Bernhard Frerich

Malignant Melanoma S3-Guideline "Diagnosis, Therapy and Follow-up of Melanoma"

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw

OBJECTIVES Bisphosphonate-related osteonecrosis of the jaw (BRONJ) seems resistant to conventional treatment approaches. We report a study with a surgical concept characterized by resection of the necrotic bone followed by sufficient wound closure. STUDY DESIGN In a clinical study of 24 patients with 33 sites of BRONJ, the surgical basis of the treatment was as follows: (1) conservative treatment with antimicrobiological rinsing, (2) resection of the entire necrotic bone and smoothening of any sharp bone edges, and (3) coverage of the remaining bone by use of a bilayered wound closure. RESULTS In 88% of cases, BRONJ could be treated with success by use of this surgical therapy. Median follow-up was 60 weeks. There was no statistically significant difference between treatment results irrespective of whether or not bisphosphonate treatment was continued. CONCLUSION Because of the high success rate of this surgical technique it seems that patients with BRONJ may benefit from this approach.

Short German guidelines: Malignant melanoma

Malignant melanoma is a malignant tu-mor which arises from melanocytic cellsand primarily involves the skin. For thebalance of these guidelines, the termsmalignant melanoma and melanoma willbe used interchangeably, because thereare no benign melanomas. Melanomascan also arise in the eye (conjunctiva anduvea), meninges and on various mucosalsurfaces. While melanomas are usuallyheavily pigmented, there are also amela-notic tumors. Even small tumors have atendency towards metastasis and thus arelatively unfavorable prognosis. Melan-omas account for 90% of the deaths as-sociated with cutaneous tumors. The incidence of melanoma is increasingworldwide in white populations, especi-ally where fair-skinned peoples receiveexcessive sun exposure. In central Europethe incidence is 10 – 12 / 100,000yearly; in the USA, 10-25 / 100,000yearly; and in Australia the highest inci-dence, 50-60 / 100,000 yearly. In indivi-duals with more pigmentation (Asians,Africans) melanomas are uncommonand almost always found on either acralor mucosal surface. Individuals withlarge numbers of melanocytic nevi andthose with melanoma precursors (dyspla-stic nevi, congenital nevi) are at greaterrisk. The inheritance of melanoma is po-lygenic; 5-10% of melanomas appear inmelanoma-prone families. In addition tothese genetic and constitutional factors,the most important exogenous factor isexposure to UV irradiation. The relativeroles of toxic substances, medicationsand hormones (pregnancy, oral contra-ceptives) are controversial. The immunestatus of the patient plays a major role indetermining the course of melanoma, asnumerous examples of spontaneous re-gression or of rapid progression in im-munosuppressed individuals bear testi-mony.A number of different types of melano-mas can be identified clinically and hi-stologically. Some tumors either repre-sent mixed forms or are not classifiable.Examples of special forms are amelanoticmelanomas, mucosal melanomas, andother extracutaneous melanomas, whichtogether account for about 5% of allmelanomas.

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma.

The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

Evidence-based and interdisciplinary consensus-based German guidelines : systemic medical treatment of melanoma in the adjuvant and palliative setting

Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.

Kurzleitlinie – Malignes Melanom der Haut

JDDG | Supplement 1 ̇2008 (Band 6) Definition Das maligne Melanom ist ein bösartiger Tumor, der vom melanozytären Zellsystem ausgeht und sich ganz überwiegend an der Haut manifestiert. Selten kommt das Melanom auch am Auge (Konjunktiva und Uvea), an den Hirnhäuten und an Schleimhäuten verschiedener Lokalisation vor. Das Melanom ist zumeist stark pigmentiert, aber auch amelanotische Formen treten auf. Im Verhältnis zur Tumormasse besteht eine frühe Tendenz zur Metastasierung und damit eine ungünstige Prognose. Das maligne Melanom ist etwa für 90 % der Mortalität an Hautkrebs verantwortlich. Die Melanominzidenz nimmt in der weißen Bevölkerungen weltweit zu, insbesondere bei stark sonnenexponierten hellhäutigen Bevölkerungsgruppen. In Mitteleuropa beträgt die Inzidenz 10–12 Fälle pro 100.000 Einwohner und Jahr, in den USA 10–25 Fälle und die höchsten Inzidenzen wurden mit 50–60 Fällen pro 100.000 Einwohner und Jahr aus Australien berichtet. In Bevölkerungen mit stärkerer Pigmentierung (Asiaten, Afrikaner) ist das Melanom hingegen selten und nahezu ausschließlich im Schleimhautbereich oder palmoplantar lokalisiert. Individuen mit hoher NävusZahl und Träger von Melanomvorläufern (sogenannte dysplastische Nävi, kongenitale Nävi) sind besonders gefährdet. Polygene Erbfaktoren können zur familiären Häufung führen und 5–10 % der Melanome treten in erblich belasteten Familien auf. Neben diesen konstitutionellen Faktoren spielt unter den exogenen Einflussgrößen die UV-Belastung eine zentrale Rolle. Kontrovers wird die Bedeutung toxischer, medikamentöser oder endokriner Einflüsse (z. B. Gravidität, Kontrazeptiva) beurteilt. Zahlreiche Beispiele (Spontanremissionen, aggressive Verläufe bei Immunsupprimierten) belegen die Bedeutung immunologischer Faktoren in der Tumorprogression dieser Neoplasie. Klinisch und histologisch lassen sich verschiedene Melanomtypen voneinander unterscheiden. Einige Typen sind jedoch nicht klassifizierbar oder repräsentieren Mischformen. Klinische Sonderformen sind z. B. amelanotische Melanome sowie Schleimhautoder andere extrakutane Melanome, die etwa 5 % aller Melanome ausmachen. Das superfiziell spreitende Melanom beginnt mit einer intraepidermalen horizontalen Ausbreitungsphase zunächst als Fleck, entwickelt sich dann invasiv flach erhaben, häufig mit farblicher Vielfalt, hellen Regressionszonen und sekundär knotigen Anteilen. Histologisch charakteristisch ist ein pagetoides Muster der intraepidermalen Tumorkomponente im Randbereich. Das noduläre Melanom imponiert hingegen als primär knotiger, exophytischer, überwiegend schwarzbrauner, häufig erosiv-blutiger Tumor, dem eine initiale horizontale Wachstumsphase und damit die Möglichkeit zur Frühdiagnose fehlt. Das Lentigo-malignaMelanom entsteht oft erst nach vielen Jahren aus einer Lentigo maligna (Insitu-Melanom) nahezu ausschließlich im Gesichtsbereich älterer Patienten. Das akral-lentiginöse (akrolentiginöse) Melanom findet sich vorwiegend palmoplantar, aber auch als suboder periunguales Melanom. Es zeichnet sich in seiner intraepidermalen Frühphase meist durch unscharf begrenzte, inkohärente Pigmentierungen aus, ehe die knotigen Anteile das invasive Wachstum signalisieren.

Comparative In Vitro Study on Magnetic Iron Oxide Nanoparticles for MRI Tracking of Adipose Tissue-Derived Progenitor Cells

Magnetic resonance imaging (MRI) using measurement of the transverse relaxation time (R2*) is to be considered as a promising approach for cell tracking experiments to evaluate the fate of transplanted progenitor cells and develop successful cell therapies for tissue engineering. While the relationship between core composition of nanoparticles and their MRI properties is well studied, little is known about possible effects on progenitor cells. This in vitro study aims at comparing two magnetic iron oxide nanoparticle types, single vs. multi-core nanoparticles, regarding their physico-chemical characteristics, effects on cellular behavior of adipose tissue-derived stem cells (ASC) like differentiation and proliferation as well as their detection and quantification by means of MRI. Quantification of both nanoparticle types revealed a linear correlation between labeling concentration and R2* values. However, according to core composition, different levels of labeling concentrations were needed to achieve comparable R2* values. Cell viability was not altered for all labeling concentrations, whereas the proliferation rate increased with increasing labeling concentrations. Likewise, deposition of lipid droplets as well as matrix calcification revealed to be highly dose-dependent particularly regarding multi-core nanoparticle-labeled cells. Synthesis of cartilage matrix proteins and mRNA expression of collagen type II was also highly dependent on nanoparticle labeling. In general, the differentiation potential was decreased with increasing labeling concentrations. This in vitro study provides the proof of principle for further in vivo tracking experiments of progenitor cells using nanoparticles with different core compositions but also provides striking evidence that combined testing of biological and MRI properties is advisable as improved MRI properties of multi-core nanoparticles may result in altered cell functions.

Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw

OBJECTIVES Principles and workflow are described to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ) when oral surgery is necessary in patients taking bisphosphonates. MATERIAL AND METHOD A total of 117 surgical procedures were performed on 68 patients taking bisphosphonates. The basis of the treatment was (1) use of perioperative antibiotics; (2) after dentoalveolar surgical procedures, bone edges were smoothed and mucoperiosteal flaps were prepared to ensure tension-free wound closure; (3) sutures were not removed until 14 days postsurgery; (4) long-term results were evaluated. RESULTS Ninety-seven percent of all procedures were simple and showed no complications. Only 3 patients with a long history of intravenous bisphosphonate medication developed BRONJ within 4 weeks after surgery. No patient receiving oral bisphosphonates developed BRONJ. No long-term failure was observed when primary wound healing was successful. CONCLUSIONS The high success rate of the described surgical procedures imply dentoalveolar surgery with low risk of development of BRONJ is possible for patients taking bisphosphonates.

[Brief guidelines: malignant melanoma of the skin].

JDDG | 4 ̇2006 (Band 4) Das insbesondere bei hellhäutigen Bevölkerungsgruppen weltweit in Zunahme begriffene Melanom entsteht als maligne melanozytäre Geschwulst ganz überwiegend an der Haut und ist für etwa 90 % der Mortalität an malignen Hauttumoren verantwortlich. Klinisch und histologisch lassen sich vier Subtypen unterscheiden: das superfiziell spreitende Melanom (SSM), das noduläre Melanom (NM), das akrolentiginöse Melanom (ALM), und das Lentigo-maligna-Melanom (LMM). Einige Melanome sind nicht sicher klassifizierbar oder stellen seltenere Sonderformen dar (z.B. das amelanotische Melanome oder Melanome in einem Riesennävus).

Evaluation of Osseointegration of Titanium Alloyed Implants Modified by Plasma Polymerization

By means of plasma polymerization, positively charged, nanometre-thin coatings can be applied to implant surfaces. The aim of the present study was to quantify the adhesion of human bone cells in vitro and to evaluate the bone ongrowth in vivo, on titanium surfaces modified by plasma polymer coatings. Different implant surface configurations were examined: titanium alloy (Ti6Al4V) coated with plasma-polymerized allylamine (PPAAm) and plasma-polymerized ethylenediamine (PPEDA) versus uncoated. Shear stress on human osteoblast-like MG-63 cells was investigated in vitro using a spinning disc device. Furthermore, bone-to-implant contact (BIC) was evaluated in vivo. Custom-made conical titanium implants were inserted at the medial tibia of female Sprague-Dawley rats. After a follow-up of six weeks, the BIC was determined by means of histomorphometry. The quantification of cell adhesion showed a significantly higher shear stress for MG-63 cells on PPAAm and PPEDA compared to uncoated Ti6Al4V. Uncoated titanium alloyed implants showed the lowest BIC (40.4%). Implants with PPAAm coating revealed a clear but not significant increase of the BIC (58.5%) and implants with PPEDA a significantly increased BIC (63.7%). In conclusion, plasma polymer coatings demonstrate enhanced cell adhesion and bone ongrowth compared to uncoated titanium surfaces.