Preliminary Clinical Validation Research Articles

Insulin-resistance and depression cohort data mining to identify nutraceutical related DNA methylation biomarker for type 2 diabetes

Insulin-resistance (IR) is one of the most important precursors of type 2 diabetes (T2D). Recent evidence suggests an association of depression with the onset of T2D. Accumulating evidence shows that depression and T2D share common biological origins, and DNA methylation examination might reveal the link between lifestyle, disease risk, and potential therapeutic targets for T2D. Here we hypothesize that integrative mining of IR and depression cohort data will facilitate predictive biomarkers identification for T2D. We utilized a newly proposed method to extract gene-level information from probe level data on genome-wide DNA methylation array. We identified a set of genes associated with IR and depression in clinical cohorts. By overlapping the IR-related nutraceutical-gene network with depression networks, we identified a common subnetwork centered with Vitamin D Receptor (VDR) gene. Preliminary clinical validation of gene methylation set in a small cohort of T2D patients and controls was established using the Sequenome matrix-assisted laser desorption ionization-time flight mass spectrometry. A set of sites in the promoter regions of VDR showed a significant difference between T2D patients and controls. Using a logistic regression model, the optimal prediction performance of these sites was AUC = 0.902，and an odds ratio = 19.76. Thus, monitoring the methylation status of specific VDR promoter region might help stratify the high-risk individuals who could potentially benefit from vitamin D dietary supplementation. Our results highlight the link between IR and depression, and the DNA methylation analysis might facilitate the search for their shared mechanisms in the etiology of T2D.

Abstract TMIM-069: PROSPECTIVE CLINICAL VALIDATION OF EX VIVO, PATIENT-SPECIFIC RESPONSE PREDICTION TO FIRST-LINE CHEMOTHERAPY

Abstract PURPOSE: Ovarian cancer remains the most lethal gynecological malignancy in the United States even though there are a number of treatment options. For the newly diagnosed ovarian cancer patient, treatment is standard with the majority of patients receiving first-line platinum/taxol treatment following surgical debulking or as part of a neo-adjuvant treatment regimen. Standard response assessment to this chemotherapy combination depends on lengthy clinical follow-up of at least 6 months following the conclusion of the chemotherapy. This course is initially effective in 70-80% of patients, but 20-30% will relapse within the 6 months post-chemotherapy or not respond at all. Additionally, most of the initial responders will also relapse. Early prediction of the patients whose cancers do not respond could lead to earlier intervention with more effective therapy. RESULTS: To perform this prediction, we developed a test utilizing live tumor tissue and 3D cell culture to predict the response of ovarian cancer patients to standard platinum and taxol chemotherapy along with the standard agents used for relapse patients. To validate the assay, we performed a prospective trial involving 86 women with newly diagnosed ovarian cancer from whom live tumor tissue was recovered at surgical resection prior to chemotherapy. Of the 79 patients whose tissues yielded a successful assay result, 27 had sufficient clinical follow-up to determine the accuracy of the response predictions made by the assay. Assay response predictions were made within 7 days following surgery while clinical response was not determined until 6 months or more following the conclusion of first-line chemotherapy. Assay results predicted first-line chemotherapy response in 100% of clinical responders (19 of 19) and first-line chemotherapy non-response in 62.5% of clinical non-responders (5 of 8) as defined by CA-125 and radiographic surveillance. This response prediction was statistically significant by Fisher's Exact test, p < 0.001. The sensitivity of the assay was 86% while the specificity was 100%. When the assay results were examined in terms of progression free survival, 19 of 19 patients identified as responders by the assay remained progression free at least 6 months post-chemotherapy with 14 remaining progression free 10 or more months post-chemotherapy. In contrast, of the 8 assay non-responders, 3 were refractory with progression within 3 months of chemotherapy conclusion and 2 progressed less than 6 months post-chemotherapy with a mean progression free survival of 4.5 months. CONCLUSIONS: Our rapid, ex vivo, 3D cellular assay is capable of accurate patient specific response prediction of first-line combination therapy in newly diagnosed ovarian cancer patients and can serve as a prognostic indicator of progression free survival. This preliminary clinical validation shows the significant potential of this assay as a future tool in personalized cancer care for ovarian cancer patients. Citation Format: Stephen Shuford, Jeffrey Elder, Larry Puls, John Weroha, Xiaonan Hou, Valentina Zanfagnin, Alpa Nick, Michael P. Stany, Larry Maxwell, Thomas Conrads, Chris Corless, Anil K. Sood, Matthew Gevaert, Howland E. Crosswell, and Teresa M. DesRochers. PROSPECTIVE CLINICAL VALIDATION OF EX VIVO, PATIENT-SPECIFIC RESPONSE PREDICTION TO FIRST-LINE CHEMOTHERAPY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-069.

Cancer Immunotherapy Is More Effective in Irradiated Tumors in Preclinical Mouse Model of Melanoma

Post-radiotherapy local recurrence is a common challenge in cancer management. Since radiotherapy induces DNA damage, tumor cells that survived radiotherapy have higher mutation burden. It is recognized that high mutation burden and high clonal neoantigen burden are associated with checkpoint inhibitor sensitivity. Therefore, we hypothesized that tumors that survived radiotherapy are more responsive to immune checkpoint treatment and cancer immunotherapy maybe an effective treatment for local recurrences after radiotherapy. To simulate recurrent tumor post radiotherapy, we irradiated B16F10 melanoma cells with 5 Gy and selected the surviving colonies for further passage. This process was repeated twice to obtain the final irradiated B16F10 cells. These irradiated B16F10 cells and parent B16F10 cells were used to generate flank xenograft tumors (5*104) in B57BL/6 mice. The mice were then treated with saline, αPD-L1 (10mg/kg), αCTLA4(5mg/kg) or αPD-L1+αCTLA4 on days 3, 6 and 9. Tumor volumes were obtained for each mouse. The tumor volumes were assessed every 2–3 days starting day 3. In the irradiated B16F10 melanoma model, our results demonstrate that both αCTLA4 alone and combination groups achieved tumor growth control (p<0.005), and there is also significant survival difference (p<0.005) with median survival 22.5, 26, 35 and 38.5 days in control, αPD-L1, αCTLA4, and combination subgroups. In the parent B16F10 melanoma model, immunotherapy treatments improved survival, though the increases were not statistically significant. Immunotherapy treatment arms were significantly more effective in irradiated B16F10 model (p value<0.005). We demonstrated that irradiated B16F10 tumors are more responsive to checkpoint inhibitor treatment than non-irradiated tumors. This finding suggest that immunotherapy may be effective for recurrent tumors after radiation. Our results are preliminary and further preclinical and clinical validation are needed.

Abstract 2240: Redefining personalized medicine by drug response profiling of patient-derived spheroids

Abstract Personalized medicine in cancer typically refers to the use of genetics and/or biomarkers to direct the use of targeted therapy or predict overall prognosis based on statistical probability. Therapy selection and predictions are not based on any physical interaction between a patient’s tumor cells to clinically relevant therapies based on their disease indication. We have developed an assay using 3D cell culture that exposes a patient’s tumor cells to standard of care chemotherapies for the purpose of predicting their clinical response to potential treatment options prior to treatment. We have analytically validated this assay enabling its performance under CLIA regulations as a Laboratory Developed Test (LDT) and prospectively validated it against clinical patient outcome in ovarian cancer. The test utilizes excess fresh patient tissue acquired during standard of care surgical debulking or biopsy and returns results within 7 business days of tissue receipt, typically well before the start of chemotherapy. Previously, we have shown in newly diagnosed ovarian cancer, the test has an accuracy of 87% with a specificity of 100% and a sensitivity of 84% in the prediction of standard first-line carboplatin/taxol combination therapy using the biomarker CA-125 and CT imaging as clinical readouts. We have similar results for the prediction of response to neoadjuvant therapy following laparoscopic biopsy using RECIST criteria. We have now analytically validated the assay in glioblastoma (GBM) and rare tumors. Preliminary clinical validation in GBM has shown the ability of the test to accurately predict response to standard first-line temozolomide using RANO criteria as the clinical readout. Rare tumor validation has included a panel of 12 drugs covering those used as standard of care for most rare tumors. Aspects of validation have included examining inter- and intra-assay variability and drug panel response in a defined number of rare tumors including sarcomas, neuroendocrine, and other tumors such as Sertoli-Leydig. In breast cancer, we have validated the assay for the use of a single diagnostic biopsy core as the tissue source and established preliminary clinical validation against standard of care such as doxorubicin and paclitaxel with pathologic complete response (pCR) as the clinical readout. We are further validating the predictive ability of the test in newly diagnosed and relapsed ovarian cancer and GBM patients (clinical trial NCT03561207). With demonstrated accurate prediction of patient specific response, the transition to cancer therapy selection based on physical evidence vs statistical probability would significantly improve patient outcomes and benefit economic stakeholders. Citation Format: Stephen Shuford, Christine Wilhelm, Ashley M. Smith, Melissa Rayner, Jeremy Stuart, Lillia Holmes, Matt Gevaert, Howland E. Crosswell, Teresa M. DesRochers. Redefining personalized medicine by drug response profiling of patient-derived spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2240.

Visceral adipose ratio as a novel predictor for acute bowel toxicity in patients receiving pelvic radiation: Preliminary dosimetric analysis and clinical validation.

During radiation treatment planning, the small bowel (SB) is often contoured as a 'bowel bag' encompassing the entire peritoneal space that may be occupied by SB. This method incorporates large volumes of visceral adipose, potentially resulting in misleading estimates of radiation dose to the SB. We evaluated the relative volume of adipose within the peritoneal space and applied this as a correction factor to standard bowel bag dosimetric measures, hypothesizing that corrected SB measures would better correlate with acute toxicity. Eighteen consecutive patients receiving pelvic radiation for gynaecologic cancers over a 1-year period at an academic medical centre were included. Bowel function was assessed with the Expanded Prostate Index Composite (EPIC) questionnaire. Bowel bags were contoured on simulation computed tomography (CT) scans. Adipose was auto-contoured using previously published Hounsfield Unit criteria and used to create an adipose correction factor (ACF). The ACF was applied to V45cc and V40% volumes to create adipose corrected measures (AC-V45cc and AC-V40%). Correlations between EPIC scores and dosimetric measures were assessed using Spearman coefficients. V45cc and V40% did not correlate with overall EPIC bowel domain score; however, AC-V40% did show a significant correlation (P=0.02). Correlations of V45cc and V40% with the bowel bother subdomain of EPIC were both significantly improved by applying the ACF (P=0.02 for AC-V45cc; P<0.01 for AC-V40%). Adipose corrected bowel bag dosimetric constraints correlate better with acute bowel toxicity than current standard practice. Longer follow-up is needed to determine if similar findings are seen with late toxicity.

Detection of Lumbar Spine Osseous Metastases Using Dual-Energy CT: Phantom Results and Preliminary Clinical Validation.

The purpose of this study was to evaluate the sensitivity, tumor conspicuity, and image quality of different material decomposition images of phantoms and patients with nearly isodense bone metastases using rapid-kilovoltage-switching dual-energy CT (DECT). Fifty-one semianthropomorphic lumbar spine phantoms embedded with 75 simulated tumors were scanned without and with outer torso-attenuating encasement under the same scan settings. Two radiologists independently reviewed the 70-keV virtual monochromatic and material decomposition images (hydroxyapatite-water, water-hydroxyapatite, cortical bone-water, water-cortical bone). The sensitivity of tumor detection, tumor conspicuity (on a 3-point scale), and image quality (on a 3-point scale) were recorded by two independent readers. McNemar and Wilcoxon signed rank tests were used to compare results between the image reconstructions. Six clinical abdominopelvic DECT scans (three men, three women; mean age, 52 years) with nine nearly isodense lumbar spine tumors missed in the clinical report but confirmed on other scans were also evaluated. The hydroxyapatite-water material decomposition algorithm showed improved sensitivity for isodense lesion detection (without torso phantom encasement, 94% vs 82%, p = 0.031; with torso phantom encasement, 38% vs 18%, p = 0.013), and higher tumor conspicuity scores (p < 0.0001) compared with 70-keV virtual monoenergetic images. Artifacts were more prevalent with all material decomposition images than with 70-keV virtual monoenergetic images. Similar results were seen in the patient study. Dual-energy CT with hydroxyapatite-water material decomposition may improve the detection of bone marrow metastases, especially for subtle isodense tumors. Further study in prospective clinical scans is warranted.

Development of up-converting phosphor technology-based lateral flow assay for quantitative detection of serum PIVKA-II: Inception of a near-patient PIVKA-II detection tool

BackgroundDevelopment of a test card based on up-conversion phosphor technology-based immune lateral flow (UPT-LF) assay as a near-patient detection tool for serum Prothrombin induced by vitamin K absence or antagonist II (PIVKA-II). MethodsUp-converted phosphor nanoparticles (UCPs) were used to bind to PIVKA-II monoclonal antibodies as labeled probes to develop the test card for detecting serum PIVKA-II. The UPT-LF test card was evaluated by the limit of detection, linearity, stability, recovery rate, precision and interference. Preliminary clinical validation was conducted by detection of 498 serum samples from 228 patients with hepatocellular carcinoma (HCC), 170 patients with liver benign lesion (LBL) and 100 healthy controls (HC). Additionally, the correlation of serum PIVKA-II detection between UPT-LF assay and Chemiluminescence enzyme immunoassay (CLEIA) assay were performed. ResultsModified and activated UCPs bound to monoclonal antibodies powerfully to form the luminescent labeled probes. Limit of detection and linear range of UPT-LF test card for serum PIVKA-II were 2.66 and 4.8–20,000 ng/ml, respectively. Test card had good 25 °C thermal and 4 °C validity period stability, 93.1%–99.2% of recovery rate, 2.6–5.8% and 5.4–8.9% of intra-assay and inter-assay CVs, and strong anti-interference ability for 8 common serum analytes. The sensitivity and specificity (vs LBL + HC group) of test card for HCC were 71.5% and 88.9%, respectively. The R2 between UPT-LF assay and CLEIA assay was 0.901. ConclusionsUPT-LF assay provides a reliable, rapid and convenient test for quantitative detection of serum PIVKA-II as well as diagnosis of HCC by a point of care testing way.

EPINETLAB: A Software for Seizure-Onset Zone Identification From Intracranial EEG Signal in Epilepsy.

The pre-operative workup of patients with drug-resistant epilepsy requires in some candidates the identification from intracranial EEG (iEEG) of the seizure-onset zone (SOZ), defined as the area responsible of the generation of the seizure and therefore candidate for resection. High-frequency oscillations (HFOs) contained in the iEEG signal have been proposed as biomarker of the SOZ. Their visual identification is a very onerous process and an automated detection tool could be an extremely valuable aid for clinicians, reducing operator-dependent bias, and computational time. In this manuscript, we present the EPINETLAB software, developed as a collection of routines integrated in the EEGLAB framework that aim to provide clinicians with a structured analysis pipeline for HFOs detection and SOZ identification. The tool implements an analysis strategy developed by our group and underwent a preliminary clinical validation that identifies the HFOs area by extracting the statistical properties of HFOs signal and that provides useful information for a topographic characterization of the relationship between clinically defined SOZ and HFO area. Additional functionalities such as inspection of spectral properties of ictal iEEG data and import and analysis of source-space magnetoencephalographic (MEG) data were also included. EPINETLAB was developed with user-friendliness in mind to support clinicians in the identification and quantitative assessment of HFOs in iEEG and source space MEG data and aid the evaluation of the SOZ for pre-surgical assessment.

WearLight: Toward a Wearable, Configurable Functional NIR Spectroscopy System for Noninvasive Neuroimaging.

Functional near-infrared spectroscopy (fNIRS) has emerged as an effective brain monitoring technique to measure the hemodynamic response of the cortical surface. Its wide popularity and adoption in recent time attribute to its portability, ease of use, and flexibility in multimodal studies involving electroencephalography. While fNIRS is still emerging on various fronts including hardware, software, algorithm, and applications, it still requires overcoming several scientific challenges associated with brain monitoring in naturalistic environments where the human participants are allowed to move and required to perform various tasks stimulating brain behaviors. In response to these challenges and demands, we have developed a wearable fNIRS system, WearLight that was built upon an Internet-of-Things embedded architecture for onboard intelligence, configurability, and data transmission. In addition, we have pursued detailed research and comparative analysis on the design of the optodes encapsulating an near-infrared light source and a detector into 3-D printed material. We performed rigorous experimental studies on human participants to test reliability, signal-to-noise ratio, and configurability. Most importantly, we observed that WearLight has a capacity to measure hemodynamic responses in various setups including arterial occlusion on the forearm and frontal lobe brain activity during breathing exercises in a naturalistic environment. Our promising experimental results provide an evidence of preliminary clinical validation of WearLight. This encourages us to move toward intensive studies involving brain monitoring.

Abstract LB-041: Novel platform to profile variants of uncertain significant (VUS) with preliminary retrospective clinical validation in non-small cell lung cancer (NSCLC)

Abstract Background: With the expanding usage of next generation sequencing (NGS) during treatment of NSCLC, an increasing number of variants of uncertain significance are being detected. Therefore, exists an urgent unmet need for a functional assay to reveal the significance of these findings both for naïve patients and those with acquired resistance to targeted therapy. We present feasibility data and retrospective clinical validation for a novel high-throughput cell-based assay (FACT) which profiles alterations by measuring downstream activation of signaling pathways to determine oncogenic grading and prioritize treatment with targeted therapies. Methods: Patients with NSCLC adenocarcinoma that underwent NGS test (tissue based/cell-free tumor DNA) were consented and enrolled. Alterations were profiled using the FACT platform to quantify oncogenic signaling activity and inhibition by targeted therapies. Patient outcomes were compared to in vitro drug sensitivities retrospectively. Results: 9 patients with NSCLC were analyzed using the FACT platform. 17 alterations were functionally profiled (EGFR - 12, ERBB2 - 2, BRAF - 1, PDGFRA - 1 and JAK2 - 1). 12 (70%) mutations were found to be oncogenic, 11 (65%) oncogenic alterations were in actionable genes (EGFR/ERBB2), 7 patients (78%) were treated with targeted therapies. 3 patients had uncommon double point mutations in EGFR profiled on the same DNA construct (cis) and separately (trans) showing distinct oncogenic profiles. Drug inhibition was measured with used targeted therapies and showed concordance with retrospective clinical responses. Conclusions: Functional profiling of alterations found in NSCLC is feasible through the FACT platform and can provide useful insights on the oncogenicity of uncommon variants. Profiling of drug sensitivity was successfully performed in the majority of patients and in vitro sensitivity correlated with observed clinical outcomes. Patient Characteristics-Molecular Profile-Treatment History-ResponsePT #AgeSexStageNGS SourceProfiled MutationsTreatment HistoryClinical Response to TKIs37534FIVTissueEGFR H773_V774insNPHcisplatin/pemetrexed/bevacizumabN/A37674FIVctDNAEGFR M277E/E282A,EGFR E282A,EGFR M277Eafatinibafatinib - no37749MIVTissueEGFR E709_T710&amp;gt;D,EGFR T790M,PDGFRA L379Vafatinib &amp;gt; mild progression of brain mets &amp;gt; addition of avastin and WBRT &amp;gt; T790M positive MAF .01% &amp;gt; osimertinib &amp;gt; progression in lung &amp;gt; osimertinib + afatinibafatinib - yes,osimertinib - no,afatinib+osimertinib - yes37866MIVTissueERBB2 A775_G776insYVMAcisplatin/pemetrexed/bevacizumab + maintenance &amp;gt; pemetrexed &amp;gt; pembrolizumab &amp;gt; afatinib toxicity/marginal response &amp;gt; trastuzumabafatinib - no39072MIVctDNABRAF N581SN/AN/A39133FIVMultipleERBB2 L755_E757&amp;gt;PKcisplatin/pemetrexed &amp;gt; trastuzumab &amp;gt; TDM1 &amp;gt; pembrolizumab &amp;gt; afatinibafatinib - ongoing39762FIVTissueEGFR H835L/L833V,EGFR H835L, EGFR L833V, JAK2 R374Kcisplatin/pemetrexed &amp;gt; afatinibafatinib - yes39866FIVTissueEGFR exon 19 Del (p.Glu746_Ala750delinsdel)osimertinibosimertinib - yes42957MIIaTissueEGFR L858R/A289V,EGFR A289VRLL Lobectomy &amp;gt; adjuvant cisplatin/vinorelbine &amp;gt; (recurrence) Brain metastasis &amp;gt; Surgery+RT &amp;gt; osimertinibosimertinib - yes Citation Format: Benjamin Miron, Gabi Tarcic, Oded Edelheit, Nitza Burck, Michael Vidne, Laila Roisman, Nir Peled. Novel platform to profile variants of uncertain significant (VUS) with preliminary retrospective clinical validation in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-041. doi:10.1158/1538-7445.AM2017-LB-041

Toward the Development of a Glucose Dehydrogenase-Based Saliva Glucose Sensor Without the Need for Sample Preparation.

Strict glycemic control is known to be a vital key in the management of diabetes mellitus (DM). However, traditional methods face limitations in their efficacy due to the pain and invasiveness of needle pricking which often discourages DM patients from performing the required number of tests per day. Saliva glucose (SG) sensing has long been considered a noninvasive alternative to blood glucose monitoring for diabetes management, however the sample preparation and sensor detection limit have been deemed as challenges to overcome. Herein, we describe a preliminary clinical validation of a disposable SG sensor without any requirement for sample preparation. The sensor utilizes glucose dehydrogenase flavine-adenine dinucleotide (GDH-FAD) in conjunction with disposable screen printed electrodes to measure glucose levels in saliva collected directly from 9 healthy subjects. Cyclic voltammetry and amperometric-time (Amp-it) assays were used to develop calibration curves and test subjects. Sensor calibration was performed using simulated saliva at 6.5 pH and 37ºC. The lower limit of detection was determined to be 0.11 mg/dL. A lag time of 15 minutes with a positive correlation between SG and BG levels was found, which agrees with literature results. The detected SG ranges from 2.38 to 3.40 mg/dL over a BG range of 90 to 143 mg/dL. This is the first reported use of measuring SG with GDH-FAD without prior sample preparation. Upon optimization, the sensor has the potential to serve as a supplement to blood glucose monitoring.

Preliminary Clinical Validation of a Differential Correction Method for Improving Measurement Accuracy in Noninvasive Measurement of Blood Glucose Using Near-Infrared Spectroscopy.

One of the main challenges in the noninvasive sensing of blood glucose by near-infrared (NIR) spectroscopy is the background variations from light source drift, sweating, and temperature change at the human-machine interface. In this paper, a differential correction method based on the spectra from the floating-reference position and measuring position is proposed to eliminate these spectral variations from background interferences. Its effectiveness was validated by invitro and invivo experiments in which the diffuse reflectance of intralipid solutions and human skin was collected at the source distances of 0.6 mm and 2 mm by the custom-built system with six super-luminescent emitting diodes (SLEDs) light source. The results showed that, for the invitro experiments of intralipid solutions, the coefficients of variations of diffuse reflectance decreased by 20.5% under all the six wavelengths after differential correction. For the invivo experiments of oral glucose tolerance tests (OGTTs), partial least squares (PLS) regression models between glucose concentrations and the diffuse reflectance from palm skin were built, and the root mean square error of cross validation (RMSECV) decreased by 38.0% on average after the differential correction. Further, the spectra of the oral water tolerance tests (OWTTs) were collected for correlation with glucose concentration in OGTTs, and their correlation coefficients (R) decreased by 35.0% on average after the differential correction. Therefore, this differential correction method based on the spectra from the floating-reference position and measuring position can weaken the influence of background variations on the NIR spectroscopy and has promising potential in invivo detection, especially for noninvasive blood glucose measurement.

Preliminary Clinical Validation of the UK English Version of the Acute Cystitis Symptom Score in UK English-speaking female population of Newcastle, Great Britain

Preliminary Clinical Validation of the UK English Version of the Acute Cystitis Symptom Score in UK English-speaking female population of Newcastle, Great Britain

Preliminary Clinical Validation of the UK English Version of the Acute Cystitis Symptom Score in UK English-speaking female population of Newcastle, Great Britain

Preliminary Clinical Validation of the UK English Version of the Acute Cystitis Symptom Score in UK English-speaking female population of Newcastle, Great Britain

Preliminary validation of an optimized algorithm for intraocular lens power calculation in keratoconus.

Purpose:This study aimed to evaluate the theoretical influence on intraocular lens power (PIOL) calculation of the use of keratometric approach for corneal power (Pc) calculation in keratoconus and to develop and validate an algorithm preliminarily to minimize this influence.Methods:Pc was calculated theoretically with the classical keratometric approach, the Gaussian equation, and the keratometric approach using a variable keratometric index (nkadj) dependent on r1c(Pkadj). Differences in PIOL calculations (ΔPIOL) using keratometric and Gaussian Pc values were evaluated. Preliminary clinical validation of a PIOL algorithm using Pkadj was performed in 13 keratoconus eyes.Results:PIOL underestimation was present if Pc was overestimated, and vice versa. Theoretical PIOL overestimation up to −5.6 D and −6.2 D using Le Grand and Gullstrand eye models was found for a keratometric index of 1.3375. If nkadj was used, maximal Δ PIOL was ±1.1 D, with most of the values ≤±0.6 D. Clinically, PIOL under- and over-estimations ranged from −1.1 to − 0.4 D. No statistically significant differences were found between PIOL obtained with Pkadj and Gaussian equation (P > 0.05).Conclusion:The use of the keratometric Pc for PIOL calculations in keratoconus can lead to significant errors that may be minimized using a Pkadj approach.

Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum κ and λ immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool.

Serum free light chains (FLC) are sensitive biomarkers used for the diagnosis and management of plasma cell dyscrasias, such as multiple myeloma (MM), and are central to clinical screening algorithms and therapy response criteria. We have developed a portable, near-patient, lateral-flow test (Seralite®) that quantitates serum FLC in 10 min, and is designed to eliminate sample processing delays and accelerate decision-making in the clinic. Assay interference, imprecision, lot-to-lot variability, linearity, and the utility of a competitive-inhibition design for the elimination of antigen-excess ('hook effect') were assessed. Reference ranges were calculated from 91 healthy donor sera. Preliminary clinical validation was conducted by retrospective analysis of sera from 329 patients. Quantitative and diagnostic results were compared to Freelite®. Seralite® gave a broad competitive-inhibition calibration curve from below 2.5 mg/L to above 200 mg/L, provided good assay linearity (between 1.6 and 208.7 mg/L for κ FLC and between 3.5 and 249.7 mg/L for λ FLC) and sensitivity (1.4 mg/L for κ FLC and 1.7 mg/L for λ FLC), and eliminated anomalous results from antigen-excess. Seralite® gave good diagnostic concordance with Freelite® (Roche Hitachi Cobas C501) identifying an abnormal FLC ratio and FLC difference in 209 patients with newly diagnosed MM and differentiating these patients from normal healthy donors with polyclonal FLC. Seralite® sensitively quantitates FLC and rapidly identifies clinical conditions where FLC are abnormal, including MM.

Preventive screening of colorectal cancer with a device based on chemoresistive sensors

Colorectal cancer is one of the widely diffused tumors. Despite its high curable rate, if diagnosed in its polyp state, an efficient screening method is highly desirable for preventing and decreasing deaths. Tumor biomarkers, emitted by the peroxidation of the cell membrane, may alter the composition of feces. We developed an array of chemoresistive sensors (both metal oxides and sulfides) capable of distinguishing between real stool samples of healthy subjects and of patients with colorectal cancer at diverse degeneration stages. Preliminary clinical validation of real samples was carried out. Results have shown the selectivity of the sensor array towards tumor affected and healthy subject samples. A quadratic discriminant analysis was performed, with a classification error of about 5%.

Ultrasound characterization of the mastoid for detecting middle ear effusion: A preliminary clinical validation.

Ultrasound detection of middle ear effusion (MEE) is an emerging technique in otolaryngology. This study proposed using ultrasound characterization of the mastoid to noninvasively measure MEE-induced mastoid effusion (ME) as a new strategy for determining the presence of MEE. In total, 53 patients were enrolled (Group I: normal, n = 20; Group II: proven MEE through both otoscopy and tympanometry, n = 15; Group III: patients with MEE having effusions observed during grommet surgery, n = 18). A 2.25-MHz delay-line transducer was used to measure backscattered signals from the mastoid. The Nakagami parameter was estimated using the acquired signals to model the echo amplitude distribution for quantifying changes in the acoustic structures of mastoid air cells. The median Nakagami parameter and interquartile range were 0.35 (0.34–0.37) for Group I, 0.39 (0.37–0.41) for Group II, and 0.43 (0.39–0.51) for Group III. The echo amplitude distribution observed for patients with MEE was closer to Rayleigh distribution than that without MEE. Receiver operating characteristic (ROC) curve analysis further revealed that the area under the ROC was 0.88, sensitivity was 72.73%, specificity was 95%, and accuracy was 81.13%. The proposed method has considerable potential for noninvasive and comfortable evaluation of MEE.

Quantitative CT Imaging of Ventral Hernias: Preliminary Validation of an Anatomical Labeling Protocol.

ObjectiveWe described and validated a quantitative anatomical labeling protocol for extracting clinically relevant quantitative parameters for ventral hernias (VH) from routine computed tomography (CT) scans. This information was then used to predict the need for mesh bridge closure during ventral hernia repair (VHR).MethodsA detailed anatomical labeling protocol was proposed to enable quantitative description of VH including shape, location, and surrounding environment (61 scans). Intra- and inter-rater reproducibilities were calculated for labeling on 18 and 10 clinically acquired CT scans, respectively. Preliminary clinical validation was performed by correlating 20 quantitative parameters derived from anatomical labeling with the requirement for mesh bridge closure at surgery (26 scans). Prediction of this clinical endpoint was compared with similar models fit on metrics from the semi-quantitative European Hernia Society Classification for Ventral Hernia (EHSCVH).ResultsHigh labeling reproducibilities were achieved for abdominal walls (±2 mm in mean surface distance), key anatomical landmarks (±5 mm in point distance), and hernia volumes (0.8 in Cohen’s kappa). 9 out of 20 individual quantitative parameters of hernia properties were significantly different between patients who required mesh bridge closure versus those in whom fascial closure was achieved at the time of VHR (p<0.05). Regression models constructed by two to five metrics presented a prediction with 84.6% accuracy for bridge requirement with cross-validation; similar models constructed by EHSCVH variables yielded 76.9% accuracy.SignificanceReproducibility was acceptable for this first formal presentation of a quantitative image labeling protocol for VH on abdominal CT. Labeling-derived metrics presented better prediction of the need for mesh bridge closure than the EHSCVH metrics. This effort is intended as the foundation for future outcomes studies attempting to optimize choice of surgical technique across different anatomical types of VH.

Improved black-blood imaging using DANTE-SPACE for simultaneous carotid and intracranial vessel wall evaluation.

The purpose of this study was to develop a three-dimensional black blood imaging method for simultaneously evaluating the carotid and intracranial arterial vessel walls with high spatial resolution and excellent blood suppression with and without contrast enhancement. The delay alternating with nutation for tailored excitation (DANTE) preparation module was incorporated into three-dimensional variable flip angle turbo spin echo (SPACE) sequence to improve blood signal suppression. Simulations and phantom studies were performed to quantify image contrast variations induced by DANTE. DANTE-SPACE, SPACE, and two-dimensional turbo spin echo were compared for apparent signal-to-noise ratio, contrast-to-noise ratio, and morphometric measurements in 14 healthy subjects. Preliminary clinical validation was performed in six symptomatic patients. Apparent residual luminal blood was observed in five (pre-contrast) and nine (post-contrast) subjects with SPACE and only two (post-contrast) subjects with DANTE-SPACE. DANTE-SPACE showed 31% (pre-contrast) and 100% (post-contrast) improvement in wall-to-blood contrast-to-noise ratio over SPACE. Vessel wall area measured from SPACE was significantly larger than that from DANTE-SPACE due to possible residual blood signal contamination. DANTE-SPACE showed the potential to detect vessel wall dissection and identify plaque components in patients. DANTE-SPACE significantly improved arterial and venous blood suppression compared with SPACE. Simultaneous high-resolution carotid and intracranial vessel wall imaging to potentially identify plaque components was feasible with a scan time under 6 min. Magn Reson Med 75:2286-2294, 2016. © 2015 Wiley Periodicals, Inc.