Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist.

In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+ -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+ -derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+ -derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγ null mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074.

Self-detection frequency and recognition patterns in medium to high-risk cutaneous melanoma patients.

BACKGROUND AND OBJECTIVES: The question of how frequently patients with medium to high-risk melanomas become aware of their tumors and which self-detection patterns exist remains unanswered. PATIENTS AND METHODS: We conducted a retrospective survey of melanoma patients who had undergone sentinel node biopsy between 2004 and 2008. One hundred twenty-seven out of a total of 133 patients completed the questionnaire. RESULTS: Twenty-five percent of patients had not noticed their tumors at all. The remaining 75 % showed three different self-detection patterns, with 25 % of individuals seeking medical advice within 0-12 weeks and another 25 % within 3-6 months. The remaining 25 % had waited for more than six months prior to tumor excision. Age, gender, and melanoma location were comparable in all self-detection subgroups. The most frequent subtypes were: SSM (59), NMM (31), ALM (9), UCM (9) and LMM (4). Rare subtypes occurred in 15 individuals. Patients with lesions previously noticed for 3-6 months revealed the highest average tumor thickness and the significantly highest number of pT4 tumors. Sixty percent of NMM patients had a disease history < 6 months. Rare subtypes such as amelanotic, spindle cell, or spitzoid melanoma were self-detected in only 50 % of cases. CONCLUSIONS: Even advanced melanoma lesions remained undetected in 25 % of patients; rare melanoma subtypes, in 50 % of cases. Thus, self-examination frequency, increased awareness of rare melanoma subtypes, and rapid referral to a specialist ought to be at the center of future awareness campaigns.

Häufigkeit und Muster der Tumorerkennung nach Selbstuntersuchung bei Mittel- bis Hochrisiko-Melanompatienten.

HINTERGRUND UND ZIELSETZUNG: Die Frage, wie oft Melanompatienten mit Mittel- bis Hochrisikomelanomen den Tumor bemerken und welche Eigenerkennungsmuster existieren ist bislang nicht beantwortet. PATIENTEN UND METHODEN: Wir haben eine retrospektive Studie an Melanompatienten durchgeführt, die sich zwischen 2004 und 2008 einer Sentinellymphknotenbiopsie unterzogen haben,. Der Fragebogen wurde von 127 der insgesamt 133 Patienten ausgefüllt. ERGEBNISSE: 25 % bemerkten den Tumor überhaupt nicht. Die restlichen 75 % zeigten verschiedene Eigenerkennungsmuster: 25 % holten nach 0-12 Wochen Rat ein, weitere 25 % innerhalb von 3-6 Monaten, und bei den restlichen 25 % wurde der Tumor mehr als sechs Monate lang beobachtet, bevor er entfernt wurde. Alter, Geschlecht und Lokalisation des Melanoms waren bei allen Eigenerkennungsgruppen vergleichbar. Die häufigsten Subtypen waren: SSM (59), NMM (31), ALM (9), UCM (9) und LMM (4). Seltene Subtypen (15) waren ebenfalls vorhanden. Patienten mit 3-6 Monate alten Läsionen zeigten die höchste durchschnittliche Tumordicke und die bei weitem höchste Anzahl von pT4-Tumoren. 60 % der Patienten mit NMM hatten eine Krankengeschichte von <6 Monaten. Seltene Subtypen wie amelanotische, Spindelzell- und spitzoide Melanome wurden in nur 50 % der Fälle selbstständig erkannt. SCHLUSSFOLGERUNGEN: Selbst fortgeschrittene Melanome blieben von den Patienten in 25 %, seltene Melanom-Subtypen in 50 % der Fälle unerkannt. Daher sollte der Eigenerkennungshäufigkeit, dem erhöhten Bewusstsein für seltene Melanome und der schnellen Überweisung an einen Spezialisten in zukünftigen Aufklärungskampagnen besondere Aufmerksamkeit zukommen.

Epigenetic modifications in cutaneous malignant melanoma: EZH2, H3K4me2, and H3K27me3 immunohistochemical expression is enhanced at the invasion front of the tumor.

Cancer stem cells and the misregulation of epigenetic modifications have been identified to possess a determinative role in carcinogenesis. The purpose of this study was to investigate the expression profile of EZH2 and H3K4me2 and H3K27me3, which constitute stem cell-like "bivalent" domains, in cutaneous malignant melanoma. A comparative analysis of their immunohistochemical expression between the invasion front (IF) and the inner tumor mass was also evaluated. Immunohistochemical methodology was performed on sections of 89 melanoma lesions from 79 patients. The 3 markers studied were identified in the cell nuclei of melanoma cells, nevus cells, and normal epidermal keratinocytes. A specific distribution pattern of H3K4me2 and H3K27me3 was found, as stronger levels were localized at the IF of the tumor (P = 0.034 and P < 0.01, respectively). In general, H3K4me2 and H3K27me3 levels were lower in metastatic with respect to primary melanoma cases (P = 0.0065 and P = 0.027, respectively). Advanced melanoma demonstrated significantly lower H3K4 immunohistochemical expression than did cases of lowest Clark level (I) (P = 0.038) or low Breslow depth (≤1 mm; P < 0.001). Furthermore, EZH2 expression in melanoma cells was higher compared with that in nevus cells (P = 0.02). A positive correlation between EZH2-H3K27me3 (P = 0.03) and H3K4me2-H3K27me3 (P < 0.01) in melanoma cells was also found. Our results suggest the possibility that combined immunohistochemical expression of EZH2, H3K4me2, and H3K27me3 might identify cancer cells with potential stem cell properties, particularly at the IF of this malignancy. This hypothesis should be further investigated, as many of the epigenetic changes are reversible via pharmacologic manipulations and new therapies, overpassing the resistance of advanced melanoma, may be developed.