Background Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm. Methods All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity. Results In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail. Conclusions Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.
Three butterfly species were recorded for the first time for the fauna of Bosnia and Herzegovina in the Herzegovina region: Danaus chrysippus, Cacyreus marshalli and Carcharodus orientalis. The records represent expansions to the known distribution, although the presence of all three species was expected as they are to be found in neighbouring countries. This is the third record that D. chrysippus has reached southern Croatia, and the first time it has been observed in Bosnia and Herzegovina. The record of the non-native C. marshalli fills the distributional gap, and the record of C. orientalis, a rare and local species in the region, represents an increase of the known distribution in the mainland of the western Adriatic coastline. In the future, additional records of rare and unrecorded species are expected in the country.
For the purpose of this research, we used a quality questionnaire related to quality, satisfaction and loyalty of students. The research was carried out a t he start and end of the academic year. This approach ascertained a gap with respect to quality, satisfaction and loyalty of students of eMPIRICA
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