scholarly journals Translation of a Circulating microRNA Signature of Melanoma to a Novel Solid-Tissue Biomarker to Improve Diagnostic Accuracy and Reproducibility.

2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Currently, histopathology examination of excised skin lesions is considered the ‘gold standard’ for diagnosis of melanoma. Multiple studies have shown the low accuracy and reproducibility of this method, underscoring the urgent need for new diagnostic tools, including disease-specific biomarkers. Previously, a 38-microRNA signature of melanoma (‘Mel38’) was previously identified in plasma and validated as novel circulating biomarker. In this study, Mel38 expression in solid biopsy tissue is examined to determine its ability to contribute to accurate and reproducible melanoma diagnoses.Methods Nanostring digital gene expression profiling was used to apply the Mel38 signature in a cohort of 308 formalin fixed paraffin embedded skin biopsies (‘Mel38’). Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Mel38 classification scores (range 0 to 10) were compared to consensus histopathology results, including MPATH-DX class, AJCC disease stage, histological subtype as well as technical assay factors.Results The Mel38 score can identify high-risk melanomas (MPATH-Dx Class IV) from less-malignant forms of the disease with an area-under-the curve of 0.96 (P < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with the melanoma progression, from benign naevi to metastatic disease (intraclass correlation coefficient: 0.85). Using a score threshold of > 2.3 identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Analysis of the Mel38 signature in spitz naevi reveal an intra-subtype profile, in common to both benign and malignant conditions.Conclusion Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The Mel38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the Mel38 score into routine practice would give physicians a genomic assessment of a patient’s disease status. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, reproducibility, and patient outcomes.

2020 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Currently, histopathology examination of excised skin lesions is considered the ‘gold standard’ for diagnosis of melanoma. Multiple studies have shown the low accuracy and reproducibility of this method, underscoring the urgent need for new diagnostic tools, including disease-specific biomarkers. Previously, a 38-microRNA signature of melanoma (‘Mel38’) was previously identified in plasma and validated as novel circulating biomarker. In this study, Mel38 expression in solid biopsy tissue is examined to determine its ability to contribute to accurate and reproducible melanoma diagnoses. Methods Nanostring digital gene expression profiling was used to apply the Mel38 signature in a cohort of 308 formalin fixed paraffin embedded skin biopsies (‘Mel38’). Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Mel38 classification scores (range 0 to 10) were compared to consensus histopathology results, including MPATH-DX class, AJCC disease stage, histological subtype as well as technical assay factors. Results The Mel38 score can identify high-risk melanomas (MPATH-Dx Class IV) from less-malignant forms of the disease with an area-under-the curve of 0.96 (P < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with the melanoma progression, from benign naevi to metastatic disease (intraclass correlation coefficient: 0.85). Using a score threshold of > 2.3 identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Analysis of the Mel38 signature in spitz naevi reveal an intra-subtype profile, in common to both benign and malignant conditions. Conclusion Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The Mel38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the Mel38 score into routine practice would give physicians a genomic assessment of a patient’s disease status. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, reproducibility, and patient outcomes.


2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-microRNA signature (“MEL38”) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign naevi to metastatic melanoma spectrum is examined. Methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin fixed paraffin embedded biopsies of naevi, melanoma in-situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate, and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analysed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx Class V or more advanced) from lower-risk skin lesions (Class I-IV) with an area-under-the curve of 0.97 (P<0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0 to IV disease. Using an optimised classification threshold of ≥2.7 accurately identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to spitz naevi reveal an intra-subtype profile, with elements of the profile in common to both naevi and melanoma. Conclusion: Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalised genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilisation, and patient outcomes.


2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-microRNA signature (“MEL38”) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign naevi to metastatic melanoma spectrum is examined. Methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin fixed paraffin embedded biopsies of naevi, melanoma in-situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate, and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analysed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx Class V or more advanced) from lower-risk skin lesions (Class I-IV) with an area-under-the curve of 0.97 (P<0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0 to IV disease. Using an optimised classification threshold of ≥2.7 accurately identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to spitz naevi reveal an intra-subtype profile, with elements of the profile in common to both naevi and melanoma. Conclusion: Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalised genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilisation, and patient outcomes.


2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-microRNA signature (“Mel38”) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, Mel38 expression in solid tissue biopsies representing the benign naevi to metastatic melanoma spectrum is examined. Methods: Nanostring digital gene expression assessment of the Mel38 signature was performed on 308 formalin fixed paraffin embedded biopsies of naevi, melanoma in-situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate, and multivariate statistical approaches. Classification scores computed from the Mel38 signature were analysed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The Mel38 score can stratify higher-risk melanomas (MPATH-Dx Class V or more advanced) from lower-risk skin lesions (Class I-IV) with an area-under-the curve of 0.97 (P<0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0 to IV disease. Using an optimised classification threshold of ≥2.7 accurately identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the Mel38 signature to spitz naevi reveal an intra-subtype profile, with elements of the profile in common to both naevi and melanoma. Conclusion: Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The Mel38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the Mel38 score into routine practice would provide physicians with previously unavailable, personalised genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilisation, and patient outcomes.


2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Abstract Background: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-microRNA signature (“Mel38”) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, Mel38 expression in solid tissue biopsies representing the benign naevi to metastatic melanoma spectrum is examined. Methods: Nanostring digital gene expression assessment of the Mel38 signature was performed on 308 formalin fixed paraffin embedded biopsies of naevi, melanoma in-situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate, and multivariate statistical approaches. Classification scores computed from the Mel38 signature were analysed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The Mel38 score can stratify higher-risk melanomas (MPATH-Dx Class V or more advanced) from lower-risk skin lesions (Class I-IV) with an area-under-the curve of 0.96 (P<0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0 to IV disease. Using an optimised classification threshold of ≥2.3 accurately identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions with 95% sensitivity and 83% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the Mel38 signature to spitz naevi reveal an intra-subtype profile, with elements of the profile in common to both naevi and melanoma. Conclusion: Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The Mel38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the Mel38 score into routine practice would provide physicians with previously unavailable, personalised genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilisation, and patient outcomes.


2021 ◽  
Author(s):  
Ryan Van Laar ◽  
Samuel King ◽  
Richard McCoy ◽  
Mirette Saad ◽  
Sian Fereday ◽  
...  

Aim: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-miRNA signature (MEL38) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign nevi to metastatic melanoma spectrum is examined. Patients & methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin-fixed paraffin-embedded biopsies of nevi, melanoma in situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analyzed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx class V or more advanced) from lower-risk skin lesions (class I–IV) with an area under the curve of 0.97 (p < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0–IV disease. Using an optimized classification threshold of ≥2.7 accurately identifies higher-risk melanomas with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to Spitz nevi reveals an intrasubtype profile, with elements in common to both nevi and melanoma. Conclusion: Melanoma-specific circulating miRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in miRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalized genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilization and patient outcomes.


2019 ◽  
Author(s):  
Uwimaana Esther ◽  
Bernard S Bagaya ◽  
Barbara Castelnuovo ◽  
David P Kateete ◽  
Anguzu Godwin ◽  
...  

Abstract Background: Tuberculosis(TB) diagnosis in the presence of HIV co-infection remains challenging. Heme oxygenase 1(HO-1) and neopterin have been validated as potential biomarkers for TB diagnosis. Infection of macrophages with Mycobacterium tuberculosis (M .tb ) causes the production of HO-1 and neopterin and previous studies have shown these to be markers of immune activation. This study was conducted to determine the levels of HO-1 and neopterin and their utility in the diagnosis of TB among individuals enrolled in the Community Health and Social Network of Tuberculosis(COHSONET) study and the Kampala TB Drug Resistance Survey(KDRS). Methods: A total of 210 participants were enrolled in a study of a diagnostic method aimed at determining the levels of HO-1 and neopterin and determine their diagnostic accuracy as biomarkers in TB diagnosis from March to May 2019. M. tb culture was performed on sputum to confirm active TB(ATB) and QuantiFERON TB gold test to confirm latent TB infection(LTBI). ELISAs were performed to determine the levels of HO-1 and neopterin. Data analysis was done using Kruskal Wallis and Receiver Operating Characteristic curves to determine the diagnostic accuracy. Results: HO-1 levels among ATB/HIV patients, LTBI/HIV patients and TB negative individuals were 10.7ng/ml (IQR: 7.3-12.7ng/ml), 7.5ng/ml (IQR: 5.4-14.1ng/ml), 3.3ng/ml (IQR: 2.0-7.1ng/ml) respectively. Neopterin levels among ATB/HIV patients, LTBI/HIV patients and TB negative individuals were 11.7ng/ml (IQR: 5.219.4ng/ml), 8.8ng/ml (IQR: 2.4-19.8ng/ml), and 5.9ng/ml (IQR: 3.410.2ng/ml) respectively. HO-1 showed a sensitivity of 78.57% and a specificity of 71.43% with area under the curve(AUC) of 0.839 when used to diagnose ATB. HO-1 showed AUC of 0.79, sensitivity of 70% and specificity 70% when used to diagnose LTB. Neopterin showed a sensitivity of 61.43% and a specificity of 74.29% with AUC 0.71 when used to diagnose ATB. Neopterin as a biomarker in LTB diagnosis showed AUC of 0.56 which was not significant. Conclusion: HO-1 and neopterin are valuable diagnostic biomarkers for ATB and LTB which could be further utilized to develop less costly rapid diagnostic tools to overcome current TB diagnostic challenges.


2019 ◽  
Vol 62 (10) ◽  
pp. 3643-3654
Author(s):  
In-Ho Bae ◽  
Soo-Geun Wang ◽  
Soon-Bok Kwon ◽  
Seong-Tae Kim ◽  
Eui-Suk Sung ◽  
...  

Purpose The purpose of this study was to investigate the characteristics of diplophonia using an auditory perception and multimodal simultaneous examination, which included sound waveform analysis, electroglottography (EGG), digital kymography (DKG), and 2-dimensional scanning digital kymography (2D DKG). Additionally, we compared the diagnostic accuracy of each method using a binary classifier in confusion matrix and convenience of discrimination, based on the time required for interpretation. Method One normophonic male, 12 patients with diplophonia, and 12 dysphonia patients without diplophonia were enrolled. A multimodal simultaneous evaluation was used to analyze the vibration pattern of diplophonia. Sensitivity, specificity, accuracy, area under the curve, and interpretation time were used to compare the various diagnostic methods. Discrimination was determined by 3 raters. Results There are 3 types of asymmetric vibratory patterns in diplophonia. The types are based on the oscillators vibrating at different frequencies: asymmetry of the left and right cords (6 subjects with unilateral palsy and 1 subject with vocal polyps), asymmetry of anterior and posterior cords (2 subjects with vocal polyps), and asymmetry of true and false cords (3 subjects with muscle tension dysphonia). All evaluation methods were useful as diagnostic tools, with all areas under the curve > .70. The diagnostic accuracy was highest with DKG (95.83%), followed by 2D DKG (83.33%), EGG (81.94%), auditory-perceptual evaluation (80.56%), and sound waveform (77.78%). The interpretation time was the shortest for auditory-perceptual evaluation (6.07 ± 1.34 s), followed by 2D DKG (10.04 ± 3.00 s), EGG (12.49 ± 2.76 s), and DKG (13.53 ± 2.60 s). Conclusions Auditory-perceptual judgment was the easiest and fastest method for experienced raters, but its diagnostic accuracy was lower than that of DKG or 2D DKG. The diagnostic accuracy of DKG was the highest, but 2D DKG allowed rapid interpretation and showed relatively high diagnostic accuracy, except in cases with space-occupying lesions. Supplemental Material https://doi.org/10.23641/asha.9911786


2015 ◽  
Vol 28 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Claire Bamford ◽  
Kirsty Olsen ◽  
Chris Davison ◽  
Nicky Barnett ◽  
Jim Lloyd ◽  
...  

ABSTRACTBackground:Positron emission tomography (PET) and single photon emission computed tomography (SPECT) brain imaging are widely used as diagnostic tools for suspected dementia but no studies have directly compared participant views of the two procedures. We used a range of methods to explore preferences for PET and SPECT.Methods:Patients and controls (and accompanying carers) completed questionnaires immediately after undergoing PET and SPECT brain scans. Pulse rate data were collected during each scan. Scan attributes were prioritized using a card sorting exercise; carers and controls additionally answered willingness to pay (WTP) questions.Results:Few differences were found either between the scans or groups of participants, although carers marginally preferred SPECT. Diagnostic accuracy was prioritized over other scan characteristics. Mean heart rate during both scans was lower than baseline heart rate measured at home (p < 0.001).Conclusion:Most participants viewed PET and SPECT scans as roughly equivalent and did not have a preference for either scan. Carer preference for SPECT is likely to reflect their desire to be with the patient (routine practice for SPECT but not for PET), suggesting that they should be able to accompany vulnerable patients throughout imaging procedures wherever possible. Pulse rate data indicated that brain imaging was no more stressful than a home visit (HV) from a researcher. The data do not support the anecdotal view that PET is a more burdensome procedure and the use of PET or SPECT scans in dementia should be based on diagnostic accuracy of the technique.


VASA ◽  
2019 ◽  
Vol 48 (6) ◽  
pp. 516-522 ◽  
Author(s):  
Verena Mayr ◽  
Mirko Hirschl ◽  
Peter Klein-Weigel ◽  
Luka Girardi ◽  
Michael Kundi

Summary. Background: For diagnosis of peripheral arterial occlusive disease (PAD), a Doppler-based ankle-brachial-index (dABI) is recommended as the first non-invasive measurement. Due to limitations of dABI, oscillometry might be used as an alternative. The aim of our study was to investigate whether a semi-automatic, four-point oscillometric device provides comparable diagnostic accuracy. Furthermore, time requirements and patient preferences were evaluated. Patients and methods: 286 patients were recruited for the study; 140 without and 146 with PAD. The Doppler-based (dABI) and oscillometric (oABI and pulse wave index – PWI) measurements were performed on the same day in a randomized cross-over design. Specificity and sensitivity against verified PAD diagnosis were computed and compared by McNemar tests. ROC analyses were performed and areas under the curve were compared by non-parametric methods. Results: oABI had significantly lower sensitivity (65.8%, 95% CI: 59.2%–71.9%) compared to dABI (87.3%, CI: 81.9–91.3%) but significantly higher specificity (79.7%, 74.7–83.9% vs. 67.0%, 61.3–72.2%). PWI had a comparable sensitivity to dABI. The combination of oABI and PWI had the highest sensitivity (88.8%, 85.7–91.4%). ROC analysis revealed that PWI had the largest area under the curve, but no significant differences between oABI and dABI were observed. Time requirement for oABI was significantly shorter by about 5 min and significantly more patients would prefer oABI for future testing. Conclusions: Semi-automatic oABI measurements using the AngER-device provide comparable diagnostic results to the conventional Doppler method while PWI performed best. The time saved by oscillometry could be important, especially in high volume centers and epidemiologic studies.


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