Line-field confocal optical coherence tomography in dermato-oncology: A literature review towards harmonized histopathology-integrated terminology.

Non-invasive diagnostics like line-field confocal optical coherence tomography (LC-OCT) are being implemented in dermato-oncology. However, unification of terminology in LC-OCT is lacking. By reviewing the LC-OCT literature in the field of dermato-oncology, this study aimed to develop a unified terminological glossary integrated with traditional histopathology. A PRISMA-guided literature-search was conducted for English-language publications on LC-OCT of actinic keratosis (AK), keratinocyte carcinoma (KC), and malignant melanoma (MM). Study characteristics and terminology were compiled. To harmonize LC-OCT terminology and integrate with histopathology, synonymous terms for image features of AK, KC, and MM were merged by two authors, organized by skin layer and lesion-type. A subset of key LC-OCT image-markers with histopathological correlates that in combination were typical of AK, squamous cell carcinoma in situ (SCCis), invasive squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and MM in traditional histopathology, were selected from the glossary by an experienced dermatopathologist. Seventeen observational studies of AK (7 studies), KC (13 studies), MM (7 studies) utilizing LC-OCT were included, with 117 terms describing either AK, KC, or MM. These were merged to produce 45 merged-terms (61.5% reduction); 5 assigned to the stratum corneum (SC), 23 to the viable epidermis, 2 to dermo-epidermal junction (DEJ) and 15 to the dermis. For each lesion, mandatory key image-markers were a well-defined DEJ and presence of mild/moderate but not severe epidermal dysplasia for AK, severe epidermal dysplasia and well-defined DEJ for SCCis, interrupted DEJ and/or dermal broad infiltrative strands for invasive SCC, dermal lobules connected and/or unconnected to the epidermis for BCC, as well as single atypical melanocytes and/or nest of atypical melanocytes in the epidermis or dermis for MM. This review compiles evidence on LC-OCT in dermato-oncology, providing a harmonized histopathology-integrated terminology and key image-markers for each lesion. Further evaluation is required to determine the clinical value of these findings.

Subclinical effects of botulinum toxin A and microwave thermolysis for axillary hyperhidrosis: A descriptive study with line-field confocal optical coherence tomography and histology.

Botulinum toxin A (BTX) and microwave thermolysis (MWT) are standard axillary hyperhidrosis treatments, but comparison of their subclinical effects is lacking. Line-field confocal optical coherence tomography (LC-OCT) is a promising non-invasive imaging tool for visualizing tissue-interactions. This study aimed to describe subclinical effects of BTX and MWT for axillary hyperhidrosis with LC-OCT-imaging compared to histology. This study derived from an intra-individual, randomized, controlled trial, treating axillary hyperhidrosis with BTX versus MWT. Subclinical effects based on LC-OCT images from baseline and 6-month follow-up (n = 8 patients) were evaluated and compared to corresponding histological samples. At baseline, LC-OCT visualized eccrine pores at the skin surface and ducts in the upper dermis (500 µm), but not deeper-lying sweat glands. Histology identified entire sweat glands. Six months post-treatment, LC-OCT revealed no detectable morphology changes in any BTX-treated axillae (100%), while recognizing obstructed eccrine pores and atrophy of eccrine ducts in most MWT-treated axillae (75%). Histology corroborated LC-OCT findings, while also showing substantial changes to entire sweat glands. LC-OCT enabled visualization of subclinical alterations of superficial eccrine ducts after MWT and unchanged morphology after BTX. LC-OCT is a promising tool for non-invasive assessment of treatment-specific tissue-interactions that can be complementary to histology.

Line-field confocal optical coherence tomography for in vivo visualization of morphological characteristics of squamous cell carcinoma in a murine model.

OBJECTIVES: Non-invasive imaging with line-field confocal optical coherence tomography (LC-OCT) can support the diagnosis of squamous cell carcinoma (SCC) through visualization of morphological characteristics specific to skin cancer. We aimed to visualize prominent morphological characteristics of SCC using LC-OCT in a well-established murine SCC model. MATERIALS AND METHODS: Nine hairless mice were exposed to ultraviolet radiation three times weekly for 9 months to induce SCC development. Visible SCC tumors (n = 9) were imaged with LC-OCT and the presence of 10 well-described morphological characteristics of SCC were evaluated in the scans by two physicians with adjudication by a third. RESULTS: Overall, murine morphological characteristics resembled corresponding features previously reported in human SCCs. Interrupted dermal-epidermal junction occurred in 100% of tumors. In epidermis, the most frequently observed characteristics were severe epidermal dysplasia (100%) and tumor budding (89%). Common dermal characteristics included broad strands (100%) and collagen alterations (78%). CONCLUSION: LC-OCT imaging can be used to non-invasively visualize morphological characteristics specific to SCC in an in vivo preclinical model.

Repeated exposure to fractional CO2 laser delays squamous cell carcinoma formation and prevents clinical and subclinical photodamage visualized by line-field confocal optical coherence tomography and histology.

OBJECTIVES: Ablative fractional laser (AFL) is a well-established modality for treating ultraviolet radiation (UVR)-induced skin photodamage. We aimed to investigate the potential of AFL to delay squamous cell carcinoma (SCC) formation and prevent photodamage in a preclinical UVR-induced SCC model. MATERIALS AND METHODS: Hairless C3.Cg-Hrhr /TifBomTac mice (n = 50) were exposed to UVR three times weekly throughout the study. UV-exposed mice were randomized to two groups that received dorsal CO2 AFL (10 mJ/mb, 10% density) or no treatment. AFL was performed every other week for a total of 16 weeks (nine treatments in total). The primary outcome was time to tumor occurrence. In a subset of mice on Day 150, prevention of clinical photodamage was assessed by examination of skin tightness and dyspigmentation. Concomitantly, assessment of subclinical photoprevention based on normalization of keratinocyte dysplasia, dermo-fiber morphology (collagen and elastin fibers), and skin thickness, was performed using line-field confocal optical coherence tomography (LC-OCT) and histology. RESULTS: Repeated AFL treatments delayed SCC tumor development compared to UVR control mice by 12, 19, and 30 days for first, second, and third tumors, respectively (p ≤ 0.0017). Compared to UVR controls, AFL prevented photodamage both clinically and subclinically, based on LC-OCT and histology. In the epidermal layer, AFL imparted photopreventative effects including reduced dyspigmentation and keratinocyte dysplasia (1 vs. 2.5, p = 0.0079) and partial normalization of the epidermal thickness (p < 0.0001). In the dermis, AFL led to twofold greater skin tightness (p = 0.0079), improved dermo-fiber structure, and dermal thickness (p = 0.0011). CONCLUSION: In conclusion, repeated AFL treatments of UVR-exposed skin significantly delayed SCC tumor formation and prevented clinical and imaging-assessed subclinical signs of photodamage, indicating a potential for AFL in prevention strategies for SCC and photodamage in high-risk populations.

Melanin-dependent tissue interactions induced by a 755-nm picosecond-domain laser: complementary visualization by optical imaging and histology.

Fractional picosecond-domain lasers (PSL) induce optical breakdown, which correlates histologically to vacuolization in the epidermis and dermis. In this ex vivo porcine study, we sought to establish a framework for the investigation of laser-tissue interactions and their dependence on melanin density. Light- (melanin index: 24.5 [0-100]), medium- (58.7), and dark-pigmented (> 98) porcine skin samples were exposed to a 755-nm fractional PSL and examined with dermoscopy, line-field confocal optical coherence tomography (LC-OCT), conventional OCT, and subsequently biopsied for digitally stained ex vivo confocal microscopy (EVCM) and histology, using hematoxylin and eosin (HE) and Warthin-Starry (WS) melanin staining. Dermoscopy showed focal whitening in medium- and dark-pigmented skin. Similarly, LC-OCT and OCT visualized melanin-dependent differences in PSL-induced tissue alterations. Vacuoles were located superficially in the epidermis in dark-pigmented skin but at or below the dermal-epidermal junction in medium-pigmented skin; in light-pigmented skin, no vacuoles were observed. Histology confirmed the presence of vacuoles surrounded by areas void of WS staining and disrupted stratum corneum in darker skin. The combined use of optical imaging for multiplanar visualization and histological techniques for examination of all skin layers may mitigate the effect of common artifacts and attain a nuanced understanding of melanin-dependent laser-tissue interactions.

Medial collateral ligament (MCL) reconstruction results in improved medial stability: results from the Danish knee ligament reconstruction registry (DKRR).

PURPOSE: The aim of this study was to compare outcome data after isolated and combined (MCL) plus anterior cruciate ligament (ACL) reconstruction based on objective and subjective measures using data from the (DKRR). There are only a few small-sized case studies on outcomes after MCL reconstruction. MCL reconstruction was hypothesised to improve both objective and subjective outcomes. METHODS: All patients who were registered in the DKRR between 2005 and 2016 (N = 25,281) and who underwent isolated ACL (n = 24,683), isolated MCL (n = 103) or combined MCL plus ACL (n = 495) reconstructions were retrospectively identified. Objective (valgus knee stability and sagittal knee laxity) and subjective (Knee Injury and Osteoarthritis Outcome Score (KOOS) and Tegner activity scale score) outcomes in these three cohorts were evaluated at the 1-year follow-up by comparing pre- and post-operative values. RESULTS: Medial stability improved significantly pre- to post-operatively after both isolated MCL and combined MCL plus ACL reconstruction, with 26 (53%) and 195 (69%) of the patients, respectively, having normal valgus stability (0-2 mm laxity). Sagittal stability was similar after MCL plus ACL reconstruction and isolated ACL reconstruction (1.7 and 1.5 mm, respectively). At the 1-year follow-up, although the KOOS of the patients in the isolated MCL and combined MCL plus ACL reconstruction cohorts improved significantly, they were lower than those of the patients in the isolated ACL reconstruction cohort. CONCLUSION: Both isolated MCL reconstruction and combined MCL plus ACL reconstruction resulted in significant and clinically relevant improvements in the subjective outcomes from pre-operative conditions to the 1-year follow-up. Valgus stability also improved significantly, with two-thirds of patients obtaining normal valgus stability after MCL reconstruction. Subjective outcomes were similar between isolated MCL reconstruction and combined MCL plus ACL reconstructions, but were poorer than isolated ACL reconstructions. LEVEL OF EVIDENCE: Level III.

Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs.

Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP+Apoe-/- and Apoe-/- mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP+ or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2+ SMCs in the cap and heterogeneous ACTA2- SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.

Myocardial and Peripheral Ischemia Causes an Increase in Circulating Pregnancy-Associated Plasma Protein-A in Non-atherosclerotic, Non-heparinized Pigs.

The usefulness of circulating pregnancy-associated plasma protein-A (PAPP-A) as a biomarker for acute coronary syndrome (ACS) is widely debated. We used the pig as a model to assess PAPP-A dynamics in the setting of myocardial ischemia. Induction of myocardial ischemia by ligation of the left anterior descending (LAD) coronary artery caused a systemic rise in PAPP-A. However, the ischemic myocardium was excluded as the source of PAPP-A. Interestingly, induction of ischemia in peripheral tissues by ligation of the left femoral artery caused a systemic rise in PAPP-A originating from the left hind limb. This is the first study to demonstrate PAPP-A elevations in the absence of atherosclerosis or heparin during myocardial ischemia. Our findings thus add to the current discussion of the usefulness of PAPP-A as a biomarker for ACS.