Prospective Clinical Validation Study Research Articles

Characteristics of Mycoplasma genitalium Urogenital Infections in a Diverse Patient Sample from the United States: Results from the Aptima Mycoplasma genitalium Evaluation Study (AMES).

Data from a large prospective multicenter clinical validation study of a nucleic acid amplification in vitro diagnostic test for Mycoplasma genitalium were analyzed to describe the prevalence of M. genitalium infection, risk factors, and disease associations in female and male patients seeking care in diverse geographic regions of the United States. Among 1,737 female and 1,563 male participants, the overall prevalence of M. genitalium infection was 10.3% and was significantly higher in persons ages 15 to 24 years than in persons ages 35 to 39 years (for females, 19.8% versus 4.7% [odds ratio {OR} = 5.05; 95% confidence interval {CI} = 3.01 to 8.46]; for males, 16.5% versus 9.4% [OR = 1.91; 95% CI = 1.20 to 3.02]). The risk for M. genitalium infection was higher in black than in white participants (for females, 12.0% versus 6.8% [OR = 1.88; 95% CI = 1.30 to 2.72]; for males, 12.9% versus 6.9% [OR = 2.02; 95% CI = 1.38 to 2.96]) and higher in non-Hispanic than in Hispanic participants (for females, 11.2% versus 6.0% [OR = 1.97; 95% CI = 1.25 to 3.10]; for males, 11.6% versus 6.8% [OR = 1.80; 95% CI = 1.14 to 2.85]). Participants reporting urogenital symptoms had a significantly elevated risk of M. genitalium infection compared to that for asymptomatic individuals (for females, OR = 1.53 [95% CI = 1.09 to 2.14]; for males, OR = 1.42 [95% CI = 1.02 to 1.99]). Women diagnosed with vaginitis and cervicitis had a higher prevalence of M. genitalium infection than women without those diagnoses, although this was statistically significant only for vaginitis (for vaginitis, OR = 1.88 [95% CI = 1.37 to 2.58]; for cervicitis, OR = 1.42 [95% CI = 0.61 to 2.96]). A diagnosis of urethritis in men was also significantly associated with M. genitalium infection (OR = 2.97; 95% CI = 2.14 to 4.13). Few characteristics distinguished asymptomatic from symptomatic M. genitalium infections. These results from persons seeking care in the United States suggest that M. genitalium infection should be considered in young persons presenting with urogenital symptoms.

Biofluid diagnostics by FTIR spectroscopy: A platform technology for cancer detection.

Fourier Transform Infrared Spectroscopy (FTIR) has been largely employed by scientific researchers to improve diagnosis and treatment of cancer, using various biofluids and tissues. The technology has proved to be easy to use, rapid and cost-effective for analysis on human blood serum to discriminate between cancer versus healthy control samples. The high sensitivity and specificity achievable during samples classification aided by machine learning algorithms, offers an opportunity to transform cancer referral pathways, as it has been demonstrated in a unique and recent prospective clinical validation study on brain tumours. We herein highlight the importance of early detection in cancer research using FTIR, discussing the technique, the suitability of serum for analysis and previous studies, with special focus on pre-clinical factors and clinical translation requirements and development.

Clinical Validation of Innovative Optical-Sensor-Based, Low-Cost, Rapid Diagnostic Test to Reduce Antimicrobial Resistance.

The antibiotic susceptibility test determines the most effective antibiotic treatment for bacterial infection. Antimicrobial stewardship is advocated for the rational use of antibiotics to preserve their efficacy in the long term and provide empirical therapy for disease management. Therefore, rapid diagnostic tests can play a pivotal role in efficient and timely treatment. Here, we developed a novel, rapid, affordable, and portable platform for detecting uropathogens and reporting antibiogram to clinicians in just 4 h. This technology replicates the basic tenets of clinical microbiology including bacterial growth in indigenously formulated medium, and measurement of inhibition of bacterial growth in presence of antibiotic/s. Detection is based on chromogenic endpoints using optical sensors and is analyzed by a lab-developed algorithm, which reports sensitivity to the antibiotic’s panel tested. To assess its diagnostic accuracy, a prospective clinical validation study was conducted in two tertiary-care Indian hospitals. Urine samples from 1986 participants were processed by both novel/index test and conventional Kirby Bauer Disc Diffusion method. The sensitivity and specificity of this assay was 92.5% and 82%, respectively (p < 0.0005). This novel technology will promote evidence-based prescription of antibiotics and reduce the burden of increasing resistance by providing rapid and precise diagnosis in shortest possible time.

Development of high-throughput ATR-FTIR technology for rapid triage of brain cancer

Non-specific symptoms, as well as the lack of a cost-effective test to triage patients in primary care, has resulted in increased time-to-diagnosis and a poor prognosis for brain cancer patients. A rapid, cost-effective, triage test could significantly improve this patient pathway. A blood test using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy for the detection of brain cancer, alongside machine learning technology, is advancing towards clinical translation. However, whilst the methodology is simple and does not require extensive sample preparation, the throughput of such an approach is limited. Here we describe the development of instrumentation for the analysis of serum that is able to differentiate cancer and control patients at a sensitivity and specificity of 93.2% and 92.8%. Furthermore, preliminary data from the first prospective clinical validation study of its kind are presented, demonstrating how this innovative technology can triage patients and allow rapid access to imaging.

Surgical Aortic Valve Replacement: Are We Able to Improve Hemodynamic Outcome?

Aortic valve replacement (AVR) does not usually restore physiological flow profiles. Complex flow profiles are associated with aorta dilatation, ventricle remodeling, aneurysms, and development of atherosclerosis. All these affect long-term morbidity and often require reoperations. In this pilot study, we aim to investigate an ability to optimize the real surgical AVR procedure toward flow profile associated with healthy persons. Four cases of surgical AVR (two with biological and two with mechanical valve prosthesis) with available post-treatment cardiac magnetic resonance imaging (MRI), including four-dimensional flow MRI and showing abnormal complex post-treatment hemodynamics, were investigated. All cases feature complex hemodynamic outcomes associated with valve-jet eccentricity and strong secondary flow characterized by helical flow and recirculation regions. A commercial computational fluid dynamics solver was used to simulate peak systolic hemodynamics of the real post-treatment outcome using patient-specific MRI measured boundary conditions. Then, an attempt to optimize hemodynamic outcome by modifying valve size and orientation as well as ascending aorta size reduction was made. Pressure drop, wall shear stress, secondary flow degree, helicity, maximal velocity, and turbulent kinetic energy were evaluated to characterize the AVR hemodynamic outcome. The proposed optimization strategy was successful in three of four cases investigated. Although no single parameter was identified as the sole predictor for a successful flow optimization, downsizing of the ascending aorta in combination with the valve orientation was the most effective optimization approach. Simulations promise to become an effective tool to predict hemodynamic outcome. The translation of these tools requires, however, studies with a larger cohort of patients followed by a prospective clinical validation study.

Measurement of extravascular lung water to diagnose severe reperfusion lung injury following pulmonary endarterectomy: a prospective cohort clinical validation study.

SummaryThe measurement of extravascular lung water is a relatively new technology which has not yet been well validated as a clinically useful tool. We studied its utility in patients undergoing pulmonary endarterectomy as they frequently suffer reperfusion lung injury and associated oedematous lungs. Such patients are therefore ideal for evaluating this new monitor. We performed a prospective observational cohort study during which extravascular lung water index measurements were taken before and immediately after surgery and postoperatively in intensive care. Data were analysed for 57 patients; 21 patients (37%) experienced severe reperfusion lung injury. The first extravascular lung water index measurement after cardiopulmonary bypass failed to predict severe reperfusion lung injury, area under the receiver operating characteristic curve 0.59 (95%CI 0.44–0.74). On intensive care, extravascular lung water index correlated most strongly at 36 h, area under the receiver operating characteristic curve 0.90 (95%CI 0.80–1.00). Peri‐operative extravascular lung water index is not a useful measure to predict severe reperfusion lung injury after pulmonary endarterectomy, however, it does allow monitoring and measurement during the postoperative period. This study implies that extravascular lung water index can be used to directly assess pulmonary fluid overload and that monitoring patients by measuring extravascular lung water index during their intensive care stay is useful and correlates with their clinical course. This may allow directed, pre‐empted therapy to attenuate the effects and improve patient outcomes and should prompt further studies.

Prospective Clinical Validation of the InVisionFirst-Lung Circulating Tumor DNA Assay for Molecular Profiling of Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSEGuidelines advocate molecular profiling in the evaluation of advanced non–small-cell lung cancer (NSCLC) and support the use of plasma circulating tumor DNA (ctDNA)-based profiling for patients with insufficient tissue. Thorough prospective clinical validation studies of next-generation sequencing (NGS)-based ctDNA assays are lacking. We report the multicentered prospective clinical validation of the InVision ctDNA assay in patients with advanced untreated NSCLC.METHODSA total of 264 patients with untreated advanced NSCLC were prospectively recruited, and their plasma was analyzed using a ctDNA NGS assay for detection of genomic alterations in 36 commonly mutated genes. Tumor tissue was available in 178 patients for molecular profiling for comparison with plasma profiling. The remaining 86 patients were included to compare ctDNA profiles in patients with and without tissue for profiling.RESULTSConcordance of InVisionFirst with matched tissue profiling was 97.8%, with 82.9% positive predictive value, 98.5% negative predictive value, 70.6% sensitivity, and 99.2% specificity. Considering specific alterations in eight genes that most influence patient management, the positive predictive value was 97.8%, with 97.1% negative predictive value, 73.9% sensitivity, and 99.8% specificity. Across the entire study, 48 patients with actionable alterations were identified by ctDNA testing compared with only 38 by tissue testing. ctDNA NGS reported either an actionable alteration or an alteration generally considered mutually exclusive for such actionable changes in 53% of patients.CONCLUSIONThe liquid biopsy NGS assay demonstrated excellent concordance with tissue profiling in this multicenter, prospective, clinical validation study, with sensitivity and specificity equivalent to Food and Drug Administration–approved single-gene ctDNA assays. The use of plasma-based molecular profiling using NGS led to the detection of 26% more actionable alterations compared with standard-of-care tissue testing in this study.

Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study

In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test. We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results. The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412). The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned. Veracyte.

Hot Off the Press: Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study.

This is a prospective observational study looking to validate a previously derived decision rule designed to help safely discharge opioid overdose patients from the emergency department after 1 hour. They included a convenience sample of 538 adult patients who had received naloxone pre-hospital and compared the Hospital Observation Upon Reversal (HOUR) rule with clinical judgement. The primary outcome of interest was a broadly defined composite of adverse events. The HOUR rule had a sensitivity of 84.1% (95% CI 76.2-92.1%) and a specificity of 62.1% (95% CI 57.6-66.5%), which was very similar to clinical judgement. Clinical judgement would have missed 12 adverse events, while the HOUR rule would have missed 13, although most of those adverse events were probably minor.

Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study.

St. Paul's Early Discharge Rule was derived to determine which patients could be safely discharged from the emergency department after a 1-hour observation period following naloxone administration for opiate overdose. The rule suggested that patients could be safely discharged if they could mobilize as usual and had a normal oxygen saturation, respiratory rate, temperature, heart rate, and Glasgow Coma Scale score. Validation of the St. Paul's Early Discharge Rule is necessary to ensure that these criteria are appropriate to apply to patients presenting after an unintentional presumed opioid overdose in the context of emerging synthetic opioids and expanded naloxone access. In this prospective, observational validation study, emergency medicine providers assessed patients 1hour after administration of prehospital naloxone. Unlike in the derivation study the threshold for normal oxygen saturation was set at 95% and patients were not immediately discharged after a normal 1-hour evaluation. Patients were judged to have a normal 1-hour evaluation if all six criteria of the rule were met. Patients were judged to have an adverse event (AE) if they had one or more of the preestablished AEs. A total of 538 patients received at least one administration of prehospital naloxone, were transported to the study hospital, and had a 1-hour evaluation performed by a provider. AEs occurred in 82 (15.4%) patients. The rule exhibited a sensitivity of 84.1% (95% confidence interval [CI]= 76.2%-92.1%), a specificity of 62.1% (95% CI= 57.6%-66.5%), and a negative predictive value of 95.6% (95% CI= 93.3%-97.9%). Only one patient with a normal 1-hour evaluation subsequently received additional naloxone following a presumed heroin overdose. This rule may be used to risk stratify patients for early discharge following naloxone administration for suspected opioid overdose.

Patient-specific requirements and clinical validation of MRI-based pressure mapping: A two-center study in patients with aortic coarctation.

Invasive peak-to-peak pressure gradients are the current clinical reference standard for assessing aortic coarctation. To obtain them, patients need to undergo arterial heart catheterization. Unless an intervention is performed, the procedure remains purely diagnostic, while the concomitant risks remain. To validate MRI-based pressure mapping against pressure drop derived from heart catheterization and to define minimal clinical requirements. Prospective clinical validation study. Twenty-seven coarctation patients with an indicated heart catheterization were enrolled at two clinical centers. 1.5T including 4D velocity-encoded MRI and 3D anatomical imaging of the aorta. Pressure drop across the stenosis was calculated by pressure mapping based on the pressure Poisson equation. Calculated pressure drops were compared with catheter measured data. Spatial and temporal resolution were analyzed using in silico phantom-based data as well as in vivo measurements. Pressure drop was compared to peak-to-peak measurements. A two-sample paired mean equivalence test was used. In patients without imaging artifacts and a required spatial resolution ≥5 voxel/diameter, significant equivalence of pressure mapping compared to heart catheterization was found (17.5 ± 6.49 vs. 16.6 ± 6.53 mmHg, P < 0.001). Pressure mapping provides equivalent accuracy to pressure drop obtained from heart catheterization in patients 1) without previous stenting and 2) with sufficient spatial image resolution (at least 5 voxels/diameter). In these patients the method can reliably be performed prior to the actual procedure, and thus allows safe noninvasive treatment planning based on MRI. 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:81-89.

Blood Pressure and Heart Rate Variability in Primary Open-Angle Glaucoma and Normal Tension Glaucoma

ABSTRACT Purpose Vascular dysfunction and ischemia are believed to play an important part in the pathogenesis of glaucoma and especially of normal tension glaucoma (NTG). The aim of the present study was to analyze the blood pressure (BP) and heart rate variability patterns in patients with primary open-angle glaucoma (POAG) and NTG compared with controls. Methods In total, 37 patients with POAG, 27 patients with NTG, and 82 control subjects were included in a prospective clinical validation study. Continuous BP and heart rate were simultaneously recorded over 30 min (Glaucoscreen, aviant GmbH, Jena, Germany) under resting conditions. Time series of heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were extracted and analyzed calculating univariate linear (time domain, frequency domain), nonlinear (symbolic dynamics), and bivariate (joint symbolic dynamics) indices. Results Overall, 12 parameters could be identified that were significantly different when comparing POAG patients and controls, whereas 80 parameters were significantly different in NTG patients compared with controls. The optimum set consisting of three indices showed a sensitivity of 81.5% at a specificity of 86.6% for NTG patients compared with a sensitivity of 62.2% at a specificity of 82.9% for POAG patients. Conclusions Alterations in BP variability and coupling with heart rate suggest impaired patterns of autonomic cardiovascular regulation in glaucoma patients especially in patients with NTG.

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic‐based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell‐derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J‐Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

ObjectivesThe purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. MethodsTumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. ResultsMolecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. ConclusionsA simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.

583P - Serum miRNA Assays for detection and management of gastric and lung cancers

Background:Lung cancer is the most prevalent cancer and the leading cause of cancer death worldwide. Prognosis remains poor for advanced stage cancer patients. Currently, LDCT is recommended as a screening test for smokers in the U.S. However, the poor specificity (73% specificity at 94% sensitivity) of LDCT has raised significant concern for its high chance of false positive (96% of nodules are benign). Gastric cancer is the 3rd leading cause of cancer deaths worldwide. Currently, endoscopy is the only reliable method for early diagnosis. However, the invasiveness and cost limit its usage as a screening test. MicroRNAs are key regulators of cancer pathogenesis. They are exceptionally stable in body fluids, making them potential noninvasive biomarker for cancers. Methods: We aim to develop serum miRNA assays to aid screening and early detection of lung and gastric cancers. Lung cancer miRNA biomarkers were identified through a Chinese male smoker case-control cohort (n = 432) and validated in 4 additional cohorts from China, Europe, Singapore and US (n = 880). Gastric cancer miRNA biomarkers were identified through a Singaporean case-control cohort (n = 472) and validated in 3 additional cohorts from Singapore, Korea and Japan (n = 467). Multivariate miRNA biomarker panels were formulated by sequence forward floating search and support vector machine using quantitative miRNA expression data. Results: More than 600 miRNAs were profiled with MiRXES miRNA qPCR assay platform. Among which, 39 miRNAs were found significantly altered between early-stage lung cancer and matched controls. A six-miR biomarker panel could classify cancer from controls with AUC>0.93 across all cohorts. A 24-miR gastric cancer panel was optimized using discovery set (AUC=0.92) and validated in two blinded studies with fixed algorithm and threshold definition. The 24-miR panel showed 90% sensitivity and 81% specificity in the Korean cohort (AUC=0.91) and had 90% sensitivity and 75% specificity in the Singaporean Chinese cohort (AUC=0.89). Conclusions: We have developed serum miRNA panels capable of detecting early-stage lung and gastric cancers. The two miRNA assays are undergoing multi-center prospective clinical validation studies (n > 15,000) to demonstrate clinical utility. Legal entity responsible for the study: MIRXES Pte Ltd Funding: MIRXES Pte Ltd Disclosure: L. Zhou: Co-founder and shareholder of MIRXES Pte Ltd.

Molecular biomarkers and prognostic factors for prostate cancer

In the era of personalized medicine and precision oncology, innovative genetic biomarkers are of emerging interest to close the diagnostic and prognostic gap that is left by current clinicopathologic risk classifiers. The current review article summarizes evidence regarding prognostic and predictive genetic biomarkers that are currently in widespread clinical use at initial diagnosis as well as following definitive treatment of prostate cancer. We give abrief summary about basic principles of biomarker research studies and present current data for the Progensa PC3 test, TMPRSS2:ERG gene fusion, ConfirmMDx, Prolaris gene panel, OncotypeDX Genomic Prostate score, and Decipher classifier. Evidence regarding those genetic biomarkers has heavily increased recently. However, there is still alack of large, multicentric and prospective clinical validation studies. Furthermore, comparative studies that investigate the prognostic value of various genetic biomarkers are needed.

Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer

IntroductionSingle nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT. Methods122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity. ResultsAll 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis. ConclusionRelevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

Molecular Profiling of Thyroid Nodules: Current Role for the Afirma Gene Expression Classifier on Clinical Decision Making.

Thyroid fine-needle aspiration biopsy results are cytologically indeterminate in 15-30% of cases. When these nodules undergo diagnostic surgery, approximately three-quarters are histologically benign. These unnecessary surgeries diminish quality of life, generate complications, and increase healthcare costs. The Afirma gene expression classifier (GEC) is validated to pre-operatively identify cytologically indeterminate nodules likely to be truly benign so that surgery can be avoided. Its performance is supported by robust multicenter prospective and blinded clinical validation studies, and supported by extensive independent clinical utility publications which show a marked reduction in surgery among patients with benign Afirma GEC results. To rule-out cancer and avoid unnecessary diagnostic surgery, Afirma’s quality and depth of validation stand alone. The accuracy of a benign result is the negative predictive value (NPV). Afirma achieves an NPV ≥94% among cytologically indeterminate nodules (Bethesda III or IV). Thirteen clinical utility studies describing 1468 GEC benign patients demonstrate that few Afirma GEC benign nodules undergo surgery, including after 3 years of follow-up. With a specificity of 52%, over half of the truly benign nodules with indeterminate cytology receive a benign GEC result. High test sensitivity is critical to safely rule out cancer. The Afirma GEC’s 90% sensitivity means that regardless of the pre-test risk of malignancy, 90% of all malignant nodules are GEC suspicious. The Afirma GEC has transformed patient care. Where the majority of cytologically indeterminate patients were once operated to determine if the nodule was benign or malignant, now nearly half of these surgeries can be avoided.

MP6-04 THE 4KSCORE TEST PREDICTS HIGH-GRADE PROSTATE CANCER ON BIOPSY WITH PSA LESS THAN 4 NG PER MILLILITER

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2015MP6-04 THE 4KSCORE TEST PREDICTS HIGH-GRADE PROSTATE CANCER ON BIOPSY WITH PSA LESS THAN 4 NG PER MILLILITER Vinita Mathur, Vincent Linder, Yan Dong, Dan Sjoberg, Richard Roberts, Michael Reeve, David Okrongly, Jay Newmark, Grannum Sant, and Mitchell Steiner Vinita MathurVinita Mathur More articles by this author , Vincent LinderVincent Linder More articles by this author , Yan DongYan Dong More articles by this author , Dan SjobergDan Sjoberg More articles by this author , Richard RobertsRichard Roberts More articles by this author , Michael ReeveMichael Reeve More articles by this author , David OkronglyDavid Okrongly More articles by this author , Jay NewmarkJay Newmark More articles by this author , Grannum SantGrannum Sant More articles by this author , and Mitchell SteinerMitchell Steiner More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.251AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES PSA values below 4ng/mL are considered “normal”, however studies have shown that up to 15% of men in the general population with these low levels will have prostate cancer on biopsy of which 2% may be high grade (Gleason score 7 or higher). The 4Kscore test utilizes 4 kallikrein biomarkers; total PSA, free PSA, intact PSA, and human kallikrein2 in addition to digital rectal exam (DRE) and previous biopsy status to access risk of high grade prostate cancer. While the 4Kscore test has previously been shown to accurately predict the risk of high grade prostate cancer, we focused on patients with low/normal concentrations of PSA and assessed the ability of the 4Kscore test to predict the risk of high grade prostate cancer. METHODS Three hundred and forty eight men with PSA levels less than or equal to 4 ng/mL were identified in a recent large prospective study enrolling 1,012 men who were previously scheduled for prostate biopsy for suspicion of prostate cancer from 26 sites across the United States. The 4Kscore was calculated and subsequent biopsy results were retrieved. We investigated whether the 4Kscore test was predicative of risk of high grade cancer at “normal” PSA values. We evaluated the accuracy of the 4Kscore as a predictive model for patients with low tPSA by fitting a logistic regression model with high grade prostate cancer as the outcome. RESULTS Of the 348 men identified in our prospective clinical validation study of 1012 men with PSA values less than 4 ng/ml, 37 were diagnosed with high grade prostate cancer (11%) on biopsy. In this subgroup, the associated 4Kscore result was elevated in 35 of 37 patients (95%). CONCLUSIONS A normal PSA level (i.e. < 4 ng/ml) does not definitively rule out high grade prostate cancer. We have shown that the 4Kscore test performs consistently well as predictive instrument, even in the lower zone of tPSA <4 ng/mL. The 4Kscore test maintains good discrimination for risk of high grade prostate cancer in this subpopulation with a sensitivity of 95% and specificity of 56%. 4Kscore for Gleason Score ≤7 at total PSA values < 4ng/ml 4Kscore for Gleason ≤7 All patients Data Set N=348 N=1012 tPSA < 4ng/mL, Median 2.8ng/mL 0.2 to > 100ng/mL, Median 4.7 Gleason Score 37 (11%) 231 (23%) HG cases with increased 4Kscore∗ 35 (10%) 218 (22%) Sensitivity of 4Kscore test∗ 0.95 0.94 Specificity of 4Kscore test∗ 0.56 0.38 4Kscore for with Gleason Score ≤7 Mean 4Kscore value 22 Mean 4Kscore value 42 < 5% 2 (5%) 12 (5%) 5-10% 5 (14%) 13 (6%) 10-15% 9 (24%) 23 (10%) > 15 21 (57%) 183 (79%) AUC 0.858 (95% CI 0.799-0.908) 0.821 (95% CI 0.790-0.852) ∗ 4Kscore ≥6% © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e55 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Vinita Mathur More articles by this author Vincent Linder More articles by this author Yan Dong More articles by this author Dan Sjoberg More articles by this author Richard Roberts More articles by this author Michael Reeve More articles by this author David Okrongly More articles by this author Jay Newmark More articles by this author Grannum Sant More articles by this author Mitchell Steiner More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

An outcome measure of functionality and quality of life in Iranian women with osteoporotic vertebral fractures: a validation study of the QUALEFFO-41

Osteoporosis is a very common disease and often results in vertebral fractures. The Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41) is a tool to measure health-related quality of life in these patients. This study aimed to cross-culturally translate and validate the QUALEFFO-41 in Iran. This was a prospective clinical validation study. A forward-backward procedure was used to translate the questionnaire from English into Persian. The translation and cross-cultural adaptation were made in accordance with published guidelines. Patients were divided into two study groups according to the World Health Organization criteria: those with at least one vertebral fracture who had undergone surgery and those with osteoporosis and no fractures as a control group. All of the participants were assessed by both the QUALEFFO-41 and SF-36. The surgery group was asked to respond to the QUALEFFO-41 at two points in time: the pre- and postoperative assessments (6-month follow-up). To test reliability, the internal consistency was evaluated using Cronbach's alpha coefficient. Validity was evaluated by assessing convergent validity between the QUALEFFO-41 and SF-36 and item-scale correlations and discriminatory ability. Internal responsiveness of the QUALEFFO-41 to the clinical intervention (surgery) also was evaluated comparing patients' pre- and postoperative scores. A total of 149 patients completed the questionnaire: 48 surgical patients and 101 as a control group. At the pre- and postoperative assessments, the QUALEFFO-41 showed adequate internal consistency in all domains (Cronbach's alpha of 0.71 to 0.81). Additionally, the correlation of each item with its hypothesized domain on the QUALEFFO-41 indicated acceptable results, suggesting that the items had a substantial relationship with their own domains. Further analysis also indicated that the questionnaire was responsive to change (P<0.0001). Significant correlations existed between scores of similar subscales of the QUALEFFO-41 and SF-36 (P<0.001). The findings show that the Iranian version of the QUALEFFO-41 is a reliable and valid measure of functionality and quality-of-life evaluation among patients with osteoporotic vertebral fractures.