Anke Hartmann

Anoxia-Induced Up-Regulation of Interleukin-8 in Human Malignant Melanoma : A Potential Mechanism for High Tumor Aggressiveness

Besides its proinflammatory properties, interleukin-8 (IL-8) has been suggested as an important promoter for melanoma growth. To study the role of IL-8 in melanoma biology, we determined the in vivo expression of IL-8 mRNA by in situ hybridization in primary melanoma lesions and metastases. High levels of melanoma cell-associated IL-8-specific transcripts were exclusively detected in close vicinity of necrotic/hypoxic areas of melanoma metastases, whereas both in primary melanomas and in non-necrotic metastases IL-8 expression was low or absent. To analyze further the up-regulation of IL-8 mRNA expression in necrotic/hypoxic tumor areas, human melanoma cell lines of different aggressiveness exposed to severe hypoxic stress (anoxia) were used as an in vitro model. Anoxia induced IL-8 mRNA and protein expression in the highly aggressive/metastatic cell lines MV3 and BLM but not in the low aggressive cell lines IF6 and 530. As shown by IL-8 promoter-dependent reporter gene analysis and mRNA stability assays, elevated mRNA levels in melanoma cells were due to both enhanced transcriptional activation and enhanced IL-8 mRNA stability. Interestingly, transcriptional activation was abolished by mutations in the AP-1 and the NF-kappaB-like binding motifs, indicating that both sites are critical for IL-8 induction. Concomitantly, anoxia induced an enhanced binding activity of AP-1 and NF-kappaB transcription factors only in the highly aggressive cells. From our in vitro and in vivo data we suggest that anoxia-induced regulation of IL-8 might be a characteristic feature of aggressive tumor cells, thus indicating that IL-8 might play a critical role for tumor progression in human malignant melanoma.

Narrow-band UVB311 nm vs. broad-band UVB therapy in combination with topical calcipotriol vs. placebo in vitiligo

Background  Recently, it has been shown that UVB phototherapy may be more effective than UVA in the treatment of vitiligo. Currently, however, no studies have compared the efficacy of UVB311 nm and broad‐band UVB therapy. Calcipotriol has recently been reported to be effective adjunctive treatment for vitiligo, enhancing the efficacy of 8‐methoxypsoralen plus UVA (PUVA) therapy.

Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebo-controlled 12-month prospective study.

Topical tacrolimus was recently introduced as a novel therapeutic option in vitiligo. Excellent results were seen mainly on the face and neck areas. We treated 30 adult vitiligo patients with tacrolimus 0.1% ointment twice daily, and compared the results with those of placebo ointment. In 20 patients, defined areas on the right arm or leg were occluded overnight with 3 different dressings. Repigmentation was evaluated quantitatively and qualitatively. Quality of life changes were assessed with the Dermatology Life Quality Index. After 6 months, treatment was stopped in 7 of 30 patients as they did not show any repigmentation, 5 of them had no occlusive therapy. After 12 months, 17 of 21 patients (81%) with facial involvement showed repigmentation of the face. Although no or minimal repigmentation occurred on the extremities when using tacrolimus ointment alone, 80% of the patients showed repigmentation on the arms when using additional occlusive, especially hydrocolloid dressings. Hands, feet and lower legs were unresponsive. The best results were obtained in patients with long-standing vitiligo. Only minimal side-effects were noted. There was no significant elevation in tacrolimus blood levels, taking into account that occlusion was performed only on limited parts of the body. In conclusion, tacrolimus 0.1% ointment proved an effective and safe treatment option for adult patients with vitiligo. Beyond the face and neck areas, repigmentation could be achieved only by additional occlusion.

Hypopigmentary Skin Disorders Current Treatment Options and Future Directions

Alterations of skin and hair pigmentation are important features that have warranted treatment from ancient history on up to modern time. In some cultures, even today patients with vitiligo are regarded as social outcasts and are affected considerably both emotionally and physically. This article presents current options and future directions for the treatment of hypopigmentary disorders.Whereas with congenital disorders, such as albinism and phenylketonuria, no causal therapy has been established up to now, several treatment options for acquired hypopigmentary disorders have been investigated. In particular, in vitiligo, one of the most prevalent hypopigmentary disorders, a number of treatment modalities have been employed in the past 30 years. However, most of them are only able to palliate, not cure, the disease. Depending on the distribution of the hypopigmented lesions (localised or generalised) and the state of the disease (active or stable), several therapeutic options, for example phototherapy, surgical skin grafts, autologous melanocyte transplantation and immunomodulators, can be applied alone or in combination. For phototherapy, because of unfavourable results and adverse effects, ultraviolet (UV) A has been largely replaced by narrow-band UVB for repigmentation of generalised vitiligo. Although immunomodulators, such as corticosteroids, have been used both topically and systemically over the past 3 decades for the treatment of disseminated vitiligo, they are only suitable for the treatment of acrofacial and localised forms because of adverse effects. Hence, new immunomodulatory agents, such as calcineurin antagonists, have recently been introduced as new promising tools to treat acquired hypopigmentary disorders. However, all therapeutic approaches are hampered by the fact that the pathophysiology of hypopigmentary disorders is still poorly understood.

Vitiligo and melanoma-associated hypopigmentation (MAH):shared and discriminative features

Background: It is unclear if differences between melanoma‐associated hypopigmentation (MAH) and classical vitiligo exist.

Circulating intercellular adhesion molecule-1 in melanoma patients : induction by interleukin-2 therapy

Intercellular adhesion molecule-1 (ICAM-1, CD54), a molecule bound to the cell surface membrane, mediates various cell-cell interactions in inflammation and immunosurveillance. By means of a new specific enzyme-linked immunosorbent assay (ELISA) for soluble ICAM-1, free circulating ICAM-1 was measured in serum from five healthy volunteers, 10 melanoma patients at different stages of their disease, and eight patients receiving high-dose interleukin-2 (IL-2) for metastatic melanoma. No correlation between the concentration of circulating ICAM-1 and the tumor burden could be detected. In melanoma patients receiving high-dose IL-2, we observed an increase of circulating ICAM-1 of up to 200%, compared to the concentration prior to therapy, ranging between 4 and 13 ng/ml. The increase in circulating ICAM-1 was associated with the induction of tumor necrosis factor-alpha and interferon-gamma.

Repigmentation of pretibial vitiligo with calcineurin inhibitors under occlusion.

Treatment of vitiligo is a challenge, especially in children. Recently, topical calcineurin inhibitors have been introduced in the management of vitiligo, but significant repigmentation is not achieved except on the face. Large pretibial lesions of a 15‐year‐old female with progressive vitiligo were treated twice daily over six months with 0.1% tacrolimus ointment on the right and 1% pimecrolimus cream on the left side without effect. Additional overnight occlusion with polyurethane and hydrocolloid foils during the following 18 months led to substantial repigmentation on both sides (tacrolimus‐treated side, 88% repigmented area; pimecrolimus‐treated side, 73%). Tacrolimus serum levels measured at four different time points did not exceed 1.8 ng/ml. This case report on a direct comparison of topical tacrolimus and pimecrolimus in vitiligo shows that on the shins considerable improvement could be induced with both agents only by additional long‐term occlusion and that tacrolimus was somewhat more effective than pimecrolimus.

Treatment of Generalised Vitiligo with Tacrolimus 0.1% Ointment vs. UVB Intense Pulsed Light Phototherapy: A Pilot Study

Fig. S3. A 38-year-old patient; A: abdominal region and shins before treatment; B: After 9 months treatment, repigmentation on the abdominal region just on the UVB-treated side, whereas better response on the legs was seen on the right, tacrolimus-treated side. Note mixture of follicular and interfollicular repigmentation on the abdominal side and follicular repigmentation on both shins. (We thank Mrs. Christine Reich and Mr. Stefan Schnetz for performing digital photography.)

Back to the roots – die Anfänge der Dermatologie in der altägyptischen Medizin

Although ancient Greek and Roman medicine is generally considered the origin of European medicine, there is evidence in ancient Egyptian texts suggesting a precursor role of ancient Egyptian medicine in this regard. What did Greek and Roman physicians learn from their Egyptian counterparts? Of the medical papyri discovered to date, the largest and most significant – the Ebers papyrus and the Smith papyrus – originate from the beginning of the New Kingdom, however, they were – at least in part – already written during the Old Kingdom. Considering the times, the spectrum of diseases treated as well as the range of conservative and surgical treatment methods was truly astounding. Taking a medical history, performing a thorough manual examination, and assessing clinical findings constituted key components in establishing a diagnosis. Apart from hygienic aspects, skin and hair disorders, the treatment of acute and chronic wounds and injuries as well as cosmetic procedures took on an important role. Even back then, physicians sought to assess inflammatory processes with respect to their cardinal features, implement graded wound therapy, and treat diseases with allopathic drugs. The ‘channel theory’ prevalent at that time, in which the unimpeded flow of bodily fluids was considered a fundamental prerequisite for health, may likely be regarded as precursor of ancient Greek humoral pathology. The latter became the basis for the subsequently established theory of the four humors, and was thus essential for the entire field of medieval medicine.

Back to the roots – dermatology in ancient Egyptian medicine

Although ancient Greek and Roman medicine is generally considered the origin of European medicine, there is evidence in ancient Egyptian texts suggesting a precursor role of ancient Egyptian medicine in this regard. What did Greek and Roman physicians learn from their Egyptian counterparts? Of the medical papyri discovered to date, the largest and most significant – the Ebers papyrus and the Smith papyrus – originate from the beginning of the New Kingdom, however, they were – at least in part – already written during the Old Kingdom. Considering the times, the spectrum of diseases treated as well as the range of conservative and surgical treatment methods was truly astounding. Taking a medical history, performing a thorough manual examination, and assessing clinical findings constituted key components in establishing a diagnosis. Apart from hygienic aspects, skin and hair disorders, the treatment of acute and chronic wounds and injuries as well as cosmetic procedures took on an important role. Even back then, physicians sought to assess inflammatory processes with respect to their cardinal features, implement graded wound therapy, and treat diseases with allopathic drugs. The ‘channel theory’ prevalent at that time, in which the unimpeded flow of bodily fluids was considered a fundamental prerequisite for health, may likely be regarded as precursor of ancient Greek humoral pathology. The latter became the basis for the subsequently established theory of the four humors, and was thus essential for the entire field of medieval medicine.