Phenotypes and Genotypes of Melanoma Patients

Introduction Melanoma is most common in populations with European ancestry. The highest incidence rates are reported from Australia and New Zealand with more than 50/100,000 new cases and 6/100 000 deaths per year compared to around 20/100,000 new cases and 3/100 000 deaths in Western Europe. Established host risk factors are the total body naevus number, fair skin and a family history of melanoma. In the last decade several new genetic loci identified through genome-wide association analyses (GWAS) were shown to influence pigmentation traits and melanoma risk. Recently an intronic SNP in PPARGC1B has been shown to modify tanning ability and melanoma survival. The aims of this thesis were to conduct phenotypic and genetic comparisons of early and late stage melanoma patients, and to compare melanoma patients from Brisbane, Australia and Tübingen, Germany. This included associations of PPARGC1B and PPARGC1A coding polymorphisms with pigmentation traits, melanoma risk and progression in both these populations. Methods Two cohorts of melanoma patients and controls from Tübingen (n=614) and Brisbane (n=893) have been collected and analysed to investigate phenotypes and genotypes associated with melanoma risk and progression. Data and material included questionnaires, clinical assessments, melanoma specific parameters and germline DNA. Genotyping was performed by Sanger Sequencing, TaqMan SNP assays and with a high throughput Illumina CoreExome Chip assay. Phenotype and genotype associations were analysed using cross tabulation and logistic regression models. Survival probabilities were assessed genome-wide and for single variables using Kaplan Meier estimates, and comparisons were done with the log rank test. Results Patients with high naevus counts had no favourable outcome in the analysed cohort from Tübingen, however being a carrier of a MC1R r allele was associated with an improved survival probability (p=0.049). Two SNPs, the intronic variants rs7551288 in DHCR24, and rs12146110 in USH2A, were found in a genome-wide association analyses to be associated with overall survival and furthermore with progression in stage IV (p<0.001). Melanoma patients from Brisbane had favourable prognostic tumour characteristics and a higher rate of familial and multiple melanomas compared to patients from Tübingen. Further-more, the influence of the PPARGC1 transcription factors (PGC-1) on pigmentation was investigated. The exon SNP rs3736265 (T612M) in PPARGC1A was found for the first time to reduce naevus count. The intronic SNPs rs251468 and rs32579 in PPARGC1B were both confirmed to increase tan-ning ability and decrease naevus count, the SNP rs32579 additionally to improve survival in a meta-analysis. Conclusion Genetic variants have been identified that influence pigmentation traits, melanoma risk and progression. New loci of potential relevance for naevus count, melanoma risk and progression have reached statistical significance. UV radiation has an overriding influence on the impact of genetic predisposition, especially in countries with high UV exposure and is leading to an increase of preventable, initially less aggressive melanomas. UV protection, early recognition and early treatment remain the most important strategies to overcome the rise of preventable melanomas and to reduce melanoma deaths

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment

The Prognostic and Predictive Value of Melanoma-related MicroRNAs Using Tissue and Serum: A MicroRNA Expression Analysis

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are = 82%) when = 4 miRNAs were expressed. Moreover, the 'MELmiR-7' panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood=11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa-c/IV M1a-b) to detect relapse following surgical or adjuvant treatment. (C) 2015 The Authors. Published by Elsevier B. V

Effectiveness of Carboplatin and Paclitaxel as First- and Second-Line Treatment in 61 Patients with Metastatic Melanoma

BACKGROUND: Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination. METHODS: Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP) at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria. RESULTS: 61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c) received CP as first-line treatment, 41 patients (90.2% M1c) had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD) (49 weeks) compared to patients with progressive disease (18 weeks). CONCLUSIONS: Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment

Functional magnetic resonance imaging of the visual cortex in children: Development and application

Die funktionelle Magnetresonanztomographie (fMRT) bietet die Möglichkeit, nicht invasiv funktionelle Hirnareale sichtbar zu machen. In dieser Arbeit wurde eine Methode etabliert, die es erlaubt, das visuelle System bei Kindern und bei Patienten mit eingeschränkter Kooperationsfähigkeit zu untersuchen. Hierfür wurde ein kindgerechtes Stimulationsprogramm entwickelt. Dazu wurde in das Zentrum eines in vier Quadranten aufgeteilten, mit einer Frequenz von 4 Hz flackernden 'Dartboards' ein kleiner Zeichentrickfilm als Fixationshilfe eingefügt. Das Stimulationsprogramm wurde wiederholt an gesunden Erwachsenen getestet und modifiziert. Anschließend wurden sechs Kinder und Jugendliche im Alter von 11 bis 22 Jahren mit okzipitalen Fehlbildungen oder Läsionen vor möglichen epilepsie–chirurgischen Eingriffen untersucht. Aktivierungen konnten stets an retinotopisch regelrechter Lokalisation im Bereich der primären Sehrinde nachgewiesen werden. Bei zwei Patienten mit perimetrisch nachgewiesenen Skotomen zeigten sich entsprechende Aktivierungsausfälle in der fMRT. Hinweise für die in der Literatur umstrittene Möglichkeit einer Reorganisation nach Schädigung der primären Sehrinde konnte mittels fMRT in keinem der hier untersuchten Fälle gefunden werden.Functional magnetic resonance imaging (fMRI) offers the possibility of acquiring functional data of different brain areas in a non invasive manner. In this work a method was established, which allows to examine the visual system of children and patients with reduced cooperation. A pediatric stimulation scheme was developed using a small cartoon located in the center of a 4 quadrant, 4 Hz flickering 'dartboard' stimulating field as a fixation assistance. This stimulation scheme was tested and modified on healthy adults, and subsequently applied to six children and young adults at the age of 11 to 22 years with occipital malformations and lesions before possible epilepsy-surgical interventions. Activations were always found at their retinotopically expected localization within the primary visual cortex. Two patients with visual field defects showed corresponding deficits of fMRI activation. No evidence for reorganization within the primary visual cortex, as controversially discussed in the literature, was observed