scholarly journals Translation of a circulating microRNA signature of melanoma into a solid tissue assay with the potential to improve diagnostic precision 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. 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 ◽  
...  

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 ◽  
...  

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.


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.


2020 ◽  
Vol 10 (1) ◽  
pp. 17
Author(s):  
Iris Wohlmuth-Wieser ◽  
Joel M. Ramjist ◽  
Neil Shear ◽  
Raed Alhusayen

The diagnosis of cutaneous T-cell lymphomas (CTCL) is frequently delayed by a median of three years and requires the clinical evaluation of an experienced dermatologist and a confirmatory skin biopsy. Dermoscopy and high-frequency ultrasound (HFUS) represent two non-invasive diagnostic tools. While dermoscopy is inexpensive and widely used for the diagnosis of melanoma and non-melanoma skin cancers, HFUS of skin lymphomas represents a novel diagnostic approach that is not yet implemented in the routine dermatologic practice. The aim of our study was to prospectively assess skin lesions of patients with either CTCL patches or plaques with dermoscopy and HFUS and to compare the findings with atopic dermatitis (AD) and psoriasis. Thirteen patients with an established diagnosis of CTCL, psoriasis, or AD were studied: Dermoscopy features including spermatozoa-like structures and the presence of white scales could assist in differentiating between early-stage CTCL and AD. HFUS measurements of the skin thickness indicated increased epidermal-, thickness in CTCL, and psoriasis compared with AD. Our results support the use of dermoscopy as a useful tool to diagnose CTCL. HFUS could augment the dermatologic assessment, but further studies will be needed to define standardized parameters.


2021 ◽  
Vol 105 (1) ◽  
pp. 254-260
Author(s):  
Gédéon Prince Manouana ◽  
Natalie Byrne ◽  
Mirabeau Mbong Ngwese ◽  
Alvyn Nguema Moure ◽  
Philipp Hofmann ◽  
...  

Abstract.Diarrheal disease is the second most frequent cause of mortality in children younger than 5 years worldwide, causing more than half a million deaths each year. Our knowledge of the epidemiology of potentially pathogenic agents found in children suffering from diarrhea in sub-Saharan African countries is still patchy, and thereby hinders implementation of effective preventative interventions. The lack of cheap, easy-to-use diagnostic tools leads to mostly symptomatic and empirical case management. An observational study with a total of 241 participants was conducted from February 2017 to August 2018 among children younger than 5 years with diarrhea in Lambaréné, Gabon. Clinical and demographic data were recorded, and a stool sample was collected. The samples were examined using a commercial rapid immunoassay to detect Rotavirus/adenovirus, conventional bacterial culture for Salmonella spp., and multiplex real-time PCR for Cryptosporidium spp., Giardia lamblia, Cyclospora cayetanensis, enterotoxigenic Escherichia coli (ETEC), and enteroinvasive Escherichia coli (EIEC)/Shigella. At least one infectious agent was present in 121 of 241 (50%) samples. The most frequently isolated pathogens were EIEC/Shigella and ETEC (54/179; 30.2% and 44/179; 24.6%, respectively), followed by G. lamblia (33/241; 13.7%), Cryptosporidium spp. (31/241; 12.9%), and Rotavirus (23/241; 9.5%). Coinfection with multiple pathogens was observed in 33% (40/121) of the positive cases with EIEC/Shigella, ETEC, and Cryptosporidium spp. most frequently identified. Our results provide new insight into the possible causes of diarrheal disease in the Moyen-Ogooué region of Gabon and motivate further research on possible modes of infection and targeted preventive measures.


2020 ◽  
Vol 6 (4) ◽  
pp. e179-e182
Author(s):  
Jacob Goodwin ◽  
Samuel Ives ◽  
Hiba Hashmi

Objective: Sweet syndrome (SS) is characterized by an inflammatory rash that has been associated with a number of drugs and malignant, inflammatory, and infectious conditions. Rare accounts of Hashimoto thyroiditis (HT) presenting with SS exist in the literature. HT is usually identified after the onset of skin lesions and without signs of overt thyroid dysfunction, and the stage of thyroid disease stage at presentation is variable. Methods: A search of the PubMed database was performed using search criteria involving combinations of “Sweet syndrome” and “Hashimoto thyroiditis,” “autoimmune thyroiditis,” or “thyroiditis,” and the search was filtered for clinical case reports. Five case reports were identified to describe the coexistence of Sweet syndrome and Hashimoto thyroiditis, and full-text versions of these reports were obtained and reviewed. Of note, cases involving subacute or other types of thyroiditis were excluded. Results: A 57-year-old man presented with painful eruptions on his hands; he was initially treated with antibiotics for presumed cellulitis without relief. Skin biopsy later confirmed SS and subsequent workup identified underlying HT with an elevated thyroid-stimulating hormone of 19.24 mU/L (normal, 0.30 to 4.30 mU/L) and positive thyroid peroxidase (TPO) antibody at 236.4 IU/mL. Conclusion: Thyroid function tests should be universally evaluated in the workup of SS, and it may be appropriate to test for TPO antibodies even in the absence of objective thyroid dysfunction. Both SS and HT show immune diathesis, so further work should be undertaken to establish whether a common immunologic trigger exists.


2021 ◽  
Author(s):  
Rowida A. Albarmaqi ◽  
Yi-Qun Kuang ◽  
Yu-Ye Li ◽  
Noha Saleh Gholais

Abstract Background: Khat chewing is a routine practice in Yemen. Associations between Khat chewing and various adverse oral-dental health conditions have been recorded, however, adverse skin health evidence is still lacking. Objective: To investigate the difference between oral and skin symptoms and signs while chewing Khat and after quitting chewing among Yemeni khat abusers. Method: A descriptive cross-sectional study was conducted on a sample of 300 Yemeni Khat ex-chewer participants in china. Khat chewing status data, a range of oral and skin symptoms and signs, and other pertinent variables were collected using self-administered questionnaires by WeChat. The mean differences between oral and skin symptoms and signs while chewing Khat and after quitting chewing were investigated using the Paired Samples t-test. Result: Of the 300 Yemeni who participated in the study, 255(85%) were men and 45(15%) were women. The oral symptoms and signs mean while chewing was 0.26, 0.022 (standard deviation [SD], whereas that after quitting chewing Khat was 0.10 (mean), 0.269 (standard deviation [SD], t (12.00), P=0.00. The skin symptoms and signs mean while chewing was 0.13, 0.28 (standard deviation [SD], whereas that after quitting chewing Khat was M=0.06, 0.21(standard deviation [SD], t (9.407), P=0.00. Conclusions: There is a statistically significant difference between the mean oral and skin symptoms and signs while chewing and after quitting, whereas long-term Khat chewing negatively affects oral and skin health.


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