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Background It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6–11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. Methods A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21–81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m 2 on days 1 and 2 and FM iv 100 mg/m 2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients. Results We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status. Conclusion This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed. Trial registration EUDRACT 2009–016487-36l ; date of registration 23 June 2010.

. The aim of this work is the historical and archaeometric investigation of a unique six-colour single-sheet relief print on paper belonging to a private collector. It is undescribed, undated and unsigned, and it depicts Charlemagne enthroned in Aachen Cathedral. The print was tentatively dated to the 16th century based on the style and iconography. This study offers a revised dating based on stylistic analysis of the design and archaeometric investigation of the six printing inks. The methodology consists of the complementary use of imaging and spectroscopic techniques, which are entirely non-invasive and non-destructive due to the rarity and fragility of the object. In particular, preliminary unaided visual analysis, UV fluorescence and IR reflectography were used to investigate the surface condition of the impression and to select the most promising areas for further analysis. Raman spectroscopy and XRF were used to identify pigments and treatments. Our results show that the paper support is in good condition. The pigments of all six inks have been identified. Results suggest that this impression was printed after 1850 and before 1900. In its conception and production, this artwork used then-modern methods and materials to pay homage to the styles and production techniques of the earliest German colour woodcuts.