two-marker panel of HSP27 and OPN that significantly improved the individual biomarker performance in discriminating UM from healthy controls. The improved discrimination of a two-marker panel of MIA and MIC-1 was also observed between metastatic UM and DF, however not statistically significant due to the small sample size.

Conclusions: The multiplex immunoassay provides sufficient analytical performance to evaluate serum biomarkers that complement each other in detection of UM, and warrants further validation with a larger number of patient samples.
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http://dx.doi.org/10.1186/s12014-019-9230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399902PMC
March 2019

Validation of a novel model for the early detection of hepatocellular carcinoma.

Clin Proteomics 2019 16;16. Epub 2019 Jan 16.

1Diagnostics Discovery Research and Development, Abbott Diagnostics, Abbott Laboratories, 100 Abbott Park Road, D09GP, AP20/1, Abbott Park, IL 60064 USA.

Background: The biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence/antagonist-II (PIVKA-II) may be useful for detecting early-stage hepatocellular carcinoma (HCC). We evaluated the performance of AFP and PIVKA-II levels, alone and in combination with clinical factors, for the early detection of HCC.

Methods: In a case-control study, serum AFP and PIVKA-II were measured using the ARCHITECT immunoassay analyzer system in a cohort of 119 patients with HCC, 215 patients with non-malignant liver disease, and 34 healthy subjects. Five predictive models for detecting HCC were developed based on age, gender, AFP, and/or PIVKA-II levels; the best model was validated in an independent cohort of 416 patients with HCC and 412 control subjects with cirrhosis.

Results: In both cohorts, AFP and PIVKA-II concentrations were higher in patients with HCC compared to healthy controls and patients with non-malignant liver disease. The model that combined AFP and PIVKA-II, age, and gender had the highest AUC of 0.95 (0.95, 95% CI 0.93-0.98), with a sensitivity of 93% and a specificity of 84% in the development cohort, and an AUC of 0.87 (95% CI 0.85-0.90), sensitivity of 74%, and specificity of 85% in the validation cohort. When limiting the validation cohort to only early-stage HCC, the AUC was 0.85 (95% CI 0.81-0.88), sensitivity was 70%, and specificity was 86%.

Conclusions: Compared to each biomarker alone, the combination of AFP and PIVKA-II with age and gender improved the accuracy of detecting HCC and differentiating HCC from non-malignant liver disease.
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http://dx.doi.org/10.1186/s12014-018-9222-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334458PMC
January 2019

Identification of Serum Biomarker Panels for the Early Detection of Pancreatic Cancer.

Cancer Epidemiol Biomarkers Prev 2019 01 17;28(1):174-182. Epub 2018 Oct 17.

Department of Pathology, Center for Biomarker Discovery and Translation, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Pancreatic cancer is a deadly disease for which available biomarkers, such as CA19-9, lack the desired sensitivity and specificity for early detection. Additional biomarkers are needed to improve both its sensitivity and specificity.

Methods: Multiplex immunoassays were developed for selected biomarkers using a Bio-Plex 200 system, and analytical performance was optimized. All proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC; = 188) or benign pancreatic conditions (131) and healthy controls (89). The clinical performance of these markers was evaluated individually or in combination for their ability to complement CA19-9 for the early detection of pancreatic cancer.

Results: A 6-plex immunoassay was developed with negligible cross-reactivity, wide dynamic range, recovery of 89% to 104%, and intra-assay and interassay precision of 10.2% to 19.6% and 13.7% to 29.3%, respectively. Individually, the best biomarkers to separate PDAC early stage from chronic pancreatitis or intraductal papillary mucinous neoplasm (IPMN) were CA19-9 and MIA or CA19-9 and MIC-1. Logistic regression modeling selected the two-marker panels that significantly improved the individual biomarker performance in discriminating PDAC early stage from chronic pancreatitis (AUC = 0.86 vs. AUC = 0.81 or AUC = 0.75 only, < 0.05) or IPMN (AUC = 0.81 vs. AUC = 0.75 or AUC = 0.73 only, < 0.05). It was observed that osteopontin (OPN) outperformed CA19-9 in separating IPMN from chronic pancreatitis (AUC = 0.80 vs. AUC = 0.70, < 0.01).

Conclusions: The biomarker panels evaluated by assays with high analytical performance demonstrated potential complementary values to CA19-9, warranting additional clinical validation to determine their role in early detection of pancreatic cancer.

Impact: The validated biomarker panels could lead to earlier intervention and better outcomes.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324978PMC
January 2019

High "phi"ve.

J Appl Lab Med 2018 Sep;3(2):333-335

Departments of Pathology and.

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http://dx.doi.org/10.1373/jalm.2018.027482DOI Listing
September 2018

Sustained influence of infections on prostate-specific antigen concentration: An analysis of changes over 10 years of follow-up.

Prostate 2018 09 30;78(13):1024-1034. Epub 2018 May 30.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Background: To extend our previous observation of a short-term rise in prostate-specific antigen (PSA) concentration, a marker of prostate inflammation and cell damage, during and immediately following sexually transmitted and systemic infections, we examined the longer-term influence of these infections, both individually and cumulatively, on PSA over a mean of 10 years of follow-up in young active duty U.S. servicemen.

Methods: We measured PSA in serum specimens collected in 1995-7 (baseline) and 2004-6 (follow-up) from 265 men diagnosed with chlamydia (CT), 72 with gonorrhea (GC), 37 with non-chlamydial, non-gonococcal urethritis (NCNGU), 58 with infectious mononucleosis (IM), 91 with other systemic or non-genitourinary infections such as varicella; and 125-258 men with no infectious disease diagnoses in their medical record during follow-up (controls). We examined the influence of these infections on PSA change between baseline and follow-up.

Results: The proportion of men with any increase in PSA (>0 ng/mL) over the 10-year average follow-up was significantly higher in men with histories of sexually transmitted infections (CT, GC, and NCNGU; 67.7% vs 60.8%, P = 0.043), systemic infections (66.7% vs 54.4%, P = 0.047), or any infections (all cases combined; 68.5% vs 54.4%, P = 0.003) in their military medical record compared to controls.

Conclusions: While PSA has been previously shown to rise during acute infection, these findings demonstrate that PSA remains elevated over a longer period. Additionally, the overall infection burden, rather than solely genitourinary-specific infection burden, contributed to these long-term changes, possibly implying a role for the cumulative burden of infections in prostate cancer risk.
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http://dx.doi.org/10.1002/pros.23660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690490PMC
September 2018

Eltrombopag mobilizes iron in patients with aplastic anemia.

Blood 2018 05 9;131(21):2399-2402. Epub 2018 Apr 9.

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1182/blood-2018-01-826784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969382PMC
May 2018

Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer.

BJU Int 2018 04 9;121(4):619-626. Epub 2018 Jan 9.

James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: To determine the performance of Prostate Health Index (PHI) density (PHID) combined with MRI and prior negative biopsy (PNB) status for the diagnosis of clinically significant prostate cancer (PCa).

Patients And Methods: Patients without a prior diagnosis of PCa, with elevated prostate-specific antigen and a normal digital rectal examination who underwent PHI testing prospectively prior to prostate biopsy were included in this study. PHID was calculated retrospectively using prostate volume derived from transrectal ultrasonography at biopsy. Univariable and multivariable logistic regression modelling, along with receiver-operating characteristic (ROC) curve analysis, was used to determine the ability of serum biomarkers to predict clinically significant PCa (defined as either grade group [GG] ≥2 disease or GG1 PCa detected in >2 cores or >50% of any one core) on biopsy. Age, PNB status and Prostate Imaging Reporting and Data System (PI-RADS) score were incorporated into the regression models.

Results: Of the 241 men who qualified for the study, 91 (37.8%) had clinically significant PCa on biopsy. The median (interquartile range) PHID was 0.74 (0.44-1.24); it was 1.18 (0.77-1.83) and 0.55 (0.38-0.89) in those with and without clinically significant PCa on biopsy, respectively (P < 0.001). On univariable logistic regression, age and PNB status were associated with clinically significant cancer. Of the tested biomarkers, PHID demonstrated the highest discriminative ability for clinically significant disease (area under the ROC curve [AUC] 0.78 for the univariable model). That continued to be the case in multivariable logistic regression models incorporating age and PNB status (AUC 0.82). At a threshold of 0.44, representing the 25th percentile of PHID in the cohort, PHID was 92.3% sensitive and 35.3% specific for clinically significant PCa; the sensitivity and specificity were 93.0% and 32.4% and 97.4% and 29.1% for GG ≥2 and GG ≥3 disease, respectively. In the 104 men who underwent MRI, PI-RADS score was complementary to PHID, with a PI-RADS score ≥3 or, if PI-RADS score ≤2, a PHID ≥0.44, detecting 100% of clinically significant disease. For that subgroup, of the biomarkers tested, PHID (AUC 0.90) demonstrated the highest discriminative ability for clinically significant disease on multivariable logistic regression incorporating age, PNB status and PI-RADS score.

Conclusions: In this contemporary cohort of men undergoing prostate biopsy for the diagnosis of PCa, PHID outperformed PHI and other PSA derivatives in the diagnosis of clinically significant cancer. Incorporating age, PNB status and PI-RADS score led to even further gains in the diagnostic performance of PHID. Furthermore, PI-RADS score was found to be complementary to PHID. Using 0.44 as a threshold for PHID, 35.3% of unnecessary biopsies could have been avoided at the cost of missing 7.7% of clinically significant cancers. Despite these encouraging results, prospective validation is needed.
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http://dx.doi.org/10.1111/bju.14098DOI Listing
April 2018

Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults.

JAMA 2017 09;318(12):1150-1160

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis.

Importance: Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults.

Objective: To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults.

Design, Setting, And Participants: Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory.

Exposure: Administration of 10 mg/d of biotin supplementation for 7 days.

Main Outcomes And Measures: Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls.

Results: Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion-associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low.

Conclusions And Relevance: In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results.

Trial Registration: clinicaltrials.gov Identifier: NCT03034707.
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http://dx.doi.org/10.1001/jama.2017.13705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818818PMC
September 2017

Evaluating the atherogenic burden of individuals with a Friedewald-estimated low-density lipoprotein cholesterol <70 mg/dL compared with a novel low-density lipoprotein estimation method.

J Clin Lipidol 2017 Jul - Aug;11(4):1065-1072. Epub 2017 Jun 1.

Division of Cardiology, Department of Medicine, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Background: A number of national and international guidelines recommend treatment to low-density lipoprotein cholesterol (LDL-C) <70 mg/dL. Comparing the performance of the Friedewald and a novel LDL-C estimate at these concentrations in a nationally representative and clinical cohorts can inform best practices.

Objectives: The objectives of the study were to evaluate concordance between Friedewald-estimated LDL-C and novel-estimated LDL-C and compare with other atherogenic parameters when the estimated LDL-C is <70 mg/dL.

Methods: Atherogenic lipid parameters were assessed in a cross-sectional analysis among participants with a Friedewald-estimated LDL-C <70 mg/dL from National Health and Nutrition Examination Survey (NHANES) 2011-2012 (n = 334), Johns Hopkins (n = 896), and Mayo Clinic (n = 1151). Novel LDL-C was estimated using an individualized factor to account for heterogeneity in the triglyceride to very low-density lipoprotein cholesterol ratio. Participants were classified as concordant if their LDL-C was <70 mg/dL by both equations and discordant if ≥70 mg/dL by the novel equation.

Results: Among NHANES participants not on statin therapy, 10% had LDL-C <70 mg/dL by both the Friedewald and novel equations. Overall, 15% of participants from NHANES, 20% from Johns Hopkins, and 20% from Mayo Clinic had discordant LDL-C values. In all 3 cohorts, nearly one-fourth of participants in the discordant group had an LDL-C estimate of ≥80 mg/dL (ie, ≥10 mg/dL higher) by the novel equation. Compared with the concordant group, the discordant group had significantly higher median concentrations of non-high-density lipoprotein cholesterol (HDL-C; 101-104 mg/dL vs 74-79 mg/dL) and apolipoprotein B (apoB; 65-72 mg/dL vs 47-57 mg/dL). In NHANES, wherein statins use was recorded, a similarly higher atherogenic burden by non-HDL-C and apoB levels was observed on and off statin therapy in the discordant group.

Conclusions: In a nationally representative sample, a hospital laboratory, and a reference laboratory, approximately one-fifth of individuals with Friedewald-estimated LDL-C <70 mg/dL have a value ≥70 mg/dL using the novel LDL-C equation. These individuals also have significantly higher non-HDL-C and apoB concentrations, conferring an increased risk for cardiovascular disease. Accordingly, ongoing use of Friedewald estimation may lead to the misclassification of high-risk individuals and subsequent under-utilization of lipid-lowering therapies. Further investigations are necessary to confirm these findings in patients using proprotein convertase subtilisin-kexin type 9 inhibitors.
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http://dx.doi.org/10.1016/j.jacl.2017.05.005DOI Listing
February 2018

Insight into infection-mediated prostate damage: Contrasting patterns of C-reactive protein and prostate-specific antigen levels during infection.

Prostate 2017 May 12;77(13):1325-1334. Epub 2017 Jul 12.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Background: To investigate mechanisms underlying our previous observation of a large rise in serum prostate-specific antigen, a marker of prostate pathology, during both sexually transmitted and systemic infections, we measured serum high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, in our previous case-control study of young, male US military members and compared our findings to those for PSA.

Methods: We measured hsCRP before and during infection for 299 chlamydia, 112 gonorrhea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases; before and after infection for 55 infectious mononucleosis (IM) and 90 other systemic/non-genitourinary cases; and for 220-256 controls.

Results: Only gonorrhea cases were significantly more likely to have a large hsCRP rise (≥1.40 mg/L or ≥239%) during infection than controls (P < 0.01). However, gonorrhea, IM, and other systemic/non-genitourinary cases were more likely to have a rise of any magnitude up to one year post-diagnosis than controls (p = 0.038-0.077).

Conclusions: These findings, which differ from those for PSA, suggest distinct mechanisms of elevation for hsCRP and PSA, and support both direct (eg, prostate infection) and indirect (eg, systemic inflammation-mediated prostate cell damage) mechanisms for PSA elevation. Future studies should explore our PSA findings further for their relevance to both prostate cancer screening and risk.
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http://dx.doi.org/10.1002/pros.23392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578879PMC
May 2017

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

JAMA Oncol 2017 Aug;3(8):1085-1093

New York University School of Medicine, New York.

Importance: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease.

Objective: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs.

Design, Setting, And Participants: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort.

Interventions/exposures: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy.

Main Outcomes And Measures: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes.

Results: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men.

Conclusions And Relevance: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.
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http://dx.doi.org/10.1001/jamaoncol.2017.0177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710334PMC
August 2017

Prostate Health Index density improves detection of clinically significant prostate cancer.

BJU Int 2017 12 6;120(6):793-798. Epub 2017 Feb 6.

Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: To explore the utility of Prostate Health Index (PHI) density for the detection of clinically significant prostate cancer (PCa) in a contemporary cohort of men presenting for diagnostic evaluation of PCa.

Patients And Methods: The study cohort included patients with elevated prostate-specific antigen (PSA; >2 ng/mL) and negative digital rectal examination who underwent PHI testing and prostate biopsy at our institution in 2015. Serum markers were prospectively measured per standard clinical pathway. PHI was calculated as ([{-2}proPSA/free PSA] × [PSA] ), and density calculations were performed using prostate volume as determined by transrectal ultrasonography. Logistic regression was used to assess the ability of serum markers to predict clinically significant PCa, defined as any Gleason score ≥7 cancer or Gleason score 6 cancer in >2 cores or >50% of any positive core.

Results: Of 118 men with PHI testing who underwent biopsy, 47 (39.8%) were found to have clinically significant PCa on biopsy. The median (interquartile range [IQR]) PHI density was 0.70 (0.43-1.21), and was 0.53 (0.36-0.75) in men with negative biopsy or clinically insignificant PCa and 1.21 (0.74-1.88) in men with clinically significant PCa (P < 0.001). Clinically significant PCa was detected in 3.6% of men in the first quartile of PHI density (<0.43), 36.7% of men in the IQR of PHI density (0.43-1.21), and 80.0% of men with PHI density >1.21 (P < 0.001). Using a threshold of 0.43, PHI density was 97.9% sensitive and 38.0% specific for clinically significant PCa, and 100% sensitive for Gleason score ≥7 disease. Compared with PSA (area under the curve [AUC] 0.52), PSA density (AUC 0.70), %free PSA (AUC 0.75), the product of %free PSA and prostate volume (AUC 0.79), and PHI (AUC 0.76), PHI density had the highest discriminative ability for clinically significant PCa (AUC 0.84).

Conclusions: Based on the present prospective single-centre experience, PHI density could be used to avoid 38% of unnecessary biopsies, while failing to detect only 2% of clinically significant cancers.
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http://dx.doi.org/10.1111/bju.13762DOI Listing
December 2017

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.

J Clin Oncol 2017 Mar 21;35(7):751-758. Epub 2016 Nov 21.

Kala Visvanathan, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; MaryJo S. Fackler, Zhe Zhang, Zoila A. Lopez-Bujanda, Stacie C. Jeter, Lori J. Sokoll, Leslie M. Cope, Christopher B. Umbricht, David M. Euhus, Saraswati Sukumar, and Antonio C. Wolff, Johns Hopkins University School of Medicine, Baltimore, MD; Elizabeth Garrett-Mayer, Medical University of South Carolina, Charleston, SC; Andres Forero, University of Alabama at Birmingham, Birmingham, AL; Anna M. Storniolo, Indiana University, Bloomington, IN; Rita Nanda, University of Chicago, Chicago, IL; Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; and James N. Ingle, Mayo Clinic, Rochester, MN.

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.
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http://dx.doi.org/10.1200/JCO.2015.66.2080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455421PMC
March 2017

Elevated Prostate Health Index (phi) and Biopsy Reclassification During Active Surveillance of Prostate Cancer.

Urol Case Rep 2016 Jul 26;7:64-6. Epub 2016 May 26.

The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

The Prostate Health Index (phi) has been FDA approved for decision-making regarding prostate biopsy. Phi has additionally been shown to positively correlate with tumor volume, extraprostatic disease and higher Gleason grade tumors. Here we describe a case in which an elevated phi encouraged biopsy of a gentleman undergoing active surveillance leading to reclassification of his disease as high risk prostate cancer.
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http://dx.doi.org/10.1016/j.eucr.2016.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909527PMC
July 2016

Validation of a Biomarker Panel and Longitudinal Biomarker Performance for Early Detection of Ovarian Cancer.

Int J Gynecol Cancer 2016 07;26(6):1070-7

*Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX; †Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; ‡Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and §Department of Biostatistics, Massachusetts General Hospital, Boston, MA.

Objectives: Longitudinal multimarker combinations have the potential to improve sensitivity while maintaining the high specificity required for the early detection of ovarian cancer. The use of multiple markers to improve sensitivity over cancer antigen 125 (CA125) in longitudinal algorithms for early ovarian cancer detection requires the selection of markers with optimal discriminatory power and low longitudinal variance relative to disease-initiated changes. Our objective was to identify a multimarker panel suitable for ovarian cancer, where each individual marker has its own baseline, permitting longitudinal algorithm development.

Materials And Methods: In this retrospective study, we measured CA125, human epididymis protein 4 (HE4), matrix metalloproteinase-7 (MMP-7), CA72-4, CA19-9, CA15-3, carcinoembryonic antigen, and soluble vascular cell adhesion molecule (sVCAM) concentrations using immunoassays in pretreatment sera from 142 stage I ovarian cancer cases and 5 annual samples each from 217 healthy controls. After random division into training and validation sets, all possible biomarker combinations were explored exhaustively using linear classifiers to identify the panel with the greatest sensitivity for stage I disease at a high specificity of 98%. To evaluate longitudinal performance of the individual markers, the within-person over time and the between-person coefficient of variation (CV) were estimated. Hierarchical modeling across women of log-concentrations enabled the borrowing of information across subjects to moderate variance estimates given the small number of observations per subject.

Results: The 4-marker panel comprising CA125, HE4, MMP-7, and CA72-4 performed with the highest sensitivity (83.2%) at 98% specificity. The within-person CVs were lower for CA125, HE4, MMP-7, and CA72-4 (15%, 25%, 25%, and 21%, respectively) compared with their corresponding between-person CV (49%, 20%, 35%, and 84%, respectively) indicating baselines in healthy volunteers. After simple log-transformations, the within-volunteer variation across volunteers was modeled with a normal distribution permitting parsimonious hierarchical modeling.

Conclusions: The multiplex panel chosen is suitable for the early detection of ovarian cancer and the individual markers have their own baseline permitting longitudinal algorithm development.
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http://dx.doi.org/10.1097/IGC.0000000000000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915986PMC
July 2016

The Creation of a Biocontainment Unit at a Tertiary Care Hospital. The Johns Hopkins Medicine Experience.

Ann Am Thorac Soc 2016 05;13(5):600-8

12 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland.

In response to the 2014-2015 Ebola virus disease outbreak in West Africa, Johns Hopkins Medicine created a biocontainment unit to care for patients infected with Ebola virus and other high-consequence pathogens. The unit team examined published literature and guidelines, visited two existing U.S. biocontainment units, and contacted national and international experts to inform the design of the physical structure and patient care activities of the unit. The resulting four-bed unit allows for unidirectional flow of providers and materials and has ample space for donning and doffing personal protective equipment. The air-handling system allows treatment of diseases spread by contact, droplet, or airborne routes of transmission. An onsite laboratory and an autoclave waste management system minimize the transport of infectious materials out of the unit. The unit is staffed by self-selected nurses, providers, and support staff with pediatric and adult capabilities. A telecommunications system allows other providers and family members to interact with patients and staff remotely. A full-time nurse educator is responsible for staff training, including quarterly exercises and competency assessment in the donning and doffing of personal protective equipment. The creation of the Johns Hopkins Biocontainment Unit required the highest level of multidisciplinary collaboration. When not used for clinical care and training, the unit will be a site for research and innovation in highly infectious diseases. The lessons learned from the design process can inform a new research agenda focused on the care of patients in a biocontainment environment.
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http://dx.doi.org/10.1513/AnnalsATS.201509-587PSDOI Listing
May 2016

Advances in mass spectrometry-based clinical biomarker discovery.

Clin Proteomics 2016 7;13. Epub 2016 Jan 7.

Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287 USA.

The greatest unmet needs in biomarker discovery are those discoveries that lead to the development of clinical diagnostic tests. These clinical diagnostic tests can provide early intervention when a patient would present otherwise healthy (e.g., cancer or cardiovascular disease) and aid clinical decision making with improved clinical outcomes. The past two decades have seen significant technological improvements in the analytical capabilities of mass spectrometers. Mass spectrometers are unique in that they can directly analyze any biological molecule susceptible to ionization. The biological studies of human metabolites and proteins using contemporary mass spectrometry technology (metabolomics and proteomics, respectively) has been ongoing for over a decade. Some of these studies have resulted in exciting insights into human biology. However, relatively few biomarkers have been translated into clinical tests. This review will discuss some key technological developments that have occurred over this time with an emphasis on technologies that will create new avenues for biomarker discovery.
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http://dx.doi.org/10.1186/s12014-015-9102-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705754PMC
January 2016

Prostate Health Index (PHI) Predicts High-stage Pathology in African American Men.

Urology 2016 Apr 10;90:136-40. Epub 2015 Dec 10.

The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD; The Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.

Objective: To evaluate the association between the Prostate Health Index (PHI) and adverse pathology in a cohort of African American (AA) men undergoing radical prostatectomy.

Materials And Methods: Eighty AA men with prostate-specific antigen (PSA) of 2-10 ng/mL underwent measurement of PSA, free PSA (fPSA), and p2PSA prior to radical prostatectomy. PHI was calculated as [(p2PSA/fPSA) × (PSA)(½)]. Biomarker association with pT3 disease was assessed using logistic regression, and covariates were added to a baseline multivariable model including digital rectal examination. Biomarker ability to predict pT3 disease was measured using the area under the receiver operator characteristic curve.

Results: Sixteen men (20%) demonstrated pT3 disease on final pathology. Mean age, PSA, and %fPSA were similar in men with and without pT3 disease (all P  >  .05), whereas PHI was significantly greater in men with pT3 disease (mean 57.2 vs 46.6, P  =  .04). Addition of PHI to the baseline multivariable model improved discriminative ability by 12.9% (P  =. .04) and yielded greater diagnostic accuracy than models, including other individual biomarkers.

Conclusion: In AA men with PSA of 2-10 ng/mL, PHI was predictive of pT3 prostate cancer and may help to identify men at increased risk of adverse pathology. Additional studies are needed to substantiate these findings and identify appropriate thresholds for clinical use.
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http://dx.doi.org/10.1016/j.urology.2015.12.004DOI Listing
April 2016

Infectious mononucleosis, other infections and prostate-specific antigen concentration as a marker of prostate involvement during infection.

Int J Cancer 2016 May 21;138(9):2221-30. Epub 2016 Jan 21.

Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD.

Although Epstein-Barr virus has been detected in prostate tissue, no associations have been observed with prostate cancer in the few studies conducted to date. One possible reason for these null findings may be use of cumulative exposure measures that do not inform the timing of infection, i.e., childhood versus adolescence/early adulthood when infection is more likely to manifest as infectious mononucleosis (IM). We sought to determine the influence of young adult-onset IM on the prostate by measuring prostate-specific antigen (PSA) as a marker of prostate inflammation/damage among U.S. military members. We defined IM cases as men diagnosed with IM from 1998 to 2003 (n = 55) and controls as men without an IM diagnosis (n = 255). We selected two archived serum specimens for each participant, the first collected after diagnosis for cases and one randomly selected from 1998 to 2003 for controls (index), as well as the preceding specimen (preindex). PSA was measured in each specimen. To explore the specificity of our findings for prostate as opposed to systemic inflammation, we performed a post hoc comparison of other infectious disease cases without genitourinary involvement (n = 90) and controls (n = 220). We found that IM cases were more likely to have a large PSA rise than controls (≥ 20 ng/mL: 19.7% versus 8.8%, p = 0.027; ≥ 40% rise: 25.7% versus 9.4%, p = 0.0021), as were other infectious disease cases (25.7% versus 14.0%, p = 0.020; 27.7% versus 18.0%, p = 0.092). These findings suggest that, in addition to rising because of prostate infection, PSA may also rise because of systemic inflammation, which could have implications for PSA interpretation in older men.
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http://dx.doi.org/10.1002/ijc.29966DOI Listing
May 2016

Urinary Biomarkers for Prostate Cancer.

Urol Clin North Am 2016 Feb;43(1):17-38

The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD 21287, USA.

In light of the overdiagnosis and overtreatment associated with widespread prostate-specific antigen-based screening, controversy persists surrounding the detection and diagnosis of prostate cancer (PCa). Given its anatomic proximity to the prostate, urine has been proposed as a noninvasive substrate for prostatic biomarkers. With greater understanding of the molecular pathways of carcinogenesis and significant technological advances, the breadth of potential biomarkers is substantial. In this review, the authors aim to provide an evidence-based assessment of current and emerging urinary biomarkers used in the detection and prognostication of PCa and high-grade PCa, with particular attention on clinically relevant findings.
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http://dx.doi.org/10.1016/j.ucl.2015.08.003DOI Listing
February 2016

Non-linearity within the primary measurement range of a lipase assay as the cause of a gap in the interpatient lipase results distribution.

Clin Biochem 2016 Jan 22;49(1-2):176-9. Epub 2015 Oct 22.

Department of Pathology, Jefferson University Hospitals, Philadelphia, PA, United States. Electronic address:

Objectives: Interpatient distribution data for lipase (Roche Cobas® assay) showed an unexpected data gap, where no results were reported. This gap occurred beginning at a point just above the assay's primary measurement range (i.e., above the cutoff (300U/L) for automated repeat-on-dilution). Calculation or other errors within the automated dilution process were ruled out. Linearity of assay results was investigated.

Design And Methods: Linearity of experimental sample dilution series data was assessed by correlation coefficient, intercept, and constancy of slope.

Results: Dilution experiment data demonstrated a discontinuity of results between 300 and 400U/L consistent with the observed gap in patient data. Although data within the presumed linear range of the assay had a high linear correlation coefficient (r2>0.99), a non-zero intercept and progressively variable slope were inconsistent with linearity. Although the assay was assessed as linear by the College of American Pathology linearity survey, survey data also demonstrated non-linearity for this assay when analyzed for slopes and intercept.

Conclusions: Non-linearity in the presumed linear range of an assay can produce gaps in patient data above a repeat-on-dilution cutoff. As in this instance, CAP linearity surveys may not identify certain forms of non-linearity.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.10.002DOI Listing
January 2016

Multiplexed Targeted Mass Spectrometry-Based Assays for the Quantification of N-Linked Glycosite-Containing Peptides in Serum.

Anal Chem 2015 Nov 21;87(21):10830-8. Epub 2015 Oct 21.

Department of Pathology, Clinical Chemistry Division, Johns Hopkins University School of Medicine , 1550 Orleans Street, CRBII Room 3M03, Baltimore, Maryland 21231, United States.

Protein glycosylation is one of the most common protein modifications, and the quantitative analysis of glycoproteins has the potential to reveal biological functions and their association with disease. However, the high throughput accurate quantification of glycoproteins is technically challenging due to the scarcity of robust assays to detect and quantify glycoproteins. Here we describe the development of multiplexed targeted MS assays to quantify N-linked glycosite-containing peptides in serum using parallel reaction monitoring (PRM). Each assay was characterized by its performance metrics and criteria established by the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (NCI CPTAC) to facilitate the widespread adoption of the assays in studies designed to confidently detect changes in the relative abundance of these analytes. An in-house developed software program, MRMPlus, was used to compute assay performance parameters including specificity, precision, and repeatability. We show that 43 selected N-linked glycosite-containing peptides identified in prostate cancer tissue studies carried out in our group were detected in the sera of prostate cancer patients within the quantitative range of the developed PRM assays. A total of 41 of these formerly N-linked glycosite-containing peptides (corresponding to 37 proteins) were reproducibly quantified based on their relative peak area ratios in human serum during PRM assay development, with 4 proteins showing differential significance in serum from nonaggressive (NAG) vs aggressive (AG) prostate cancer patient serum (n = 50, NAG vs AG). The data demonstrate that the assays can be used for the high throughput and reproducible quantification of a panel of formerly N-linked glycosite-containing peptides. The developed assays can also be used for the quantification of formerly N-linked glycosite-containing peptides in human serum irrespective of disease state.
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http://dx.doi.org/10.1021/acs.analchem.5b02063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708883PMC
November 2015