Human skin models are essential for understanding dermatological diseases and testing new treatment strategies.
Objective Lidocaine acts as a local anesthetic by blocking transmembrane sodium channel permeability, but also induces the synthesis of heat shock proteins and sensitizes cells to hyperthermia. A previous study reported two cases of deep focal skin ulceration at points corresponding to depot local lidocaine injection sites after treatment with non‐ablative fractional resurfacing and it was hypothesized that lidocaine had focally sensitized keratinocytes to the thermal damage of laser treatment. The objective of this study was to investigate whether lidocaine potentiates hyperthermia damage to both normal and cancerous skin cells using an in vitro model. Methods Normal skin cell lines (fibroblasts, keratinocytes), skin cancer cell lines (melanoma, basal cell carcinoma), and a mucosal cancer cell line (cervical carcinoma) were exposed to various concentrations of lidocaine (0–0.3%) with or without hyperthermia (37°C, 42°C). Results Compared to normal skin cells, we demonstrate that cancer cell lines show significantly increased cell toxicity when a moderate temperature (42°C) and low lidocaine concentrations (0.1–0.2%) are combined. The toxicity directly correlates with a higher percentage of cells in S‐phase (28–57%) in the cancer cell lines compared to normal skin cell lines (13–19%; R‐square 0.6752). Conclusion These results suggest that lidocaine potentiates thermal sensitivity of cell cycle active skin cells. The direct correlation between cell toxicity and S‐phase cells could be harnessed to selectively treat skin and mucosal cancer cells while sparing the surrounding normal tissue. Additional research pre‐clinically and clinically using several different heat sources (e.g., lasers, ultrasound, etc.) and lidocaine concentrations is needed to confirm and optimize these results. Lidocaine‐enhanced hyperthermia may provide a non‐invasive, alterative treatment option for highly proliferating, superficial skin, and mucosal lesions such as cancer or warts. Lasers Surg. Med. 51:88–94, 2019. © 2018 Wiley Periodicals, Inc.
Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.
Introduction The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFL delivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL‐assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL‐assisted delivery, this study examined the impact of vasoregulative interventions on AFL‐assisted 5‐fluorouracil (5‐FU) concentrations in in vivo skin. Methods 5‐FU uptake was assessed in intact and AFL‐exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5‐FU cream application. At 0, 1, 4, 48, and 72 h, 5‐FU concentrations were measured in 500 and 1500 μm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. Results Compared to intact skin, AFL facilitated a prompt peak in 5‐FU delivery that remained elevated up to 4 hours (1500 μm: 1.5 vs. 31.8 ng/ml [1 hour, p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5‐FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5‐FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5‐FU concentrations than AFL alone in both skin layers by 1 hour (e.g., 500 μm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone], p ≤ 0.024), and remained significantly elevated at 4 hours (p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5‐FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hours in the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. Conclusion Vasoregulative intervention in conjunction with AFL‐assisted delivery enhances and prolongs 5‐FU deposition in in vivo skin.
ZusammenfassungSeltene Erkrankungen (SE) werden durch die im deutschen Gesundheitssystem verwendete Diagnosenklassifikation ICD-10-GM (International Statistical Classification of Diseases and Related Health problems, 10th Revision, German Modification) nur zu einem kleinen Teil eindeutig erfasst. Daher sind Aussagen zur Häufigkeit von SE sowie zum speziellen Versorgungs- und Finanzierungsbedarf nicht möglich, was zu einer lückenhaften Datenlage als Entscheidungsgrundlage für Krankenkassen, Leistungserbringer und Gesundheitspolitik führt. Das Fehlen exakter Informationen behindert auch die wissenschaftliche Arbeit. Daher wird deutschlandweit ab 2023 die Verwendung der Alpha-ID-SE-Datei und der ORPHAcodes für die spezifische Erfassung von SE bei stationären Fällen verpflichtend.Die Alpha-ID-SE-Datei verknüpft die ICD-10-GM-Kodes mit den international anerkannten ORPHAcodes für die Diagnose von SE. Kommerzielle Anbieter stellen zunehmend die benötigten IT-Tools zur Kodierung von SE zur Verfügung. An mehreren Universitätskliniken mit Zentren für SE wurden Lösungen etabliert, die eine vollständige Kodierung gewährleisten sollen. Hierzu gehören finanzielle Anreize für die kodierenden Bereiche, konkrete Nachfragen nach dem Vorliegen einer SE beim Kodiervorgang und eine semiautomatische Kodierung bei Patient*innen, die schon einmal mit einer SE an der Einrichtung betreut worden waren. Eine Kombination der verschiedenen Ansätze verspricht die höchste Wahrscheinlichkeit einer vollständigen Kodierung.Für ein umfängliches Bild der SE im Gesundheitssystem und um dem speziellen Versorgungs- und Finanzierungsbedarf besser Rechnung tragen zu können, wäre auch im ambulanten Bereich eine möglichst spezifische und eindeutige Kodierung wünschenswert. Für komplexe SE und bisher undiagnostizierte Patient*innen wird zusätzlich eine strukturierte Erfassung des Phänotyps benötigt.
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Background: Hyperproliferative cutaneous lesions, such as non-melanoma and melanoma skin cancers, are the most commonly diagnosed cancers in the United States. While surgery remains the gold standard, treatment can be costly and complications can include pain, scarring, infections. Hyperthermia (40-44 C) has been utilized for many years to treat various cancer types as it induces localized cell toxicity. Combining local anesthetics, such as lidocaine, with hyperthermia has been shown in vitro to enhance cell death. Objective: We investigated whether the combination of hyperthermia with lidocaine enhanced cell toxicity in cutaneous cell lines and whether the effect is specific for rapidly proliferating cells. Methods: We exposed normal skin cell lines (fibroblasts, keratinocytes), skin cancer cell lines (melanoma, basal cell carcinoma), and a mucosal cancer cell line (cervical carcinoma) to various concentrations of lidocaine (0.0-0.4%) over a range of temperatures (37-44 C) for 10 minutes. Cell viability was assessed with an MTT assay and cell cycle with propidium iodide and flow cytometry. Results: We demonstrate that cancer cell lines show significantly increased cell toxicity at a moderate temperature (42 C) and lidocaine concentration (0.2%) compared to normal skin cells (p<0.05). Further, we show that cancer cell lines have a higher percentage of cells in S-phase (28-57%) compared to normal skin cell lines (13-19%), which directly correlated with cell toxicity from combined hyperthermia and lidocaine (R-square 0.6752). Conclusions: In the future, combined mild hyperthermia with lidocaine may provide a non-invasive alterative to treatment of skin cancer. This treatment demonstrates selectivity for rapidly dividing cancer cells compared to normal skin cells. Further, lidocaine can be applied specifically to cutaneous lesions to potentially minimize unwanted side effects on the surrounding tissue. Additional investigation via clinical trials are needed to confirm these in vitro data.
Primary melanomas >1 mm thickness can be cured by resection, but may recur metastatically. We assessed the prognostic value of "T cell fraction" (TCFr) and "repertoire T cell clonality", as measured by high-throughput sequencing of the T cell receptor beta-chain (TCRB), in primary melanomas (n¼377) from patients followed five years. We included T2-T4 melanomas. All samples were scored for TIL content by histopathology. To assess T cell subsets, we further stained sections by multiplex immunohistochemistry (mIHC) for CD3, CD8, CD4, FoxP3, CD39 and CD103. TCFr accurately predicted progression-free survival (PFS) and was fully independent of melanoma thickness, ulceration, mitotic rate, or age, all of which were co-dependent predictive variables. TCFr was second only to tumor thickness in its predictive value, using a gradientboosted model. A cutoff of 20% TCFr performed best (HR 0.39 high-vs-low TCFr, p ¼ 1.28E-5). Only 23.4% of T3 melanomas with ! 20% TCFr progressed in five years, compared to 54.2% progression of those with < 20% (HR 0.3, p ¼ 0.0076). A TCFr >20% was protective regardless of tumor ulceration or mitotic rate. Patients with resected regional nodal disease and high TCFr in the primary had a markedly decreased risk of progression (HR 0.37, p¼0.0046) and had a PFS rate similar to that of patients without nodal disease and a low TCFr. TCFr high and TCFr low samples had comparable numbers of CD4+, CD8+ and "tumor-specific" CD8+CD39+CD103+/-T cells by mIHC. Finally, TCFr by HTS was more accurate than conventional histopathological TIL grading to predict 5-year PFS (AOD, p ¼ 0.0055). Our study suggests that a successful T cellmediated antitumor response exists in primary melanomas. Combined with Breslow thickness, this test provides the most accurate prognostic staging of primary melanomas to date.
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