Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

Randomized standard-of-care-controlled trial of a silica gel fibre matrix in the treatment of chronic venous leg ulcers

Background: Chronic venous leg ulcers (CVU) are a common, unresolved medical problem. Silica gel fibre (SGF) is a novel biodegradable inorganic material developed to serve as a carrier substrate for the local release of pharmaceutical agents facilitating tissue repair. Objectives: To assess the performance and safety of SGF in subjects with CVU. Methods: Open, randomized, standard-of-care-controlled, multi-centre trial. Subjects (ITT 120 patients) received either SGF in addition to standard treatment or standard-of-care treatment (S-o-C) alone. The primary performance variable was the time to healing of the target ulcer until the end of a 12 week treatment period. Results: SGF was well tolerated. Mean time to healing up to week 12 was 85.62 days for the SGF group (SE +/- 1.5) and 79.66 days for the S-o-C group (SE +/- 1.77) (p-value = 0.217). There was no statistically relevant difference regarding the incidence of complete healing of the target ulcers by weeks 12 and 24 between the SGF and the S-o-C groups (p-value >0.05). Conclusion: SGF is well tolerated and offers a promising perspective as a carrier substrate for the local release of active pharmaceutical agents into the wound site to promote tissue repair

Grundlagen zur Entwicklung einer personenbezogenen Risikoabschaetzung durch UV-B-Strahlung. T. A: Exogene Biomarker zur UV-Personendosimetrie. T. B: Mechanismen der UV-Suszeptibilitaet Schlussbericht

In this cooperative effort of the DLR and the University Hospital of Cologne fundamental molecular mechanisms of the individual susceptibility against UV-induced damage to nucleic acids and signal transduction pathways of key genes involved in tumorigenesis and metastasis are addressed. New prototypes of individual integrated optoelectronic-biological dosimeters were developed and the responses were compared to the clinical and molecular responses of human skin. UV dosimetry with UV-sensitive spores of Bacilus subtilis proved to be especially qualified for the documentation of the individual UV load of UV-susceptible persons. The DLR-biofilm for measuring DNA damage following UVA or UVB exposure in a biologically weighted manner was further improved, as well as the electronical UV broadband meter X2000. A continuous instead of a stepwise color change of the skin was observed. Personal dosimetry resulted in the identification and correlation of biologically weighted effective dose ranges with the clinical parameters MED, IPD, and PPD. The conclusion is: it will be possible to measure individual UV exposure of unknown amounts directly with the DLR-biofilm, and to translate these biological measurements into relative units of an UV-dependent cellular damage in vivo, for documentation in some cases of the individual UV load in vivo and correlation to UV-dependent effects involved in the pathogenesis of skin tumor and metastasis. (orig.)In einem Gemeinschaftsprojekt zwischen dem DLR und dem Universitaetsklinikum Koeln wurden molekulare Grundlagen einer individuellen Empfindlichkeit fuer UV-induzierte Schaeden an Nukleinsaeuren und Signalwegen wesentlicher, die Hauttumorentstehung und -asubreitung foerdernder Schluesselgene untersucht. Neue Prototypen integrierter optoelektronisch-biologischer UV-Personendosimeter wurden entwickelt und mit der klinischen und molekularen Antwort der Haut abgeglichen. Die biologische UV-Personendosimetrie mit UV-sensitiven Bacillus subtilis-Sporen erwies sich als besonders geeignet, die UV-Belastung einzelner Individuen zu dokumentieren. Der DLR-Biofilm, der die Schaedigung der DNA nach UVA und UVB-Exposition biologisch wichtend erfasst, wurde parallel mit dem elektronischen UV-Breitbandmessgeraet X2000 weiterentwickelt. Es zeigte sich, dass die Farbaenderungen in der Haut sich nicht stufenfoermig, sondern trotz einer Dosisabhaengigkeit kontinuierlich ausbilden. Die Personendosimetrie fuehrte zur Bestimmung und Korrelation biologisch gewichteter effektiver Dosisbereiche der klinischen Parameter MED, IPD und PPD. Die Identifizierung einer in vitro fuer diverse Biomarker dosisabhaengig ablaufenden Zellantwort liess sich nicht generell in das komplexe in vivo System der Haut uebertragen. Es konnte herausgearbeitet werden, dass es moeglich ist, in der Praxis UV-Expositionsdosen unbekannter Groesse ueber den DLR-Biofilm direkt und unmittelbar in relative Einheiten eines biologisch erzeugten Schadens in vivo zu uebersetzen. Mit diesen Arbeiten ist eine personenbezogene in vivo Dosiserfassung und Korrelation der UV-Effekte in der Pathogenese von Hauttumorentstehung und -ausbreitung durch UV-Strahlung zumindest partiell moeglich geworden. (orig.)SIGLEAvailable from TIB Hannover: F04B1387+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman

Synthesis of mono-dispersed spherical silica particles containing covalently bonded chromophores

Organic–inorganic ultraviolet (UV) active hybrid materials have been prepared by a sol-gel process from benzophenone derivatives and tetraethylorthosilicate. The silica particles are spherical in shape and have a narrow size distribution which remains unchanged up to organic chromophore concentrations of 0.2 mmol g)1. At higher concentrations the spheres become less regular and fuse. A dependence of the material absorption properties on the particle size (at the same organic chromophore concentration) and on the concentration of surface grafted chromophores was noted. The most effective UV filter materials were found in a combination of silica incorporated chromophores and surface grafted chromophores at an overall low chromophore concentration. A comparison of the photostability of chromophores at standardized UV irradiation revealed an increase in stability for silica incorporated and surface immobilized benzophenone compared to benzophenone in a homogeneous solution