Metabolites, lipids, and other small molecules are key constituents of tissues supporting cellular programs in health and disease. Here, we present METASPACE, a community-populated knowledge base of spatial metabolomes from imaging mass spectrometry data. METASPACE is enabled by a high-performance engine for metabolite annotation in a confidence-controlled way that makes results comparable between experiments and laboratories. By sharing their results publicly, engine users continuously populate a knowledge base of annotated spatial metabolomes in tissues currently including over 3000 datasets from human cancer cohorts, whole-body sections of animal models, and various organs. The spatial metabolomes can be visualized, explored and shared using a web app as well as accessed programmatically for large-scale analysis. By using novel computational methods inspired by natural language processing, we illustrate that METASPACE provides molecular coverage beyond the capacity of any individual laboratory and opens avenues towards comprehensive metabolite atlases on the levels of tissues and organs.

Background and Objectives Rising incidences of basal cell carcinoma (BCC) have increased the need for effective topical therapies. By enhancing cutaneous uptake of the chemotherapeutic agents, cisplatin and 5‐fluorouracil (5‐FU), laser‐assisted delivery may provide a new combination treatment for BCC. Accordingly, this study aimed to evaluate tumor response, safety, and drug biodistribution in tumors and blood after topical laser‐assisted 5‐FU + CIS treatment in BCC patients. Study Design/Materials and Methods This open‐label, proof‐of‐concept trial investigated laser‐assisted combination cisplatin + 5‐FU treatment in 20 patients with histologically verified, low‐risk superficial or nodular BCCs on the face (<20 mm) or trunk/extremities (<50 mm). After tumor demarcation guided by optical coherence tomography (OCT), BCCs were exposed to ablative fractional CO2 laser followed by 60 minutes topical cisplatin solution and 7‐day exposure to 5% 5‐FU cream under occlusion. After 30 days, treatment was repeated if any tumor residual was identified. Tumor response at day 30 and month 3 was assessed clinically as well as by OCT, reflectance confocal microscopy, and ultrasound, supplemented by histological verification at 3 months. Local skin reactions (LSRs) and side effects were evaluated on days 1, 3–5, 14, 30, and month 3. Drug detection in tumors and blood was performed in a subset of patients 1‐ and 24 hours after treatment. Results Nineteen patients completed the trial, with 32% (6/19) receiving a single treatment and 68% (13/19) treated twice. At 3 months, clinical clearance was seen in 18/19 patients with a corresponding 94% (17/18) achieving histological clearance. Baseline tumor thickness and subtype did not influence treatment number or clearance rate (P ≥ 0.61). LSRs were well‐tolerated and consisted of erythema, edema, and erosion, followed by crusting by day 14. Erythema declined gradually by month 3, with 94% of patients and 79% of physicians rating cosmesis as “good” or “excellent.” Scarring or hyperpigmentation was noted in 50% and 56%, respectively, while pain and infection were not observed during the follow‐up period. Although chemotherapy uptake was visualized extending to deep skin layers, no systemic exposure to cisplatin or 5‐FU was detected in patient blood. Conclusion Laser‐assisted cisplatin + 5‐FU shows potential as an effective and tolerable treatment option for low‐risk BCC, particularly in instances where self‐application is not possible or where in‐office, non‐surgical therapy is preferred. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Bleomycin exhibits antiproliferative effects desirable for use in dermato-oncology but topical use is limited by its 1415 Da molar mass. Ablative fractional laser (AFL)-assisted drug delivery has been shown to enhance drug uptake in skin. The aim of this study was with AFL to deliver bleomycin into skin, quantify uptake, and visualize biodistribution with mass spectrometry. In a Franz diffusion cell study, pig skin samples (n = 66) were treated with AFL (λ = 10,600 nm), 5% density, and 0, 5, 20, or 80 mJ/microbeam (mb) pulse energies before exposure to bleomycin for 0.5, 4, or 24 h. Bleomycin was quantified in biopsy cryosections at depths of 100, 500, and 1500 µm using high-performance liquid chromatography-mass spectrometry (LC-MS), and drug biodistribution was visualized for 80 mJ/mb samples by matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The pulse energies 5, 20, and 80 mJ/mb resulted in microscopic ablation zones (MAZs) reaching superficial, mid, and deep dermis respectively. Bleomycin was successfully delivered into the skin and deeper MAZs and longer exposure time resulted in higher skin concentrations. After 24 h, AFL exposure resulted in significant amounts of bleomycin throughout all skin layers (≥510 µg/cm3, p ≤ .002). In comparison, concentrations in intact skin exposed to bleomycin remained below limit of quantification. MALDI-MSI supported the quantitative LC-MS results by visualizing bleomycin biodistribution and revealing high uptake around MAZs with delivery into surrounding skin tissue. In conclusion, topical drug delivery of the large and hydrophilic molecule bleomycin is feasible, promising, and should be explored in an in vivo setting.

Background and Objectives Porcine skin is a widely used model in diffusion studies, but its usefulness for laser‐assisted drug delivery (LADD) has not been evaluated in comparison with human skin. This study compared porcine and human skin in ex vivo LADD diffusion studies. Study Design/Materials and Methods Ex vivo ablative fractional laser (AFL) treatments (5, 20, and 80 mJ/mb) were applied to skin samples from three sources: human, normal pig (Duroc × Landrace × Yorkshire breed), and a hyperkeratotic pig phenotype. Samples were stained using hematoxylin and eosin, photo‐documented, and measured digitally. Samples (20 mJ/mb) were exposed to bleomycin or 5‐fluorouracil (5‐FU) for 19 hours in Franz diffusion cells. Drug uptake was quantified at three skin depths (100, 500, and 1,500 µm) by high‐performance liquid chromatography‐mass spectrometry. Drug biodistribution and endogenous lipids were visualized by matrix‐assisted laser desorption/ionization‐mass spectrometry imaging. Results Epidermal and dermal thicknesses of human and normal pig skin were similar (76–87 µm and 1,668–1,886 µm, respectively; P = 0.082–0.494). Endogenous lipids were investigated, and 116 compounds were identified. Of these compounds, 100 were found in all three skin types, while six were present exclusively in human skin. Laser channel depths (20 mJ/mb) in human and normal pig skin were similar (1,081 vs. 1,126 µm; P = 0.588). Bleomycin uptake was similar in all skin types at all depths (101.4–175.6 µg/cm3; P = 0.132–0.699). 5‐FU uptake in human and normal pig skin was similar at 100 and 500 µm (80.5 vs. 140.3 µg/cm3 and 131.2 vs. 208.1 µg/cm3, respectively; P = 0.065–0.093). At 1500 µm, 5‐FU concentrations in the porcine skin types differed from those in human skin (104.7 vs. 196.7–344.8 µg/cm3; P = 0.002–0.026). Drug biodistribution was similar among skin types, but differences between bleomycin and 5‐FU biodistribution were observed. Conclusions Normal porcine and human skin showed similar morphology, the composition of endogenous lipids, and AFL‐assisted cutaneous uptake, and biodistribution of chemotherapeutics. Therefore, normal porcine skin, but not hyperkeratotic pig phenotype skin, is a practical and reliable model for healthy human skin in ex vivo LADD diffusion studies. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Background Matrix‐assisted laser desorption ionisation mass spectrometry imaging (MALDI‐MSI) is a mass spectrometry‐based technique, which can be applied for compound‐specific imaging of pharmaceuticals in tissues samples. MALDI‐MSI technology is widely used to visualise penetration and distribution profile through different tissues but has never been used with nail tissue. Objectives This study used MALDI‐MSI technology to visualise distribution profile and penetration into ex vivo human mycosis‐infected toenails of three antifungal active ingredients amorolfine, ciclopirox and naftifine contained in topical onychomycosis nail treatment preparations, marketed as Loceryl®, Ciclopoli® and Exoderil®. Methods Three mycosis‐infected toenails were used for each treatment condition. Six and twenty‐four hours after one single topical application of antifungal drugs, excess of formulation was removed, nails were cryo‐sectioned at a thickness of 20 μm, and MALDI matrix was deposited on each nail slice. Penetration and distribution profile of amorolfine, ciclopirox and naftifine in the nails were analysed by MALDI‐MSI. Results All antifungal actives have been visualised in the nail by MALDI‐MSI. Ciclopirox and naftifine molecules showed a highly localised distribution in the uppermost layer of the nail plate. In comparison, amorolfine diffuses through the nail plate to the deep layers already 6 hours after application and keeps diffusing towards the lowest nail layers within 24 hours. Conclusions This study shows for the first‐time distribution and penetration of certain antifungal actives into human nails using MALDI‐MSI analysis. The results showed a more homogeneous distribution of amorolfine to nail and a better penetration through the infected nails than ciclopirox and naftifine.