Summary
Background
Even though progress has been made, the detection of melanoma still poses a challenge. In light of this situation, the Nevisense electrical impedance spectroscopy (EIS) system ...(SciBase AB, Stockholm, Sweden) was designed and shown to have the potential to be used as an adjunct diagnostic tool for melanoma detection.
Objectives
To assess the effectiveness and safety of the Nevisense system in the distinction of benign lesions of the skin from melanoma with electrical impedance spectroscopy.
Methods
This multicentre, prospective, and blinded clinical study was conducted at five American and 17 European investigational sites. All eligible skin lesions in the study were examined with the EIS‐based Nevisense system, photographed, removed by excisional biopsy and subjected to histopathological evaluation. A postprocedure clinical follow‐up was conducted at 7 ± 3 days from the initial measurement. A total of 1951 patients with 2416 lesions were enrolled into the study; 1943 lesions were eligible and evaluable for the primary efficacy end point, including 265 melanomas – 112 in situ and 153 invasive melanomas with a median Breslow thickness of 0·57 mm 48 basal cell carcinomas (BCCs) and seven squamous cell carcinomas (SCCs).
Results
The observed sensitivity of Nevisense was 96·6% (256 of 265 melanomas) with an exact one‐sided 95% lower confidence bound estimated at 94·2% and an observed specificity of 34·4%, and an exact two‐sided 95% confidence bound estimated at 32·0–36·9%. The positive and negative predictive values of Nevisense were 21·1% and 98·2%, respectively. The observed sensitivity for nonmelanoma skin cancer was 100% (55 of 48 BCCs and seven SCCs) with an exact two‐sided 95% confidence bound estimated at 93·5–100·0%.
Conclusions
Nevisense is an accurate and safe device to support clinicians in the detection of cutaneous melanoma.
What's already known about this topic?
Although progress has been made in the detection of melanoma it still poses a challenge.
Electrical impedance spectroscopy (EIS) may potentially be used as a diagnostic aid for the detection of melanoma.
What does this study add?
In the largest international prospective study of its kind in melanoma detection, the EIS system Nevisense was shown to be both accurate and safe in the lesion cohort studied.
In the absence of a perfect gold standard, the accuracy of a device should be compared with the consensus diagnosis from multiple experts.
Summary
Background
The diagnostic criteria for basal cell carcinoma (BCC) using optical coherence tomography (OCT) have been described previously, but the clinical value of these findings remains ...unknown.
Objectives
To investigate the diagnostic value of OCT for BCC in a typical clinical setting. The primary efficacy end point was a diagnosis of BCC for each lesion. Secondary end points were the diagnosis of other possible conditions.
Methods
This was an observational, prospective, multicentre study in which consecutive patients with nonpigmented pink lesions suspicious for BCC underwent clinical assessment, dermoscopy and OCT, with the diagnosis recorded at each stage. Once all diagnoses had been recorded, the histological results were disclosed. In total 164 patients with 256 lesions were recruited. Histology was missing for 21 lesions, leaving 235 lesions in 155 patients for analysis.
Results
Sixty per cent of lesions (141 of 235) were identified as BCC by histology. A slight increase of sensitivity was noted following OCT, which did not reach statistical significance. The specificity increased significantly from 28·6% by clinical assessment to 54·3% using dermoscopy and to 75·3% with the addition of OCT (P < 0·001). The positive predictive value for the diagnosis of BCC using OCT was 85·2% 95% confidence interval (CI) 78·6–90·4, and the negative predictive value was 92·1% (95% CI 83·6–97·0). The accuracy of diagnosis for all lesions increased from 65·8% with clinical evaluation to 76·2% following additional dermoscopy and to 87·4% with the addition of OCT.
Conclusions
OCT significantly improved the diagnostic specificity for BCC compared with clinical assessment and dermoscopy alone.
What's already known about this topic?
The diagnostic criteria of basal cell carcinoma (BCC) by optical coherence tomography (OCT) have previously been defined.
Recent studies have also described the OCT criteria of actinic keratoses.
What does this study add?
The results of this study support the additional diagnostic value of OCT for the diagnosis of pink patches.
The diagnostic specificity for BCC may be increased by the use of OCT.
Summary
Background
We previously described the principal results from an observational, prospective, multicentre, clinical trial of the diagnostic value of optical coherence tomography (OCT) for ...basal cell carcinoma (BCC) in a clinical setting. In this trial, much additional useful information was gathered that warranted further analysis, presented here.
Objectives
To investigate the influence of candidate diagnostic criteria, OCT image quality, lesion location, and observer confidence and interobserver variability on the diagnostic performance of OCT, and to assess its potential use for diagnosis of BCC subtypes.
Methods
A total of 234 clinically unclear ‘pink lesions’ were evaluated in three steps: after clinical examination, after adding dermoscopy and after adding OCT. In addition to the diagnoses (including lesion subtype), observers recorded which of 15 diagnostic criteria the OCT image contained, their confidence in the diagnoses, the OCT image quality and the anatomical location of the lesion.
Results
Diagnostic performance of OCT did not depend on the lesion's anatomical location. Good OCT image quality was correlated with improved diagnostic performance, but diagnostic performance for lesions with mediocre image quality was still better than by clinical and dermoscopic examination. The main reason for reduced image quality was superficial scales and crusting. Observer confidence in diagnosis was correlated with diagnostic performance. Interobserver diagnostic performance was consistently higher than clinical examination and dermoscopy across all sites. BCC subtype could be determined with moderate accuracy, but further independent image markers are required.
Conclusion
OCT is useful in the diagnosis of BCC.
What's already known about this topic?
Optical coherence tomography (OCT) is an emerging imaging modality that has been shown to have utility in the noninvasive diagnosis of basal cell carcinoma (BCC), and is more sensitive and more specific than clinical or dermoscopic examination alone.
What does this study add?
Lesion location does not affect diagnostic performance with OCT.
Poor OCT image quality is associated with superficial scales and crusting, reducing diagnostic performance, but in these cases diagnosis with OCT is better than by clinical or dermoscopy examination alone.
Observers’ diagnostic confidence increases when using OCT and their performance reflects this.
Diagnostic performance is consistent between trained observers.
BCC subtype can be diagnosed from OCT images with moderate accuracy.
Linked Editorial: Rossi et al. Br J Dermatol 2018; 178:994–996.
Plain language summary available online
Respond to this article
Summary
Background
Multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun‐damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective ...therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial.
Objectives
To evaluate the efficacy, safety and cosmetic outcome of BF‐200 ALA (a nanoemulsion formulation containing 10% aminolaevulinic acid hydrochloride) combined with the BF‐RhodoLED® lamp for the field‐directed treatment of mild‐to‐moderate AK with PDT.
Methods
The study was performed as a randomized, multicentre, double‐blind, placebo‐controlled, parallel‐group, phase III trial with BF‐200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF‐200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF‐RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm−2 was achieved.
Results
BF‐200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority” should not be skipped since this is an important result. Treatment‐emergent adverse events (TEAEs) were experienced by 100% of the BF‐200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF‐200 ALA group compared with placebo.
Conclusions
Field‐directed therapy with BF‐200 ALA and BF‐RhodoLED lamp is highly effective and well tolerated for multiple mild‐to‐moderate AK lesions, providing greatly improved skin quality.
What's already known about this topic?
BF‐200 ALA is an exceptionally effective, well‐tolerated drug for photodynamic therapy (PDT) of actinic keratosis (AK).
AK affects extended skin areas and requires field‐directed treatment.
PDT with BF‐200 ALA is most effective with narrowband light‐emitting diode lamps.
What does this study add?
This study evaluates the safety and efficacy of BF‐200 ALA when used together with the BF‐RhodoLED lamp for the field‐directed treatment of AK.
This trial demonstrates a strong rejuvenation effect of PDT with BF‐200 ALA on an entire treatment field.
Our results show that field‐directed therapy with BF‐200 ALA and BF‐RhodoLED lamp is highly effective and well tolerated for multiple mild‐to‐moderate AK lesions.
Linked Comment: Gilaberte. Br J Dermatol 2016; 175:668–669.
Plain language summary available online
Summary
Background
Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair‐skinned individuals. The World Health Organization ...distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC.
Objectives
To demonstrate noninferiority of BF‐200 ALA (a nanoemulsion gel containing 5‐aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF‐200 ALA was no worse than that for MAL, within a statistical margin of Δ = −15%.
Methods
The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5‐year follow‐up. Of 281 randomized patients, 138 were treated with BF‐200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm−2). The results shown include clinical end points and patients’ reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013‐003241‐42).
Results
Of the BF‐200 ALA‐treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one‐sided 97·5% confidence interval of −6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%.
Conclusions
Treatment of nonaggressive BCC with BF‐200 ALA‐PDT is highly effective and well tolerated with proven noninferiority to MAL‐PDT. It demonstrates low recurrence rates after 1 year of follow‐up.
What's already known about this topic?
Photodynamic therapy (PDT) using BF‐200 aminolaevulinic acid (ALA) gel is registered and highly effective in the treatment of mild‐to‐moderate actinic keratosis and field cancerization.
BF‐200 ALA gel was recently approved for the treatment of superficial and/or nodular basal cell carcinoma (BCC) unsuitable for surgical treatment.
PDT using methyl aminolaevulinate (MAL) cream is approved for the treatment of thin or nonhyperkeratotic and nonpigmented actinic keratoses, Bowen disease, and superficial and nodular BCCs when other therapies are considered less appropriate.
What does this study add?
BF‐200 ALA‐PDT is confirmed to be significantly noninferior to MAL‐PDT for the treatment of nonaggressive BCC.
Treatment‐emergent adverse events were comparable between the two patient groups, with similar or slightly lower recurrence rates for BF‐200 ALA gel compared with MAL cream after 12 months.
Plain language summary available online
Respond to this article
Background
As an in situ carcinoma, actinic keratoses should be treated early. Previous studies on the efficacy of a low‐dose 0.5% 5‐fluorouracil solution in combination with 10% salicylic acid ...(low‐dose 5‐FU/SA) are mostly related to lesions appearing on the head and face. In contrast, actinic keratoses (AK) lesions of the upper extremities are considered to be difficult to treat.
Objective
The efficacy of low‐dose 5‐FU/SA in the treatment of actinic keratoses on the hands and/or forearms was studied for the first time in this non‐interventional study (NIS) under practical conditions in a large patient population. In addition to the clinical course during therapy and a follow‐up period, the length of application and adherence were documented.
Methods
As part of this NIS, 649 patients with AK were treated at 207 centres with low‐dose 5‐FU/SA. The data of the study were recorded at baseline, optionally during an intermediate examination, at the end of therapy and during a final assessment.
Results
The average number of AK lesions decreased during the entire observation period by 92%. Side‐effects were documented only rarely in the form of local skin reactions (2%). The attending physicians assessed the efficacy, tolerability and safety of the therapy as being predominantly very good or good (in each case ≥90%).
Conclusion
AK lesions on the hands and/or forearms were effectively treated with low‐dose 5‐FU/SA under routine conditions in dermatological practice and the treatment was well tolerated.
Background To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. Objectives This phase I, multicentre, single-arm, ...open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. Methods Patients (n = 108) aged greater than or equal to 18 years with histologically confirmed AK within a 25-cm super(2) contiguous treatment area on the trunk and extremities received ingenol mebutate 0.05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8. Results The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81.9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72.9% and 81.4%, respectively. Overall, 30 patients (27.8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3.7%) was the most common treatment-related AE inside the treatment area. Conclusions Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance. What's already known about this topic? * Ingenol mebutate treats the deeper layers of the epidermis and the observed clinical clearance is not just a superficial effect. What does this study add?* This study confirms that clinical clearance correlates with histopathological clearance. * Agreement between reflectance confocal microscopy and histopathological diagnosis of clear skin was high, indicating that diagnosis of clearance using reflectance confocal microscopy may preclude the need for histopathological assessment and invasive biopsies. Linked Comment: Rivers. Br J Dermatol 2017; 176:8-9 . Plain language summary available online
Background
Actinic keratosis (AK) is a common skin disorder that can progress to invasive squamous‐cell carcinoma. AK can present as clinical (visible) or subclinical (invisible) lesions within areas ...of chronic sun damage. The importance of treating subclinical AK is gaining support. We present a subanalysis of a previously published Phase III, double‐blind, vehicle‐controlled study (NCT02289768), to assess 5‐fluorouracil (5‐FU) 0.5%/salicylic acid 10% treatment of subclinical AK lesions, based on reflectance confocal microscopy (RCM).
Objective
To determine the efficacy of 5‐FU 0.5%/salicylic acid 10% as field‐directed treatment for subclinical AK lesions using RCM.
Methods
For inclusion in this subanalysis, patients had to have at least three subclinical AK lesions within a 25 cm2 area of skin. Subclinical AK lesions were diagnosed according to the presence of three key RCM criteria: architectural disarray; keratinocyte atypia and pleomorphism at the basal, spinous and granular layer. Subclinical AK lesions were evaluated by RCM at baseline, after 4, 6 and 12 weeks of 5‐FU 0.5%/salicylic acid 10% treatment or vehicle, and 8 weeks following the end of treatment.
Results
Twenty‐seven patients were included: 17 mean age = 72.2 years, standard deviation (SD) = 6.3 received 5‐FU 0.5%/salicylic acid 10% treatment and 10 (mean age = 76.4 years, SD = 3.9) received vehicle. Eight weeks following the end of treatment, the mean number of subclinical lesions declined (from 3.0 at baseline) to 0.3 (95% confidence interval CI 0.06–0.57) for the 5‐FU 0.5%/salicylic acid 10% group and 1.6 (95% CI 0.52–2.68) in the vehicle group (reductions of 90% 95% CI 72.1–107.1 vs. 47% 95% CI 24.8–69.5, respectively; P = 0.005). The proportion of patients receiving 5‐FU 0.5%/salicylic acid 10% showing complete clearance of three preselected subclinical AK lesions was numerically greater than in the vehicle group (69% vs. 40%, respectively; P = 0.183).
Conclusion
To the best of our knowledge, this is the first randomized, vehicle‐controlled study investigating 5‐FU 0.5%/salicylic acid 10% treatment for subclinical AK lesions. The present data suggest some treatment efficacy for subclinical AK lesions detected using RCM. However, this subanalysis was not sufficiently powered and should be reproduced in a larger, subsequent cohort.
Summary
Background
To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint.
Objectives
This phase I, multicentre, ...single‐arm, open‐label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis.
Methods
Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25‐cm2 contiguous treatment area on the trunk and extremities received ingenol mebutate 0·05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8.
Results
The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8‐week complete clearance rate was 41% (95% confidence interval 32–50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application‐site pain (four patients, 3·7%) was the most common treatment‐related AE inside the treatment area.
Conclusions
Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.
What's already known about this topic?
Ingenol mebutate treats the deeper layers of the epidermis and the observed clinical clearance is not just a superficial effect.
What does this study add?
This study confirms that clinical clearance correlates with histopathological clearance.
Agreement between reflectance confocal microscopy and histopathological diagnosis of clear skin was high, indicating that diagnosis of clearance using reflectance confocal microscopy may preclude the need for histopathological assessment and invasive biopsies.
Linked Comment: Rivers. Br J Dermatol 2017; 176:8–9.
Plain language summary available online
PDF
